Annual Report 2012 - Istituto di Ricerche Farmacologiche Mario Negri

Transcript

Annual Report 2012 - Istituto di Ricerche Farmacologiche Mario Negri
IRFMN
PREFACE
ANNUAL REPORT
MARIO NEGRI INSTITUTE, MILAN
www.marionegri.it
DEPARTMENTS
Department of Oncology ………………….………………………….………………………
Department of Environmental Health Sciences ……….………….……….………………
Department of Neuroscience ………………….………………………….…………………
Department of Cardiovascular Research ………………….…………………….…………
Department of Molecular Biochemistry and Pharmacology .…….………….…………
Department of Epidemiology……………………………..…….………….………………..
Department of Public Health.............................................................................
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LABORATORIES AND CENTERS
Laboratory of Regulatory Policies ……….………………………..……….………….………
Centre of Computer Science Engineering………………………………………….…………
The Catullo and Daniela Borgomainerio Center……………………………………………
Library ……….….…………………………………………………………….………….…………
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301
303
ANNA MARIA ASTORI CENTER
DEPARTMENTS
Department of Molecular Medicine ……….……………………………………….………… 309
Department of Biomedical Engineering……….……………………………………………… 333
ALDO and CELE DACCO’ CENTER
DEPARTMENT
Department of Renal Medicine…………….…………………………………………………… 355
LABORATORIES AND CENTERS
Rare Diseases Documentation and Research..................................................…..… 393
International Relations Office of rare Diseases........................................................ 405
The Transplant Research Center…………….………………………………………………… 411
EDUCATIONAL ACTIVITIES
413
STAFF
417
All the staff of the Institute is listed on its website www.marionegri.it
PUBLICATIONS
A comprehensive list of the Institute’s publications is available on the www.marionegri.it
website – Section Publications
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Edited by Isabella Bordogna
printed May 2013
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PREFACE
In 2012 the Mario Negri Institute for Pharmacological Research celebrated 51 years since its
foundation. It was a year of serious difficulty for research, not only in Italy but throughout Europe. The
economic crisis has certainly affected scientific research and the Italian government has abandoned
the sector completely to its own resources – the exact opposite of what should be done in hard times.
Nevertheless, this report of the Institute’s activities is still meaty, packed with fascinating descriptions
of experimental and clinical results.
Much of the research described has been published and there are still many results soon to appear.
In 2012 the Institute’s scientists published more than 400 papers in international scientific journals.
As in previous reports, we describe the work of each department, and in some cases of individual
laboratories. There are details of the scientific results, which merit some brief comments here.
The new “Negri Bergamo” laboratories in the Km Rosso Science Park (Red kilometer, named after its
long colored wall) have completed their move from the Conventino, and are now working at full
steam in modern premises with the very latest scientific equipment, developing and using new
technology.
Particular efforts are focused on translational research, using the “mouse clinic” schemes: nuclear
magnetic resonance, microCAT, echography, Doppler, two-photon microscopy, are just some of the
techniques employed in clinical medicine that are now available for studying models of human
diseases in mice. Fewer animals are needed, and the findings can be transferred more reliably.
On this point, the European Directive on animal experimentation has led to a violent campaign
against the use of animals in research that risks making it even more complicated to do in vivo
studies. Mario Negri Institute scientists have taken the lead in initiatives aimed at convincing the
public that research on animals is still essential if we are to uncover new knowledge and achieve
better ways to treat disease. Regrettably, the available “alternative techniques”, mainly cell cultures,
can only be considered complementary, not substitutes.
Imaging methods such as electron microscopy, time-lapse contrast microscopy and atomic force
microscopy have made major contributions. Much work is now being done with molecular biology
methods, especially for investigating the mechanisms of action of drugs. Cells grown in vitro – in
culture – are fundamental for thorough investigations, but there is still a substantial amount of
research that can only be done in vivo. This is still the only way we can validate the results of in
vitro work, and design models that reproduce human diseases as closely as possible. Transgenic
animals are increasingly employed.
The Institute’s traditional research areas are oncology, neursciences, cardiovascular and renal
diseases, organ transplantation, rare diseases, cell biology, and molecular biochemistry. We are
particularly proud of being the first to offer real hope of “building” a functioning kidney starting from
normal cells transformed into stem cells.
Other significant studies involve the environment and human health.
We have reinforced our
research on rare diseases and “orphan” drugs, with experimental, clinical and epidemiological work.
The Mario Negri Institute’s approach to research always involves developing a network of strategies
around each of the main areas: these range from basic research to pharmacokinetics, pharmacology,
controlled clinical trials, epidemiological analysis and, when possible, the epidemiology of health care
services.
We have recently completed clinical trials in cardiology (Ricerca e Prevenzione – Research and
Prevention). With the participation of 800 general practitioners the studies have shown that omega-3
fatty acids do not help prevent cardiovascular disease. Numerous studies are continuing, thanks to
the opportunities offered by the AIFA project for independent controlled clinical trials.
An on-line register of the controlled clinical trials conducted by the Institute can now be consulted,
where anyone can see at what stage are the various trials. At end-December 2012 there were 113
trials in progress, planning to recruit a total of 87,380 patients.
Training young scientists is one of the foundation stones of research. In the Institute laboratories
they not only have a chance to express their own ideas, but their training leads to a professional
qualification, recognized by the Lombardy Region; so far 947 young researchers have obtained this
diploma. Graduates can carry on studying to earn a Ph.D. degree, in collaboration with the Open
University, U.K. and 76 have completed this course so far.
Another basic feature at the Mario Negri Institute is information at all levels. We run an Information
Center for Rare Diseases (www.marionegri.it click on Centro Malattie Rare), as part of the Drug
Information Center, on the Institute’s Centro di Informazione sui Farmaci web site www.marionegri.it.
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We work constantly to make sure up-to-date information reaches doctors, nurses, patients’
associations, and the general public, using all available media. Between 2000 and 2012 a total of
1781 articles were published in the lay press. The health care participation site
www.partecipasalute.it has grown impressively.
Times are increasingly hard for research, and scientists are being called to make ever greater efforts.
We count on as much help as possible from all those involved: the government, public bodies,
charities and private citizens.
Silvio Garattini
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Mario Negri
INSTITUTE FOR PHARMACOLOGICAL RESEARCH
Milan
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departments and laboratories
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DEPARTMENT OF ONCOLOGY
STAFF
Chief
Maurizio D’INCALCI, M.D.
Oncological Studies Office and Documentation
Scientific Documentalist
Stefania FILIPPESCHI, Chemist
Laboratory of Cancer Pharmacology
Head
Maurizio D’INCALCI, M.D.
Biophysics Unit
Head
Paolo UBEZIO, Phys.D.
Flow Citometry Unit
Head
Eugenio ERBA, Biochem.D
Translational Genomic Unit
Head
Sergio MARCHINI, Biol.Sci.D., Ph.D
Cancer Clinical Pharmacology Unit
Head
Massimo ZUCCHETTI, Chem.Pharm.D.
Laboratory of Molecular Pharmacology
Head
Massimo BROGGINI, Ph.D.
Molecular Genetics Unit
Head
Mirko MARABESE, Biol.Sci.D., Ph.D.
DNA Repair Unit
Head
Giovanna DAMIA, M.D.
Laboratory of Biology and Treatment of Metastases
Head
Raffaella GIAVAZZI, Biol.Sci.D., Ph.D.
Tumor Angiogenesis Unit
Head
Unit located in Bergamo
Giulia TARABOLETTI, Biol.Sci.D.
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Molecular Cancer Therapeutics Unit
Head
Maria Rosa BANI, Biol.Sci.D., Ph.D.
Laboratory of Cancer Cachexia AIRC Start-Up
Head
Rosanna PICCIRILLO, Biotec. Med. D.,
Ph.D.
Laboratory of Methodology of Biomedical Reseach
Head
Valter TORRI, M.D.
Systematic reviews methodology and guidelines production Unit
Head
Michela CINQUINI, Stat. D.
Computational Statistics Unit
Head
Luca Porcu
Clinical Research Laboratory
Head
Irene FLORIANI, Dr.Sci.Biol., Dr.Stat., Ph.D.
Coordinating, Management and Monitoring Unit
Head
Davide POLI, Phys.D.
Statistics Unit
Head
Quality Assurance Unit
Head
Eliana RULLI, Stat. D.
Marlen Victoria Llerena Mesa, Pharm. D.
Laboratory of Translational and Outcome Research in Oncology
Head
Giovanni APOLONE, M.D.
Gynecology Oncology Unit
Head
Roldano FOSSATI, M.D.
CERP: Center for the Evaluation and Research on Pain
Head
Giovanni APOLONE, M.D.
Oscar CORLI, M.D.
Laboratory of Medical Research and Consumer Involvement
Head
Paola MOSCONI, Biol.Sci.D.
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CURRICULA VITAE
Maurizio D'Incalci obtained his Medical Degree cum Laude from the University of Milan in 1977. After
specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of
Genoa, he worked in the Laboratory of Molecular Pharmacology of the National Cancer Institute in
Bethesda, MD, USA. Since 1986 he has been chief of the Laboratory of Cancer Chemotherapy at the
Mario Negri Institute and since 1996 he has become chief of the Department of Oncology at the Mario
Negri Institute.
He has been President of the Pharmacology and Molecular Mechanisms Group of the European
Organization for Research and Treatment of Cancer (EORTC). From 1994 to 1997 he was Chairman of
the New Drug Development Coordinating Committee and from 1997 to 2000 he was chairman of the
Research Division of the EORTC. He has been member of the Board of the EORTC from April 2000 to
2003.
Since 1995 he is member of the Board of Directors of the Nerina and Mario Mattioli Onlus Foundation. From 1997 to 2012 he has been the Preclinical Coordinator of the Southern Europe New Drug
Organization (SENDO) and from 2005 to 2012 he has been the Chairman of the New Agents Committee
(NAC) of SENDO.
From 2006 he is president of the Scientific Committee of the Mario Negri Gynecologic Oncology group
(MaNGO).
From 2007 he is member of the Scientific Committee of the Italian Association for Cancer Research
(AIRC).
From 2009 he is member of the Board of Directors of the Italian Cancer Society (SIC).
From 2010 he is member of the Scientific Committees of the ABO (Application of Biotechnologies in
Oncology) Foundation, a national foundation for cancer research, and of the Buzzi Unicem Onlus
Foundation for the research, diagnosis and cure of malignant mesothelioma.
He is on the editorial board of many international cancer-related scientific journals and from September
2000 to December 2010 he has been Editor for Experimental Oncology of the European Journal of
Cancer. Dr D'Incalci is author of more than 450 papers on cancer chemotherapy published in peer
reviewed international journals, and of several chapters in books on cancer chemotherapy.
Selected publications

Uboldi S., Calura E., Beltrame L., Fuso Nerini I., Marchini S., Cavalieri D., Erba E., Chiorino G., Ostano P., D’Incalci M.,
Romualdi C. A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in
vitro model of myxoid liposarcoma. PLoS ONE, 7(4): e35423 (2012).

Marchini S., Poynor E., Barakat R.R., Clivio L., Cinquini M., Fruscio R., Porcu L., Bussani C., D’Incalci M., Erba E.,
Romano M., Cattoretti G., Katsaros D., Koff A., Luzzatto L. The zinc finger gene ZIC2 has features of an oncogene and its
overexpression correlates strongly with the clinical course of epithelial ovarian cancer. Clin. Cancer Res., 18: 4313-4324
(2012).

Sergio Marchini, Duccio Cavalieri, Robert Fruscio, et al Association between miR-200c and survival of stage I epithelial
ovarian cancer patients. A retrospective study on two independent tumour tissue collections. The Lancet Oncology, Vol. 12,
Issue 3, Pages 273 - 285, March 2011.

Frapolli R., Tamborini E., Virdis E., Bello E., Tarantino E., Marchini S., Grosso F., Sanfilippo R., Gronchi A., Tercero J.C.,
Peloso G., Casali P., Pilotti S., D’Incalci M. Novel models of myxoid liposarcoma xenografts mimicking the biological and
pharmacological features of human tumors. Clinical Cancer Res., 16(20): 4958-4967 (2010).

Germano G., Frapolli R., Simone M., Tavecchio M., Erba E., Pesce S., Pasqualini F., Grosso F., Sanfilippo R., Casali P.,
Gronchi A., Virdis E., Tarantino E., Pilotti S., Greco A., Nebuloni M., Galmarini C.M., Tercero J.C., Mantovani A.,
D’Incalci M., Allavena P. Anti-tumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells.
Cancer Res., 70(6): 2235-2244 (2010).

Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C, Carminati P,
D'Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patient variability is related to
α(1)-acid glycoprotein plasma levels. Eur. J. Cancer, 46: 505-516 (2010)
Giovanni Apolone, got his Medical degree in 1982 (Pavia, Italy) and his post-doctoral specializations in
Internal Medicine in 1987 (Pavia, Italy) and Pharmacological Research (1992). He is Head of the
Laboratory of Translational and Outcome Research. He is also Vice-President of the Ethics Committee
of the European Institute of Oncology in Milan (Italy). His main fields of interest are:
 Methodological, ethical and regulatory aspects of clinical research, with special emphasis on oncology
and the cancer pain.
 Health care evaluation with special emphasis on oncology;
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 Development and validation of case-mix and patient-reported outcome measures;
 Education and health promotion research and programs.
He is author or co-author of more than 270 publications, most in International peer-reviewed Journals.
Mean Impact Factor, computed on peer-reviewed papers: 3.2. H-index (from ISI-Web of knowledge,
March 2010): 30. Number of citations: 4111. Average citation per item: 32.37. Number of papers with
>50 citations: 19.
Selected publications

Greco M T, Corli O, Montanari M, Deandrea S, Zagonel V, Apolone G, CPOR SG Investigators. Epidemiology and pattern
of care of Breakthrough cancer Pain (BTcP) in a longitudinal sample of cancer patients. Results from the CPOR-SG. Clin J
Pain 2010, e-pub.
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Mannucci E, Petroni M L, Villanova N, Rotella C M, Apolone G, Marchesini G, QUOVADIS Study Group. Clinical and
psychological correlates of health-related quality of life in obese patients. Health Qual Life Outcomes 2010 8 : 90.
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Knudsen K A, Brunelli C, Kaasa S, Apolone G, Corli O, Montanari M, Fainsinger R, Aass N, Fayers P, Caraceni A, Klepstad
P, European Palliative Care Research Collaborative (EPCRC), European Pharmacogenetic Study (EPOS).Which variables
are associated with pain intensity and treatment response in advanced cancer patients? Implications for a future classification
system for cancer pain. Eur J Pain 2010, e-pub.
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Gacci M, Corona G, Apolone G, Lanciotti M, Tosi N, Giancane S, Masieri L, Serni S, Maggi M, Carini M. Influence of
serum testosterone on urinary continence and sexual activity in patients undergoing radical prostatectomy for clinically
localized prostate cancer. Prostate Cancer Prostatic Dis 2010 13 : 168-172.
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Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone M V, Detoma P, Giacomin A,
Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta M G, Riva E. Prevalence, incidence and types of mild
anemia in the elderly: the " Health and Anemia" population-based study. Haematologica 2010 95 : 1849-1856.
Massimo Broggini followed the faculty of Science of the University of Milan, got the specialization in
Biochemistry at Mario Negri Institute, and the PhD degree at the Open University, London,UK.
He worked in the laboratory of Molecular Pharmacology of the National Cancer Institute of Bethesda,
Md, in 1986. From 1991 he is the head of the Molecular Pharmacology Unit of the Mario Negri Institute
and from 1999 he his the head of the Laboratory of Molecular Pharmacology of the same Institute.
His main fields of interest are the study of the mechanism of action of new anticancer agents, the search
of altered proteins and genes in human cancer and the study of oncosuppressor genes. He is member of
the "Pharmacology and Molecular Mechanisms Group" of the European Organisation for the Research
and Treatment of Cancer (EORTC) and of the American Association for Cancer Research. He is in the
Editorial board of the European Journal of Cancer.
He is author of more than 100 articles published in international journals.
Selected publications

Mazzoletti M, Bortolin F, Brunelli L, Pastorelli R, Di Giandomenico S, Erba E, Ubezio P, Broggini M. Combination of
PI3K/mTOR inhibitors: antitumor activity and molecular correlates. Cancer Res. 2011 Jul 1;71(13):4573-84

Garassino MC, Marabese M, Rusconi P, Rulli E, Martelli O, Farina G, Scanni A, Broggini M. 10.Different types of K-Ras
mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol. 2011 Jan;22(1):2357.

Previdi S, Abbadessa G, Dalò F, France DS, Broggini M.Breast Cancer-Derived Bone Metastasis Can Be Effectively
Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown. Mol Cancer Ther. 2012
Jan;11(1):214-23.

Floriani I, Garassino MC, Broggini M, Veronese S, Marsoni S, Marabese M, Farina G, Scanni A. Role of cetuximab in the
treatment of patients with NSCLC: are we throwing out the baby with the bath water? J Clin Oncol. 2010 ;28:467.
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Sala G, Dituri F, Raimondi C, Previdi S, Maffucci T, Mazzoletti M, Rossi C, Iezzi M, Lattanzio R, Piantelli M, Iacobelli S,
Broggini M, Falasca M. Phospholipase Cgamma1 is required for metastasis development and progression. Cancer Res. 2008
Dec 15;68(24):10187-96.
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Falasca M, Chiozzotto D, Godage HY, Mazzoletti M, Riley AM, Previdi S, Potter BV, Broggini M, Maffucci T. A novel
inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate. Br J Cancer. 2010 Jan
5;102(1):104-14. PubMed PMID: 20051961;
Irene Floriani got her degree in Biological Sciences at the University of Milan in 1988, her degree in
Biostatistics and Experimental Statistics at the University of Milan in 2003 and her phD in Life Sciences
at Open University of London (UK) in 2005. After ten-year experience in pharmaceutical industry, in
2002 she became Head of the Biometry and Data Management Unit of the Laboratory of Clinical
Research in Oncology and since 2006 she is Head of Laboratory of Clinical Research (until 2012
Laboratory of Clinical Trials).
She is President of the Ethics Committee of the Ospedale Sant’Anna of Como, Vice-President of that of
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the Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ of Milan, and member of further two Ethics
Committees. Her main fields of interest are: statistical aspects of methodology of clinical research with
focus on Controlled Clinical Trials in Oncology; Systematic Review sof the medical literature and
Methodological aspects of diagnostic test evaluation.
Selected publications

Floriani I, D'Onofrio M, Rulli E, Chen MH, Li R, Musicco L. Performance of Imaging Modalities in the Diagnosis
of Hepatocellular Carcinoma: a Systematic Review and Meta-Analysis. Ultraschall Med. 2012 Dec 13.

Quaranta L, Biagioli E, Riva I, Rulli E, Poli D, Katsanos A, Floriani I. Prostaglandin Analogs and Timolol-Fixed Versus
Unfixed Combinations or Monotherapy for Open-Angle Glaucoma: A Systematic Review and Meta-Analysis. J Ocul
Pharmacol Ther. 2012 Dec 11.

Macera A, Lario C, Petracchini M, Gallo T, Regge D, Floriani I, Ribero D, Capussotti L, Cirillo S. Staging of colorectal liver
metastases after preoperative chemotherapy. Diffusion-weighted imaging in combination with Gd-EOB-DTPA MRI
sequences increases sensitivity and diagnostic accuracy. Eur Radiol. 2012 Sep 14.
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Milan E, Lazzari C, Anand S, Floriani I, Torri V, Sorlini C, Gregorc V, Bachi A. SAA1 is over-expressed in plasma of non
small cell lung cancer patients with poor outcome after treatment with epidermal growth factor
receptor
tyrosinekinase inhibitors. J Proteomics. 2012 Dec 5;76 Spec No.:91-101.

Ferrari D, Codecà C, Bertuzzi C, Broggio F, Crepaldi F, Luciani A, Floriani I, Ansarin M, Chiesa F, Alterio D, Foa P.Role of
plasma EBV DNA levels in predicting recurrence of nasopharyngeal carcinoma in a Western population. BMC Cancer. 2012
May 30;12:208.
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Lazzari C, Spreafico A, Bachi A, Roder H, Floriani I, Garavaglia D, Cattaneo A, Grigorieva J, Viganò MG, Sorlini C, Ghio
D, Tsypin M, Bulotta A, Bergamaschi L, Gregorc V. Changes in plasma mass-spectral profile in course of treatment of nonsmall cell lung cancer patients with epidermal growth factor receptor tyrosine kinase inhibitors. J Thorac Oncol. 2012
Jan;7(1):40-8.
Raffaella Giavazzi obtained her Biological Sciences degree (1979) at the University of Milan and her
PhD in Pharmacology at the Mario Negri Institute of Milan (1984), followed by a specialization in
pharmacology (1994) at the University of Milan. From 1981 to 1983 she was a post-doc Fellow in the
Cancer Metastasis and Treatment Laboratory, NCI-FCRDC, Frederick, MD, and from 1983 to 1985
Assistant Professor at the Department of Cell Biology of M.D. Anderson Hospital and Tumour Institute,
University of Texas System Cancer Centre in Houston, TX.
From 1986 to 1993 she was Head of the Cancer Metastasis Treatment Unit and since 1993 she has been
the Head of the Laboratory of Biology and Treatment of Metastasis at Mario Negri Institute for
Pharmacological Research.
She was adjuvant Professor of Oncology at the Medical School of the University of Brescia (2007-2010)
and of the University of Pisa (1999-2010) and in the Teaching Committee for the PhD course in
Physiology-Pharmacology-Molecular and Cellular Toxicology at the University of Siena. Since 2012 she
is member of the Board of Directors (CdA) at the University of Trento.
She was consulting scientist for the NCI-Drug Therapeutics Program, USA (1996-2006), and member of
the Executive Committee at the Southern Europe New Drug Development Organization (1988-2012).
She was in the Board (1994-204) and President (2005-2007) of the Italian Cancer Society, member of the
Executive Committee of the European Association for Cancer Research (2008-2012) and in the Board of
the International Metastasis Research Society (2000-2004). From 2008 she is member of the Pezcoller
Foundation Scientific Committee.
In 1996 she was Honorary Research Fellow and Visiting Professor, Division of Oncology, Richard
Dimble Department of Cancer/ICRF, London, UK. In 2003 she received the Researcher Career Award
“Italian League Against Tumor” and in 2012 she gave the “Giorgio Prodi” Lecture at the Italian Cancer
Society.
She is on the Editorial Board of a number international scientific journals. She has published
approximately 200 articles on “peer reviewed” scientific journals and is coauthor of several chapters in
books on cancer biology and therapy. She has been invited as speaker at numerous national and
international congresses on cancer research.
Selected publications

Silini A, Ghilardi C, Figini S, Sangalli F, Fruscio R, Dahse R, Pedley RB, Giavazzi R, Bani MR. Regulator of G-protein
signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor’s proangiogenic
microenvironment. Cell Mol Life Sci 2012 69 : 1167-1178

Moschetta M, Pretto F, Berndt A, Galler K, Richter P, Bassi A, Oliva P, Micotti E, Valbusa G, Schwager K, Kaspar M,
Trachsel E, Kosmehl H, Bani MR, Neri D, Giavazzi R. Paclitaxel enhances the therapeutic efficacy of the F8-IL2
immunocytokine to EDA-fibronectin positive metastatic human melanoma xenografts. Cancer Res 2012 72 :1814-1824
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Oliva P, Decio A, Castiglioni V, Bassi A, Pesenti E, Cesca M, Scanziani E, Belotti D, Giavazzi R. Cisplatin plus paclitaxel
and maintenance of bevacizumab on tumor progression, dissemination, and survival of ovarian carcinoma xenograft models.
British Journal of Cancer 2012 107 : 360-369
Borgia B., Rösli C., Fugmann T., Schliemann C., Cesca M., Neri D., Giavazzi R. A proteomic approach for the identification
of vascular markers of liver metastasis. Cancer Research, 70(1):309-18, 2010.
Cesca M., Frapolli R., Berndt A., Scarlato V., Richter P., Kosmehl H., D’Inclaci M., Ryan A.J., Giavazzi R. The effects of
vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma.
Neoplasia, 11(11):1155-64, 2009.
Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through gene
expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008.
Paola Mosconi got her Biological Science degree (Milan 1982) and the specialisation in Pharmacological
Research (Milan 1984). Paola Mosconi is involved in several national projects on issues pertaining the
patient involvement in care aspects and outcome research. She published more than 300 articles in
leading national and international journals (120), as well as books on issues related to her main areas of
interest.
Significant experiences has been coordinated:
 development of research projects and strategies to involve patients or consumer associations in
health debate, and clinical research, as consensus conferences or Jury citisens
 training for consumers on quality of information, and methodological aspects of clinical research;
 studies for estimate the type of information on diseases and treatments received by patients, mainly
in cancer patients; set-up of websites targeted on consumers/patients www.partecipasalute.it,
www.paincare.it, www.fondazionemattioli.it;
 projects on the assessment of Quality of Life in randomised clinical trials or in epidemiological
survey; translation and cultural adaptation of questionnaires for Quality of Life;
 evaluation of the consumers’ satisfaction with the health services and the care received.
Paola Mosconi has participated as teacher, or coordinator, to the realization of training course on
“Methodological aspects of clinical research” or “Evaluation of quality of life” for health care
professionals and representatives of voluntary associations.
Major present functions
- President of the Ethical Committees of the AUSL Bologna
- Elected member of Associazione Alessandro Liberati – network Italiano Cochrane
- Founding member of Europa Donna Italia, the European breast cancer coalition
Selected publications

Mosconi P, Roberto A. Open-access clinical trial registries: an Italian scenario. Trials 2012. DOI:10.1186/1745-6215-13-194

Colombo C, Moja L, Gonzalez-Lorenzo M, Liberati A, Mosconi P. Patient empowerment as a component of health system
reforms: rights, benefits and vested interests. Intern Emerg Med 2012; 7:183-187.

Mosconi P, Satolli R, Colombo C, Villani W. Does a consumer training work? A follow-up survey of the PartecipaSalute
training programs. Health Res Policy Syst, 2012, 10:27.

Colombo C, Mosconi P, Villani W, Garattini S. Patient organizations’ funding from pharmaceutical companies: is disclosure
clear, complete and accessible to the public? An Italian survey Plos One 2012; 7(5): e34974.

Mosconi P, Lionello L, Di Spazio L, Alberghini L. Are the voice of women and men equally represented in ethics
committees? An Italian survey. J Clin Res Bioeth 2012; 3:129.

Hill S, Filippini G, Synnot A, Summers M, Beecher D, Colombo C, Mosconi P, Battaglia MA, Shapland S, Osborne R,
Hawkins M. Presenting evidence-based health information for people with multiple sclerosis: the In-Deep project protocol.
BMC Medical Informatics & Decision Making 2012, 12:20. www.biomedcentral.com/1472-6947/12/20 .
Rosanna Piccirillo graduated summa cum laude in Medical Biotechnologies in 2001 with a thesis in
Experimental Oncology at the Istituto Nazionale dei Tumori in Milan. In 2006, she obtained the
international PhD in Molecular and Cellular Biology at the San Raffaele Scientific Institute in Milan,
studying the intracellular sorting and transport of a protein implied in a human genetic disease (Ocular
Albinism Type 1). In 2006, this original research work was awarded with the prestigious Premio Sapio
Junior per la Ricerca Italiana
(http://www.premiosapio.it/2011/pagine/dynamic_art.php?id=6&table_name=2012_edizioni). In 2007,
she worked as Visiting Assistant Researcher in the Department of Human Genetics at the University of
California, Los Angeles (UCLA), where she acquired useful biochemical skills. From 2007 to 2012, she
worked as Postdoctoral Research Fellow in the lab headed by Prof. Alfred L. Goldberg in the Cell
Biology Department at Harvard Medical School in Boston, MA, where she expanded her knowledge
about protein ubiquitination and degradation in neurodegenerative diseases as well as in muscle atrophy.
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Since March 2012, she is head of the laboratory Cancer Cachexia AIRC Start-up in the Oncology
Department at Mario Negri Research Institute, where she is leading a research group aimed at dissecting
the molecular mechanisms causing muscle wasting during cancer growth in the attempt to block this
devastating condition.
Selected Publications

R. Piccirillo, F. Demontis, N. Perrimon and A. L. Goldberg (2013). Mechanisms of Muscle Atrophy and Degeneration in
Drosophila and Mammals. (Review in preparation for Developmental Cell).

R. Piccirillo and A. L. Goldberg (2012). The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation
of muscle proteins. EMBO J. 31(15):3334-50.

N. Bhutani+, R. Piccirillo+, R. Hourez, P. Venkatraman and A. L.
Goldberg (2012). Cathepsins L and Z are critical in degrading polyglutamine-containing proteins within lysosomes. J Biol
Chem. 287(21):17471-82.
+: These authors contributed equally to this paper.

Sitaram, R. Piccirillo, I. Palmisano, D.C. Harper, E.C.
Dell’Angelica, M.V.Schiaffino, M.S. Marks (2009). Localization to mature melanosomes by virtue of cytoplasmic dileucine
motifs is required for human OCA2 function. Mol Biol Cell. 20(5): 1464-77.

R. Piccirillo, I. Palmisano, G. Innamorati, P. Bagnato, D. Altimare, M.V. Schiaffino (2006). An unconventional dileucinebased motif and a novel cytosolic motif are required for the lysosomal and melanosomal targeting of OA1. J Cell Sci. 119:
2003-2014.
Valter Torri got his Medical degree in 1985 and the specialization in medical Oncology in 1989 at the
University of Milano.
Education: 1985: MD Degree with full honors cum Laude, University of Milano; 1988 Post-Doctoral
Degree in Pharmacological Research, Mario Negri Institute, Milano; 1989 Post-Doctoral Degree in
Medical Oncology, University of Milano; 1989-1991 Research Fellow at the Biometric Research Branch
of Cancer Treatment Evaluation Program, NCI, Bethesda, MD (USA).
Areas of Interest: Statistical aspects of clinical research methodology with focus on Controlled Clinical
Trials in Oncology; Systematic Overview of the medical literature; Methodological aspects of diagnostic
test evaluation.
Present Position: Head of Laboratory of Methodology of Biomedical Research, Oncology Department,
Mario Negri Institute, Milano.
Chronology of Professional Appointments: 1983-1985: Clinical research Fellow in Internal Medicine at
the University Hospital, University of Milan; 1985-1989: Research assistant at the Clinical Trial Unit of
the Laboratory of Clinical Epidemiology, Mario Negri Institute for Pharmacological Research, Milano;
1989-1991: Research fellow at the Biometric Research Branch of Cancer Treatment Evaluation Program,
NCI, Bethesda, MD (USA); 1994: Head of Biometric Unit of the Laboratory of Cancer Clinical
Epidemiology, Oncology Department, Mario Negri Institute for Pharmacological Research, Milano, Italy;
1995 Vice Director of the Italian “Cochrane” Center; 2001: Head of Laboratory of Clinical Research In
Oncology, Oncology Department, Mario Negri Institute, Milano. 2006: Head of Laboratory for the
development of new pharmacological strategies , Oncology Department, Mario Negri Institute, Milano;
2011: Head of Laboratory of Methodology of Biomedical Research.
Member of Consiglio Direttivo Nazionale dell’Associazione Italiana di Oncologia Medica.
Member of Independent data monitoring committee of International Randomised Clinical trials in
NSCLC and ovarian carcinoma.
Co-author of more than 160 paper published on peer reviewed journals and of 5 chapters of scientific
books relative to clinical research methodology for therapeutic and diagnostic studies.
Selected publications

Pinto C, Novello S, Torri V, Ardizzoni A, Betta PG, Bertazzi PA, Casalini GA, Fava C, Fubini B, Magnani C, Mirabelli D,
Papotti M, Ricardi U, Rocco G, Pastorino U, Tassi G, Trodella L, Zompatori M, Scagliotti G. Second Italian Consensus
Conference on Malignant Pleural Mesothelioma: State of the art and recommendations. Cancer Treat Rev. 2012 Dec 11. [Epub
ahead of print] PubMed PMID: 23244777

Milan E, Lazzari C, Anand S, Floriani I, Torri V, Sorlini C, Gregorc V, Bachi A. SAA1 is over-expressed in plasma of non
small cell lung cancer patients with poor outcome after treatment with epidermal growth factor receptor tyrosine-kinase
inhibitors. J Proteomics. 2012 Dec 5;76 Spec No.:91-101.

Gao F, Miller JP, Miglior S, Beiser JA, Torri V, Kass MA, Gordon MO. The effect of changes in intraocular pressure on the
risk of primary open-angle glaucoma in patients with ocular hypertension: an application of latent class analysis. BMC Med
Res Methodol. 2012 Oct 4;12:151

Pietrantonio F, Garassino MC, Torri V, de Braud F. Reply to FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as
first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS-mutatedtumours in
the randomised German AIO study KRK-0306. Ann Oncol. 2012 Oct;23(10):2771-2.
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
Sartore-Bianchi A, Fieuws S, Veronese S, Moroni M, Personeni N, Frattini M, Torri V, Cappuzzo F, Vander Borght S, Martin
V, Skokan M, Santoro A, Gambacorta M, Tejpar S, Varella-Garcia M, Siena S. Standardisation of EGFR FISH in colorectal
cancer: results of an international interlaboratory reproducibility ring study. J Clin Pathol. 2012 Mar;65(3):218-23.
Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, Maiorino L, Hetzel M, Leschinger M,
Visseren-Grul C, Torri V. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine
in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol. 2012 Jan 10;30(2):172-8.
Maria Rosa Bani got her Biological Sciences degree at the University of Milan in 1998 attaining the
Italian Government Qualification to practice as Biologist in 1990. She obtained the specialization in
Pharmacological Research from the Department of Education of the Regional Government of
Lombardia in 1991 and the specialization in Biomedical Research from the Department of Education of
the Regional Government of Abruzzo in 1993.
In 2005 she was awarded the degree of Doctor of Philosophy (PhD), Discipline of Life Sciences of the
Open University Research School (UK).
From 1991 to 1995 she was a Post Doctoral Fellow at the Cancer Research Division, Sunnybrook Health
Science Centre, University of Toronto (Canada); from 2000 to 2001 she was Guest Scientist at the
Advance Technology Centre, National Cancer Institute, National Institute of Health (USA).
From 1996, she was a Fellow Research Scientist at the Mario Negri Institute for Pharmacological
Research, Laboratory of Biology and Treatment of Metastasis and she became a staff research scientist
in 2003. Since 2004 she was appointed Head of the Molecular Cancer Therapeutics Unit in the same
laboratory.
She has been the Scientific Manager of STROMA and ADAMANT, two Integrated Projects funded in
the 6th and 7th Framework Programs of the European Commission.
She is a member of the American Association for Cancer Research (AACR), the European Association
for Cancer Research (EACR) and the Italian Cancer Society (SIC).
Maria Rosa Bani research interests are in the field of cancer biology and therapeutics, with a focus on
molecular studies of the malignant progression and on the preclinical efficacy of therapeutics modalities.
She is co-author of 37 peer reviewed publications, 2 book chapters and 70 abstracts of which 17 selected
for oral presentations at international meetings.
Selected publications

Moschetta M, Pretto F, Berndt A, Galler K, Richter P, Bassi A, Oliva P, Micotti E, Valbusa G, Schwager K, Kaspar M,
Trachsel E, Kosmehl H, Bani MR, Neri D, Giavazzi R. Paclitaxel enhances therapeutic efficacy of the F8-IL2
immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts. Cancer Research 72: 1814-1824, 2012

Silini A, Ghilardi C, Figini S, Sangalli F, Fruscio R, Dahse R, Pedley RB, Giavazzi R, Bani M. Regulator of G-protein
signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor's proangiogenic
microenvironment. Cellular and Molecular Life Sciences. 69:1167-1178, 2012

Silini A., Ghilardi C., Ardinghi C., Bernasconi S., Carraro F., Naldini A., Bani M.R., Giavazzi R. Protease-activated receptor1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype. Clinical Experimental
Metastasis, 27 (1) : 43-53, 2010

Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through gene
expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008.

Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccardi E., Scanziani E., Eccles S.A., Bani M.R. Giavazzi R.
The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing apoptosis
of endothelial cells and inhibition of angiogenesis. Clinical Cancer Research 12: 1839-1849, 2006

Bani M.R., Nicoletti M.I., Alkharouf N.W., Ghilardi C., Petersen D., Erba E., Sausville E.A., Liu E.T. and Giavazzi R. Gene
expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Molecular Cancer Therapeutics 3: 111121, 2004.
Michela Cinquini got her degree in Statistical Science in 2005 at the University of Milano-Bicocca and
her specialization in ”Specialist in Pharmacological Research " at the Mario Negri Institute in 2008.
She has been working at Mario Negri Institute since 2004. She is now head of the “Systematic reviews
methodology and guidelines production” unit by the Laboratory of Methodology of Biomedical Research.
In 2009-2010 she worked as a Fellow at the Centre for Statistics in Medicine - Oxford, UK (Supervisor
Doctor Altman DG).
Since 2006 she has been teaching in several post-doctoral Masters in Clinical Research Methodology at
Ferrara and Parma University and since 2010 in Systematic reviews at Milano University.
Since 2008 she has been member of the Italian Cochrane Centre.
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Reasearch interest: Statistical and methodological aspects of Systematic reviews and Meta-analysis of
intervention; Quality evaluation of evidence-based medicine and production of oncological guidelines
using the GRADE approach.
Selected publications

Banzi R, Cinquini M, Liberati A, Moschetti I, Pecoraro V, Tagliabue L, Moja L.Speed of updating online evidence based
point of care summaries: prospective cohort analysis. BMJ. 2011 Sep 23;343:d5856

Galfrascoli E, Piva S, Cinquini M, Rossi A, La Verde N, Bramati A, Moretti A, Manazza A, Damia G, Torri V, Muserra G,
Farina G, Garassino MC; ORION Collaborative Group. Risk/benefit profile of bevacizumab in metastatic colon cancer: a
systematic review and meta-analysis. Dig Liver Dis. 2011 Apr;43(4):286-94.

Rossi A., Garassino MC., Cinquini M., Sburlati P., Borgonovo K., La Verde N., Farina G. and Torri V. Maintenance or
consolidation therapy in Small Cell Lung Cancer (SCLC) with non chemotherapic agents: a systematic overview. Lung
Cancer. 2010 Nov;70(2):119-28

Marchini S, Mariani P, Chiorino G, Marrazzo E, Bonomi R, Fruscio R, Clivio L, Garbi A, Torri V, Cinquini M, Dell'Anna T,
Apolone G, Broggini M, D'Incalci M. Analysis of gene expression in early-stage ovarian cancer. Clin Cancer Res. 2008 Dec
1;14(23):7850-60.
Giovanna Damia obtained her Medical Degree cum Laude from the University of Milan in 1985. After
specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of
Milan, she worked as a post-doctoral fellow in the Laboratory of Experimental Immunology of the
National Cancer Institute, Frederick, USA. She worked as a research fellow in the Laboratory of Cancer
Chemotherapy at the Mario Negri Institute and since April 2003 she has become chief of the DNA Repair
Unit at the Mario Negri Institute. From 1992 to1995 she has been consultant of the General Secretariat of
the Progetto Finalizzato CNR "Applicazioni Cliniche della Ricerca Oncologica". Since September 2005
she is Deputy Editor for Experimental Oncology of the European Journal of Cancer.
Her main fields of interest are: mechanism of action of anticancer drugs, cell cycle checkpoints
and natural compounds.
Selected publications

Foroni C, Broggini M, Generali D, Damia G. Epithelial-mesenchymal transition and breast cancer: Role, molecular
mechanisms and clinical impact. Cancer Treat Rev. 2011 Nov 25. [Epub ahead of print]

Damia G, Broggini M, Marsoni S, Venturini S, Generali D. New omics information for clinical trial utility in the primary
setting. J Natl Cancer Inst Monogr. 2011;2011(43):128-33

Ganzinelli M, Mariani P, Cattaneo D, Fossati R, Fruscio R, Corso S, Ricci F, Broggini M, Damia G. Expression of DNA
repair genes in ovarian cancer samples: biological and clinical considerations. Eur J Cancer. 2011 May;47(7):1086-94. Epub
2011 Jan 7.

Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, Serra SC, D'Incalci M, Cavalletti E, Giavazzi R, Damia G,
Camboni G. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical
models Cancer Res. 2011 Feb 15;71(4):1396-405..

Damia G, D'Incalci M. Genetic instability influences drug response in cancer cells. Curr Drug Targets. 2010
Oct;11(10):1317-24. Review

Carrassa L, Montelatici E, Lazzari L, Zangrossi S, Simone M, Broggini M, Damia. G. Role of Chk1 in the differentiation
program of hematopoietic stem cells. Cell Mol Life Sci. 2010 May;67(10):1713-22.
Eugenio Erba has obtained his Biological and Biochemistry Analysis Degree at the University of
Urbino. He worked as a research fellow in the Laboratory of Cancer Chemotherapy at the Mario Negri
Institute and since 1984 he is head of the Flow Cytometry Unit in the Department of Oncology at the
Mario Negri Institute of Milan. He has worked as a visiting fellow in the Department of Istochemistry
and Cytochemistry of the University of Leiden, The Netherlands in 1983. Since 1997 he is Teacher of
Post-Graduate Studies in Cytometry at the University of Milan and Co-ordinator and Teacher of PostGraduate Studies in Cytometry for the Italian Cytometry Group. He has been President of the Italian
Cytometry Group from 1999 to 2001. Since 2001 he is member of the Executive Board of the Italian
Cytometry Group.
Scientific areas of interest: studies on the mechanism of action of different compounds with provided
antitumoral activity evaluating the mechanism of cell death and cell cycle phase perturbations induced
on different human cancer cell lines by using flow cytometry. Co-ordinator of working-group in a
quality control study on flow cytometric DNA content analysis in human tumors.
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Selected publications

Urru S.A.M., Veglianese P., De Luigi A., Fumagalli E., Erba E., Gonella Diaza R., Carrà A., Davoli E., Borsello T., Forloni
G., Pengo N., Monzani E., Cascio P., Cenci S., Sitia R., Salmona M. A new fluorogenic peptide determines proteasome
activity in single cells. J.Med.Chem., 53: 7452-7460 (2010).

Germano G., Frapolli R., Simone M., Tavecchio M., Erba E., Pesce S., Pasqualini F., Grosso F., Sanfilippo R., Casali P.,
Gronchi A., Virdis E., Tarantino E., Pilotti S., Greco A., Nebuloni M., Galmarini C.M., Tercero J.C., Mantovani A.,
D’Incalci M., Allavena P. Anti-tumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells.
Cancer Res., 70(6): 2235-2244 (2010).

C. Forni, M Minuzzo, E. Virdis, E. Tamburini, M. Simone, M. Tavecchio, E. Erba, F. Grosso, A. Gronchi, P.Aman, P. Casali,
M. D’Incalci, S. Pilotti , R. Mantovani. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol.
Ca. Ther. 8(2), 449-57, 2009

E. Marrazzo, S. Marchini, M. Tavecchio, T. Alberio, S. Previdi, E. Erba, V. Rotter, M. Broggini. The expression of the
Np73isoform of p73 leads to tetraploidy. Eur J Ca 45, 443-53, 2009
 M.Tavecchio, M. Simone, E.Erba, I. Chiolo, G. Liberi, M. Foiani, M. D’Incalci, G. Damia. Role of homologous
recombination in trabectedin-induced DNA damage. Eur. J. Ca 44:609-618 (2008)
 Paulis M., Bensi M., Orioli D., Mondello C., Mazzini G., D’Incalci M., Falcioni C., Radaelli E., Erba E., Raimondi
E., De Carli L. Transfer of a Human Chromosomal Vector from a Hamster Cell Line to a Mouse Embryonic Stem
Cell Line. Stem Cell , 25:2543-2550 (2007)
Roldano Fossati got his Medical Degree cum Laude from the University of Milan in 1980, his PostDoctoral Degree in Endocrinolgy cum Laude from the University of Verona in 1983 and his PostDoctoral Degree in Medical Statistics from the University of Milan in 1992. He has been consultant at
the Mario Negri Institute since 1983 and, at present, he is head of the Gynecology and Oncology Unit of
the Laboratory of Translational and Outcome Research.
Areas of Interest: Statistical and methodologic aspects of clinical research with focus on Controlled
Clinical Trials in Oncology; Systematic Overview of the medical literature.
Selected publications

Hogberg T, Signorelli M, de Oliveira CF, Fossati R, Lissoni AA, Sorbe B, Andersson H, Grenman S, Lundgren C,
Rosenberg P, Boman K, Tholander B, Scambia G, Reed N, Cormio G, Tognon G, Clarke J, Sawicki T, Zola P, Kristensen
G. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Eur J
Cancer. 2010 Sep;46(13):2422-31. Epub 2010 Jul 7.

Signorelli M, Lissoni AA, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R,
Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, Fossati R. Modified Radical Hysterectomy Versus
Extrafascial Hysterectomy in the Treatment of Stage I Endometrial Cancer: Results From the ILIADE Randomized Study.
Ann Surg Oncol. 2009 Oct 16

Andrea Alberto Lissoni, Nicoletta Colombo, Antonio Pellegrino, Gabriella Parma, Paolo Zola, Dionyssios Katsaros,
Stefania Chiari, Alessandro Buda, Fabio Landoni, Michele Peiretti, Tiziana Dell’Anna, Robert Fruscio, Mauro Signorelli,
Roberto Grassi, Irene Floriani, Roldano Fossati , Valter Torri, Eliana Rulli. A phase II, randomized trial of neoadjuvant
chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide and cisplatin (TIP) versus paclitaxel and
cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap02 Italian Collaborative Study. Annals of Oncology, 20:660-665;2009

Fruscio R, Colombo N, Lissoni AA, Garbi A, Fossati R, Ieda' N, Torri V, Mangioni C.A phase II randomised clinical trial
comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced
epithelial ovarian cancer: long-term survival analysis. Br J Cancer. 2008 Feb 5;

Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, Colombo A, Fossati R. Adjuvant chemotherapy vs
radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006 Aug 7;95(3):266-71

Maggioni A, Benedetti Panici P, Dell'anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E,
Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C.Randomised
study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br
J Cancer. 2006 Sep 18;95(6):699-704.
Marlen Victoria Llerena Mesa got her degree in Pharmaceutic Science at the University of Havana
(Cuba) in 1993.
In 2003 she got the Lead Auditor Certificate according to ISO 9000-2000 standard at the Institute for
Standardization Research, Havana, Cuba. In 2005 and 2006 she got the title of Master in Pharmacologic
Science and in Clinical Trials, respetctively. Since Aprile 2012 she has been head of the Quality
Assurance Unit. Main areas of interest are the control and improvement of the quality assurance system,
the approval of standard operative procedures (SOPs) and development of a documentation system meant
to guarantee the traceability of all the activities in accord to the Norme of Good Clinical Practices (GCP)
and legal directives.
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Selected publications

Llerena Mesa M, Biagioli E. Importanza della assicurazione della qualità negli studi clinici. Medical Oncology Progress &
Perspectives 2012 ; Update 41 : 13-16.

Álvarez S, Rodríguez O, Llerena M. Unidad de Calidad: desarrollo e importancia para el Centro Nacional Coordinador de
Ensayos Clínicos. Revista Cubana de Farmacia 2010:44(Suplemento Especial 2).

Llerena M, Rodríguez OM, Pérez B, Álvarez S. Necesidad de información sobre Gestión de Calidad: programa de
entrenamiento. Revista Cubana de Farmacia 2004:38(Suplemento 1): 443-446.

Llerena M, Rodríguez OM, Pérez B, Álvarez S . Plegable, herramienta para comunicar información sobre Gestión de la
Calidad. Revista Cubana de Farmacia 2004:38(Suplemento 1):439-442.

Pérez B, Pérez A, Llerena M, Rodríguez OM, Álvarez S. Aseguramiento de la calidad en el sitio de ejecución de los ensayos
clínicos coordinados por el CENCEC en el periodo 2000-2002. Revista Cubana de Farmacia 2003: 37(Suplemento Especial).

Pérez B, Pérez A, Llerena M. Manual de instrucciones al farmacéutico que participa en un ensayo clínico coordinado por el
CENCEC. Revista Cubana de Farmacia 2003:37(Suplemento Especial).
Mirko Marabese got his Biological Sciences degree at the University of Milan in 2001 attaining the
Italian Government Qualification to practice as Biologist in 2002. He obtained the specialization in
Pharmacological Research from the Mario Negri Institute for Pharmacological Research in 2005. In the
same year he was awarded the degree of Doctor of Philosophy (PhD), Discipline of Life Sciences of
the Open University Research School (UK). From 2001, he was a Fellow Research Scientist at the
Mario Negri Institute for Pharmacological Research, Laboratory of Molecular Pharmacology and he
became a staff research scientist in 2008. From 2003 to 2004 he was a Visiting Fellow at Apoptosis &
Cancer Laboratory at Medical Research Council (MRC) Toxicology Unit of Leicester (UK).Since 2011
he was Head of the Molecular Genetics Unit in the Oncology Department at Mario Negri Institute for
Pharmacological Research.
Selected publications

Garassino MC, Marabese M, Rusconi P, Rulli E, Martelli O, Farina G, Scanni A, Broggini M. 10.Different types of K-Ras
mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol. 2011 Jan;22(1):2357.

Caiola E, Porcu L, Fruscio R, Giuliani D, Milani R, Torri V, Broggini M, Marabese M. DNA-damage response gene
polymorphisms and therapeutic outcomes in ovarian cancer. Pharmacogenomics J. Dec 13. 2011.

Floriani I, Garassino MC, Broggini M, Veronese S, Marsoni S, Marabese M, Farina G, Scanni A. Role of cetuximab in the
treatment of patients with NSCLC: are we throwing out the baby with the bath water? J Clin Oncol. 2010 ;28:467.

Sabatino MA, Marabese M, Ganzinelli M, Caiola E, Geroni C, Broggini M.. Down-regulation of the nucleotide excision
repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells. Mol Cancer. Sep 24;9:259.
2010.

Marabese M, Mazzoletti M, Vikhanskaya F, Broggini M. HtrA2 enhances the apoptotic functions of p73 on bax. Cell Death
Differ. May;15(5):849-58. 2008
Sergio Marchini was graduated summa cum laude, in Biological Science, University of Milan in
1993.,attaining the Italian Government Qualification to practice as Biologist in 1996. He obtained the
specialization in Pharmacological Research from the Department of Education of the Regional
Government of Lombardia in 1997 and the in 2000 he was awarded in advanced studies in Pharmacology,
University of Pavia, Italy. In 2003 he got the Ph. D. degree at the Open University, London UK.
Professional Positions: 2001-up to now: permanent position as a researcher at the "Mario Negri" Institute
for Pharmacological research. Since 2011 he was appointed Head of of Translational Genomic Unit,
Laboratory of Cancer Chemotherapy. In 2001, he was visiting scientist at MGH, Boston, Ma, US and
1998 he was visiting scientist at the Birmingham University (U.K.), Department of Medical Genetic.
Honour and Awards: 2001: First rank in the prize "ONLUS-AICC 2001" for young Italian scientists.
1995: First rank in the prize "MIGLIORI POSTER S.I.C." XIII Riunione Nazionale di Oncologia
Sperimentale e Clinica (Verona, 15-18 ottobre 1995). Research activities: translational research activities
are mainly focused on ovarian cancer tumors as well as on mixoid liposarcomas. By exploiting “-omic”
approaches on different cohort of tumor biopsies, the research activities of the Translational Genomic
Unit are focused on defying and integrate the transcriptional and mutational landscape of ovarian cancer
and mixoid liposarcomas tumors to identify molecular determinant with prognostic and diagnostic value.
Research activities are focused on the identification on the molecular determinat of cellular sensitivity to
anticancer agent by exploiting high throughput technologies, like arrays and qRT-PCR. In particular
these thecnologies have been applied to size and integrate the genomic features of ovarian cancer tumor
tissues.
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Selected publications

The zinc finger gene ZIC2 has features of an oncogene and its over- expression correlates strongly with the clinical course of
epithelial ovarian cancer. Sergio Marchini, Elizabeth Poynor, Richard R Barakat, Luca Clivio, Michela Cinquini, Robert
Fruscio, Luca Porcu, Cecilia Bussani, Maurizio D’Incalci, Eugenio Erba, Michela Romano, Giorgio Cattoretti, Dionyssios
Katsaros, Andrew Koff, Lucio Luzzatto. Clin Cancer Res. 2012 Aug 15;18(16):4313-24.

Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian
cancer. Sergio Marchini, Robert Fruscio, Luca Clivio, Luca Beltrame, Luca Porcu, Ilaria Fuso Nerini, Duccio Cavalieri,
Giovanna Chiorino, Giorgio Cattoretti, Costantino Mangioni, Rodolfo Milani, Valter Torri, Chiara Romualdi, Alberto
Zambelli, Michela Romano, Mauro Signorelli, Silvana di Giandomenico, Maurizio D’Incalci. Eur J Cancer. 2012 Aug 13.

Association between miR-200c and survival of stage I epithelial ovarian cancer patients. A retrospective study on two
independent tumour tissue collections Sergio Marchini*, Duccio Cavalieri*, Robert Fruscio, et al. The Lancet Oncology, Vol.
12, Issue 3, Pages 273 - 285, March 2011

Novel models of Myxoid Liposarcoma Xenografts mimicking the biological and pharmacological features of human tumors.
Roberta Frapolli, Elena Tamborini, EmanuelaVirdis, Ezia Bello, Eva Tarantino, Sergio Marchini, et al. Clin. Cancer Res.
2010 Oct 15;16(20):4958-67

Analysis of gene expression in early-stage ovarian cancer. Sergio Marchini, Pietro Mariani, Giovanna
Chiorino, Eleonora Marrazzo, Riccardo Bonomi, Robert Fruscio, Luca Clivio, Annalisa Garbi, Valter Torri,
Tiziana Dell’Anna, Giovanni Apolone, Massimo Broggini, and Maurizio D’Incalci. Clin. Cancer Res
2008;14(23) 7850-7860.

Np63 expression associated with poor survival in ovarian cancer. Sergio Marchini, Mirko Marabese, Eleonora
Marrazzo, Pietro Mariani, Dario Cattaneo, Roldano Fossati, Anna Compagnoni, Robert Fruscio, Andrea
Alberto Lissoni and Massimo Broggini. Ann Oncol. 2008 Mar;19(3):501-7
Davide Poli got his master’s degree in Physics at the University of Milan in 2007 and his specialization
in “Biochemical Research Technician" at the Mario Negri Institute for Pharmacological Research in
2004. Since November 2012 is a Head of Coordination, Management and Monitoring in the Laboratory of
Clinical Research.
His areas of interest are: design of eCRF in Clinical Trials, new electronic aspects of Clinical Research
especially towards technologies of Web-based Electronic Data Capture, methodology and data
management aspects in Clinical Research.
Selected Publications

Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group (EGPS), Poli D. The accuracy
and clinical application of predictive models for primary open-angle glaucoma in ocular hypertensive individuals.
Ophthalmology, Volume 115, Number 11 pp. 2030-2036, November 2008

Porcu L, Poli D, Torri V, Rulli E, Cropalato di Tullio M, Cinquini M, Bajetta E, Labianca R, Di Costanzo F, Nitti D, Floriani
I. Impact of recent legislative bills regarding clinical research on Italian ethics committee activity. Journal of Medical Ethics
2008, Volume 34, pp. 747-750

Gordon MO, Torri V. Miglior S, Beiser JA, Floriani I, Miller JP, Gao F, Adamsons I, Poli D, D'Agostino RB, Kass MA. A
validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension.
Ophthalmology, Volume 114, Number 1, pp. 10-19, January 2007

The European Glaucoma Prevention Study (EGPS) Group, Poli D. Results of the European Glaucoma Prevention Study.
Ophthalmology, Volume 112, Number 3, pp. 366-375, March 2005

Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, Wheeler S, Swart AM, Qian W, Torri V,
Floriani I, Jayson G, Lamont A, Tropé C; ICON and AGO Collaborators, Poli D. Paclitaxel plus platinum-based
chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGOOVAR-2.2 Trial. Lancet 2003; 361: 2099-2106
Luca Porcu obtained his degree as “Biochemical Research Technician" from the Mario Negri Institute
for Pharmacological Research in 2005. From 2001 to 2007 he has been employed as Coordinator and
Data Manager of Clinical Trials in the Clinical Epidemiology Laboratory; from 2007 to 2009 he has been
employed as Contract Research Associate in charge for the auditing of Clinical Trials; from 2007 up to
now he is employed for data analysis, meta-analysis, statistical computing in Biomedical Research in the
Laboratory of Methodology for Biomedical Research.
His scientific focus is the methodology of Biomedical Research, in particular the probabilistic models
implemented in the oncological setting.
Selected Publications

Procopio G, Verzoni E, Iacovelli R, Biasoni D, Testa I, Porcu L, De Braud F. Prognostic factors for survival in patients with
metastatic renal cell arcinoma treated with targeted therapies Br J Cancer. 2012 Sep 11

Marchini S, Fruscio R, Clivio L, Beltrame L, Porcu L, Nerini IF, Cavalieri D, Chiorino G, Cattoretti G, Mangioni C, Milani
R, Torri V, Romualdi C, Zambelli A, Romano M, Signorelli M, Giandomenico SD, D'Incalci M. Resistance to platinum-
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based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer. Eur J Cancer. 2012
Aug 13
Marchini S, Poynor E, Barakat R, Clivio L, Cinquini M, Fruscio R, Porcu L, Bussani C, D'Incalci M, Erba E, Romano M,
Cattoretti G, Katsaros D, Koff A, Luzzatto L. The zinc finger gene ZIC2 has features of an oncogene and its over- expression
correlates strongly with the clinical course of epithelial ovarian cancer. Clin Cancer Res. 2012 Jun 25
Caiola E, Porcu L, Fruscio R, Giuliani D, Milani R, Torri V, Broggini M, Marabese M. DNA-damage response gene
polymorphisms and therapeutic outcomes in ovarian cancer. Pharmacogenomics J. 2011 Dec 13
Porcu L, Poli D, Torri V, Rulli E, Di Tullio MC, Cinquini M, Bajetta E, Labianca R, Di Costanzo F, Nitti D, Floriani I.
Impact of recent legislative bills regarding clinical research on Italian ethics committee activity. J Med Ethics. 2008
Oct;34(10):747-50
Eliana Rulli got her master’s degree in Biostatistics and Experimental Statistic in 2007, her degree in
Statistical Science in 2004 at the University of Milano-Bicocca and her specialization in ”Specialist in
Pharmacological Research " at Mario Negri Institute in 2007.
She has been working at institute Mario Negri since 2003, at this time she is in charge of Statistic unit at
the laboratory of Clinical Trials.
Areas of Interest: methodology and statistical aspects of clinical research, systematic reviews and quality
assessment of medical literature.
Selected publications

Quaranta L, Biagioli E, Riva I, Rulli E, Poli D, Katsanos A, Floriani I. Prostaglandin analogs and timolol-fixed versus
unfixed combinations or monotherapy for open-angle Glaucoma: A systematic review and meta-analysis. J Ocul Pharmacol
Ther 2012 ; E-pub

Caiola E, Rulli E, Fruscio R, Buda A, Broggini M, Marabese M. KRas-LCS6 polymorphism does not impact on outcomes in
ovarian cancer. Am J Cancer Res 2012 ; 2 : 298-308

Garassino M C, Marabese M, Rusconi P, Rulli E, Farina G, Scanni A, Broggini M. Different types of K-Ras mutations
could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol 2011 ; 22 : 235-237

Graziano F, Galluccio N, Lorenzini P, Ruzzo A, Canestrari E, D'Emidio S, Catalano V, Sisti V, Ligorio C, Andreoni F, Rulli
E, Di Oto E, Fiorentini G, Zingaretti C, De Nictolis M, Cappuzzo F, Magnani M. Genetic activation of the MET pathway and
prognosis of patients with high risk, radically-resected gastric cancer. Clin Oncol 2011 ; 29 : 4789-4795

Floriani I, Torri V, Rulli E, Garavaglia D, Compagnoni A, Salvolini L, Giovagnoni A. Performance of imaging modalities in
diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. Magn Reson Imaging. 2010
Jan;31(1):19-31. Review.

Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi Gianluca, Graziano F, Cremolini C, Rulli E, Canestrari
E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A. PTEN Expression
and KRAS Mutations on Primary Tumors and Metastases in the Prediction of Benefit From Cetuximab Plus Irinotecan for
Patients With Metastatic Colorectal Cancer. Clin Oncol 2009 27 : 2622-2629
Giulia Taraboletti got her degree cum laude in Biological Sciences at the University of Pavia (Pavia,
Italy) in 1983, and the specialization in Pharmacological Research at the Mario Negri Institute, Milano,
Italy in 1986. From 1986 to 1988 she was a post-doctoral fellow at the Laboratory of Pathology, NCI,
NIH, Bethesda, MD, and from 1988-1995 research scientist at Mario Negri Institute in Bergamo, Italy.
Since 1995 she is Head of the Unit of Tumor Angiogenesis, at Mario Negri Institute, in Bergamo.
Research interests include tumor angiogenesis, endogenous inhibitors of angiogenesis (thrombospondin1) and preclinical studies of antiangiogenic and vascular disrupting compounds, including tubulintargeting agents. She is member of Metatasis Research Society (MRS), American Association for Cancer
Research (AACR), European Association for Cancer Research (EACR), and the Italian Society of
Oncology (SIC). She is on the editorial board of European Journal of Cancer, TheScientificWorldJournal,
and Current Cancer Therapy Reviews.
Selected publications

Bonezzi K, Belotti D, North BJ, Ghilardi C, Borsotti P, Resovi A, Ubezio P, Riva A, Giavazzi R, Verdin E, and Taraboletti
G. Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: implications for antineoplastic combination therapies.
Neoplasia, 14(9): 846–854, 2012.

Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis DS, Stravalaci M, Tomaselli S, Giavazzi R, Rusnati M,
Presta M, Zetta L, Mosher DF, Ribatti D, Gobbi M, Taraboletti G. Non-peptidic thrombospondin-1-mimics as fibroblast
growth factor-2 inhibitors: an integrated strategy for the development of new antiangiogenic compounds. J Biol Chem, 285:
8733-8742, 2010.

Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular disrupting activity of tubulin-binding 1,5diaryl-1H-imidazoles. J Med Chem 52, 7906–7910, 2009.

Margosio B, Rusnati M, Bonezzi K, Cordes B-lA, Annis DS, Urbinati C, Giavazzi R, Presta M, Ribatti D, Mosher DF, and
Taraboletti G. Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain.
Int J Biochem Cell Biol 40: 700-709, 2008.
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Giavazzi R., Bani M.R.,Taraboletti G. Tumor–host interaction in the optimization of paclitaxel-based
combination therapies with vascular targeting compounds. Cancer Metastasis Rev, 26:481–88, 2007.

Margosio B., Marchetti D., Vergani V., Giavazzi R., Rusnati M., Presta M., and Taraboletti G. Thrombospondin-1 as a
scavenger for matrix-associated fibroblast growth factor-2. Blood 102: 4399-4406, 2003.
Paolo Ubezio got his B.Sc. degree in Physics at the University of Milan, in 1982, and the specialisation
in Pharmacological Research Specialist" at the Mario Negri Institute for Pharmacological Research in
1986.
Main activities are: i) Computer simulation of tumor proliferation during/after treatments using models
based on the cell cycle; ii) Development of new methods and data analysis tools in flow cytometry and in
time-lapse imaging of living cells; iii) Optimization of anticancer drug scheduling; iv) Cellular uptake of
nanoparticles loaded with anticancer drugs.
Since 1991 is Head of the Unit of Biophysics at the Mario Negri Institute
Selected publications

Ubezio P., Falcetta F. and Lupi M. Challenges in the integration of flow cytometry and time-lapse live cell imaging data
using a cell proliferation model in: New Challenges for Cancer Systems Biomedicine, A. d’Onofrio, P. Cerrai, A. Gandolfi
(Eds.), SIMAI Springer Series, Springer-Verlag Italia 2012, pp377-398

Della Vittoria Scarpati G, Falcetta F, Carlomagno C, Ubezio P, Marchini S, De Stefano A, Singh VK, D'Incalci M, De
Placido S, Pepe S. A Specific miRNA Signature Correlates with Complete Pathological Response to Neoadjuvant
Chemoradiotherapy in Locally Advanced Rectal Cancer. Int J Radiat Oncol Biol Phys (2012) 83:1113-9

Colombo V, Lupi M., Falcetta F, Forestieri D, D'Incalci M, Ubezio P. Chemotherapeutic activity of silymarin combined
with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells. Cancer Chemother Pharmacol (2011)
67 : 369-379

Ubezio P; Lupi M, Branduardi D, Cappella P, Cavallini E, Colombo V, Matera G, Natoli C, Tomasoni D, D’Incalci M.
Quantitative assessment of the complex dynamics of G1, S and G2M checkpoint activities. Cancer Res (2009) 69: 52345240

Ubezio P and Cameron D. Cell killing and resistance in pre-operative breast cancer chemotherapy. BMC Cancer (2008)
8:201

Lupi M, Matera G, Branduardi D, D'Incalci M and Ubezio P. Cytostatic and cytotoxic effects of topotecan decoded by a
novel mathematical simulation approach. Cancer Res (2004) 64: 2825-2832
Massimo Zucchetti obtained his Chem. Pharm. Degree from the University of Milan in 1982. After
specializing in Pharmacology at the Mario Negri Institute of Milan (1988), he worked in the Laboratory
of Clinical Pharmacology of Department of Oncology at San Giovanni Hospital, Bellinzona, Switzerland
(1988-1990). Since 1996 he has been chief of the Cancer Clinical Pharmacology Unit at the Mario Negri
Institute. He is member of the Pharmacology and Molecular Mechanisms Group of the European
Organization for Research and Treatment of Cancer (EORTC) from 1988 up to date. His main field of
interest are:
- Clinical pharmacology, phase I and Phase II studies
- Analysis of drugs, development of new analytical method, pharmacokinetic and
pharmacodynamic studies in humans in GCP and GLP conditions
- Pharmacokinetic, toxicokinetic and metabolic studies in animals
- Pharmacokinetic drug interaction
Dr Zucchetti is author of more than 100 papers on pre-clinical and clinical cancer chemotherapy
published in peer reviewed international journals.
Selected publications

Gallerani E, Zucchetti M, Brunelli D, Marangon E, Noberasco C, Hess D, Delmonte A, Martinelli G, Bohm S, Driessen C, de
Braud F, Marsoni S, Cereda R, Sala F, D'Incalci M, Sessa C. A first in human phase I study of the proteasome inhibitor CEP18770 in patients with advanced solid tumours and multiple myeloma. Eur J Cancer 2013 49 : 290-296.

Bello E, Taraboletti G, Colella G, Zucchetti M, Forestieri D, Licandro S A, Berndt A, Richter P, D'Incalci M, Cavalletti E,
Giavazzi R, Camboni G, Damia G. The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth of
advanced-stage triple-negative breast cancer xenografts. Mol Cancer Ther 2012 E-pub

Sala F., Bagnati R., Livi V., Cereda R., D’Incalci M., Zucchetti M. Development and validation of a HPLC-MS/MS
method for the determination of the novel inhibitor of angiogenesis E-3810 in human plasma and its application in a clinical
pharmacokinetic study. J Mass Spectrom. 2011; 46: 1039-45.

Sala F., Marangon E., Bagnati R., Livi V., Cereda R., D’Incalci M., Zucchetti M. Development and validation of a
HPLC-MS/MS method for the determination of the novel proteasome inhibitor CEP-18770 in human plasma and its
application in a clinical pharmacokinetic study. J Mass Spectrom. 2010; 45: 1309-15.
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Frapolli R., Zucchetti M., Sessa C., Marsoni SA., Viganò L., Locatelli A., Rulli E., Compagnoni A., Bello E., Pisano C.,
Carminati P., D’Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the intra-patients variability is
related to 1-acid glycoprotein plasma levels. Eur J Cancer 2010, 66:635-41
Sala F., Zucchetti M., Bagnati R., D’Incalci M., Pace S., Capocasa F., Marangon E. Development and validation of a
HPLC-MS/MS method for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in
human plasma of patients partecipatig in a phase I study. J Chromatogr B: Anal. Tecnol. Biomed. Life Sci. 2009; 31: 18-26.
ACTIVITIES
The Oncology Department comprises four preclinical experimental laboratories (Laboratory of
Cancer Pharmacology, Laboratory of Molecular Pharmacology,Laboratory of Biology and
Treatment of Metastases and Laboratory of Cancer Cachexia AIRC Start-Up) and four
laboratories dealing with clinical research and clinical trials (Laboratory of Methodology of
Biomedical Reseach, Laboratory of Clinical Trials, Laboratory of Translational and Outcome
Research in Oncology and Laboratory for Medical Research and Consumer Involvement). The
Oncology department hosts the coordination center of two networks of hospitals that carry on
clinical research in gynecologic cancer (MaNGO: Mario Negri Gynecologic Oncology) and in
cancer pain (CPOR-SG: Cancer Pain Outcome Research Study Group) and a center for cancer
pain assessment and research (CERP:Center for the Evaluation and Research on Pain). In some
cases research projects are carried out by single laboratories or research units, in other cases by
collaborations between different laboratories of the Oncology Department or other departments,
or other groups outside the Institute (see National and International Collaborations).
Preclinical laboratories focus on the discovery and development of new antitumor and
antimetastatic drugs and their new combinations; on tumor biology, not only to acquire new
scientific knowledge, but particularly as a base for more selective therapeutic approaches and to
identify and evaluate experimental models for discovering and studying new drugs or
treatments.
Clinical new drug development has been developed in collaboration with many oncological
clinical centres and is based on the preclinical evidences obtained by the Laboratory of Cancer
Pharmacology, the Laboratory of Molecular Pharmacology and the Laboratory of Biology and
Treatment of Metastases. Laboratory of Methodology of Biomedical Research, the Laboratory
of Clinical Trials, the Laboratory of Translational and Outcome Research in Oncology and the
Laboratory for Medical Research and Consumer Involvement are involved in the evaluation of
the effects of new therapeutic modalities in phase I/II and in phase III comparative and
effectiveness outcome studies.
Outcome Research implies organizing trials to clarify the results of certain health care practices
and interventions in clinical practice. Observational (surveys) and outcome research
(effectiveness) studies are carried out, in collaboration with regional and national health
authorities and other scientific associations.
At the preclinical and clinical level there are studies of various human tumors, with particular
emphasis on ovarian tumors and more recently on soft tissue sarcomas.
MAIN FINDINGS
At nanomolar concentrations, Trabectedin affects the regulatory mechanisms of the
transcription. Cells that are deficient in Homologous Recombination DNA Repair -e.g. with
mutations of BRCA1 or BRCA2 genes- are hypersensitive to the drug Nucleotide excision
repair deficient cells that are hypersensitive to UV rays and to other DNA damaging drugs are
resistant to Trabectedin.
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Exploiting a Mixoid liposarcoma cell lines resistant to trabectedin, we used an integrated
approach based on miRNA-genes and proteins expression to shape the molecular pathways
involved in trabectedin resistance.
The selective activity of Trabectedin against human myxoid liposarcoma appears related to the
drug ability to modulate the transcription of genes involved in adipocytic differentiation.
Trabectedin modulates the transcription of genes involved in pro-inflammatory mechanisms that
are potentially relevant for tumor growth and progression and inhibits the production of
cytokines and chemokines by macrophages that are tumor associated.
New sarcoma experimental models have been obtained. They will be useful to investigate new
drugs for these diseases.
Use of mathematical models of tumor growth and anticancer treatment to interpret experimental
data and to manage the complexity of underlying biological phenomena.
A new method enabling to perform dynamical measures of cell cycle checkpoint activities in
response to anticancer treatments.
Gene profiling analysis shows specific molecular signatures according to the histotype and
prognosis of stage I ovarian carcinoma. Analysis of miRNA expression profile in a cohort of
stage I patients gathered together from two independent tumor tissue collection revealed miR200c as an independent prognostic factor of relapse and overall survival.
Zic2, a transcription factor involved in embryogenesis, was found upregulated in biopsies taken
from epithelial ovarian cancer compared to its expression in borderline biopsies. Within stage I
ZIC2 expression levels were associated with poor prognosis.
Patients with ovarian cancer have a different expression of genes involved in DNA repair that is
dependent on the tumor stage and pharmacological response to treatment.
Through the screening of a siRNA library a gene (wee1) synthetically lethal with CHK1 has
been identified. The simultaneous inhibition of CHK1 and wee1 strongly affects the in vitro
growth of several cancer cell lines but not that of normal cells. These data are of potential
interest.
The use of combinations of PI3K/akt/mTOR inhibitors acting at different sites of the same
target, induces a pronounced antitumor effect. Mechanistically there is a selective inhibition of
the translation of proteins involved in the cellular growth.
Mutations in the K-RAS gene have a different impact on the response to treatment that is
dependent from the type of aminoacid substitution present at codon 12.
The growth of breast cancer cells in the bones is slowed down by selective c-met inhibitors.
A population of potential stem cell origin has been characterised from ovarian cancer patients.
These cells represent a unique tool to study new potential anticancer agents affecting these cells
considered the most resistant cancer cells.
The vascular endothelial growth factor (VEGF) released by cancer cells modifies gene
expression of the tumor microenvironment and response to treatment. Specifically, the
Regulator of G-protein signaling 5 (RGS5) was highly expressed by the stroma of VEGF rich
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tumors and its protein was selectively demonstrated in the vasculature of ovarian carcinoma
specimens.
Genes expressed by endothelial cells isolated from human cancer specimens were identified.
We have discovered that PRSS3/TrypsinogenIV is fundamental for the regulation of tumorendothelial cell motility mediated by the proangiogenic environment. Its role as marker of
tumor angiogenesis is under investigation.
A new antiangiogenic domain of thrombospondin (a physiological inhibitor of angiogenesis)
that binds the angiogenic factor FGF-2 has been identified and characterized. Non-peptidic
small molecules, mimetic of this domain, have been identified and are studied as potential
inhibitors of angiogenesis.
Vascular Endothelial Growth Factor C (VEGFC, the main mediator in lymphoangiogenesis)
promotes ovarian carcinoma progression through paracrine and autocrine mechanisms. Selective
inhibitors of VEGF/VEGFRs pathway inhibit ovarian tumor growth and invasion.
Preclinical studies have shown that bevacizumab combined with chemotherapy not only affects
ovarian carcinoma progression, but when administrated as maintenance regimen significantly
prolonged mouse survival, reducing ascites and tumor dissemination.
The addition of chemotherapy counteracts metastasis augmentation caused by VEGF/VEGFR
inhibitors in preclinical tumor models, thus highlighting the importance of testing ad hoc
combination to abrogate unwanted effects.
Paclitaxel by acting on tumor stroma potentiates therapeutic efficacy of the immunocytokine
F8-IL2 in metastatic melanoma positive for EDA-fibronectin recognized by the antibody F8.
Inhibitors of the histone deacetylase SIRT2, by acting through the transcription factor FOXO3a;
potentiate the anti-motility activity of paclitaxel.
The MaNGO group collaborated in the CALYPSO phase III trial that compared CD
(carboplatin-pegylated liposomal doxorubicin (PLD)) with CP (carboplatinpaclitaxel) in
patients with platinum-sensitive recurrent ovarian cancer. These two chemotherapic regimens
showed similar results in terms of disease free survival and overall survival in the 976 patients
enrolled onto the trial. Their toxicity profiles, however, were very different and the clinicians
can now rely upon a broader therapeutic supply in order to tailor cancer therapies on patients’
needs.
An Italian randomized phase III trial has assessed the role of systematic aortic and pelvic
lymphadenectomy (SAPL) at second-look surgery in early stage or optimally debulked
advanced ovarian cancer. This trial enrolled 308 patients and showed that the median operating
time, blood loss, percentage of patients requiring blood transfusions and hospital stay were
higher in the SAPL than in the control arm. Inspite of this higher toxicity the SAPL did not
improve either disease free survival of overall survival.
Results from a systematic review of literature and from a prospective epidemiologic study
suggest that an important proportion of patients with cancer pain (up to 43%) receive an
analgesic treatments that is not appropriate with the intensity of pain.
Results from a survey carried out on a national level on a sample of 1801 patients with cancer
pain confirm that in Italy a relevant part of cancer patients does not receive an appropriate
information about their prognosis: physicians reported that according to their knowledge only
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31% received information about their prognosis. An independent survey carried out in a
Northern Italian Region confirmed this finding: among 550 patients treated at home for cancer
pain with palliative care , only 58% were classified to be fully aware of their prognosis.
An observational longitudinal study carried out in 110 Italian centers and involving about 1800
patients with metastatic cancer and pain have documented that that in terms of analgesics
effectiveness, that each drugs prescribed by investigators (morphine, fentanyl, buprenorphine
and oxycodone) were able to reduce the intensity of pain of about 2 points on a 11-eleven point
numerical rating scale (p<0.001). The application of specific pe-planned algorithm identified
about 30% cases who were classified as non-responders. Preliminary analyses documented
some differences between drugs in terms of size of the analgesic effect, dosages required and
side effects reported.
Furthermore it has been possible to report as the different opioid analgesics drugs have been
able to ensure a substantially equi-analgesia but a different behavior in terms of other outcome
and endpoints (as dose variations over time, use of switch, use of adjuvants co-treatments).
Always in 2012 an analysis has been conducted to propose a method of evaluation of the
clinical outcomes in the treatment of cancer pain. From this investigation some cut-offs that
delimit a satisfactory result from the patient in comparison to one not satisfactory have been
underlined.
A prospective study, conducted in collaboration with a group of primary care physicians, has
allowed the identification of the presence of some social determinants, classified as factors
related to social vulnerability, which are associated with lack of use of health services in the
area of secondary prevention. Further analyses are underway to evaluate possible associations
between some social determinants and lack of secondary prevention programs.
The training and information activity organized with the associations of citizens & patients in
the framework of the PartecipaSalute project has been finalized to the organization of the Parita
task “Participate to the research project with the associations”. Parita is organised to discuss
with the scientific community the grey areas of the medical assistance and clinical research
identified from the patients and their associations, and to develop specific protocols for future
research programs.
One of the first experience of deliberative democracy in medicine has been carried out, in
particular the method of juries of citizens in the case of carrier screening for cystic fibrosis.
NATIONAL COLLABORATIONS
Age.Na.S. Agenzia Nazionale per i Servizi Sanitari Regionali, Roma
Agenzia Sanitaria Regionale (ASR), Bologna
Agenzia Italiana del Farmaco (AIFA), Roma
Alleanza Contro il Tumore Ovarico (ACTO), Milano
Associazione Donne Operate Carcinoma Mammario ADOCM Crisalide, Rimini
Associazione Serena a Palermo, Palermo
Azienda Sanitaria Locale, Rimini
Azienda Sanitaria Locale, Vercelli
Assessorato Sanità, Regione Emilia Romagna
Associazione Italiana di Oncologia Medica (AIOM)
Associazione Italiana di Ematologia Pediatrica (AIEOP)
Associazione Italiana Sclerosi Multipla, Genova
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Associazione Volontari Assistenza Pazienti Oncologici (AVAPO)
Azienda Sanitaria Unica Regionale, Regione Marche
Azienda Ospedaliera di Reggio Emilia Arcispedale S. Maria Nuova
Azienda Ospedaliera San Gerardo, Università Milano-Bicocca, Monza
Casa Sollievo della Sofferenza, San Giovanni Rotondo (IRCCS)
Centro Ricerche Bracco–Bracco Imaging Spa, Colleretto Giacosa (TO)
Centro Servizi Volontariato Toscana CESVOT, Pistoia
CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, Milano
CNR IGBE, Pavia
CNR, Istituto di Chimica del Riconoscimento Molecolare, Milano
CNR, Istituto per lo Studio delle Macromolecole, Milano
Cochrane Collaboration
ENEA Centro Ricerche, Unità di Tossicologia e Scienze Biomediche, Roma
Europa Donna Italia, Milano
Fondazione Attilia Pofferi, PistoiaFondazione IRCCS Istituto Nazionale dei Tumori (INT),
Milano
Fondazione Centro San Raffaele del Monte Tabor - MILANO
Fondazione Fibrosi Cistica, Verona
Fondazione GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente)
Fondazione IRCCS Istituto Neurologico, C. Besta, Milano
Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milano
Fondazione Nerina e Mario Mattioli Onlus, Milano
Fondazione Piemontese Ricerca sul Cancro, Candiolo
Fondazione Salvatore Maugeri, Pavia
Fondo Edo Tempia, Laboratorio di Bioinformatica e Farmacogenomica, Biella
Gruppo Italiano di Oncologia Geriatrica (GIOGer)
I.A.S.I., Roma
Istituti Ospitalieri di Cremona
Istituto Clinico Humanitas, Rozzano MI
Istituto Dermopatico dell'Immacolata, Roma
Istituto Ortopedico Galeazzi, Milano
Istituti Ortopedici Rizzoli, Bologna
Istituto di Endocrinologia ed Oncologia Sperimentale (IEOS), CNR, Napoli
Istituto Europeo di Oncologia (IEO), Milano
Istituto di Fisica, Politecnico di Milano
Istituto di Genetica Molecolare CNR, Sezione di Istochimica e Citometria, Pavia
Istituto Nazionale per la Ricerca sul Cancro (IST), Genova
Istituto Nazionale Tumori Fondazione G. Pascale, Napoli
Istituto Neurologico Carlo Besta, Milano
Istituto Regina Elena, Roma
Istituto Superiore di Sanità
Istituto Toscano Tumori, Firenze
Laboratorio Cell factory, Policlinico di Milano
LNCIB- Area Science Park & Dipartimento Scienze della Vita, Università di Trieste
Nerviano Medical Sciences Oncology
Ospedale Fatebenefratelli e Oftalmico, Milano
Ospedale San Matteo, Pavia
Ospedale Santa Chiara, Trento
Presidio Ospedaliero Riabilitativo Beata Vergine Consolata Fatebenefratelli, San Maurizio C.se
(TO)
Regione Toscana
Rete Oncologica Lombarda (ROL), Milano
ANNUAL REPORT
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2012
IRFMN
Spedali Civili di Brescia
Università Cattolica del Sacro Cuore, Roma
Università di Bari
Università di Brescia
Università di Catania
Università di Chieti
Università degli Studi di Ferrara
Università di Milano
Università di Modena e Reggio Emilia
Università di Monza
Università degli Studi di Napoli
Università di Pavia
Università di Padova
Università di Pisa
Università “La Sapienza”, Roma
Università di Siena
Università di Torino
Università di Verona
Zadig, Agenzia di Giornalismo Scientifico, Milano
INTERNATIONAL COLLABORATIONS
ARCAGY (Association de Recherche sur les Cancers Gynécologiques), France
Barts and The London School of Medicine & Dentistry , Londra, UK
Breakthrough Breast Cancer Center, Institute of Cancer Reasearch, London, U.K.
Cancer Biomarkers and Prevention Group, University of Leicester, U.K.
Cancer Research UK, London, U.K.
Centre for Health Communication and Participation, Australian Institute for Primary Care and
Ageing, La Trobe University, Melbourne, Australia
Cochrane Consumer network (via The Cochrane Collaboration), UK
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York,
USA
EORTC, Brussels, Belgium
European Agency for the Evaluation of Medicinal Products (EMEA), London, U.K.
European AIDS Treatment Group, Belgium
European Association for Palliative Care – research network (EAPC rn)
European Network of Gynaecological Oncology Trials groups (ENGOT)Eusoma – (European
Society of European Palliative Care Research Network (PRC), Trondheim, Norway
Breast Cancer Specialist) Florence, Italy
Executive Board of GCIG (Gynecologic Cancer Intergroup)
Frontier science & technology Research Foundation Southern Europe (FSE), Switzerland
Genome Institute of Singapore (GIS), Singapore
German Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Heidelberg,
Germany
German Network of the Coordinating Centres for Clinical Trials U Koeln , Germany
Goteborg University, Lundberg Laboratory for Cancer Research, Goteborg, Sweden
Gynecologic Cancer Intergroup (GCIG)
Helios Klinikum Erfurt GmbH, Institute of Pathology, Germany
Institute National de la Santè et de la Recherche Médicale, France
ANNUAL REPORT
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2012
IRFMN
Institute of Pathology, Friedrich Schiller University, Jena, Germany
Institut Villejeouf, ParisIstituto Oncologico della Svizzera Italiana, Switzerland
Johns Hopkins University, USA
La Trobe University, Melbourne, Australia
Ludwig Institute for Cancer Research, London, U.K.
Ludwig-Maximilians-Universität MünchenNational Cancer Center, Singapore
Stony Brook University, New York, USA
Massachusetts General Hospital and Harvard Medical School, USA
MD Anderson Cancer Center, Houston, Texas, USA
Memorial Sloan Kettering, New York, USA
MRC, London, U.K.
Multiple Sclerosis Australia
National Cancer Institute (NCI), Bethesda and Frederick, MD, USA
Ospedale San Giovanni, Bellinzona, Switzerland
Oxford University Hospitals,UK
Paterson Institute for Cancer Research, Manchester, U.K.
Rigshospitalet, Copenaghen University Hospital, Denmark
SAKK (Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung)
Southern Europe New Drug Organization (SENDO), Milan, Italy
Swiss Federal Institute of Technology, Zurich, Switzerland
The Sackler Institute, University College London, U.K.
Tumor Biology and Metastasis Institute of Cancer Research, Sutton, U.K.
University College, London Medical School, London, U.K.
University of Birmingham, U.K.
University of Cincinnati, USA
University of Crete Medical School, Greece
University of Liège, Belgium
University of Newcastle, U.K.
University of Pau, France
University of Ulm, Germany
University of Wisconsin, Madison, WI, USA
University Medical Center Freiburg (Universitäsklinikum Freiburg), Germany
Kyoto University, Japan
Weizmann Institute of Science, Israel
EDITORIAL BOARD MEMBERSHIP
American Journal of Cancer Research (Maurizio D’Incalci, Massimo Broggini, Giovanna
Damia)
Attualità in Senologia (Paola Mosconi)
British Journal of Cancer (Maurizio D’Incalci)
Chemotherapy (Maurizio D’Incalci)
Clinical Experimental Metastasis (Raffaella Giavazzi)
Current Opinion in Oncologic, Endocrine and Metabolic Drugs (Maurizio D’Incalci)
Current Cancer Therapy Reviews (Raffaella Giavazzi, Giulia Taraboletti)
European Journal of Cancer (Raffaella Giavazzi, Massimo Broggini e Giulia Taraboletti)
Frontiers in Cancer Genetics (Massimo Broggini)Frontiers in Pharmacology (Maurizio
D’Incalci)
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IRFMN
Health and Quality of Life Outcomes (Giovanni Apolone, Paola Mosconi)
International Journal for Quality in Health Care (Giovanni Apolone)
Journal of Ambulatory Care and Management (Giovanni Apolone)
Journal of B.U.ON. (Maurizio D’Incalci)
Journal of Chemotherapy (Raffaella Giavazzi)
Journal of Experimental Therapeutics and Oncology (Raffaella Giavazzi)
Journal of Medicine and the Person (Giovanni Apolone)
Journal of Preventive Medicine anf Hygiene (Giovanni Apolone)
Molecular Cancer Therapeutics (Maurizio D’Incalci)
Oncology Research (Maurizio D’Incalci)
PLoS ONE (Maurizio D’Incalci)
The International Journal of Biological Markers (Raffaella Giavazzi)
The Journal of Cancer Microenvironment (Raffaella Giavazzi)
TheScientificWorldJournal, (Maurizio D’Incalci, Giulia Taraboletti)
Tumori (Maurizio D’Incalci, Raffaella Giavazzi)
www.PartecipaSalute.it (Paola Mosconi)
www.fondazionemattioli.it (Maurizio D’Incalci)
PEER REVIEW ACTIVITIES
Acta Orthopaedica, American Journal of Pathology, Annals of Hematology, Annals of
Oncology, Anti-cancer Drugs, Biochemical Pharmacology, BioMed Central Editorial,British
Journal of Cancer, British Journal of Pharmacology, British Medical Journal, Cancer
Chemotherapy and Pharmacology, Cancer Detection and Prevention, Cancer Letters, Cancer
Research, Carcinogenesis, Chemico-Biological Interactions, Clinical & Experimental
Metastasis, Clinical Cancer Research, Cytometry, Expert Review of Anticancer Therapy,
European Journal of Cancer, European Journal of Immunology, Faseb Journal, Gynecologic
Oncology, Health and Quality of Life Outcomes, Health Expectations, European Journal of
Neurology, Intensive Care Medicine, International Journal of Biological Markers, International
Journal of Cancer, International Journal of Gynecological Cancer, International Journal for
Quality in Health Care, Journal of Ambulatory Care and Management, Journal of Biological
Chemistry, Journal of Biological Markers, Journal of Cell Biochemistry, Journal of Cellular
and Molecular Medicine, Journal of Chemotherapy, Journal of Clinical Oncology, Journal of
Experimental Therapeutics and Oncology, Journal of Medicinal Chemistry, Journal of Medicine
and the Person, Journal of the National Cancer Institute, Journal of Neurology, Journal of
Nucleic Acids, Journal of Preventive Medicine and Hygiene, Journal of the National Cancer
Institute, Leukemia, Molecular Cancer Therapeutics, Molecular Medicine, Nature
Biotechnology, Nature Reviews, Oncology Research, PharmacoEconomics, PLoS ONE,
Psycho-Oncology, Programma di Ricerca Regione Università Regione Emilia Romagna,
Quality of Life Research, Science, The Patient: patient-centered outcomes research,
TheScientificWorldJournal, Tumori, ZEG Centre for Epidemiology & Health Research.
ANNUAL REPORT
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2012
IRFMN
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
Ethical Committee, Centro di Riferimento Oncologico, Aviano PN, Italy
Ethical Committee, Ente Ospedaliero San Paolo, Milan, Italy
Comitato Etico Fondazione CNAO - Centro Nazionale di Adroterapia Oncologica, Pavia
Comitato Etico Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milano
Comitato Etico Istituto Clinico Humanitas, Rozzano, MI
Comitato Tecnico-Scientifico Fondazione Regionale Ricerca Biomedica
Consiglio di Amministrazione, Università di Trento
Ethical Committee, Istituto Europeo di Oncologia, Milan, Italy
Ethical Committee, Istituto Neurologico Carlo Besta, Milan, Italy
Ethical Committee, Ospedale San Gerardo, Monza, Milan, Italy
Ethical Committee, Ospedale Sant’Anna, Como, Italy
Ethical Committee, Ospedale della Valtellina e Valchiavenna, Sondrio, Italy
Ethical Committee, IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
Ethical Committee, Azienda USL di Bologna, Italy
Comitato Scientifico, Fondazione Buzzi Unicem Onlus
Comitato Strategico e di Studio per la Leucemia Linfoblastica Acuta (CSS - LLA)
Comitato Tecnico-Scientifico, Alleanza Contro il Tumore Ovarico (ACTO), Milano
Scientific Committee, Associazione Italiana Ematologia e Oncologia Pediatrica, Monza, Milan,
Italy
Scientific Committee, Pezcoller Foundation, Trento, Italy
Technical-Scientific Commitee, Associazione Italiana per la Ricerca sul Cancro, Milan, Italy
Board of Directors, Fondazione Nerina e Mario Mattioli Onlus, Milan, Italy
Board of Directors, Società Italiana di Cancerologia (SIC)
Board of Directors, Società Italiana di Citometria (GIC)
Directional Council Areas- Centro Cochrane Italiano (CCI), Milan
National Advisory Board 8th World Congress of Psycho-Oncology
Developmental Therapeutics Program, National Cancer Institute (NCI)
Decision Network and Executive Committee, South Europe New Drug Organization (SENDO)
Executive Committee, European Asociation for Cancer Research (EACR)
Fondazione Attilia Pofferi, Pistoia, Italy
NHS R&D National Coordinating Centre for Health Technology Assessment, UK
Pezcoller Foundation-EACR Award
EVENT ORGANIZATION
Training Course: Conoscere per scegliere: orientarsi in salute e sanità. CESVOT, Pistoia (Italy), February 25,
March 23-24, 2012
Citizens’ jury: Il Servizio Sanitario deve o no organizzare uno screening nella popolazione con
lo scopo di individuare persone sane che potrebbero avere figli malati di fibrosi cistica? Verona
(Italy), May 5, 2012
Meeting: Il Comitato Etico: attività, ricerca e servizio. La nota informativa al Consenso
Informato: lo studio del Comitato Etico. Bologna (Italy), May 23, 2012
Meeting: “Antiangiogenic therapies in oncology, working in progress” and 9° Assemblea
MaNGO. Milan (Italy), June 15.16, 2012
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CONFERENCE AND WORKSHOP CONTRIBUTIONS
Conference: IV International Conference on Angiogenesis in Memory of Judah Folkman. Rome
(Italy), January 13-14, 2012.
“Round Table II: How to improve the interaction between bench and bedside?”
“Round Table III: New therapeutic strategies for antiangiogenic therapy”
Meeting: Comitati Etici a confronto. Azienda Prov.le Servizi Sanitari Provincia di Trento.
Incontro tra rappresentanti dei Comitati Etici per costituire un gruppo collaborativo permanente.
Trento (Italy), January 20, 2012
Meeting: 33rd EORT-PAMM Winter Meeting. Puerto de la Cruz, Tenerife (Spain), January 2528, 2012.
“The mechanism of action and the clinical activity of the marine natural product trabectedin and
related compounds”
Meeting: Il sistema di monitoraggio della qualità percepita: i primi risultati. La qualità percepita
in una società che cambia. Treviso (Italy), February 15, 2012
Course: CESVOT Conoscere per scegliere: orientarsi in salute e sanità. Pistoia (Italy), February
25, 2012.
“Come si costruisce un protocollo di uno studio di efficacia”
“I Comitati Etici”
Congress on “Cellular Oncology” -new insights leading to clinical advancement (bi-annual
meeting ISCO and EWCMGST). Palma de Majorca (Spain), March 4-8, 2012.
“Inhibition of tumor angiogenesis & metastasis: combination with chemotherapy”.
Meeting: Convegno Nazionale sulla Ricerca Indipendente in Italia: La qualità degli studi nonprofit per la ricerca e per i pazienti.
Partecipazione al Convegno FADOI. Rome (Italy), March 6, 2012
Meeting: European Medica Reasarch Councils (EMRC). FLIP Implementation of Medical
Research in clinical practice. Session I: Patient and public. Copenhagen (Denmark), March 14,
2012
Course: CESVOT Conoscere per scegliere: orientarsi in salute e sanità. Pistoia (Italy), March
23, 2012
“Navigare in internet alla ricerca di informazioni di qualità”.
“L’agopuntura, una questione da mal di testa. Dalle revisioni sistematiche ai giornali”.
Meeting: AIOM. Linee Guida “Assistenza psicosociale dei malati”. Rome (Italy), March 28,
2012
Course: 11° Corso di Formazione avanzata: Medicina genomica e terapia personalizzata in
ematologia/oncologia. Pavia (Italy), April 16-20, 2012.
“Eredità e risposta ai farmaci”
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2012
IRFMN
Conference: 6th International Conference on Thrombosis and Hemostasis Issues in Cancer.
Bergamo (Italy), April 20-22, 2012.
“Cancer cells modify the microenvironment: RGS5 a novel endothelial protein of the abnornal
tumor vasculature”.
“TrypsinogenIV, a new player in tumor angiogenesis”.
“Inhibition of FGF-2 angiogenic activity by novel small molecules mimetic of thrombospondin1 (TSP-1)”.
“Role of the FGF-2-binding fragment of thrombospondin-1 (TSP-1) in tumor progression”.
Course: 2° Corso Educazionale Tumori Rari. Marsala (Italy), May 3-5, 2012.
“Chemioterapia o target therapy”
Meeting: 25th Annual Meeting of the European MusculoSkeletal Oncology Society. Simposio
satellite “Trabectedin: consolidating the evidence in patients with soft tissue sarcoma”. Bologna
(Italy), May 15-16, 2012.
“Chemotherapy or target therapy in soft tissue sarcoma?”
Meeting ACTO Onlus: Tumore ovarico. Secondo incontro pazienti, ricercatori e clinici. Milan
(Italy), May 18, 2012.
“Incontro tra pazienti, ricercatori e clinici un anno dopo”
“Nuove acquisizioni sulla sensibilità e resistenza alle terapie”
“Resoconto e continuazione del progetto di ricerca Ieo/IFOM/Mario Negri adottato da ACTO
Onlus
Annual Seminar: L.I.L.A. associazioni di pazienti e industria farmaceutica: un abbraccio
pericoloso? Milan (Italy), May 19, 2012
Meeting AILS: Sclerosi sistemica: presente e futuro. Il coinvolgimento delle Associazioni nel
dibattito sulla salute. Milan (Italy), May 19, 2012
Congress: 5° Congresso Nazionale SIMPIOS. Una maggiore attenzione al controllo delle
infezioni acquisite in terapia intensiva: la compartecipazione dei pazienti/consumatori. Pisa
(Italy), May 30, 2012
Meeting: ASCO Annual Meeting. Chicago (USA), June 1-5, 2012.
“Association between body weight and efficacy outcomes during trabectedin therapy for
recurrent advanced soft tissue sarcoma (STS)”
Meeting: Agenas: Le Buone Pratiche per la sicurezza del paziente. Prospettive nazionali ed
internazionali. Una metodologia per il trasferimento delle Buone Pratiche. Rome (Italy), June 5,
2012
Symposium on Tumor microenvironment in cancer biology and targeting. Jena (Germany), June
08-09, 2012.
“Therapeutic targeting of tumor-microenvironment interactions: a preclinical study”.
Simposium: 24th Pezcoller Symposium. Trento (Italy), June 14-16, 2012.
“VEGF retrains paclitaxel response: molecular analyses of the tumor microenvironment”.
Meeting: The international Biochemistry of exercise. Stockolm (Sweden), June 17-21, 2012.
“The p97/VCP ATPase is critical in muscle atrophy and for the accelerated degradation of most
muscle proteins”
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IRFMN
Meeting: Cachexia in End-stage Organ Failure. ISMETT, Palermo (Italy), June 22, 2012.
“Molecular Mechanisms of muscle wasting”.
Meeting: LILT Lecce: da 20 anni la sfida del Salento al cancro. Cittadini, pazienti e
associazionismo: il valore della partecipazione al dibattito sulla salute. Lecce (Italy), June 30,
2012
Meeting: 22nd Meeting of the European Association for Cancer Research. Barcelona (Spain),
July 07-10, 2012.
“Cediranib affects tumor progression and survivalof mice bearing human ovarian carcinoma
xenografts expressing VEGFC”.
“TrypsinogenIV, a new target to impair tumor endothelial cells motility”.
Congress: 14th World Congress on Pain, Milan (Italy), August 28-31, 2012.
“Effect of spinal noradrenaline depletion on the antinociceptive activity of tapentadol in rats.”
Congress: 5th European Congress for Integrative Medicine. Round Table: Experimenting models
of CAM integration in the health systems: How can the patients play their needed role? (C.
Colombo). Florence (Italy), September 21, 2012
Meeting: Cancer Cachexia: Molecular Mechanisms and Therapeutics Approaches. Boston,
USA, September 21-23, 2012.
“The p97/VCP ATPase is critical in muscle atrophy and for the accelerated degradation of most
muscle proteins”
Meeting Regione Lombardia: Il potere del cittadino e del paziente nelle scelte sulla salute. Il
caso dell’oncologia. Il ruolo delle organizzazioni di patients’ advocacy nelle scelte sanitarie in
Italia e all’estero. Milan (Italy), September 25, 2012.
Round-Table: Coinvolgere il paziente sui costi della sanità: sì, no, come. Milan (Italy),
September 25, 2012.
Meeting: 54th Annual Meeting of the Italian Cancer Society. Bologna (Italy), October 01-04,
2012.
“Angiogenesis inhibitors: enthusiasm and disappointment”
“The importance of translational research in drug development. The example of trabectedin”
Meeting DOXA: La situazione del mercato farmaceutico italiano a seguito delle iniziative del
governo Monti. Confronto tra esponenti di: FIMMG, Regione Piemonte, Istituto Mario Negri,
Federfarma. Milan (Italy), October 9, 2012.
Meeting: IX Annual Meeting of the Istituto Interuniversitario di Miologia. Lecce (Italy),
October 12-14, 2012.
“The p97/VCP ATPase is critical in muscle atrophy and for the accelerated degradation of most
muscle proteins”
Workshop: FEBS workshop on molecular and cellular mechanisms in angiogenesis. Capri
(Italy), October 14-17, 2012.
“TrypsinogenIV is elicited by a pro-angiogenic environment and affects tumor endothelium
motility”.
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IRFMN
Meeting: Neoplasie ginecologiche – aggiornamenti. Padua (Italy), October 15, 2012.
“Caratterizzazione molecolare della neoplasia ovarica e cenni per la neoplasia dell’endometrio”
Congress: XIV Congresso Nazionale AIOM. Rome (Italy), October 27-29, 2012.
Simposio “Sono davvero intelligenti i farmaci target-specifici per la terapia di tumori eterogenei
e geneticamente instabili?”
Round-table: MNIAA Mario Negri Institute Alumni Association. La cultura e la divulgazione
scientifica nel mondo di oggi: perché diffidare della scienza? Milan, October 29, 2012
Meeting Network Italiano Cochrane. Cochrane Collaboration incontra il Network Italiano
Cochrane e l’Associazione Alessandro Liberati. Modena (Italy), November 12, 2012
Seminar: Seminario Eupolis Lombardia: La paura del rischio o il rischio della paura: il medico
di medicina generale e la medicina difensiva. Tavola rotonda: i diritti del paziente e il dovere
del medico, i diritti del medico e i doveri dei pazienti. Milan, November 13, 2012
Meeting: 6th World Meeting of Interdisciplinary Melanoma Skin Cancer Centres & 8th EADO
Congress. Barcelona (Spain), November 14-17, 2012.
“Vascular targeting: combination strategies in metastatic melanoma”.
Course: L’evoluzione della medicina contemporanea nelle decisioni in clinica. Cittadini,
pazienti e associazioni tra diritti individuali e gestione delle risorse: l’empowerment. Naples
(Italy), November 16, 2012
Meeting: XX Riunione Nazionale MITO “Il tumore dell’ovaio: una storia senza ombre”. Milan
(Italy), November 19-20, 2012.
“Farmaci in sviluppo di possibile impiego nei tumori ginecologici”
Meeting: Forum Risk Management in Sanità 2012. Prevenzione del rischio e sicurezza nelle
cure. Sessione di apertura della II edizione Accademia del cittadino. Florence, November 20,
2012
Conference: II Conferenza governativa sull’amianto e le patologie correlate: stato dell’arte e
prospettive. Venice (Italy), November 22-24, 2012.
“La ricerca farmacologica”
Meeting: II Edizione Assemblea Territoriale per l’Oncologia. Progetti di umanizzazione a
confronto. Come informare e rendere partecipi e consapevoli i pazienti ed i cittadini in ambito
sanitario e di ricerca. Il progetto PartecipaSalute. Milan (Italy), November 28, 2012
Seminar: X Convention of investigators in cystic fibrosis. Cystic fibrosis: to screen or not to
screen? Involving citizens’ jury in decision on carrier screening. FFC project. Verona (Italy),
November 30, 2012
Meeting: Insight on Genitourinary cancers. New pathogenetic and clinical aspects. Bari (Italy),
November 30 –December 01, 2012.
“mRNAs as prognostic markers in early epithelial ovarian cancers”
Meeting: La sanità tra ragione e passione. Bologna (Italy), December 14, 2012
“Leggerezza”
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IRFMN
GRANTS AND CONTRACTS
ABO Project SpA
Arcispedale Santa Maria Nuova di Reggio-Emilia
Azienda Sanitaria Locale, Reggio Emilia
Azienda Sanitaria Locale - Rimini
Azienda Sanitaria Unica Regionale - Marche
Agenzia Italiana del Farmaco
Amgem SpA, Milano
AIRC Associazione Italiana per la Ricerca sul Cancro
ArQule USA
ASL Padova
ASL Provincia di Lodi
Astra Zeneca SpA
Astra Zeneca UK
AVAPO (Associazione Volontari Assistenza Pazienti Oncologici)
Azienda Ospedaliera Fatebenefratelli e Oftalmico- Milano
Azienda Sanitaria Locale, Rimini
Azienda Sanitaria Unica Regionale, Marche
Azienda Ospedaliera “Spedali Civili di Brescia”
Centro Cochrane Italiano
Chiesi Farmaceutici SpA
CIPOMO (Collegio Italiano dei Primari Oncologi Medici Ospedalieri)
CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, Milano
CNR Consiglio Nazionale delle Ricerche
CNR-MIUR Ministero Istruzione Università e Ricerca
Compagnia di San Paolo
Dompé
Eli Lilly Italia SpA
EOS SpA
FIRB-MIUR Fondo per gli Investimenti della Ricerca di Base-Ministero Istruzione Università e
Ricerca
FIRC Fondazione Italiana per la Ricerca sul Cancro
Fondazione Buzzi Unicem
Fondazione Cassa di Risparmio delle Province Lombarde
Fondazione Fibrosi Cistica
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano
Fondazione Lilly
Fondazione Lu.V.I.
Fondazione Nerina e Mario Mattioli Onlus
FSE Frontier Southern Europe
GISCAD(Gruppo Italiano Studi di Carcinomi Apparato Digerente)
GlaxoSmithKline, Verona
Grunenthal Italia, Milano
Indena SpA
Institut de Recherche Pierre Fabre
Istituto Clinico Humanitas – Rozzano
Istituto Nazionale dei Tumori, Milano
Istituto Superiore di Sanità
Italfarmaco SpA
KemoTech Srl
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2012
IRFMN
Komen Italia Onlus
Lottomatica
Marie Curie International Reintegration Grant
Medac
Merck Sharp & Dome
Ministero della Salute
Novartis
Novartis Farma SpA
Optigenex Inc.
Pfizer Global Research and Development
Pfizer Italia
Pharma Mar, SA
Pharminox Ltd, UK
Philogen S.p.A., Siena, Italy
Policlinico di Padova / C.O.R.
Regione Emilia Romagna
Regione Lombardia
Regione Veneto
Regione Toscana
Roche SpA
SAKK
Sanofi-Aventis Pharma
Sara Bet, Roma
SENDO-Tech Srl
SIA SpA
Sigma-Tau SpA
Università degli Studi di Padova
Università Federico II – Napoli (Dipartimento di Endocrinologia ed Oncologia molecolare e
clinica)
Volontarimini - Associazione per lo Sviluppo del Volontariato della Provincia di Rimini
SCIENTIFIC PUBLICATIONS (2012)
Sulaiman G M, A'dhiah A H, Al Sammarrae K W, Bagnati R, Frapolli R, Bello E, Uboldi S, Romano M, Panini N,
Scanziani E, Pezzolato M, Erba E, D'Incalci M
Assessing the anti-tumour properties of Iraqi propolis in vitro and in vivo
Food Chem Toxicol 2012 50 : 1632-1641
Silini Antonietta, Ghilardi C, Figini S, Sangalli F, Fruscio R, Dahse R, Pedley R B, Giavazzi R, Bani M R
Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the
tumor's proangiogenic microenvironment
Cell Mol Life Sci 2012 69 : 1167-1178
Gori S, Greco M T, Catania C, Colombo C, Apolone G, Zagonel V, AIOM Group
A new informed consent form model for cancer patients: Preliminary results of a prospective study by the Italian
Association of Medical Oncology (AIOM)
Patient Educ Couns 2012 87 : 243-249
Marchini S, Poynor E, Barakat R R, Clivio L, Cinquini M, Fruscio R, Porcu L, Bussani C, D'Incalci M, Erba E,
Romano M, Cattoretti G, Katsaros D, Koff A, Luzzatto L
The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical
course of epithelial ovarian cancer
Clin Cancer Res 2012 18 : 4313-4324
ANNUAL REPORT
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IRFMN
Mannino S, Villa M, Apolone G, Weiss N S, Groth N, Aquino I, Boldori L, Caramaschi F, Gattinoni A, Malchiodi G,
Rothman K
Effectiveness of adjuvanted influenza vaccination in elderly subjects in Northern Italy
Am J Epidemiol 2012 176 : 527-533
Corli O, Montanari M, Deandrea S, Greco M T, Villani W, Apolone G
An exploratory analysis on the effectiveness of four strong opioids in patients with cancer pain
Pain Med 2012 13 : 897-907
Mosig R A, Lin L, Senturk E, Shah H, Huang F, Schlosshauer P, Cohen S, Fruscio R, Marchini S, D'Incalci M,
Sachidanandam R, Dottino P, Martignetti A
Application of RNA-Seq transcriptome analysis: CD151 is an invasion/migration target in all stages of epithelial
ovarian cancer
J Ovarian Res 2012 5 : 4
Moschetta M, Pretto F, Berndt A, Galler K, Richter P, Bassi A, Oliva P, Micotti E, Valbusa G, Schwager K, Kaspar
M, Trachsel E, Kosmehl H, Bani M R, Neri D, Giavazzi R
Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic
human melanoma xenografts
Cancer Res 2012 72 : 1814-1824
Brunelli L, Llansola M, Felipo V, Campagna R, Airoldi L, De Paola M, Fanelli R, Mariani Alessandro, Mazzoletti M,
Pastorelli R
Insight into the neuroproteomics effects of the food-contaminant non-dioxin like polychlorinated biphenyls
J Proteomics 2012 75 : 2417-2430
Marchiò S, Soster M, Cardaci S, Muratore A, Bartolini A, Barone V, Ribero D, Monti M, Bovino P, Sun J, Giavazzi
R, Asioli S, Cassoni P, Capussotti L, Pucci P, Bugatti A, Rusnati M, Pasqualini R, Arap W, Bussolino F
A complex of α(6) integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic
angiopoietin-like 6
EMBO Mol Med 2012 4 : 1156-1175
Bonezzi K, Belotti D, Northover B J, Ghilardi C, Borsotti P, Resovi A, Ubezio P, Riva A, Giavazzi R, Verdin E,
Taraboletti G
Inhibition of SIRT2 Potentiates the anti-motility activity of taxanes:Implications for antineoplastic
combination therapies
Neoplasia 2012 14 : 846-854
Mosig R A, Lobl M, Senturk E, Shah H, Cohen S, Chudin E, Fruscio R, Marchini S, D'Incalci M, Sachidanandam R,
Dottino P, Martignetti A
IGFBP-4 tumor and serum levels are increased across all stages of epithelial ovarian cancer
J Ovarian Res 2012 5 : 3
Della Vittoria Scarpati G, Falcetta F, Carlomagno C, Ubezio P, Marchini S, De Stefano A, Kumar Singh V, D'Incalci
M, De Placido S, Pepe S
A specific miRNA signature correlates with complete pathological response to neoadjuvant chemoradiotherapy in
locally advanced rectal cancer
Int J Radiat Oncol Biol Phys 2012 83 : 1113-1119
Galler K, Junker K, Franz M, Hentschel J, Richter P, Gajda M, Gohlert A, Von Eggeling F, Heller R, Giavazzi R,
Neri D, Kosmehl H, Wunderlich H, Berndt A
Differential vascular expression and regulation of oncofetal tenascin-C and fibronectin variants in renal cell
carcinoma (RCC): implications for an individualized angiogenesis-related targeted drug delivery
Histochem Cell Biol 2012 137 : 195-204
Di Francesco A M, Ubezio P, Torella A R, Meco D, Pierri F, Barone G, Cusano G, Pisano C, D'Incalci M, Riccardi R
Enhanced cell cycle perturbation and apoptosis mediate the synergistic effects of ST1926 and ATRA in
neuroblastoma preclinical models
Invest New Drugs 2012 30 : 1319-1330
Paroni G, Fratelli M, Gardini G, Bassano C, Flora M, Zanetti A, Guarnaccia V, Ubezio P, Centritto F, Terao M,
Garattini E
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Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of
ERBB2 and RARA
Oncogene 2012 31 : 3431-3443
Colombo C, Mosconi P, Villani W, Garattini S
Patient organizations' funding from pharmaceutical companies: is disclosure clear, complete and accessible to the
public? An italian survey
PLoS One 2012 7 : e34974
Riva I, Quaranta L, Russo A, Katsanos A, Rulli E, Floriani I
Dynamic contour tonometry and Goldmann
applanation tonometry: correlation with intracameral
assessment of intraocular pressure
Eur J Ophthalmol 2012 22 : 55-62
Rizzetto L, Bushow S, Beltrame L, Figdor C, Schierer S, Schuler G, Cavalieri D
The modular nature of dendritic cell responses to commensal and pathogenic fungi
PLoS One 2012 7 : e42430
Oliva P, Decio A, Castiglioni V, Bassi A, Pesenti E, Cesca M, Scanziani E, Belotti D, Giavazzi R
Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of
ovarian carcinoma xenograft models
Br J Cancer 2012 107 : 360-369
Mosconi P, Satolli R, Colombo Cinzia, Villani W
Does a consumer training work? A follow-up survey of the PartecipaSalute training programs
Health Res Policy Syst 2012 10 : 27
Hill S, Filippini G, Synnott A, Summers M, Beecher D, Colombo C, Mosconi P, Battaglia M A, Shapland S, Osborne
R
Presenting high quality health information for people with multiple sclerosis: the IN-DEEP project protocol
BMC Medical Informatics & Decision Making 2012 12 : 20
Grosso F, D'Incalci M, Cartoafa M, Nieto A, Fernandez-Teruel C, Alfaro V, Lardelli P, Roy E, Gomez J, Kahatt C,
Soto-Matos A, Judson I
A comprehensive safety analysis confirms rhabdomyolysis as an uncommon adverse reaction in patients treated with
trabectedin
Cancer Chemother Pharmacol 2012 69 : 1557-1565
Uboldi S, Calura E, Beltrame L, Fuso Nerini I, Marchini S, Cavalieri D, Erba E, Chiorino G, Ostano P, D'Angelo D,
D'Incalci M, Romualdi C
A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in vitro model
of myxoid liposarcoma
PLoS One 2012 7 : e35423
Mosconi P, Lionello L, Di Spazio L, Alberghini L
Are the voices of women and men equally represented in ethics committees? An Italian survey
J Clin Res Bioeth 2012 3 : 1-4
Lazzari C, Spreafico A, Bachi A, Roder H, Floriani I, Garavaglia D, Cattaneo A, Grigorieva J, Vigano M G, Sorlini
C, Ghio D, Tsypin M, Bulotta A, Bergamaschi L, Gregorc V
Changes in plasma mass-spectral profile in course of
treatment of non-small cell lung cancer patients with epidermal growth factor receptor tyrosine kinase inhibitors
J Thorac Oncol 2012 7 : 40-48
Cervo L, Torri V
Comment on: &quot;Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in
mice&quot; (Magnani P, Conforti A, Zanolin E, Marzotto M and Bellavite P, Psychopharmacology, 2010)
Psychopharmacology (Berl) 2012 220 : 439-440
Previdi S, Abbadessa G, Dalò F, France D S, Broggini M
Breast cancer-derived bone metastasis can be effectively reduced through specific c-MET inhibitor tivantinib (ARQ
197) and shRNA c-MET knockdown
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Mol Cancer Ther 2012 11 : 214-223
Mandalà M, Clerici M, Corradino I, Vitalini C, Colombini A, Torri V, De Pascale A, Marsoni S
Incidence, risk factors and clinical implications of venous thromboembolism in cancer patients treated within the
context of phase I studies: the 'SENDO experience'
Ann Oncol 2012 23 : 1416-1421
Foroni C, Broggini M, Generali D, Damia G
Epithelial-mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact
Cancer Treat Rev 2012 38 : 689-697
Rusconi P, Caiola E, Broggini M
RAS/RAF/MEK inhibitors in oncology
Curr Med Chem 2012 19 : 1164-1176
Damia G, D'Incalci M
Targeting DNA repair
Drug Discov Today Dis Models 2012 E-pub :
Pagano K, Torella A R, Foglieni C, Bugatti A, Tomaselli S, Zetta L, Presta M, Rusnati M, Taraboletti G, Colombo
G, Ragona L
Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic,
thrombospondin-1-mimic small molecule
PLoS One 2012 7 : e36990
Perale G, Rossi F, Santoro M, Peviani M, Papa S, Llupi D, Torriani P, Micotti E, Previdi S, Cervo L, Sundstrom E,
Boccaccini A R, Masi M, Forloni G, Veglianese P
Multiple drug delivery hydrogel system for spinal cord injury repair strategies
J Control Release 2012 159 : 271-280
Corli O, Deandrea S
The impact of analgesic treatment: the patient's perspective
Eur J Pain 2012 16 : 326
Apolone G, Deandrea S, Montanari M, Corli O, Greco M T, Cavuto S
Evaluation of the comparative analgesic effectiveness of transdermal and oral opioids in cancer patients: A propensity
score analysis
Eur J Pain 2012 16 : 229-238
D'Angelo D, Borbone E, Palmieri D, Uboldi S, Esposito F, Frapolli R, Pacelli R, D'Incalci M, Fusco A
The impairment of the High Mobility Group A (HMGA) protein function contributes to the anticancer activity of
trabectedin
Eur J Cancer 2012 E-pub :
Knudsen K A, Brunelli C, Klepstad P, Aass N, Apolone G, Corli O, Montanari M, Caraceni A, Kaasa S
Which domains should be included in a cancer pain classification system? Analyses of longitudinal data
Pain 2012 153 : 696-703
Sartore-Bianchi A, Fieuws S, Veronese S, Moroni M, Personeni N, Frattini M, Torri V, Cappuzzo F, Vander Borght
S, Martin V, Skokan M, Santoro A, Gambacorta M, Tejpar S, Varella-Garcia M, Siena S
Standardisation of EGFR FISH in colorectal cancer: results of an international interlaboratory reproducibility ring
study
J Clin Pathol 2012 65 : 218-223
Santarlasci V, Laura D, Capone M, Querci V, Beltrame L, Cavalieri D, D'Aiuto E, Cimaz R, Nebbioso A, Liotta F,
De Palma R, Maggi E, Cosmi L, Romagnani S, Annunziato F
Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their
expansion
Immunity 2012 36 : 201-214
Caiola E, Rulli E, Fruscio R, Buda A, Broggini M, Marabese M
KRas-LCS6 polymorphism does not impact on outcomes in ovarian cancer
Am J Cancer Res 2012 2 : 298-308
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Ricci F, Bernasconi S, Perego P, Ganzinelli M, Russo G, Bono F, Mangioni C, Fruscio R, Signorelli M, Broggini M,
Damia G
Ovarian carcinoma tumor-initiating cells have a mesenchymal phenotype
Cell Cycle 2012 11 : 1966-1976
Bello E, Taraboletti G, Colella G, Zucchetti M, Forestieri D, Licandro S A, Berndt A, Richter P, D'Incalci M,
Cavalletti E, Giavazzi R, Camboni G, Damia G
The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth of advanced-stage triple-negative
breast cancer xenografts
Mol Cancer Ther 2012 E-pub :
Elli L, Bonura A, Garavaglia D, Rulli E, Floriani I, Tagliabue G, Contiero P, Bardella M T
Immunological comorbity in coeliac disease: associations, risk factors and clinical implications
J Clin Immunol 2012 32 : 984–990
Damia G, Colella G, Camboni G, D'Incalci M
Is PDGFR an important target for E-3810?
J Cell Mol Med 2012 16 : 2838-2839
Citerio G, Pesenti A, Latini R, Masson S, Barlera S, Gaspari F, Franzosi M G, Perico L, Bernasconi R, Stucchi N,
Cannata A N, Nicolis E B, Cappellini G, Ferrario L, Tognoni G, Torri V, NeuroMorfeo Study Group
A multicentre, randomised, open-label, controlled trial evaluating equivalence of inhalational and intravenous
anaesthesia during elective craniotomy
Eur J Anaesthesiol 2012 29 : 371-379
Giustina A, Mazziotti G, Torri V, Spinello M, Floriani I, Melmed S
Meta-analysis on the effects of octreotide on tumor mass in acromegaly
PLoS One 2012 7 : e36411
Carrassa L, Chilà R, Lupi M, Ricci F, Celenza C, Mazzoletti M, Broggini M, Damia G
Combined inhibition of Chk1 and Wee1: In vitro synergistic effect translates to tumor growth inhibition in vivo
Cell Cycle 2012 11 : 2507-2517
Sansone V A, Ricci C, Montanari M, Apolone G, Rose M, Meola G, INQoL Group
Measuring quality of life impairment in skeletal muscle channelopathies
Eur J Neurol 2012 19 : 1470-1476
Zatulovskiy E A, Skvortsov A N, Rusconi P, Ilyechcova E, Babich P S, Tsymbalenko N V, Broggini M, Puchkova L
V
Serum depletion of holo-ceruloplasmin induced by silver ions in vivo reduces uptake of cisplatin
J Inorg Biochem 2012 116 : 88-96
Milan E, Lazzari C, Anand S, Floriani I, Torri V, Sorlini C, Gregorc V, Bachi A
SAA1 is over-expressed in plasma of non small cell lung cancer patients with poor outcome after treatment with
epidermal growth factor receptor tyrosine-kinase inhibitors
J Proteomics 2012 76 Spec No. : 91-101
Rizzetto L, Buschow S I, Beltrame L, Figdor C G, Schierer S, Schuler G, Cavalieri D
The modular nature of dendritic cell responses to commensal and pathogenic fungi
PLoS One 2012 7 : e42430
Pappalardo G, Gualdi G F, Nunziale A, Masselli G, Floriani I, Casciani E
The impact of magnetic resonance in the preoperative staging and the surgical planning for treating small bowel
neoplasms
Surg Today 2012 E-pub :
Dell'Anna T, Signorelli M, Benedetti Panici P, Maggioni A, Fossati R, Fruscio R, Milani R, Bocciolone L, Buda A,
Mangioni C, Scambia G, Angioli R, Campagnutta E, Grassi R, Landoni F
Systematic lymphadenectomy in ovarian cancer at second-look surgery: a randomised clinical trial
Br J Cancer 2012 107 : 785-792
Mosconi P, Roberto A
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Open-access clinical trial registries: the Italian scenario
Trials 2012 13 : 194
Colombo Cinzia, Moja L, Gonzalez-Lorenzo M, Liberati A, Mosconi P
Patient empowerment as a component of health system reforms: rights, benefits and vested interests
Intern Emerg Med 2012 7 : 183-187
Fruscio R, Corso S, Ceppi L, Garavaglia D, Garbi A, Floriani I, Franchi D, Cantu M G, Bonazzi C M, Milani R,
Mangioni C, Colombo N
Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series
Ann Oncol 2012 24 : 138-144
Ferrari D, Codecà C, Bertuzzi C, Broggio F, Crepaldi F, Luciani A, Floriani I, Ansarin M, Chiesa F, Alterio D, Foa
P
Role of plasma EBV DNA levels in predicting recurrence of nasopharyngeal carcinoma in a western population
BMC Cancer 2012 12:208 :
Raimondi M T, Balconi G, Boschetti F, Di Metri A, Mohammed S A A, Quaglini V, Araneo L, Galvez B G, Lupi M,
Latini R, Remuzzi A
An opto-structural methods to estimate the stress-strain field induced by cell contraction on substrates of controlled
stiffness in vitro
J Appl Biomater Function Mater 2012 E-pub :
Macera A, Lario C, Petracchini M, Gallo T, Regge D, Floriani I, Ribero D, Capussotti L, Cirillo S
Staging of colorectal liver metastases after preoperative chemotherapy. Diffusion-weighted imaging in combination
with Gd-EOB-DTPA MRI sequences increases sensitivity and diagnostic accuracy
Eur Radiol 2012 E-pub :
Scagliotti G V, Pastorino U, Vansteenkiste J F, Spaggiari L, Facciolo F, Orlowski T M, Maiorino L, Hetzel M,
Leschinger M, Visseren-Grul C, Torri V
Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to
IIIA non-small-cell lung cancer
J Clin Oncol 2012 30 : 172-178
Ubezio P, Falcetta F, Lupi M
Challenges in the integration of flow cytometry and time-lapse live cell imaging data using a cell proliferation model
In :New challenges for cancer systems biomedicine Springer-Verlag Italia, Milano, 2012; 377-398
Corli O, Montanari M, Greco M T, Brunelli C, Kaasa S, Caraceni A, Apolone G
How to evaluate the effect of pain treatments in cancer patients: Results from a longitudinal outcomes and endpoint
Italian cohort study
Eur J Pain 2012 E-pub :
Damia G, Garassino M
Alkylating agents
In :Clinical pharmacology of anti-cancer agents ESMO, Lugano, 2012; 31-43
Rusconi P, Broggini M
Cancer -related receptor targeting: Bcr-Abl, KIT, MET
In :Clinical pharmacology of anti-cancer agents ESMO, Lugano, 2012; 161-169
Quaranta L, Biagioli E, Riva I, Rulli E, Poli D, Katsanos A, Floriani I
Prostaglandin analogs and timolol-fixed versus unfixed combinations or monotherapy for open-angle Gglaucoma: A
systematic review and meta-analysis
J Ocul Pharmacol Ther 2012 E-pub :
Pinto C, Novello S, Torri V, Ardizzoni A, Betta P G, Bertazzi P A, Casalini G A, Fava C, Fubini B, Magnani C,
Mirabelli D, Papotti M, Ricardi U, Rocco G, Pastorino U, Tassi G, Trodella L, Zompatori M, Scagliotti G
Second Italian Consensus Conference on Malignant Pleural Mesothelioma: State of the art and recommendations
Cancer Treat Rev 2012 E-pub :
Gao F, Miller J P, Miglior S, Beiser J A, Torri V, Kass M A, Gordon M O
ANNUAL REPORT
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IRFMN
The effect of changes in intraocular pressure on the risk of primary open-angle glaucoma in patients with ocular
hypertension: an application of latent class analysis
BMC Med Res Methodol 2012 12 : 151
LAY PRESS SELECTION (2012)
Mosconi P.
La formazione di cittadini, pazienti e loro rappresentanze
Sclerodermia, Novembre 2012; 3: 6-8
Deledda G, Mosconi P, Renzi C, Goss C.
Il coinvolgimento del paziente nel processo clinico decisionale
Recenti Progressi in Medicina 2012; 103:384-390
Colombo C, Daghini R, Mosconi P.
Indagine su conoscenze, attitudini e pratica rivolta agli operatori sanitari
Roma: Istituto Superiore di Sanità, 2012. Rapporto ISTISAN 12/27: 28-31
Donati S, Senatore S, Satolli R, Colombo C, Mosconi P.
Offerta attiva delle raccomandazioni alle donne: il lavoro del medico di medicina generale, del ginecologo e del
farmacista
Roma: Istituto Superiore di Sanità, 2012. Rapporto ISTISAN 12/27: 24-27
Donati S, Senatore S, Satolli R, Colombo C, Mosconi P.
Formazione a cascata dei professionisti sanitari nelle Asl di intervento
Roma: Istituto Superiore di Sanità, 2012. Rapporto ISTISAN 12/27: 13-18
Colombo C, Oprandi Nadia, Mosconi P.
Messa a punto di materiale divulgativo
Roma: Istituto Superiore di Sanità, 2012. Rapporto ISTISAN 12/27: 10-12
Colombo C, Condorelli D, Villani W, Mosconi P.
Analisi della stampa medico-divulgativa e di quella rivolta al grande pubblico
Roma: Istituto Superiore di Sanità, 2012. Rapporto ISTISAN 12/27: 5-9
Mosconi P, Satolli R, Senatore S, Colombo C, Donati S.
Articolazione del progetto “Con Me”
Roma: Istituto Superiore di Sanità, 2012. Rapporto ISTISAN 12/27: 1-4
Colombo C.
PROGETTO IN-DEEP: nascita e sviluppo di un modello di informazione online
http://www.partecipasalute.it/cms_2/node/193630/10/2012
Colombo C.
Progetto IN-DEEP: un modello di informazione online messo alla prova
http://www.marionegri.it/mn/it/aggiornamento/news/indeep.html novembre 2012,
Mosconi P.
Comunicare i costi delle cure: il documento del CNB
http://www.partecipasalute.it/cms_2/node/1928 , 12/10/2012
Mosconi P, Colombo C, Villani W.
Funziona? Non funziona? Indagine sui percorsi formativi PartecipaSalute
http://www.partecipasalute.it/cms_2/node/1929 , 12/10/2012
Mosconi P.
Studi clinici indipendenti: al via il progetto ECRAN
http://www.partecipasalute.it/cms_2/node/1913 , 8/10/2012
Senatore S, Donati S, Mosconi P, Satolli R, Colombo C, Cotichini R, Spila Alegiani S, Da Cas R.
Terapia ormonale e menopausa: risultati preliminari del progetto “Con Me”
ANNUAL REPORT
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http://www.iss.it/binary/publ/cont/sostonline.06.pdf
Colombo C
Le donne hanno stipendi più bassi degli uomini,
http://www.partecipasalute.it/cms_2/node/189522/06/2012
Colombo C.
Associazioni di pazienti: una questione di trasparenza
http://www.partecipasalute.it/cms_2/node/1892 1/06/2012
Mosconi P.
Carta dei Servizi: a che punto siamo
http://www.partecipasalute.it/cms_2/node/1898 , 6/7/2012
Mosconi P, Satolli R, Castellani C.
Giurie dei Cittadini: verdetto e motivazioni
http://www.partecipasalute.it/cms_2/node/1885 , 18/5/2012
Mosconi P.
Consenso Informato: ma non dovevamo non pensarci più?
http://www.partecipasalute.it/cms_2/node/1873, 12/4/2012
Albolino S, Beleffi E, Mosconi P.
In Regione Toscana dopo l’Accademia del cittadino, nasce il GART, gruppo di cittadini al servizio della qualità e
sicurezza delle cure
Toscana Medica 2012, 3/12:29
Mosconi P, Satolli R, Castellani C, Villani W.
Giurie dei Cittadini e fibrosi cistica
http://www.partecipasalute.it/cms_2/node/1840 , 3/2/2012
Mosconi P, Bonazzi L, Giovannini G, Alberghini L.
Comitati etici al bivio: profit o no-profit?
Dialogo sui farmaci 1/2012: 31-32 Lettera di risposta (vedi art 4697/11)
Mosconi P, Buratti MG, Braun C, Nicelli AL, Bassi M.
Informarsi, conoscere e partecipare per migliorare la qualità della vita: il caso di asma, diabete di tipo 2 e cancro al
seno.
Tendenze 2011; 6: 539-556
Mosconi P, Roberto A.
Ad ogni donna il suo parto
http://www.partecipasalute.it/cms_2/node/1846 , 17/2/2012
Mosconi P.
Rispondere a un quesito clinico…
http://www.partecipasalute.it/cms_2/node/1844 , 17/2/2012
Mosconi P, Roberto A.
Il coinvolgimento dei cittadini: appunti dalle revisioni
http://www.partecipasalute.it/cms_2/node/1841 , 3/2/2012
Llerena Mesa M, Biagioli E
"Importanza della assicurazione della qualità negli studi clinici"
Medical Oncology Progress & Perspectives 2012 ; Update 41 : 13-16
D'Incalci M.
Trabectedina - dalla sperimentazione alla pratica clinica.
Il Pensiero Scientifico Editore, 2012
Corli O., Pizzuto M., OICP Research Group
Dolore neuropatico da cancro - Quando il dolore è "fuoco"
CIC Edizioni Internazionali, Roma, 2012
ANNUAL REPORT
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RESEARCH ACTIVITIES
Laboratory of Cancer Pharmacology
Mode of action of Ecteinascidins
A project ongoing since several years is about the characterization of marine natural products
possessing antitumor activity. In particular we carried on the studies on the effects of ET-743 in
cells defective for some DNA repair mechanisms. Cells deficient for Homologous
Recombination (HR) are very sensitive to the drug, while cells deficient for Non Homologous
End-Joining (NHEJ) are only slightly more sensitive, but surpraisingly cell lines defective for
Nucleotide Excision Repair (NER) are less sensitive to ET-743. Flow cytometric analysis
coupled to a software of computer simulation, developed in our laboratory, has demonstrated
that NER defective cells showed, after ET-743 treatment, cell cycle perturbations different than
those occurring in NER proficient cells, probably for the activation of different and more
efficient repair mechanisms.
We study also a functional evaluation of the DNA repair mechanisms by the cell capacity to
recognize and repair double helix breaks with a recently introduced test that is very sensitive to
detect the phosphorylation of histone H2AX. An in vitro study is ongoing with flow cytometry
and immunofluorescence techniques to evaluate in different tumor cell lines the phosphorylation
level of histone H2AX in relation to the distribution of the cells in the different phases of the
cell cycle and the cytotoxic effect induced after treatment with ET-743.
Studies are in progress on the mechanism of action of new ET-743 derivates compounds that
have shown antitumoral activity on cell lines with different DNA repair mechanisms.
A new project is the study of the selective action of ET-743 on mixoid lyposarcoma, a
pathology representing 10% of all soft tissue sarcomas, trying to understand if the significative
antitumor effect is due to a selective action of the compound on pathogenetic alterations
characteristic of this pathology. In particular we are trying to evaluate how ET-743 interact with
the transcriptional modifications of specific genes due to the translocation FUS-CHOP that
characterizes mixoid sarcomas or those caused by the interaction host-tumor, modifying
inflammatory and angiogenetic processes. Studies are in progress to obtain cell lines and
xenografts of mixoid lyposarcomas exhibiting the same molecular features of the patients’
tumors.
Combinations of natural products of marine origin with other anticancer
drugs
We have observed additive or synergistic activity of ET-743 combined with other anticancer
drugs such as cisplatin, doxorubicin, campthotecin,inhibitors of telomerase, bleomicin and
varinostat.
Analysis of cell cycle data and interactions of different drugs
The Biophysics Unit is engaged in theoretical and methodological studies aimed at a critical
evaluation of current techniques of investigation of drug effects on heterogeneous cell
populations. Several computing tools have been produced to simulate the cell proliferation at
different levels (from molecular interactions to in vivo growth of solid tumours) and the process
of measure.
Collaborations are ongoing with other research groups for design and data analysis of drug
combination studies in vitro. In this field, a number of computer programs have been developed,
allowing comparative data analysis with the most common models of drug interaction.
ANNUAL REPORT
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Evaluation of the complexity of the response of cell populations to
treatment with anticancer drugs
This project of the Biophysics Unit addresses the issue of establishing a connection between the
intracellular drug interactions and the resulting cell cycle perturbations. It starts from the singlecell level of investigation to reach the cell-population level where the relevant end points of
treatment efficacy are evaluated by flow cytometry and growth inhibition/cytotoxicity assays.
The complexity of the experimental data can be deciphered by using a mathematical model able
to rebuild the cell response to anticancer treatments. For this process we start with the
reproduction of the unperturbed growth and we describe the response to the drug's challenge,
using parameters measuring either the strength of cell cycle arrest, damage repair or cell death
in every phase (G1, S and G2M). In this way, it is possible to reach an interpretation of the
experimental results that overcomes the current qualitative and partial approaches to this
problem, which are unable to resolve the overlapping of cytostatic and cytotoxic effects, and to
establish a connection with phase-related events.
Recently, we focused our attention on the application of this method to the detailed description
of the time and dose dependence of cell cycle perturbations induced on a pancreatic cancer cell
line by treatments with erlotinib or gemcitabine. The information coming from these
experiments, with the cells treated with the two compounds singularly, represents the base
towards the comprehension of the origin of synergism or antagonism phenomena that can be
observed in schedules of treatment with erlotinib and gemcitabine given together.
In silico rendering of the response to anticancer treatments integrating timelapse imaging and flow cytometric techniques
We use flow cytometric (cell-population based analysis) and time-lapse imaging (single cell
lineage based analysis) techniques to generate data that will be used to predict drug responses in
term of the major components of cytostatic/cytotoxic actions of anticancer drugs: specific cell
cycle perturbations (detecting accumulation or depletion of cells in G1, S and G2M phases) and
the commitment to cell death (apoptosis).
Time lapse data are currently integrated with those from single and multiparametric flow
cytometric experiments, and univocally interpreted with a common computer program
developed by the Biophysics Unit that renders in silico the proliferation process through the cell
cycle and in the cell generations during and after treatment. This kind of dynamic rendering
establishes a connection between the available “macroscopic” data (time-lapse and flow
cytometric) and the activity of molecular pathways which are in charge to the several functions
that concur in the pharmacological response with individual timing and dose-dependence, and
which are not otherwise measurable. Final aim is to achieve a quantitative level of
understanding of the dynamics of response to anticancer treatment, enabling a full appreciation
of the role and relative importance of the main cellular functions contributing to the overall
response. Methods and computing tools with intuitive interface developed for these tasks will be
shared with the scientific community.
Use of nanotechnologies to design new therapeutic strategies for
anticancer treatments
In these last years nanotechnologies have been largely used for biomedical purposes and the
interest in this field and its application is still increasing.
The laboratory of Cancer Pharmacology is supporting a multicentre and multidisciplinary
project focused on the use of polymeric, biodegradable and biocompatible nanoparticles or
clusters of nanoparticles (eteronanoclusters) to design new therapeutic strategies for anticancer
treatment of triple negative breast cancer.
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In this contest, the Biophysics Unit performed preliminary in vitro studies to clarify some
aspects of the interaction between cells and nanoparticles. The use of polymeric biocompatible
and non-biodegradable nanoparticles labeled with Rhodamine-B allowed us to use flow
cytometric techniques and fluorimetric measurements for the evaluation of the number of
nanoparticles internalized in a cell population and its dependence on the environmental
conditions or on the physical parameters characterizing the nanoparticles (labeling
concentrations, dimension and Z potential). By joining the information from both platforms we
obtained a reliable quantification of the mean number of nanoparticles in each cell, which
represents an important preliminary step to optimize the design of these nanoparticles as
potential drug delivery systems.
From in vitro to in vivo experiments, the Pharmacokinetic Unit will perform analitycal
measurements to monitor the distribution in the tumor and in other organs of the anticancer
agents delivered by the nanoparticles.
Clinical pharmacokinetics of E-3810 (a novel inhibitor of angiogenesis)
The Phase II clinical trial, began in late 2011, continued in 2012 and it is still ongoing in
patients with solid tumors carrying FGFR amplfication. In the months before we developed the
method for measuring the drug in human plasma by HPLC-mass- spectrometry and thanks to
this we studied the pharmacokinetic profile in patients who participated the Phase I. Currently,
after the definition of the pharmacokinetic in the expansion phase, the study is continuing in a
phase II study in which we have to arruolate 16 patients . The study is surely encouraging, 16
partial responses have been reported and the next schedule of administration, orally for 21
consecutive days, will be tested. Pharmacokineti study evedencied that the drugprovides
adequate plasma exposure reaching steady state plasma concentrations potentially active after
one week of therapy.
Quality assurance program
During the year 2012 we completed the quality assurance program aims to bring the
pharmacokinetic unit, inside the laboratory of Cancer Pharmacology, in compliance with Good
Laboratory Practice (GLP). Now a consolidation phase is planned to test the entire quality
system developed , this phase includes the review and the optimization of most of the
procedures in the routine of the laboratory.
Also in the clinical setting, we continued in 2012 and wewill continue in 2013 a large
multicenter study, in collaboration with the Italian Association of Pediatric Hematology, for
monitoring the activity e tolerability of a new type of asparaginase, PEG asparaginase, used in
children with lymphoblastic leukemia. This new treatment is included in the multichemotherapy protocol: AIEOP-BFM-ALL 2009 .
Antitumoral activity and pharmacokinetic properties of new drugs and
combinations
The antitumor activity, pharmacokinetic properties and toxicity of novel anticancer drugs with
specific targets (e.g. different kinase inhibitors), conventional anticancer drugs (taxanes and
trabectedin and its derivatives) and combinations is being investigated using rodent tumors and
novel human tumor xenografts.
Life Science Informatics activity
The team in charge of Life Science Informatics initiative (LSI, http://lsi.marionegri.it) during
the year 2012 has created for the departments of Oncology and Neuroscience several electronic
case report forms for clinical studies and biobanks using Heavybase (eCRF management
system), an internally developed
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integrated and multi-platform peer to peer database designed for the management of clinical
data and the creation of randomized trials in accordance with FDA, 21 CFR part 11 directives.
In particular, for the Department of Oncology have been started the
following studies: B490, GLAUCOMA, TERAPIE-ORALI, BEVATRABE, ATREUS , and
updated INOVATYON, ALC, ECT Vs ICT, PACT 18, MUCOSITIS, ATREUS and RER, are
in preparation. For the Department of Neuroscience, the following clinical registries has been
prepared: EURALS, ANACONDA, EL ESCORIAL. Two more registers are being making:
Fatal Familiary Insomnia (FFI) and Evaluation of the Geriatric Care Needs (RF2009-1502045).
The activity of the support group for the use of HeavyBase, in addition to the activities more
closely associated with the IT aspects, covers any aspect of the remote assistance to the
investigators for a proper use of the eCRF management system, and a technical followup for a
continuously software development.
From the bioinformatics point of view it has been preparated a computational cluster of about
500 elaborative units in cooperation with the banks Intesa San Paolo and Unicredit and thanks
to the cooperation with SIA, for better handling the high-throughput analysis for microarray and
deep-sequencing platforms, with the aim of starting a sensitivity analysis to deeply
understanding these kind of data.
Laboratory of Molecular Pharmacology
G2 checkpoint and cell cycle
Chk1 and the synthetic lethality with Wee1
CHK1 is a key player of the signal transduction pathway activated in response to DNA
damage which ensures maintainance of genomic stability. In the last years our laboratory
has clarified the role of the Chk1 protein kinase in the cell cycle checkpoints induced by
different chemotherapeutic drugs and also has deeply investigated the role of Chk1 under
unstressed conditions, finding out that in some experimental conditions the lack of Chk1
may be deleterious depending on specific genetic background which characterizes some
tumors. Recently a siRNA high-throughput screening performed in our laboratory by using
a siRNA library against 700 human protein kinases identified WEE1 as in synthetic lethality
with CHK1. WEE1 is another molecular player of the DNA damage checkpoint which
regulates cell cycle transitions. Combined CHK1 and WEE1 inhibitor treatment showed a
strong synergistic cytotoxic effect in human cancer cell lines from solid tumors and this
effect could also be observed in an vivo setting with a tumor growth inhibition in
xenotransplanted mice treated with the inhibitors. Few evidences have been reported on the
activity of CHK1 and WEE1 inhibitors in lymphomas. Since CHK1 inhibitors were recently
shown to be active in Myc-driven mouse model malignancies such as B cell lymphomas, a
deeper understanding of the role of this kinase in lymphomas may disclose important
therapeutic implications and warrants further study. Thus we are now investigating the role
of CHK1 and WEE1 as therapeutic targets in an aggressive non-Hodgkin lymphoma: mantle
cell lymphoma (MCL). The results obtained in 4 MCL cell lines by inhibiting Chk1 and
Wee1 are encouraging showing a remarkable synergistic effect of the combination of these
inhibitors at concentrations not toxic as single agents. Interestingly these MCL cell lines
appeared very sensitive to both the CHK1 inhibitor and Wee1 inhibitors as single agents
with a median IC50 value for these cell lines ten-fold lower than the ones obtained treating
solid tumors cell lines with the same molecules. The study of the molecular markers
responsible of such sensitivity is undergoing The data obtained in vitro will be corroborated
in an in vivo setting, studying the tumor sensitivity to the drugs as single agents and in
combination in xenotransplanted mice. Taken together this investigation will help to define
a new therapeutic tool to treat lymphomas.
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Chk1 and the mitotic spindle checkpoint
Chk1 also plays a role in the mitotic spindle checkpoint, which ensures the fidelity of
mitotic segregation during mitosis, preventing chromosomal instability and aneuploidy.
Mad2 is one of the main mitotic checkpoint components and also exerts a role in the
cellular response to DNA damage. To investigate a possible crosslink existing between
Chk1 and Mad2, starting from previous observation made in our laboratory showing that
some cancer cell lines lacking Chk1 undergo cell death because of a defect of mitotic
spindle checkpoint (decrease in Mad2 protein levels), we studied Mad2 protein levels after
Chk1 inhibition either by specific siRNAs or by a specific and selective Chk1 inhibitor (PF00477736) finding out that after Chk1 inhibition Mad2 protein levels decrease only in
tumor cells sensitive to Chk1 depletion. We then mapped on Mad2 protein six Chk1’s
phosphorylatable sites and found that Chk1 is able to phosphorylate in vitro Mad2 in more
than one site. Moreover we found that Chk1 co-localizes and physically associates with
Mad2 in cells both under unstressed conditions and after DNA damage, thus providing a
new and interesting evidence on Chk1 and Mad2 crosstalk both in the DNA damage
checkpoint and in the mitotic spindle checkpoint.
Characterization of new potential oncosuppressor genes
DRAGO gene, identified and cloned in our laboratory is one of the most interesting projects of
the group. The characterization of the response of KO mice for DRAGO to ionising radiation is
similar to normal mice.
Mice KO for DRAGO have been crossed with with p53 KO mice to evaluate the potential
oncosuppressive function of DRAGO. The double mutants are viable and the genotypes arising
from the crossing are at the normal Mendelian ratio, indicating that no specific genotypes
(p53;DRAGO) are favoured.
In a p53KO background, removal of DRAGO gene accelerates tumor development suggesting a
cooperative role of the two genes in the prevention of tumnor formation. The analysis of the
spectra of tumor formation did not show significant differences among the different genotypes.
we are at present investigating the role of the gene as potential regulator of the p53-dependent
immune response.
Molecular characterization of ovarian carcinoma
We have retrospectively characterised polymorphisms in genes participating in the response to
damage such as mdm2, ERCC1 and XPG as possible predictors of response to treatment in
patients with ovarian cancer. 420 patients have been genotyped and the allelic frequency found
is the expected one for a Caucasian population. The data generated will be analysed together
with the clinical parameters and with the follow-up data available for all the samples analysed.
As for K-RAS gene, we have studied a polymorphism present in the coding region of the gene,
called KRAS-LCS6, which is located in the region which binds the miRNA let7. The
polymorphism determines the substitution of the more abundant T-allele to a G-allele which
was observed to increase the KRAS expression and in turn to activate the downstream pathway
at higher levels if compared to the T-allele. We assessed the role of the KRAS-LCS6
polymorphism in 97 early (stages I and II) and 232 advanced (stages III and IV) ovarian cancer
patients. Our data indicate that KRAS-LCS6 polymorphism is not relevant in ovarian cancer, in
fact, in our cohort of patients, is not associated to any outcome or physiopathological
characteristic.
Expression of gene involved in DNA repair in human ovarian cancer
By Real Time PCR, the expression of genes involved in DNA repair has been evaluated in 77
stage I, 81 stage III and 13 borderline samples of ovarian cancer. The genes analysed include
those belonging to the nucleotide excision repair, in the fanconi anemia repair, in the base
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excision repair. In addition, genes important for the cellular response to damage, such as chk1
and claspin have been studied.
Two were the aims of the study: 1) to understand whether there are genes differentially
expressed in the three categories analysed that could help us in understanding the biology of
ovarian cancer; 2) to correlate mRNA levels of the different genes with the response to
treatment with the idea of finding new possible response markers.
Data analysis showed that genes involved in the Fanconi Anemia pathway and some of the
genes involved in checkpoints are more expressed in stage I carcinoma than stage I borderline
tumors. These data might suggest that the malignant phenotype is associated with an upregulation of these genes that would endow tumor ovarian cell with higher growth and
metastatic potentials. In Stage III ovarian patients a number of correlation between the
expression of the repair genes and the response to therapy have been performed; however no
clear cut statistically significant correlation could be found. The data, even if negative, have
been obtained in a quite large sample size and we think pose some doubts on role of the
expression of single gene as predictive of response, as suggested by other studies.
Inhibition of the signal mediated by PI3K/akt
Pi3K/akt axis represents one of the major altered pathway in human cancers and therefore is a
good target for the development of new drugs. The laboratory has been involved in the
pharmacological characterisation of new molecules able to inhibit the pathway.
We have characterised the molecular mechanism at the basis of the interaction between two
molecules able to inhibit mTOR (the kinase downstream PI3K/akt) at two different portion of
the protein. In vitro and in vivo data indicate that the strategy to inhibit the same target acting at
different level could be an intersting strategy to shut down a transduction signal. The
combination of the molecules, in fact, is able to inhibit tumor growth more than the single
drugs, even when these are used at doubled doses. The mechanism of activity of the
combination is the ability to selectively inhibit one of the downstream effectors of mTOR
leading to a selective inhibition of translation. The study combines cellular, molecular and
proteomic analysis.
Mechanisms of action of new antitumor drugs
In collaboration with the laboratory of Biology and Therapy of Metastasis, we have
characterised the mechanism of action and the antitumor activity of a new antiangiogenic drug,
E3810. This drug is a small molecule able to inhibit receptors playing important roles in the
tumor angiogenesis processes (VEGFR, FGFR). Our studies allowed us to define that the drug
has a potent antiangiogenic activity, with a broad spectrum of activity in different human tumors
transplanted in immunodeficient mice. We are currently investigating combinations of E3810
with other anticancer agents and we are better characterising the spectrum of activity by
analysing the drug’s activity in cells with different expression of FGFR.
Generation of new cellular systems for in vivo imaging
We have generated new cell clones derived from human cancer cells growing in vitro, which
stably express fluorescent or luminescent probes which can allow us to follow in vivo the
growth of primary tumors and metastasis in mice. These systems generated in human ovarian,
breast and prostate cancer cell lines, can be implanted in nude mice and the growth and response
to therapy followed by either optical and luminescent imaging or microTAC analysis.
We have in particular set up models derived from human breast cancer, which are able to
metastasis to the bone which can be evidentiated by optical imaging and microTC techniques in
laboratory animals. Utilising different reporter genes, we have generated fluorescent and
luminiscent human cancer cell lines which can be transplanted in immunodeficient mice. These
cells can then be visualised in organs such as peritoneum and lungs were these cells were
previously be observed only after sacrifice of the animal. The cells generated to be fluorescent
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or bioluminiscent will also have specific gene defects which will be useful for understanding the
mechanism of action of new molecules. These systems will be particularly useful to study the
antimetastatic potential of new drugs.
Studies on the bone metastatic processes
Using a model of human breast cancer cells metastatizing to the bones, we have characterised
some molecular pathways involved in the colonisation and metastatic growth. In particular, we
have evaluated the role of cMet receptor and of its activation both in vitro and in vivo.
The in vivo model utilized develops bone metastasis following intraventricular injection of
cancer cells. The bone metastasis can be visualized by optical imaging already after 10 days
from cancer cell inoculum. By microTC analysis, bone osteolytic lesions can be evidentiated
after 3-4 weeks from tumor cells injection.
In this model we have evaluated the response in vivo to a c-Met inhibitor, tivantinib, alone or in
combination with a bisphosphonate, zoledronic acid, largely used in the clinical practice. The
aim of the work was to determine whether combining drugs which hit different target, (cancer
cells for tivantibi and host cells for zoledronic acid) we could have an enhanced response.
The data obtained indicated that the combination is well tolerated and is able to increase the
response and survival of animals with bone metastasis compared to the same drugs given as
single agents. These effcets were observed either when the drugs were given in the early phases
of the metastatic process or when the bone metastisis were well detectable. Thiese results could
have impotant clinical application being bone metastasi at present treated with scanty success.
Identification of cancer stem cells from ovarian cancer
This project is aimed at isolating and characterizing a possible cancer stem cell from ovarian
cancers. There are increasing evidences supporting the idea that few important multipotent
cancer cells, termed cancer stem cells, are among the most relevant cells to be killed in a tumor.
Normally present as quiescent cells inside the tumors, they are able to rapidly generate dividing
and growing cancer cells. The current hypothesis is that normally dividing cancer cells can be
preferentially killed by chemotherapy while the cancer stem cells would be more difficult to kill
and would be responsible for the relapse following treatment. The possibility to identify and
characterize the cancer stem cell would theoretically open the way to the selection of new
generation molecules able to preferentially kill these cells.
Several studies have been conducted in ovarian fresh tumor samples, obtained from the
Gynecological Department of Ospedale San Gerardo di Monza, directed by Prof Mangioni, that
lead to the identification of a cell bearing the characteristic of a tumor initiating cells. We have
almost completed the molecular and pharmacologycal characterisation of ovarina cancer stem
cell. The results of this characterisation will possibly lead to the identification of specific genes
that could be targeted in the ovarian tumor initiating cells with the final aim to improve the
therapy of this tumor.
From these studies new models of ovarian cancer growing in vivo have been established. These
models have been characterised both at pharmacological and molecular level. We have shown
that these models well ricapitulate the tumor from which they originate and hence will represent
a very useful tool for the discovery of new potential treatments.
Determination of the impact of EGFR mutations in the activity of tyrosine
kinase inhibitors in patients with NSCLC
The clinical study on the characterisation of the response of patients with NSCLC to therapy
with or without EGFR inhibitors is terminated. The data obtained so far indicate that patients
not presenting mutations in the EGFR gene, respond less to treatment with the EGFR inhibitor
erlotinb than to stadard chemotherapy with docetaxel. The inferiority of erlotinib compared to
docetaxel, is eveident both in terms of response to treatment and in terms of progression free
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survival and overall survival. The trial, conducted with the collaboration of more than 50
centers, will have impact on the clinical practice, where, at present, the EGFR inhibitor is
registerd for the second line treatment of NSCLC patients independently from the presence of
mutations in the EGFR gene. We have clearly showed that in the absence of mutations the
EGFR inhibitors is less efficacious.
Determination of the impact of K-RAS mutations on the activity of
anticancer agents
The K-RAS gene results mutated in significantly higher percentage of NSCLC patients than
EGFR. The spectrum of mutation found in NSCLC is different from that observed in other
tumor types such as colorectal cancer. The different mutations could explain the different
impact of K_RAS on the selction of patients for therapies. In fact in colon cancer mutation in
the K_RAS gene is an exclusion criteria for treatment with anti EGFR drugs such as cetuximab.
In NSCLC the role fo K-RAS is more controversial. From the available clinical data we went
back to the laboratory generating isogenic cellular systems differning for the type of K-RAS
mutation. In particular we have generated in NSCLC cell lines clones overexpressing the wt KRAS or mutants in which the glycine at codon 12 is substituted with aspartic acid, cysteine or
valine. These mutants have indeed a different impact on the response to treatment of these cells
with drugs such as cisplatin, sorafenib or taxol. Our data suggest that for the stratification of
patients it is necessary to consider not only the presence of K-RAS mutation, but also the kind
of mutation present which could modify the selection of the best therapeutic options.
In this context new cellular models have been generated. These model have been obtained
through the use of a new technology,(Zinc finger technology) which allows the insertion of the
desired mutation directly in the gene locus. This has the big advantage of generating clones
without overexpression and without perturbing other genomic regions.
Laboratory of Biology and Treatment of Metastasis
Physiologic regulation of angiogenesis
Angiogenesis - the neoformation of blood vessels from existing ones - has a critical role in
tumor progression. A delicate balance between pro- and antiangiogenic factors finely tunes this
process. We have extensively studied endogenous angiogenesis-regulatory factors, as a basis to
develop new inhibitors. In particular, our studies focus on thrombospondin-1 (TSP-1), an
endogenous angiogenesis inhibitor of angiogenesis. The ability to directly bind to angiogenic
factors, in particular FGF-2 (Fibroblast Growth Factor-2), reducing its bioavailability and
activity is one of the manifold functions of this molecule. In a structure/function relationship
analysis of different active domains of TSP-1, we have identified its binding site for FGF-2.
This active sequence of TSP-1 is being used as a model to design new antiangiogenic and
antineoplastic compounds. Moreover, we are investigating the possibility to develop
pharmacological interventions or gene therapy approaches to upregulate the expression of TSP1, as a strategy to block tumor angiogenesis and progression.
Angiogenesis and tumor-stroma interaction
We have observed that the production of vascular endothelial growth factors (VEGF) from
tumor cells and its release in the tumor microenvironment is accompanied by an altered
response to some chemotherapeutics. Bevacizumab (Avastin®) – an antibody directed to
VEGF – restores the therapeutic responsivity, suggesting that the tumor environment might play
a role in modulating the sensitivity to therapy. The transcriptional activity of the stroma
microdissected from the tumor tissue was investigated. The results indicate that 294 gene
transcripts were preferentially expressed by the stroma of tumors producing high levels of
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VEGF . For some of them it was demonstrated that the protein preferentially localizes in the
stroma associated to the vasculature of VEFG-rich tumors. Specifically, the regulator of Gprotein signalling 5 (RGS5 ) was demonstrated in the vasculature of ovarian carcinoma
specimens, but not in human ovaries and its expression by the endothelial cells was sustained by
a milieu of proangiogenic factors related to the tumor microenvironment (including VEGF).
Furthermore we have identified gene expression differences between tumor derived endothelial
cells (EC) with respect to EC from healthy tissues. Notably, for some of the genes the
expression was modified by conditions simulating the “tumor/angiogenic” microenvironment.
Studies are underway to study the functional relevance of selected gene transcripts and their role
as potential biomarker on tumor vasculature.
The bio-bank of preclinical models of epithelial ovarian carcinoma (EOC)
The classification of epithelial ovarian cancer has been recently revised based on distinctive
morphologic and molecular genetic features. The whole laboratory has been involved since the
90’ in the characterization and continuous updated of preclinical models derived from EOC
patients and transplanted in immudeficient mice (Xeno-HOC). The Xeno-HOC molecularly,
biologically and pharmacologically characterized, together with a large available bio-bank,
provide basis for the study of novel selective pharmacological interventions.
As an example inhibitors of angiogenesis are being investigated on the panel of Xeno-HOC. We
have shown that bevacizumab, the antibody anti VEGF, is active on Xeno-HOC in combination
with chemotherapy, depending on the different XENO-HOC, its chemo-sensitivity and the
schedule of treatment administration. Combinations with novel inhibitors of angiogenesis are
under investigation.
Lymphangiogenesis in ovarian carcinoma
Lymphatic spread in epithelial ovarian cancer is an important predictor of outcome both in early
and advanced stages of this cancer. We have developed preclinical tumor models derived from
human ovarian cancer transplanted under the bursa (orthotopic xenograft), expressing luciferase
and disseminating in the peritoneal cavities of immunodeficient mice. The levels of soluble
VEGFC --the main factor stimulating the formation of lymphatic vessels (measured in plasma
and ascites of mice bearing ovarian cancer)-- correlates with the tumor growth (measured
through optical fluorescence) as well as the lymphatic invasion. Tumor VEGFC promotes
ovarian carcinoma progression through paracrine and autocrine mechanisms. Selective
inhibitors of VEGF/VEGFRs pathway inhibit, in vivo, ovarian carcinoma growth and
metastatization and, in vitro, VEGFC autocrine effects.
Preclinical evaluation of inhibitors of angiogenesis and combination
therapies
For the last decade we have investigated the antiangiogenic/antivascular activity of novel
antitumor molecules of interest for the clinical development, in particular: a) peptides and nonpeptidic small molecules, which mimic endogenous inhibitors of angiogenesis, including
compounds similar to thrombospondin-1; b) small molecules inhibiting tyrosin kinase
receptors, in particular VEGFRs, FGFR and PDGR, which mediate the signal with the
angiogeneic growth factors ; c) vascular disrupting compounds, in particular tubulin-binding
molecules)which, causing a depolymerization of microtubules, selectively deteriorate the tumor
blood vessels. The study of these classes of molecules in combination with conventional
chemotherapy is one of the main interests of our laboratory. In particular, studies have been
conducted and more are in progress to optimize the modalities of administration of the
combinations (i.e. selection of the drugs accordingly to the molecular characteristics of the
tumor, dose and treatment schedules accordingly to their mechanism of action), which are
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connected to the pharmacokinetic (tumor distribution of the drug) and pharmacodynamic
profiles (biomarker and imaging analysis) associated to the treatment efficacy.
Metastasis, Resistance and angiogenesis
The development of resistance and progressive disease after treatment with angiogenesis
inhibitors is becoming a controversial issue. We are investigating the experimental conditions
that cause multikinase receptor inhibitors (RTKI) to augment metastasis and whether opportune
combinations with chemotherapy could counteract this pro-metastatic effect. On relevant
murine metastatic tumor models, we have shown that while the administration of drugs such as
sunitinib alone, in neo-adjuvant setting, caused increased metastasis, the opportune combination
with cytotoxic chemotherapy was able to counteract this unwanted tumor dissemination and
overcome resistance to angiogenesis inhibitors. Initial findings indicated that, hypoxia in the
primary tumor, due to angiogenesis inhibition, is responsible for metastasis acceleration and this
can be impaired by appropriated drugs and combination regimens. Studies are in progress to
understand what mechanism/s associated to metastasis formation are driven by HIF-1α
activation and to test optimal combination modalities to impair this effect.
Tumor biomarkers for early diagnosis and risk assessment of pancreatic
cancer
Pancreatic ductal adenocarcinoma (PDAC) has bad prognosis and is highly chemoresistant.
Early detection is the only means to substantially impact long-term survival, but screening
methods are lacking.
In particular, PDAC are characterized by intense fibrotic reaction called dysplasia in which
extracellular matrix reorganization occurs in terms of composition and structural organization.
Studies are in progress a) to study extracellular matrix remodelling (synthesis, organization,
composition) during PDAC progression; b) to identify extracellular matrix related molecules in
plasma of PDAC patients and in vivo tumor models; c) to validate plasma extracellular matrix
related molecules as biomarkers predicting the risk of PDAC development and progression.
Laboratory of Cancer Cachexia AIRC Start-Up
Cancer cachexia is a very debilitating loss of muscle mass that affects up to 80% of cancer
patients. Remarkably, 20-48% of cancer-related deaths are caused by respiratory failure due to
loss of mass from the diaphragm muscle. Anti-cachexia therapies could thus increase the
survival
of cancer patients. The "Cancer Cachexia AIRC Start-up" lab is interested in dissecting the
molecular mechanisms governing the cross-talk between muscle and cancer. Some of the
questions we will try to address are:
How can we stop/delay the lethal muscle wasting associated to many forms of cancers?
Why are skeletal muscles exceptionally resistant to cancers?
Answering these questions may improve greatly the quality of life of cancer patients.
Laboratory of methodology of biomedical research
The laboratory was born out of the consideration that the advent of oncological drugs endowed
with mechanisms of action different from those of traditional chemiotherapics, introduces new
treatment opportunities. At the same time, new problems arise concerning the choice of the
most appropriate and effective design for research into the clinical activity profile of these new
treatments.
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The traditional paradigm where the choice of dose is based on the maximal tolerated toxicity,
and the screening of therapeutic activity focus on tumor mass reduction, may not necessarily be
suitable for the evaluation of new agents whose targets may include the extracellular
compartment or specific molecular targets.
The clinical development of ‘non toxic’ anti tumor molecules requires a critical review of the
existing models as well as of all the aspects relative to the conduction of clinical trials
including: dose selection criteria, methods for determination and confirmation of
pharmacological activity, and the validation of new technologies and laboratory methods.
This is where the need for a profound integration of the ‘clinical screening’ and the preclinical
research lies. It is a prerequisite for the construction of the pharmacological rationale for the
identification of the most interesting molecules, the choice of dose, the hypotheses of
combination with other drugs, and of the most appropriate indicators of clinical activity.
The acquisition of know how and the development and application of new designs for clinical
activity studies, including the use of randomization, the introduction of groups of patients
treated with placebo, and new discontinuation designs, proceed in parallel to the above.
Another fundamental issue in laboratory research is the recognition that the genomic
characterization of any single tumor may now play a more relevant role in drug development
and treatment identification.
This notwithstanding, numerous uncertainties remain regarding the role of biomarkers in drug
development and in the implementation of genomic technologies in clinical trials. It is therefore
necessary to improve the methodology and more biomarkers evaluation already in the early
stages of research, thus shifting translational research from a simple process of correlation
search to one producing knowledge regarding the predictive role of the clinical activity of the
investigational treatments.
Therefore, the primary focus of the laboratory is to provide a methodological support for the
activity of other laboratories of the Oncology Department, in order to optimize the methods for
evaluating the activity of cytotoxic drugs, particularly for those therapies aimed at specific
molecular targets, as well as the identification of factors predictive of therapeutic response.
The laboratory carries out training activities and supports the methodological aspects of various
projects managed within the department of oncology. In particular, it is involved in the
conduction of various theoretical and practical courses, masters in clinical research
methodology and systematic reviews and in the production of guidelines in oncology.
Laboratory of Clinical Research
The Laboratory of Clinical Research, formerly Laboratory of Clinical Trials until September
2012, started in 2006 and inherited the nearly thirty-year experience acquired by the Institute in
oncological clinical trials. Our goal is to keep mission and identity of a not-for-profit
organization, working with high standards of quality in order to comply with the National and
International laws in force for the clinical research.
The Laboratory has therefore widened and modified its structure involving statisticians, data
managers, informatics and local monitors, to plan, organize and conduct experimental and
observational studies. A Unit of Quality Assurance has been created and a data collection
system has been in-house developed and validated.
The studies are conducted in cooperation with a network of medical oncologists. Main covered
research areas are gastric, colorectal, breast, head & neck, and lung cancer.
Besides these areas, the Laboratory has gained long-standing experience in ophthalmology field.
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Oncological diseases
Gastric cancer
Gastric cancer is the second leading cause of cancer mortality in the world. The prognosis is
poor if the cancer is diagnosed at a very early stage. In Western countries, the 5-year survival is
less than 20%, but in countries like Japan, where screening is widespread this is higher than
60%.
Surgical resection remains the only potentially curative treatment, but the recurrence rate of 4080% is still high, and the effect of chemotherapy in surgically resected patients may depend on
the extension of surgery.
A clinical important survival improvement was reached adding peri-operative or post-operative
chemo-radiation with fluorouracil (5-FU) and folinic acid (LV) to surgical resection.However,
the limited surgery extension, not always adequate, could have influenced the results. Indeed,
during the past decade, different studies have clarified the benefit of a D2 gastrectomy and that
the surgical under-treatment negatively affected survival.Thus, the D2 gastrectomy is now
worldwide accepted as standard surgery
Moreover, four types of cytotoxic drugs are used for the chemotherapy treatment in the gastric
cancer: fluoropyrimidine, platinum-based compounds, taxanes, and irinotecan (CPT-11)
Inside the laboratory two trials on gastric cancer are open:
ITACAS - ”Intergruppo Nazionale Adiuvante Gastrico” study is a randomised, open-label,
multicenter, trial aimed at assessing the role of adjuvant chemotherapy in the treatment of
gastric cancer. It compares the efficacy and safety of a sequential treatment (campto plus
flurouracil/leucovorin, followed by taxotere and cisplatin) versus flurouracil/leucovorin
regimen, used as standard reference in patients with radically resected adenocarcinoma of the
stomach or gastroesophageal junction. The study, sponsored by Mario Negri Institute, involves
11 oncological collaborative groups and is being conducted in more than 110 Italian
experimental centers. From February 2005 to August 2009, 1106 patients have been enrolled.
The follow-up ends for all patients after the achievement of the target number of events. The
final results will be published during the first half of 2013.
ITACA-S 2 (Intergroup Trial in Adjuvant Chemotherapy for Adenocarcinoma of the Stomach):
randomized multicenter open label superiority phase III factorial trial, conducted on patients
with histologically confirmed, localized gastric adenocarcinoma, that is considered operable.
According to factorial design the study consist of two independent studies, the Timing Study
and the RTX Study, that aim two different objectives: to compare the efficacy in terms of
overall survival of a peri-operative chemotherapy (3 cycles before and after surgery) versus a
post-operative chemotherapy (Timing Study) and to compare the efficacy in terms of relapse
free survival of a post-surgical chemo-radiotherapy versus no other treatment (RTX Study).
Approximately 1000-1180 patients are needed in the Timing study and 420-520 in the RTX
study. This trial supported by “Agenzia Italiana del Farmaco” (AIFA) - Bando per la ricerca
Indipendente 2008, currently provides more than 80 Italian sites participating and it has
enrolled 55 patients, until December 2012.
Lung tumors
The burden of cancer is increasing with the aging of the population. One every three men and
one every four women are likely to have a diagnosis of cancer during their life course. With
more than 1.6 million new cases diagnosed each year, lung cancer is the leading cause of cancer
death worldwide.
In Italy the estimated annual incidence of lung cancer is approximately 34,000 new cases in
people aged up to 84 years. In Italy, the annual mortality from lung cancer amounts to
approximately 27,500 persons (of which 22,000 men and 5,500 women), representing the
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leading cause of cancer death in men and the second in women, after breast cancer.
Tobacco smoking is the risk factor implicated in the genesis of approximately 85% of all
malignant tumors of the lung. Other causes of lung cancer include: passive smoking, asbestos
exposure, air pollution with particulate materials and radioactive radiations. Several genes,
implicated in the development of lung cancer (as is the case of the gene codifying for the
Epidermal Growth Factor Receptor - EGFR), are also under study as potential targets for new
drugs for the treatment of these tumors.
Lung Carcinomas
This is a group of several tumors which can be classified into two broad categories according to
the histological and prognostic characteristics, as follows:
Small Cell Lung Carcinoma (SCLC) – aggressive, high mortality tumors, originating from
neuro-endocrine cells.
Non-Small Cell Lung Cancer (NSCLC) – representing approx. 85% of all lung carcinomas.
These tumors can be further divided into four hystological sub-classes with differing prognoses.
With the development of targeted anticancer agents, the therapeutic strategy based on standard
protocols for all NSCLC subtypes will be substituted by a reasoned approach, taking into
consideration the molecular characteristics of the tumor for the creation of personalized
treatment regimens.
Malignant pleural mesothelioma (MPM)
This tumor is a relatively rare and very aggressive form of cancer originating from the
mesothelium. Among all forms of malignant mesothelioma, MPM is the most frequent,
accounting for approximately 80% of all mesotheliomas. The incidence of this cancer is on the
rise worldwide with approximately 2.2 cases per million inhabitants. The single identified risk
factor for the development of mesothelioma is exposure to asbestos. Asbestos in itself is not a
mutagen, but is able to promote self-phosphorylation of EGFR activating the proliferative RASMAP kinase pathway. The crystalline forms, also containing iron (crocidolites), are able to
catalyze the synthesis of reactive oxygen species that are carcinogenic.
Unfortunately, MPMs are most often diagnosed at at an advanced stage. The delay is probably
due to the unspecific clinical picture and the considerable length of time from exposure to the
onset of clinical disease.
In 2012, three clinical studies on lung tumors were being conducted at the laboratory of clinical
research. Two clinical studies involved in patients with advanced NSCLC - TAILOR study and
one on the efficacy of Acetyl-L-carnitine. An additional study - ATREUS -, a phase II
study investigating the use of trabectedin in patients with malignant pleural mesothelioma
(MPM), is currently completing its approval stage.
Tailor study (Optimization of erlotinib for the treatment of patients with advanced non-small
cell lung cancer: an Italian randomized trial: the Tailor study is a multicentre, randomized,
Italian study which started on September 2007. The aim of this trial is the optimization of the
second line therapy in patients with advanced NSCLC.
The development of target-therapy suggested to evaluate the treatment’s efficacy according to
molecular features of the tumoral cell. In particular the epidermal growth factor receptor
(EGFR) is a promising target for anticancer therapy. A "tailored therapy" based on individual
molecular features may result in better responses and optimization of resources and costs.
Treatment with EGFR tyrosine kinase inhibitors has shown clear benefits in EGFR mutated
NSCLC patients whereas their role in EGFR wild-type patients is still unclear. Indirect
evidences on subgroup analyses on randomized trials suggest that chemotherapy might be
superior to erlotinib in wild-type EGFR patients.
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The aim of the study is to compare the efficacy in terms of overall survival of erlotinib and
docetaxel as second-line treatment in NSCLC patients without exons 19 or 21 EGFR mutations.
Based on the sample size assumptions, the total number of required patients is 220. As the target
number of randomizations has been accomplished on April 2012, accrual was stopped. Followup and data validation will continue until the first trimester of 2013, when trial close out is
planned.
This study is the only one conducted with tyrosine kinase inhibitors addressing which is the best
therapy choice in a population of patients which is entirely EGFR wild-type for exons 19 or 21.
Randomised, double-blind, placebo-controlled, phase III, superiority trial to assess the efficacy
and safety of acetyl-L-carnitine in combination with a cisplatin-containing chemotherapy as
first line treatment of advanced or metastatic non small cell lung cancer: on July 2011 a
multicentre, double-blind, placebo-controlled, phase III study, investigating the combination of
acetyl-L-carnitine (ALC) with a cisplatin-containing chemotherapy as first line treatment of
advanced or metastatic NSCLC started recruiting.
ALC facilitates the uptake of acetyl CoA into the mitochondria during fatty acid oxidation,
enhances acetylcholine production and stimulates protein and membrane phospholipid
synthesis.
Several lines of evidence support that acetyl-L-carnitine plays a relevant role as modulator of
cellular energetic metabolism and protein acetylation and may have a protective action in
chemotherapy-induced neurotoxicity.
A neuroprotective role of ALC against cytotoxic drug-induced neuropathy was assessed in
several preclinical models and it has been shown that ALC increased the carboplatin antitumor
activity in NSCLC tumor cells.
The aim of the trial is to assess whether acetyl-L-carnitine prolongs toxicity free survival in
patients with advanced or metastatic NSCLC and reduces neurotoxicity due to platinum
compounds. In fact, in patients receiving chemotherapy administered with legitimate “curative
intent” many toxicities can be justified to accomplish this goal, while in patients with metastatic
cancer, for whom the goal is to “palliate symptoms” and optimise the quality of life, toxicity is
less acceptable and justified.
The target number of patients is 650 over a 30-month period, but recruitment was closed on
November 2012, due to low accrual rate. A total of 107 patients were randomized. Follow-up
and data validation will be completed on April 2014.
ATREUS: A phase II study on the Activity of TRabectedin in pretreated epithelioid or
biphasic/sarcomatoid malignant plEUral meSothelioma (MPM): there is no active second-line
treatment for MPM recurring after first-line treatment, except for patients who respond to the
standard platinum-based plus pemetrexed regimen for at least 6 months; in such cases rechallenge with the same therapy may be effective.
Biphasic and sarcomatoid MPM are generally resistant to the aforementioned standard
chemotherapy, there is not a standard first line treatment for this histological type, which
represents an unmet medical need.
Trabectedin binds in the minor groove of DNA, alkylating the N2 of guanine and affecting
transcription regulation in gene- and promoter-dependent fashion. Considering the unique
features of the mechanism of action of trabectedin and the preclinical and clinical evidence that
the drug can be effective against tumors that are poorly responsive to conventional
chemotherapeutics, we consider worthy testing its activity in MPM.
ATREUS study is a phase II non-randomized multicentre study conducted in patients with
unresectable MPM with epithelioid subtype previously treated with pemetrexed plus platinumbased chemotherapy, or patients with biphasic and sarcomatoid histotypes who are either
chemonaive or previously treated with pemetrexed plus platinum-based chemotherapy.
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The study shall enrol 79 patients, of which 62 with epithelioid sub-type MPM in progression
notwithstanding a previous course of treatment with pememtrexed and platinum derivates and
17 with sarcomatoid or biphasic MPM irrespective of treatment history.
The primary objective of the study is to assess the activity of trabectedin in patients with
epithelial MPM relapsing after treatment with pemetrexed plus platinum-based drugs.
Additional aims include the assessment of trabectedin activity in patients with biphasic or
sarcomatoid either as first line treatment or following a previous course of platinum derivates
and pemetrexed, and the evaluation of its safety and tolerability profile. In addition, the
performance of trabectedin with respect to some biological features of MPM, shall be evaluated.
The study has obtained a suspensive judgment from the coordinating ethics committee subject
to modifications to the patient liability insurance policy.
Colorectal cancer
Colorectal cancer is a cancer from uncontrolled cell growth in the colon or rectum (parts of the
large intestine), or in the appendix. Symptoms of colorectal cancer typically include rectal
bleeding and anemia which are sometimes associated with weight loss and changes in bowel
habits.
In western countries this neoplasm is the third malignant tumor after lung cancer for men and
breast cancer for women.
Most colorectal cancer occurs due to lifestyle and increasing age with only a minority of cases
associated with underlying genetic disorders. It typically starts in the lining of the bowel and if
left untreated, can grow into the muscle layers underneath, and then through the bowel wall.
Screening is effective at decreasing the chance of dying from colorectal cancer and is
recommended starting at the age of 50 and continuing until a person is 75 years old. Localized
bowel cancer is usually diagnosed through sigmoidoscopy or colonoscopy.
There are three open studies on this disease:
PROGNOSTIC FACTORS FOR PATIENTS WITH ADVANCED COLORECTAL CANCER
TREATED WITH CETUXIMAB. AN ITALIAN TRIAL – This is an Italian multi-center,
phase II clinical trial. The recruitment, started in April, 2009, was completed in June, 2012.
Target population is patients with histologically documented metastatic KRAS wildtype colorectal cancer not suitable for curative-intent resection.
The aim of the study is to assess the prognostic value of PTEN mutation in terms of Progression
Free Survival (PFS) in patients receiving Cetuximab plus FOLFIRI as first line therapy for
colorectal cancer.
The efficacy secondary end-points are: overall survival; response rate assessed by RECIST
criteria and Quality of Life assessed by QLQ-C30 questionnaire. The safety secondary endpoints are: toxicity, frequency and nature of serious adverse reactions. Sample size is
approximately 50 KRAS wild type patients.
The patient accrual period was approximately 36 months. To assess PFS, all patients will be
followed for up to 12 months after the last patient is enrolled.
This study, sponsored by Regione Lombardia, has foreseen the involvement of 8 centers.
The last patients enrolled are completing to treatment and the number of events is almost
reached.
TOSCA - On June 2007 started the accrual of this study, a multicenter, open label, randomised,
phase III clinical trial of not inferiority aimed at identifying the best therapeutic adjuvant
strategy in radically resected colon cancer (stage II/III) patients. The study is sponsored by
“Fondazione Giscad per la Cura dei Tumori” and supported by the “Agenzia Italiana del
Farmaco” (AIFA) - Bando per la ricerca Indipendente 2005.
According to the factorial design this project consists of two independent substudies, following
specific eligibility criteria and different randomisation schemes studies, called DURATION
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study and BEV study. Once randomised in the duration study, patients fulfilling eligibility
criteria for BEV study may also be randomized to receive BEV or no BEV, in addition to
FOLFOX-4 chemotherapy only.
Duration study is designed to optimize FOLFOX-4 treatment duration, evaluating the efficacy
and safety of a 3-month FOLFOX-4 treatment vs. a 6-month FOLFOX-4 treatment .
Bev study is designed to assessing the benefit of the addition of BEV to the FOLFOX-4
regimen.
Since 2010, after substantial amendment, it was given the possibility to use XELOX regimen
(12 vs 24 weeks) as an alternative to FOLFOX-4 treatment, for patients that not participating in
the sub-study with bevacizumab.
The objective and the primary endpoints are:
- To assess whether a 3-month (6 cycles) FOLFOX-4 treatment or 12-week (4 cycles) XELOX
treatment is at least not inferior to a 6-month (12 cycles) FOLFOX-4 treatment or 24-week (8
cycles) XELOX treatment in terms of RFS in patients with radically resected stage II/III colon
cancer
- To assess whether the combination of BEV and FOLFOX-4 is superior to FOLFOX-4 alone in
terms of RFS in patients with radically resected high-risk stage III (T4, N+, M0, or any T, N2,
M0) colon cancer
This is an event driven study. The study will continue until approximately 1270 and 390 events
have occurred in patients enrolled in the DURATION study and BEV study, respectively. In
order to achieve this targeted number of events in the DURATION study, it will be necessary
to randomise 2860-4100 patients, based on the observed case-mix of the patients, while in the
BEV study it will be necessary randomise 430-620 patients.
Duration study is ongoing and up to December 2012, 3611 patients have been randomised.
BEV study was prematurely closed in December 2010 incorporating the recommendation of
Data Safety Monitoring Committee following the negative results of the NSABP C-08 and
AVANT trials. Patients are still being followed-up.
COMETS - On September 2009 the accrual of COMETS study was started, a randomised,
phase III clinical trial aimed at comparing the efficacy and safety of two different sequences of
chemotherapeutic agents in order to optimize the treatment of patients with metastatic colorectal
cancer progressed to a first line chemotherapy with FOLFIRI and Bevacizumab.
The study is sponsored by “Fondazione Giscad per la Cura dei Tumori” and supported by the
“Agenzia Italiana del Farmaco” (AIFA) - Bando per la ricerca Indipendente 2006.
The primary objective is to compare the efficacy of FOLFOX-4 followed by Irinotecan +
Cetuximab versus Irinotecan + Cetuximab followed by FOLFOX-4 in terms of progression free
survival.
The secondary objective are overall survival, quality of life, toxicity, health resource utilization
and economic evaluation.
This is an event driven study. The study will continue until approximately 101 events have
occurred in patients enrolled . In order to achieve this targeted number of events, it will be
necessary to randomise 110 patients
The study enrolment is ongoing and up to December 2012, 88 patients have been randomized.
Head & neck cancer
Squamous cell carcinoma of the head and neck represents 5% of newly diagnosed cancers in
adult patients. Worldwide more than 500.000 new cases are projected annually. It is a
potentially curable malignancy when diagnosed at an early stage. Unfortunately, 60% of the
patients present with advanced inoperable locoregional disease and a considerable proportion of
the patients relapse either locally or at distant site.
Concomitant chemo-radiotherapy is the standard treatment for locally advanced squamous cell
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carcinoma of the head and neck while, for resectable patients, standard treatment is surgery and
post-operative radiotherapy with or without adjuvant chemotherapy.
Three trials on head and neck cancer are open:
H&N07- randomized multicenter (60 Italian sites participating) open label phase III factorial
trial, and it is sponsored by AVAPO-Ricerche Venezia. Patients with locally advanced
squamous cell carcinoma of the head and neck are eligible. The total study period is 6 years
approximately (4 years of recruitment + 2 years of follow-up); the total number of patients
enrolled is 420. According to factorial design the trial aimed to compare the efficacy in terms of
overall survival of a neoadjuvant chemotherapy on TPF regimen (docetaxel, cisplatin, 5fluorouracil), followed by a of concomitant chemo-radiotherapy or radiotherapy plus
Cetuximab. This study also compared the tolerability of the concomitant chemo-radiotherapy
vs. radiotherapy plus Cetuximab treatment, irrespectively of prior neadjuvant chemotherapy.
Accrual was completed on April 2, 2012 and patients are being followed until the reachment of
the target number of events.
B490 - On June 2012 started the accrual of B490 study, a randomised, phase II-B clinical trial
aimed at is to assessing wheather a treatment based on Cetuximab and Cisplatin is at least not
inferior to a treatment based on Cetuximab and Cisplatin and Paclitaxel. The primary endpoint
is the progression free survival. The secondary endpoint are the overall survival, response rate,
toxicity profile and the study of predictive and prognostic markers in tumor tissue
The study is sponsored by “Istituto Nazionale dei Tumori di Milano”.
The objective of the study The study will continue until approximately 164 events have
occurred. In order to achieve this target number of events it will be necessary to randomise
approximately200 patients.
The study is on-going and up to December 2012, 4 patients have been randomized.
MUCOSITIS DUE TO CHEMO-RADIOTHERAPY – Double-blind randomised parallel trial
comparing morphine mouthwashes to placebo mouthwashes. The study, which is promoted by
A.O. Santa Maria di Terni, is supported by AIFA trough an announcement for Indipendent
research in 2007. Study population is represented by head and neck opioid naïve cancer patients
receiving chemo-radiotherapy both as exclusive and postoperative intent and developing painful
mucositis due to treatment. Patients will be randomized to receive topical morphine as
mouthwashes plus rescue doses of normal release oral morphine if needed or topical placebo as
mouthwashes plus rescue doses of normal release oral morphine if needed. A number of 140
enrolled patients is expected.
Primary objective is to assess the analgesic efficacy of morphine mouthwashes versus placebo
mouthwashes in terms of difference in total dose requirement of systemic opioids (as rescue
morphine medication or continuous opioids administration) via oral (morphine), transdermal
(fentanyl patch) or parenteral (morphine) routes, expressed as equivalent oral morphine dose
during the treatment.
Secondary objective are: mean intensity of pain during the entire period of study and number of
days spent with a level of pain intensity ≥4, assessed daily by means of numerical rating scale
0-10 (0=no pain; 10= the worst pain) during the previous 24 hours; opioid related adverse
effects (drowsiness, nausea, vomiting, constipation and confusion) are assessed by means of a
verbal scale with four grade intensity (No, a little, much, very much); total number of doses of
NSAIDs required in case of failure of rescue opioids; quality of life, evaluated weekly through
EORTC QLQ-C30 and EORTC QLQ-HN35 questionnaires; the need for nutritional support,
expressed as number of days spent with feeding tube; percentage of weight loss from
randomization; number of days of hospitalization and day hospital required for support therapy
due to oral mucositis.
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Twenty patients will take part in the pharmacokinetic study. Ten patients will receive topical
morphine and 10 patients topical placebo as described in the intervention section. Venous blood
samples will be taken for measurement of plasmatic morphine concentrations just prior to the
dose on day 1. On day 1 additional samples will be drawn at time 1 (30’ after rinses), time
2(60’), time 3 (120’), time 4 (time 180’) time 5 (240’).
The trial is now completing its activation phase and the patient enrollment is expected to begin
by the first half of 2013.
Other
ORAL THERAPY – Oral anticancer drugs: nurse interventions to improve therapy menagement
and patient safety.
Recent published data suggest the benefit of an active monitoring to improve the efficiency and
safety of anticancer oral therapy administration, confirmed by the Italian monocentric pilot
study experienced by Sacro Cuore Don Calabria Hospital of Negrar; these results show the
potentiality of nurse active monitoring on patients in decreasing the improper accesses into first
aid and in controlling the toxicity trough: 1) accurate information given to the patient, 2)
administration of a daily record on which the patients will take note of taken drug dose and
symptomatology eventually occurred, 3) a telephone monitoring by means two phone
interviews during first month of therapy and one during the second month. The experience of
Negrar produced the reduction of proportion of graded 3 toxicities among the patients from 12%
to 6% and the number of improper accesses into first aid from 17% to 7% compared with
obtained data in the same hospital in the previous year.
So that an observational, multicenter randomized study is in progress; Hospital centre will be
used as stratification factor. Study is sponsored by Associazione Italiana di Oncologia Medica
(AIOM).
Patients will be randomized to an “Active” intervention arm or to a control group arm.
“Active” intervention consists of: an accurate information given by nurse to the patients before
starting therapy; toxicity survey by nurse according to CTCAE grade; giving a daily record to
the patients and phone interviews to check out the presence of toxicities eventually occurred
during therapy.
Patients enrolled in “control” group will be followed according to standard organizational and
informative ways of each centre.
The observation will last the first two cycles of therapy independently from single cycle last (3,
4 or 6 weeks). The observation will last at least 12 weeks from the beginning of therapy.
The enrollment of 430 patient number in 28 oncological centres is expected.
The first objective is to assess the proportion of patients with improper accesses into first aid,
whereas the secondary objectives are to assess the proportion of patients with severe toxicity,
the concordance between toxicity observed during the medical examination and the toxicity
deduced from phone interviews and the adherence to nurse intervention protocol.
The study is concluding the authorization process and soon will start the recruitment.
GLIOBLASTOMA - Glioblastoma is the most common and most aggressive malignant primary
brain tumor in humans, involving glial cells. Glioblastoma occurs mostly in adults (median age
of 64 years at diagnosis) with an estimated incidence of 2–3 cases per 100.000 people in Europe
and North America
With 1- and 5-year overall survival (OS) rates of 29% and 3%, respectively, the prognosis of
gliobalstoma is poor and the development of more effective therapeutic approaches is
imperative. Although important progress has been made in the last few years, the treatment of
glioblastoma is still one of the greatest challenges in the field of oncology. The management of
glioblastoma requires a multidisciplinary approach including repeat surgery, stereotactic radiosurgery, combinations of repeat surgery with local/second line chemotherapy, anti-angiogenic
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treatment with Bevacizumab, treatment with Fotemustine. In Europe, Fotemustine, a third
generation nitrosourea, is one of the most practiced options in the setting of glioblastoma
relapse. All of these treatments, however, ultimately fail, due to a number of factors, among
which failure to achieve persistent tumoricidal concentrations of the drug in the tumor is one of
the most relevant.
The Laboratory is planning a clinical trial in patients with recurrent glioblastoma.
This study is a multicenter, Italian, non-comparative, randomized, phase II clinical trial aiming
to assess the Ortataxel efficacy in recurrent glioblastoma. Ortataxel is the experimental
treatment, a third-generation taxane that crosses the blood-brain barrier and which is
distinguished from the currently approved taxanes because it is not a substrate for the Pglycoprotein (Pgp-170); Fotemustine is the calibration arm treatment. Patients fulfilling the
eligibility criteria will be randomized to receive Ortataxel or Fotemustine with a 2:1 ratio,
respectively.
The study is divided in two stages: 50 patients will be enrolled in the first stage and the number
of patients will reach 87 at the end of the second stage. At each stage the results of the
calibration arm will be evaluated to assess the adequacy of the enrolled sample; only if the
results of the calibration arm (Fotemustine) are consistent with those expected, the analysis of
experimental arm (Ortataxel) will be performed.
The study primary objective is to evaluate the efficacy of Ortataxel in terms of progression free
survival at 6 months (PFS-6) from the randomization. The secondary objectives are the
objective response, safety and treatment compliance. The study will start in the first half year of
2013.
Non-oncological diseases
Glaucoma
Glaucoma is one of the main causes of visual impairment and is now recognized as the second
most frequent cause of blindness in industrialized countries. In patients with glaucoma, there
has been a progressive increase in intraocular pressure, resulting in damage to the optic nerve,
cause visual field defects, which are usually asymptomatic until the macula is affected, the
location of central vision.
The objective of the treatments available for the treatment of glaucoma is to reduce the
intraocular pressure, up to a level considered safe for the eye, to preserve the visual quality (and
thus of life) of patients. The therapeutic choices available are represented by drugs for topical
use, followed by more invasive procedures such as laser trabeculoplasty and incisional surgery.
These therapies due to their side effects play an important role on the quality of life of patients,
in view of the fact that it sometimes requires them to start treatment before the development of
appreciable visual disturbances.
There are two studies on this disease:
IRFMN-OG1 - Observational, multicenter (22 centers in Italy) study, evaluating the QoL in
patients with glaucoma (transversal phase). A sub-study (longitudinal phase) will followed
prospectively (for one year) the QoL trend in the same subset of patients.
Approximately 3000 patients aged > 18 years and with instrumental diagnosis of primary openangle glaucoma (POAG) should be enrolled in the study.
If the patient is already receiving treatment at the center and his diagnosis is well known, he will
enter the transversal phase (which requires one visit only).
If the patient is at the time of first diagnosis, he will enter the longitudinal phase. These patients
newly diagnosed (about 200) will be followed prospectively for one year with two consecutive
visits at 6 and 12 months. The evaluation of the QoL in glaucoma patients (transversal phase)
and evaluation of changing in QoL in relationship with the trend of the disease (longitudinal
phase), by using validated questionnaires (the National Eye Institute Visual Function
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Questionnaire - NEI-VFQ-25 and the Glaucoma Symptom Scale - GSS) are the end points of
the study. The study is currently recruiting patients: a total of 1148 patients are included, 67 of
which are in the longitudinal phase. The centers are almost all active (19).
The remaining three are expected have their permissions soon.
If the current rate of recruitment is maintained, the closure of the enrollment phase is expected
at the end of June 2013
PEDIATRIC GLAUCOMA - Experimental, prospective, phase II, single-arm study conducted
in children with pediatric congenital glaucoma, refractory to surgery and treated with
prostaglandin analogues and / or carbonic anhydrase inhibitors. The study is enrolling children,
aged 0 to 12 years, with diagnosis of congenital open angle glaucoma. The study is divided in
three phases: the registration phase, surgical treatment and medical treatment.
The protocol evaluates the efficacy and safety of prostaglandin analogues and carbonic
anhydrase inhibitors administered topically, in the treatment of pediatric congenital glaucoma.
The primary objective is the evaluation of hypotensive effect of latanoprost and dorzolamide in
a population refractory to surgical treatment. As a secondary endpoint the safety of treatments
will be considered.
The study is supported by “Agenzia Italiana del Farmaco” (AIFA) - Bando per la ricerca
Indipendente 2008, and the first patient was enrolled in July 2009. At the moment it is still
active to enrollment: the enrolled eyes are currently 49.
Due to the difficulty of finding these kinds of patients, AIFA agreed to extend the contract until
January 2014.
Otorhinolaryngology
Obstructive sleep disordered breathing (OSDB) is a common and serious cause of metabolic,
cardiovascular, and neurocognitive morbidity in children. The spectrum of OSDB ranges from
habitual snoring to partial or complete airway obstruction, termed obstructive sleep apnea
(OSA). The etiology and pathophysiology of OSA in children are multifactorial, however
adenotonsillar hypertrophy plays a major role in its pathogenesis. The volume of lymphoid
tissue in the upper airway increases from about six months of age up to puberty, with maximum
proliferation occurring in the preschool years, which coincides with the peak incidence of
obstructive sleep apnea syndrome (OSAS) in children. The traditional surgical procedure for
treating OSAS in children is extra-capsular tonsillectomy (ECT) that involve the complete
removal of the tonsil by anatomic extra-capsular dissection. The widespread use of classic ECT
is decreasing in our days despite the development of several new techniques, aimed at reducing
post-operative morbidity. Among those, the intra-capsular tonsillotomy (ICT) or partial
tonsillectomy has been advocated in the last few years as an effective and safer than ETC
method in OSDB treatment. The rationale to perform ICT is that tonsillar capsule and
pharyngeal muscles are not violated, preventing them from sustained injury and inflammation,
thus resulting in lower post-operative pain and a more rapid recovery.
Evidences of the efficacy of the two different surgical procedures derive from not randomized,
retrospective, mono institutional studies, carried out on a restricted number of patients and
involving a single instrumental technique. There is one trial open on this disease:
EXTRA-CAPSULAR TONSILLECTOMY (ECT) VS INTRA-CAPSULAR
TONSILLOTOMY (ICT) IN CHILDREN WITH SYMPTOMATIC TONSILLAR
HYPERTROPHY - “ECT vs ICT” is an Italian, multicenter, randomized, open-label study
comparing two different surgical techniques (Extra-capsular tonsillectomy - ECT vs. Intracapsular tonsillectomy - ICT) in children with symptomatic tonsillar hypertrophy. In this study
patients fulfilling the eligibility criteria will be randomized to undergo ECT surgery or ICT
surgery. This study is adherent to the clinical practice, that leaving the surgeon the possibility
to choose among all the current instrumental techniques.
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The primary aim of the study is to compare and evaluate the safety of ICT versus ECT in terms
of postoperative hemorrhage risk in children with symptomatic tonsillar hypertrophy.
Secondary objectives include quality of life in terms of post operative pain, convalescence
duration, improvement of clinical conditions; long-term effects (after 6 months and 1 year) in
terms of apnea control and number of patients that need re-operation. This study, sponsored by
Associazione Otorinolaringologi Ospedalieri Italiani, foresees the involvement of 10 centers and
3 are going to start-up. The recruitment is ongoing from September 2011.
Other activities
Quality Assurance
Our quality management system is on-going and it will be apply in the Clinical Trials
Laboratory. Our scope is to have a system developed for implementing and maintaining quality
assurance and quality control systems with written SOPs to ensure that clinical trials are
conducted and data are generated, documented, and reported in compliance with Good Clinical
Practices and the applicable regulatory requirements. Every activity developed for a clinical trial
has to be recorded and documented according to procedures agreed and set in the Laboratory.
Up to now procedures have been set for study initiation, data management, monitoring, SAE
management, drug management, filing, both in paper and electronic format, of all documents,
and, finally, data capture system that has been fully validated in accordance with the current
regulations for the informatic systems used in clinical trials.
Monitoring
The Laboratory carries out monitoring activities thanks to its certificated monitor. These
activities involves studies sponsored by the Institute, by other research institutions or
collaborative groups, whose entrust the management to Laboratory, but also trials for those
only the monitoring activities are requested to the laboratory. The Laboratory works in
cooperation with Gruppo Italiano Mammella (GIM) for a Phase III trial called “First Adjuvant
Trial on All aromatase inhibitors in early breast cancer” (FATA). The aim of this study is to
compare anastrozole, letrozole and exemestane used up-front (for 5 years) to sequentially
(anastrozole, letrozole and exemestane administered for 3 years after 2 years of tamoxifen) as
adjuvant treatment for postmenopausal patients with endocrine-responsive breast cancer.
Furthermore the Laboratory collaborates with the collaborative group "Swiss Group for Clinical
Cancer Research" (SAKK) for an international phase II trial with rituximab or rituximab plus
lenalidomide monotherapy for patients with follicular lymphoma. Finally, the Laboratory is also
involved in another international project for which monitoring is carried out at the Italian center
" IRCCS Ca’ Granda Policlinico” di Milano. The project is sponsored by the Department of
Neonatology of the Rigshospitalet in Copenhagen and aims to assess the feasibility of
instrumentation used in the monitoring of the oxygenation of brain tissue in premature infants.
Meta-analysis and Systematic Reviews
The laboratory, through a dedicated unit, offers methodological support and statistical analysis
cooperating with clinicians developing projects in oncology, diagnostic and prognostic factors
fields.
Furthermore, through the experience gained over the years, the laboratory performs systematic
reviews and meta-analyses, mainly in the oncologic, diagnostic and ophthalmologic areas.
The systematic reviews completed or ongoing in 2012 were about:
• Performance of different diagnostic techniques in use in clinical practice in the diagnosis of
hepatocellular carcinoma.
• Efficacy and safety of non-penetrating surgical techniques, compared to the standard
technique (trabeculectomy), in reducing intraocular pressure and incidence of complications in
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the treatment of open-angle glaucoma.
• Efficacy and safety of timolol and prostaglandin analogues administered as fixed or
extemporaneous combinations, or as monotherapy in the treatment of open-angle glaucoma or
ocular hypertension.
• Effects of acromegaly on bone metabolism
• Efficacy and safety profile of pre/post surgery thromboprophylaxis pharmacological tratment
in major surgery of the hip and knee.
• Efficacy and safety profile of a concomitant chemo-radiotherapeutic treatment compared with
a radiotherapeutic treatment in patients with head and neck carcinoma.
Laboratory of Translational and Outcome Research in Oncology
The Laboratory is mainly aimed at documenting, by using either Systematic Literature Review,
Randomized or Outcome Research studies, the value of new diagnostic and therapeutic
interventions in oncology, paying particular attention to two critical steps: the passage from
early to late clinical research (from the activity to efficacy evaluation) and from phase III to
clinical practice (from efficacy to effectiveness). The principal lines of research are three:
cancer pain evaluation, clinical research on gynecologic cancers and evalution of the
effectiveness of complex clinical programs in oncology care. In order to facilitate the research
activities and optimize the outputs, the Laboratory hosts the Coordination Centers of two multidisciplinary Groups (MANGO: Mario Negri Gynecologic Oncology and the CP-OR: Cancer
Pain Outcome Research Study Groups). As from 2007 on, all the activities of research and
training in the field of chronic pain has been coordinated by a dedicated center (CERP:Center
for the Evaluation and Research on Pain).
The Center for Evaluation and Research on Pain (CERP)
CERP is active since early 2008. It coordinates several studies and other activities regarding
chronic pain, particularly of oncologic nature. CERP is aimed at advancing the scientific
knowledge in this field and at improving the quality of palliative care and pain treatment. CERP
activities mainly focus on clinical research, but pre-clinical research (in vivo), information and
educational activities are also considered.
During 2011, was started the clinical study CERP, a multi-center, open-label, prospective study
evaluating the effects of different pharmacological strategies to treat pain in cancer patients.
This study also includes an ancillary pharmaco-genomic project: Evaluation, in parallel to the
main project, of the genetic profiles of patients and their potential correlations to observed
clinical effects. In May 2010 CERP has been completed the writing of the study protocol and
the CRF. After obtaining, in July 2010, the single option by the Ethic Committee of IRCCS
Fondazione INT, Milan, started the submission the entire documentation to all Centers that will
participate in the study (85 Centers in total, divided into oncology wards and palliative care
centers).
In April of 2011 the first patient was recruited and, despite for some centers the ethical and
administrative phase is not over yet, most are enrolling patients. At the end of 2012 the number
of patients recruited is 258. It is planned an investigator meeting in January 2013 with
researchers from the 45 centers that collaborate actively in the study.
In parallel, we completed the planning of the research and the start up of the project “validation
of algorithm and electronic form for the management of patients with non-oncological chronic
pain in General Medicine, in collaboration with S.I.M.G. (Italian Society of General Medicine).
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This study aims to change the prescribing habits of family doctors in patients with chronic pain.
In particular, thanks to a training-type intervention implemented by the Ministry of Health, the
aim is to increase the prescriptions of paracetamol and opioids and reduce those of NSAIDs.
Further analysis are currently of the database containing data collected by the physicians
involved and, during the last congress of the SIMG in November 2011, were presented the
preliminary results of this study.
In October 2011, will begin the drafting of the protocol of the observational study prospective
longitudinal observational study to evaluate clinical characteristics and treatments using opioids
in patients with breakthrough cancer pain defined as R.E.R. study, with relative CRF and
questionnaire for the patient. The coordination of the research project on BTcP, to be
implemented at the oncology and oncohematology network centers of the Emilia-Romagna, has
been entrusted to the CERP. During 2012 was obtained the Ethics approvation of the study’s
centre participants. Moreover has been prepared the electronic CRF study.
The main objective of this study is to evaluate the clinical characteristics of BTcP (number and
duration of episodes, time to reach the peak of pain, maximum intensity, trigger mechanisms)
and the related patterns of care, in a sample of cancer patients suffering from pain of moderatesevere intensity based, already in therapy or in the beginning phase of treatment with opioids of
3rd-step, and with episodes of BTcP, treated with rescue therapy with opioids, followed
longitudinally for a period of 28 days (visits on days 0, 7, 14, 21, 28).
In March 2012, in the context of formative activities organized by CERP, at Mario Negri Istitute
were held lessons of the clinical module of the 12th “Master in Palliative Care at the End of
Life” in collaboration with the University of Milan. At year end, a meeting was organized on
the clinical use of the association oxycodone-naloxone to which were invited the leading experts
in the field.
Continued collaboration with the European network for research in the field of palliative care
that has produced some scientific papers (published or in press).
The website http://crc.marionegri.it/cancerpain dedicated to all activities of CERP was
completely renewed and updated.
The collaborative group in clinical gynecologic oncology named MaNGO
The Mario Negri Gynecologic Oncology group (MaNGO) is a new name for a collaborative
group that has been active in clinical gynecologic oncology for several years. Infact, this group
consolidated its network and logistics while running the ICONs studies which were conducted
in very close partnership with researchers at the Medical Research Council, Clinical Trial Unit,
UK. MaNGO was formally set up in May 2006 and is mainly representative of the northern part
of Italy, although there are important sites in the central and southern part of the country too.
Participating centers are either general public and private hospitals or university clinics. One of
MaNGO’s main statutory objectives was to foster an active collaboration with the Gynecologic
Cancer Intergroup (GCIG), and the European Network of Gynaecological Oncology Trials
groups (ENGOT) that represent two International Forum circulating the scientific proposals
from many national collaborative groups. MaNGO group is actively involved in many
international phase III trials.
MaNGO has been coordinating the Italian participation to the PORTEC 3 study: this is an
academic randomized phase III trial in endometrial cancer promoted by the Dutch collaborative
group. MaNGO received government funds from the Italian Agency for Drugs (AIFA)
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supporting its national coordinating role. In 2012 the MaNGO network was represented by 22
clinical sites throughout Italy that randomized 81 patients into the trial. In 2009 MaNGO
launched the TAUL study, a randomized phase II trial aimed to evaluate the efficacy of
trabectedina in the treatment of patients with uterine leiomyosarcoma. During 2012, the number
sites activated in Italy was 33 and 79 patients suffering from this rare disease have been
enrolled into the study. During 2012 a first translational study was drawn and it was planned to
analyze all the tissue samples collected up to May 2013, looking for possible prognostic or
predictive biomarkes. During 2011 the MaNGO implemented the INOVATYON protocol. This
is an academic, international, phase III, randomized clinical trial aimed at comparing the
combination of pegylated liposomal doxorubicin+carboplatin with the combination of pegylated
liposomal doxorubicin (PLD) and trabectedin in partially platinum sensitive ovarian carcinoma
relapses. During all 2012 this trial was kept “on hold” due to the world wide shortage of PLD.
This happend because of the shut down of the only site of PLD manufacturing in the USA.
INOVATYON trial should be reactivated by the fist half year 2013. During 2012, MaNGO in
partnership with the other onco-gynecologic group named MITO, has started activating a phase
IV protocol aimed at evaluating the translational aspect of the use of the antiangiogenic
treatment with bevacizumab in patients with ovarian cancer undergoing the standard first line
chemotherapy with carboplatin and taxol.
During 2012 MaNGO launched a phase II randomized but non-comparative trial aimed to assess
the efficacy and toxicity profiles of the therapeutic regimens (trabectedin and bevacizumab +/carboplatin) in partially platinum sensitive ovarian cancer patients. The planned sample size is
about 80 patients and the trial will be implemented in about 5 site of the MaNGO network.
During 2012, MaNGO’s Technical-Scientific Committee met quarterly while MaNGO affiliates
were conveyed at the 9° General Assembly that was held in June.
Laboratory of Medical Research and Consumer Involvement
The Laboratory promotes various research activities aimed at developing the participation of
citizens & patients and their representatives to the choices and decisions regarding health. The
laboratory organized training courses and information discussion that would enable consumers
to deal effectively with physicians and researchers. The laboratory carried out research projects
to evaluate the type of information provided on illness and treatment, development of internet
website and information on health issues (www.partecipasalute.it); projects involving groups of
patients for publication of information material; projects to assess quality of life and health.
ECRAN project
The ECRAN (European Communication on Research Awareness Needs) project is designed to
develop a portfolio of open educational resources, including a film, for the general population
about the challenges raised by independent clinical research.
The European Commission (FP7 Health Priority) decided to allocate substantial funding to
independent (investigator-driven) clinical trials. Together with member states, the FP7
infrastructure unit supports the preparation and operation of a pan-European infrastructure for
clinical trials (ECRIN). Through these instruments, Europe has the capacity to design and
conduct independent, multinational clinical trials.
The objective of the ECRAN project is to develop tools to communicate key messages to
citizens, patients, healthcare professionals, researchers, policymakers and society about
independent, multinational clinical research. These messages will focus on:
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i)
the importance of public understanding of the need for and basic principles of clinical
trials, fostering active involvement of patients in trials and of their representatives in trial
design;
ii)
the need for independent clinical trials driven by healthcare issues, to optimise treatment
strategies through comparison of benefits and harms of multiple therapeutic options,
supporting evidence-based clinical practice and reduction in healthcare inequalities;
iii) the need for transparency and optimal use of data, to promote the cost-effectiveness of
treatments and to reduce the economic burden of diseases;
iv) the need for multinational cooperation, taking advantage of Europe’s population size and
diversity, and of its medical expertise.
These objectives will be addressed using communication tools, including: a website, with an
online database of open educational resources in different European languages; a film on
clinical trials, dubbed in many languages, which is envisaged as a keystone of this initiative; an
international event on multinational clinical trials.
This 24 months long project involves 9 partners, included group of pattients and citizen
representatives.
The IN-DEEP project (Integrating and deriving evidence, experiences and preferences:
Developing research-based health information applicable to decision making and selfmanagement by people with MS)
It is a collaboration between project teams in Australia Italy, conducted in parallel. In Italy INDEEP is promoted by Fondazione IRCCS Istituto Neurologico Carlo Besta, Istituto di Ricerche
Farmacologiche Mario Negri, in collaboration with Associazione Italiana Sclerosi Multipla
(AISM). It is supported by a grant of the Federazione Italiana Sclerosi Multipla (FISM).
The aim of the project is to explore how people with MS integrate health information with their
needs, experiences, preferences and values and how these factors can be integrated into an
online resource of evidence-based health information provision for people with MS and their
families. To reach this aim, a four-stage process has been developed: organization of focus
groups and a forum; developmente of a template summarizing evidence-based information; set
up of a website; evaluation of the website through a survey. On the basis of the focus groups
findings, a template on interferons has been developed, structured in three levels (in brief, in
details, in deeper). The graphic layout of benefits and adverse effects has been discussed with
people with multiple sclerosis. Other kinds of information are available alongside the main text:
what the interferons are, details on studies used as sources of information, different ways to
express benefits of interferons, and 4 sections dedicated to: patients’ experiences with the drug;
practical information on interferons management; information on the methodology of research;
form to evaluate the quality of information on the press and on the web. A glossary is also
available.
The template has been implemented into a website (http://indeep.istituto-besta). A questionnaire
was developed and put online to evaluate the website. The website and the survey were
launched through the press, the websites of the partnerts of the project, social networks, mailing
lists and congresses. The survey closed on January 2013 and the results will be discussed
through the promoters and will shape the further version of the website. Fatigue will be the next
topic.
Citizen Jury: the case of Cystic fibrosis
In the latest years the continuous molecular biology techniques improvements have made carrier
detection available for several genetic conditions, including CF. An observational study
provides evidence on the impact of two different policies: in the eastern part of north-eastern of
Italy CF carrier screening has been offered and performed extensively; in the western part the
carrier screening was not actively offered.The choice of an active offering of the carrier
screening at a population level should not be done by the local health authorities only, without
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any consultation of the citizen's preferences. There is the necessity to consider all the possible
consequences at the social level.
A possible way could be a method of citizens’ Jury.Citizens’ jury is a method of deliberative
democracy to directly involve the citizens in health decisions. It is based on the idea that many
issues are best decided by a group of lay people who have no vested interests, and who apply
their common sense and experience, having been presented with the best possible evidence.
The members of the Jury, without FC experience, have been involved in one day meeting
assisted by medical experts and disinterested ‘facilitator’. Citizens were asked to answer the
question: “Should or shouldn't the Health Service organize a screening of the population in
order to identify healthy people that may have children suffering from CF?”
Informative materials, documents, and pre-post evaluation questionnaires have been developed
for this project. The meeting has been held in Verona on May 5, 2012.
The vast majority of the Jury was in favor of the Yes, providing reasons covering human,
scientific, economic and social justice aspects. The final document is available on the website
www.PartecipaSalute.it.
The relevance to the Italian CF Foundation is related to the impact of the issue discussed and to
the novelty of the method adopted. In particular:
- specific for FC patients, physicians and researchers in the field of FC, and policy maker who
will have access to a shared final report on FC carrier screening;
- generic, i.e. the development of a feasible and reproducible method to involve citizen in
health decisions that can be easily exported to other situations.
A manual on the method of Citizen’s Jury is also available as additional product of the project.
PartecipaSalute: a strategic alliance between patient groups, citizens and
scientific medical communities
This project is carried out in collaboration with the Italian Cochrane Centre and the Agency for
Science Journalism Zadig, began in September 2003. This project experiments initiatives with
the aim of directing:
- patients' associations and citizens to increased participation and discussion on health care
issues and choices in medicine;
- professional and scientific organizations in a constructive relationship with patients and
citizens and their associations to accept and satisfy their demands and their expectations about
the production (clinical research) and dissemination of scientific information.
In the course of 2012 were organized:
• the VII training course "Orientarsi in salute e sanità", in collaboration with CESVOT, Pistoia;
• a survey on the follow-up of the first five training courses dedicated to representatives of
associations of patients, the survey involved about one hundred subjects, the results are being
published;
• a survey on the availability of register of clinical research for patients and citisens;
• Italania translation of the Press Relese of The Cochrane Collaboration
A strong point of the project is the development and the site of PartecipaSalute. The site is
updated with new articles and insights every week, while every two weeks is sent to a mailing
list of more than 2,500 people the newsletter.
MDS-GA Project: Development and validation of the short version of an
instrument for multidimensional evaluation of elderly patients with acute
myeloid leukemia or advanced myelo-dysplastic syndrome
The aim of the project is to evaluate, in the Italian setting, the quality (content / face validity)
and impact (feasibility and effects on management indicators of elderly patients) of a "short"
instrument. The validation process in the Italian context was organized in five sequential phases
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of activity, which contributed to the overall assessment of the goodness/quality of the
questionnaire.
Phase 0. Preparation and discussion of the feasibility of the project, identification of potential
participants and partners, acquisition of background material, writing of the protocol of the first
phase of the study and set up of the study boards.
Phase 1. Content validity of the instrument according to two different approaches a) a review of
the literature aimed to compare the new tool with the other currently available to demonstrate
that, in terms of size and items, the new instrument covers different and relevant concepts; b) a
multidisciplinary team of 7-10 people rated the quality/validity of the new instrument in terms
of content, feasibility, expected utility in clinical research and clinical practice.
Phase 2. Translation from English to Italian language, using standardized procedures. Two
professional translators were involved. These two independent translations have been compared
with two other translations (made by board researchers) during a joint meeting where the
various discrepancies were solved by discussion and the best version was defined. Later, this
version has been further discussed in the Working Group and a final version was produced.
Phase 3. Assessment of the internal validity of the final version of the instrument. To achive
this aim, it is necessary to collect data from a sample of cases, estimated about 100-120
subjects. In 2012 the first version of the phase 3 protocol was written.
Phase 4. Empirical evaluation of the clinical validity of the new instrument compared to other
instruments and/or external and independent indicators considered the gold standard.
Project Age.Na.S. - Italian Cochrane Network. Observatory of best
practices for patient safety
A literature review was conducted about some of the good clinical and organizational practices
available in the Observatory of Good Practices for Patient Safety, launched online in 2008 by
Age.Na.S (National Agency for Regional Health services). The observatory was established
with the aim to boost the sharing and transfer of experiences among Regions, health care
organizations and professionals to enhance patient safety and care.
The aim of the revision was to evaluate whether the best practices included in the Observatory
were based on strong evidence, and define from the literature how to implement them in
practice. The choice of the practices to be evaluated was made starting from a list of 10
practices indicated by Age.Na.S and selecting the areas considered to be of greater clinical and
organizational importance. The practices selected were 4, 2 clinical and 2 organizational. For
the clinical area: Effects of evidence-based diagnostic, therapeutic and care pathways for stroke;
Management of anticoagulation-antiplatelet-thrombolysis in acute coronary syndromes; for the
organizational area: patient identification in hospital setting; Pills of good clinical practice for
physicians and pills of health education for citizens and consumers.
For each revision a protocol has been produced, the four revisions were included in a final
report and presented to Age.Na.S. in Rome in November 2012.
AFAR project
This is a pilot project to assess the feasibility of an initivative to define research questions with
patients with dementia, caregivers, general practitioners and clinicians. It is coordinated by the
hospital Presidio Ospedaliero Riabilitativo Beata vergine Consolata Fatebenefratelli, San
Maurizio C.se (TO) and it is developed with the collaboration of Istituto di Ricerche
Farmacologiche Mario Negri and the scientific agency Zadig.
The project is funded by A.Fa.R. Associazione Fatebenefratelli per la Ricerca Biomedica e
Sanitaria for the first stage. The main aim is to define research questions regarding therapy,
rehabilitation or healthcare assistance, that could shape future studies in dementia in the elderly.
The first stage involves a small group of patients to define a form and a method to collect
questions from a broader sample, during the next steps of the project. A literature search was
conducted to draft the form, submitted to 12 patients (for now, february 2013), during single
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interviews. The questionnaire was modified according to the comments and feedback collected
during the interviews.
Follow-up in oncology setting
Two studies on follow-up have been designed and carried out in collaboration with the
Laboratory of Giovanni Apolone.
The first in collaboration with the Network Oncologica Piemontese regards the follow-up of
patients with endometrial cancer organization for which the evidence available is not sufficient
to draw a path of sure effectiveness. TOTEM study that has the characteristics of an open
randomized multicenter study comparing two different modulations of visits and examinations.
The second study that takes place in the context of the 6th Integrated Project Oncology (Health
Ministry) provides for the comparative assessment of two follow-up for women at moderatelow risk with a diagnosis of breast cancer and lead to a randomization minimalist follow-up
coordinated by the oncologist or by general practitioner. The study starts the randomization in
September 2010.
Quality of life projects
No specific research projects have been carried out on quality of the life evaluation. However
we have been supporting and coordinating other groups using the instruments of quality of life
translated and validated by our research group, SF-36, SF-12, PGWBI.
During the year the website http://crc.marionegri.it/qol has been periodically updated.
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DEPARTMENT OF ENVIRONMENTAL
HEALTH SCIENCES
STAFF
Head
Roberto FANELLI, Biol.Sci.D.
Laboratory of Analytical Biochemistry
Head
Chiara CHIABRANDO, Biol.Sci.D.
Laboratory of Environmental Chemistry and Toxicology
Head
Emilio BENFENATI, Chem.D.
Industrial and Environmental Health Unit
Head
Marco LODI, Chemist
Laboratory of Food Toxicology
Head
Ettore ZUCCATO, M.D.
Environmental Biomarkers Unit
Head
Sara CASTIGLIONI, Biol.Sci.D.
Laboratory of Mass Spectrometry
Head
Enrico DAVOLI, Anim.Sci.D.
Laboratory of Molecular Toxicology
Head
Luisa AIROLDI, Pharm.D.
Protein and Gene Biomarkers Unit
Head
Roberta PASTORELLI, Biol.Sci.D
Department’s Units
Environmental Pollutants' Risk Assessment Unit
Head
Elena FATTORE, Biol.Sci.D
Analytical Instrumentation Unit
Head
Renzo BAGNATI, Chem.D.
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CURRICULA VITAE
Roberto Fanelli, Head of the Environmental Health Sciences Department since 1997, Laboratory Head
1978-97, Researcher 1975-78, Research fellow 1969-74 at the Mario Negri Institute.
Doctoral Degree in Biological Sciences (University of Milan, 1973), Assistant Professor in Biochemistry
at Baylor College of Medicine (Houston, Texas). Member of the Commissione Consultiva Prodotti
Fitosanitari (Ministero Salute), Member of the Scientific Panel on Contaminants in the Food Chain
(European Food Safety Authority, 2003-2006), Certified Italian Toxicologist.
Research areas: Sources, diffusion, toxicology, human exposure and risk assessment of persistent
environmental pollutants. Environmental risk of plant protection products. Development of analytical
methods for identification and measurement of biomarkers in toxicology. Mechanisms of toxic action by
proteomic techniques.
Selected publications:
1.
Scornavacca G, Gesuete R, Orsini F, Pastorelli R, Fanelli R, De Simoni M G, Airoldi L. Proteomic analysis of mouse brain
cortex identifies metabolic down-regulation as a general feature of ischemic pre-conditioning. J Neurochem 122: 12191229(2012)
2.
De Paola M, Mariani Alessandro, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P, Castellaneta V,
Boldrin V, Rossetti C, Chiabrando C, Forloni G, Mennini T, Fanelli R. Neuroprotective effects of Toll-like receptor 4
antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration. Mol Med 18: 971-981(2012)
3.
Bertoldi M, Borgini A, Tittarelli A, Fattore E, Cau A, Fanelli R, Crosignani P G. Health effects for the population living near a
cement plant: An epidemiological assessment. Environ Int 41: 1-7(2012)
4.
Castiglioni S, Bagnati R, Melis M, Panawennage D, Chiarelli M P, Fanelli R, Zuccato E, Identification of cocaine and its
metabolites in urban wastewater and comparison with the human excretion profile in urine, Water Res 45: 5141-5150 (2011)
5.
Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometric analysis of illicit drugs in wastewater and
surface water. Mass Spectrom Rev 2008 ; 27 : 378-394
6.
Zuccato E, Chiabrando C, Castiglioni S, Bagnati R, Fanelli R. Estimating community drug abuse by wastewater analysis.
Environ Health Perspect 2008 ; 116 : 1027-1032
Luisa Airoldi, Head of the Molecular Toxicology Laboratory since 1994, Unit Head 1987-94, Researcher
1978-87, Technician 1967-75 at the Mario Negri Institute.
Doctoral Degree in Pharmacy (University of Milan, 1975), Postdoctoral fellow at the Massachusetts
Institute of Technology (Cambridge, MA, 1976) and at the Northwestern University Medical School
(Chicago, Il, 1977), Researcher at the Yale University Medical School (New Haven, CT, 1980-81).
Research areas: Proteomics in toxicology with particular interest on the study of proteome changes in
tissues and biological fluids from animals and humans after exposure to toxic compounds; clinical
proteomics aimed at the identification of protein biomarkers as diagnostic tools; molecular epidemiology
focused on the identification and measurement of biomarkers of exposure to environmental carcinogens
and disease susceptibility.
Selected publications:
1.
Scornavacca G, Gesuete R, Orsini F, Pastorelli R, Fanelli R, de Simoni MG, Airoldi L. Proteomic analysis of mouse brain
cortex identifies metabolic down-regulation as a general feature of ischemic pre-conditioning. J Neurochem. 2012; 122: 121929.
2.
Brunelli L, Llansola M, Felipo V, Campagna R, Airoldi L, De Paola M, Fanelli R, Mariani A, Mazzoletti M, Pastorelli R.
Insight into the neuroproteomics effects of the food-contaminant non-dioxin like polychlorinated biphenyls. J Proteomics.
2012; 75: 2417-30.
3.
Campagna R, Brunelli L, Airoldi L, Fanelli R, Hakansson H, Heimeier R. A, De Boever P, Boix J, Llansola M, Felipo V and
Pastorelli R. Cerebellum proteomics addressing the cognitive deficit of rats perinatally exposed to the food-relevant nondioxin like polychlorinated biphenyl PCB138. Toxicol Sci 2011; 123: 170-9
4.
Gallo V, Neasham D, Airoldi L, Ferrari P, Jenab M, Boffetta P, Overvad K, Tjonneland A, Clavel-Chapelon F, Boeing H, Pala
V, Palli D, Panico S, Tumino R, Arriola L, Lund E, Bueno-De-Mesquita H B, Peeters P H, Melander O, Hallmans G, Riboli E,
Saracci R, Vineis P. Second-hand smoke, cotinine levels, and risk of circulatory mortality in a large cohort study of neversmokers. Epidemiology 2010 ; 21 : 207-214.
5.
Airoldi L, Magagnotti C, Iannuzzi AR, Marelli C, Bagnati R, Pastorelli R, Colombi A, Santaguida S, Chiabrando C, Schiarea
S, Fanelli R. Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun. 2009 381: 397402.
6.
Carpi D, Korkalainen M, Airoldi L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R. Dioxinsensitive proteins in differentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci. 2009 108: 330-43.
Emilio Benfenati, Head of the Laboratory of Environmental Chemistry and Toxicology since 1997, Unit
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Head 1987-97, Researcher 1986-87, Research fellow 1981-86 at the Mario Negri Institute. Researcher at
Istituto Biochimico Italiano 1979-1981.
Doctoral Degree in Chemistry (University of Milan, 1979). Postdoctoral fellow at Stanford University,
California (1983-1984). Member of Commissione Consultiva Prodotti Fitosanitari (Ministero Salute
1997-99), Certified Italian Chemist. Member of the External Scientific Advisory Panel, CEFIC (since
2011). Coordinator of the working group on computer toxicology of the Ministero della Salute (since
2012).
Research areas: Computer-based models for chemistry and toxicology; Molecular descriptors; QSAR;
Toxicity prediction; Metabolism studies; Characterization and assessment of wastes, industrial effluents,
emissions from landfill and incinerator; Integration of chemical analysis and eco-toxicological data;
Chemical analysis of organic compounds by mass spectrometry.
Selected publications:
1.
Maggioni S, Balaguer P, Chiozzotto C, Benfenati E. Screening of endocrine-disrupting phenols, herbicides, steroid
estrogens, and estrogenicity in drinking water from the waterworks of 35 Italian cities and from PET-bottled mineral water.
Environ Sci Pollut Res 2012 E-PUB DOI: 10.1007/s11356-012-1075-x
2.
Fernández A, Lombardo A, Rallo R, Roncaglioni A, Benfenati E, Giralt F. Quantitative consensus of bioaccumulation
models for integrated testing strategies. Environ Int 2012 45 : 51-58
3.
Mays C, Benfenati E, Pardoe S. Use and perceived benefits and barriers of QSAR models for REACH: findings from a
questionnaire to stakeholders. Chem Cent J 2012 6 : 159
4.
Toropov A A, Toropova A P, Rasulev B, Benfenati E, Gini G, Leszczynska D, Leszczynski J. CORAL: QSPR modeling of
rate constants of reactions between organic aromatic pollutants and hydroxyl radical. J Comput Chem 2012 33 : 1902-1906
5.
Benfenati E, Gonella Diaza R, Cassano Antonio, Pardoe S, Gini G, Mays C, Knauf R, Benighaus L, The acceptance of in
silico models for REACH: Requirements, barriers, and perspectives, Chem Cent J 2011 5 : 58
6.
Colombo A, Benfenati E, Bugatti S G, Celeste G, Lodi M, Rotella G, Senese V, Fanelli R, Concentrations of PCDD/PCDF
in soil close to a secondary aluminum smelte, Chemosphere 2011 85 : 1719-1724
Chiara Chiabrando, Head of the Analytical Biochemistry Laboratory since 1997, Unit Head 1987-97,
Researcher 1978-87, Research fellow 1975-78 at the Mario Negri Institute.
Doctoral degree in Biological Sciences (University of Milan, 1974), Postdoctoral fellow at the Baylor
College of Medicine (Houston, Texas, 1974-75). Postgraduate degree in Pharmacological Research,
Mario Negri Institute (1977).
Research areas: Development and application of bio-analytical methods based on mass spectrometry in
the fields of biochemistry, metabolism, clinical chemistry and pharmacology. Identification and
characterization of proteins and peptides of biomedical interest by proteomic approaches and mass
spectrometry. Structural characterization of proteins by mass spectrometry. Proteomics in oncology.
Comparative characterization of cancer cell lines secretomes by a global proteomic approach and systems
biology tools.
Selected publications
1.
De Paola M, Mariani A, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P, Castellaneta V, Boldrin V,
Rossetti C, Chiabrando C, Forloni G, Mennini T, Fanelli R. Neuroprotective effects of toll-like receptor 4 antagonism in spinal
cord cultures and in a mouse model of motor neuron degeneration. Mol Med 2012 18:971-981.
2.
Schiarea S, Solinas G, Allavena P, Scigliuolo GM, Bagnati R, Fanelli R, Chiabrando C. Secretome analysis of multiple
pancreatic cancer cell lines reveals perturbations of key functional networks. J Proteome Res. 2010;9:4376-92.
3.
Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C, Mantovani A,
Allavena P. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization,
influencing tumor cell motility. J Immunol. 2010;185:642-52.
4.
Airoldi L, Magagnotti C, Iannuzzi AR, Marelli C, Bagnati R, Pastorelli R, Colombi A, Santaguida S, Chiabrando C, Schiarea
S, Fanelli R. Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun. 2009; 381:397402.
5.
Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E, Noris M, Buelli S, Zoja C, Corna D, Mele C, Fanelli
R, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am Soc
Nephrol 2009 ; 20 : 123-130.
6.
Zuccato E, Chiabrando C, Castiglioni S, Bagnati R, Fanelli R. Estimating community drug abuse by wastewater analysis.
Environ Health Perspect 2008; 116: 1027-1032.
Enrico Davoli, Head of the Mass Spectrometry Laboratory since 1997, Unit Head 1994-97, Researcher
1989-94, Research Fellow 1985-87 at the Mario Negri Institute. Fellow at USDA, Beltville, MD 1977-78.
Doctoral Degree in Animal Sciences (University of Milan, 1983), Postdoctoral fellow at the University of
Nebraska (Lincoln, NE, 1987) and at the University of Colorado Health Sciences Center (Denver, CO,
1988). Postgraduate degree in Pharmacological Research, Mario Negri Institute (1988). Member of the
American Association for Mass Spectrometry (ASMS) of the Environment and Energy Commission, of
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the Safety Commission of IGQ and of the ETS (Emission Trading System) commission. Member of the
National Biomass Research Center Scientific Committee. Environmental Applications Interest Group
Coordinator (ASMS).
Research areas: Development of methodology, instrumentation and software for environmental research.
Studies of urban air pollution and characterization of environmental odor annoyance.
Selected Publications
1.
Capelli L, Sironi S, Del Rosso R, Bianchi G, Davoli E. Olfactory and toxic impact of industrial odour emissions.Water Sci
Technol 2012 ; 66 : 1399-1406
2.
Scaglia B, Orzi V, Artola A, Font X, Davoli E, Sanchez A, Adani F. Odours and volatile organic compounds emitted from
municipal solid waste at different stage of decomposition and relationship with biological stability. Bioresour Technol 2011 ;
102 : 4638-4645
3.
Martinez Bueno M J, Ucles S, Hernando M D, Davoli E, Fernandez-Alba . Evaluation of selected ubiquitous contaminants in
the aquatic environment and their transformation products. A pilot study of their removal from a sewage treatment plant.
Water Res 2011 ; 45 : 2331-2341
4.
Ulaszewska M M, Zuccato E, Davoli E. PCDD/Fs and dioxin-like PCBs in human milk and estimation of infants’ daily intake:
A review. Chemosphere 2011 ; 83 : 774-782
5.
Bagnati R, Davoli E. Analytical methods for the detection of illicit drugs in wastewaters and surface waters. In: Illicit drugs in
the environment: Occurrence, analysis, and fate using mass spectrometry
Wiley, Hoboken, 2011; 55-67
6.
Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Fanelli R, Rossi A N, Il Grande M. Waste management health risk
assessment: A case study of a solid waste landfill in South Italy. Waste Manag 2009, DOI 10.1016/j.wasman.2009.10.013.
Ettore Zuccato, Head of the Food Toxicology Laboratory since 2005, Unit Head 1997-2005, Researcher
1986-97, Technician 1975-86 at the Mario Negri Institute.
Doctoral degree in Medicine (University of Milan, 1986), Postdoctoral degree in Human Nutrition
(1999), Postdoctoral fellow at the King’s College School of Medicine (London, UK, 1988-89).
Member of the ANSISA, EMEA expert, member of the Commissione Consultiva per i Prodotti
Fitosanitari, and expert for the evaluation of plant protection products for registration within the EU.
Research areas: Food safety, including the study of dietary chemical contaminants, safety assessment of
GMO in human nutrition, food allergens and toxicants, emerging issues in food toxicology, risk
perception and risk communication to the consumers, and evaluation of plant protection products for
registration within the European Union. Environmental pollution by pharmaceuticals, and monitoring of
illicit drugs in surface waters to estimate community drug abuse.
Selected publications
1.
Zuccato E, Castiglioni S, Tettamanti M, Olandese R, Bagnati R, Melis M, Fanelli R. Changes in illicit drug consumption
patterns in 2009 detected by wastewater analysis. Drug and Alcohol Dependence 2011, 118: 464-469
2.
Ulaszewska M M, Zuccato E, Capri E, Iovine R, Colombo A, Rotella G, Generoso C, Grassi P, Melis M, Fanelli R. The effect
of waste combustion on the occurrence of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans
(PCDFs) and polychlorinated biphenyls (PCBs) in breast milk in Italy. Chemosphere 2011 ; 82 : 1-8
3.
Ulaszewska M M, Zuccato E, Davoli E. PCDD/Fs and dioxin-like PCBs in human milk and estimation of infants’ daily intake:
A review. Chemosphere 2011 ; 83 : 774-782
4.
Zuccato E, Castiglioni S, Bagnati R, Melis M, Fanelli R. Source, occurrence and fate of antibiotics in the Italian aquatic
environment. J Hazard Mater 2010 ; 179 : 1042-1048
5.
Zuccato E, Chiabrando C, Castiglioni S, Bagnati R, Fanelli R. Estimating community drug abuse by wastewater analysis.
Environ Health Perspect 2008, 116: 1027-1032.
6.
Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometry analysis of illicit drugs in wastewater and
surface water. Mass Spectrom Rev, 2008, 27: 378-394.
Renzo Bagnati, Head of the Analytical Instrumentation Unit since 2005, Researcher 1992-2005,
Research fellow 1986-92 at the Mario Negri Institute.
Doctoral degree in Chemistry (University of Turin, 1985), Postgraduate degree in Pharmacological
Research, Mario Negri Institute (1989).
Research areas: Mass spectrometry applied to the analysis of biological and environmental relevant
substances (proteins, peptides, hormones, pharmaceuticals, drugs of abuse, pesticides).
Selected Publications
1.
Bonati M, Severino F, Bagnati R, Carrà A, Fanelli R. Millet-porridge with Artemisia annua as first aid for African children
with malaria? Journal Alternative Complementary Medicine 2011 ; 17 : 371-373.
2.
Bagnati R, Davoli E. Analytical methods for the detection of illicit drugs in wastewaters and surface waters. In: Illicit drugs in
the environment: Occurrence, analysis, and fate using mass spectrometry. Wiley, Hoboken, 2011; 55-67.
3.
Schiarea S, Solinas G, Allavena P, Scigliuolo G, Bagnati R, Fanelli R, Chiabrando C. Secretome analysis of multiple
pancreatic cancer cell lines reveals perturbations of key functional networks. J Proteome Res 2010; 9: 4376-4392.
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4.
5.
6.
Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giudice C, Scanziani E, Mancuso A, Tiveron C,
Garattini E. Role of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoic acid: generation and
characterization of a knockout mouse. Mol Cell Biol 2009; 29: 357-377.
Zuccato E, Castiglioni S, Bagnati R, Chiabrando C, Grassi P, Fanelli R. Illicit drugs, a novel group of environmental
contaminants. Water Res 2008; 42: 961-968.
Castiglioni S, Zuccato E, Crisci E, Chiabrando C, Fanelli R, Bagnati R. Identification and measurement of illicit drugs and
their metabolites in urban wastewater by liquid chromatography-tandem mass spectrometry. Anal Chem 2006; 78: 8421-8429.
Elena Fattore, Head of the Environmental Pollutants Risk Assessment Unit since 2005, Researcher
2001-2004, Research fellow 1991-1997 at the Mario Negri Institute.
Doctoral Degree in Biological Sciences (University of Milan, 1991), Postgraduate degree in
Pharmacological Research, Mario Negri Institute (1994), Postdoctoral fellow at the National Institute of
Environmental Medicine, Karolinska Institutet, Stockholm (1998-2000). Member of the Working Group
of External Scientific Experts to externally review the quality of the scientific outputs of the European
Food Safety Authority (EFSA) in the area of activity of chemical risk assessment and connected fields
(2010-2012).
Research areas: Environmental chemistry, toxicology, assessment of human exposure and risk from
environmental pollutants with emphasis on dioxins and dioxin-like compounds.
Selected publications
1.
Bertoldi M, Tittarelli A, Borgini A, Fattore E, Cau A, Fanelli R and Crosignani P. Health effects for the population living near
a cement plant: an epidemiological assessment. Environ. Int. 2012; 41: 1-7.
2.
Fattore E, Paiano V, Borgini A, Tittarelli A, Bertoldi M, Crosignani P, Fanelli R. Human health risk in relationship to Air
Quality in two municipalities in an Industrialized area of northern Italy. Environmental Research 2011, 111: 1321-1327.
3.
Grassi P, Fattore E, Generoso C, Fanelli R, Arvati M, Zuccato E. Polychlorobiphenyls (PCBs), polychlorinated dibenzo-pdioxins (PCDDs) and dibenzofurans (PCDFs) in fruit and vegetables from an industrial area in northern Italy. Chemosphere
2010; 79: 292-298
4.
Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Rossi A N, Il Grande M, Fanelli R. Waste management health risk
assessment: A case study of a solid waste landfill in South Italy. Waste Manag 2010; 30: 1608-1613.
5.
Fattore E, Fanelli R, Dellatte E, Turrini A, Di Domenico A. Assessment of the dietary exposure to non-dioxin-like PCBs of the
Italian general population. Chemosphere 2008, 73: S278-S283.
6.
Hodgson S, Thomas L, Fattore E, Lind P M, Alfven T, Hellstrom L, Hakansson H, Carubelli G, Fanelli R, Jarup L Bone
mineral density changes in relation to environmental PCB exposure. Environmental Health Perspective 2008, 116: 1162-1166.
Marco Lodi, Head of the Industrial and Environmental Unit since 2002, Consultant 1997-2002 at the
Mario Negri Institute.
General Certificate of Education in Industrial Chemistry (Milan, 1974).
Member of AIDII (Italian Industrial Hygiene Association), certified by ACGIH (American Conference of
Governmental Industrial Hygienist).
Research areas: Emission sources, environmental diffusion, toxicology, human exposure and risk
assessment of persistent environmental pollutants. Environmental risk of chemical pollution products.
Development of sampling methods for environmental toxic compounds.
Selected publications
1.
Colombo A, Benfenati E, Bugatti S G, Celeste G, Lodi M, Rotella G, Senese V, Fanelli R, Concentrations of PCDD/PCDF
in soil close to a secondary aluminum smelte, Chemosphere 2011 85 : 1719-1724
2.
Baderna D, Maggioni S, Boriani E, Gemma S, Molteni M, Lombardo A, Colombo A, Bordonali S, Rotella G, Lodi M,
Benfenati E, A combined approach to investigate the toxicity of an industrial landfill’s leachate: chemical analyses, risk
assessment and in vitro assays, Environmental Research 2011 111 : 603-613
3.
Ulaszewska M M, Zuccato E, Capri E, Iovine R, Colombo A, Rotella G, Generoso C, Grassi P, Melis M, Fanelli R. The effect
of waste combustion on the occurrence of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans
(PCDFs) and polychlorinated biphenyls (PCBs) in breast milk in Italy. Chemosphere 2011 82 : 1-8
4.
Boriani E, Mariani Alessandro, Baderna D, Moretti C, Lodi M, Benfenati E. ERICA: A multiparametric toxicological risk
index for the assessment of environmental healthiness. Environ Int 2010 36 : 665-674
5.
Colombo A, Benfenati E, Mariani G, Lodi M, Marras R, Rotella G, Senese V, Fattore E, Fanelli R. PCDD/Fs in ambient air in
north/east Italy: The role of a MSWI inside an industrial area. Chemosphere 2009 ; 77 : 1224-1229.
6.
Benfenati E, Azimonti G, Auteri D, Lodi M Environmental and ecological toxicology: computational risk assessment.
Computational toxicology. Risk assessment for pharmaceutical and environmental chemicals John Wiley, Hoboken, NJ, 2007;
625-650
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Roberta Pastorelli, Head of Protein and Gene Biomarkers Unit since 2004, Researcher 1992-2003,
Research fellow 1983-92 at the Mario Negri Institute.
Doctoral Degree in Biological Sciences (University of Milan, 1982), Postgraduate degree in
Pharmacological Research, Mario Negri Institute (1986), Postdoctoral fellow at the Massachusetts
Institute of Technology, Cambridge, MA (1987-89 and 1991).
Research areas: Proteomics-Metabolomics-System Biology. Investigations of global protein/metabolite
expression profiles and their modulation in different biological compartments as a mean for biochemical
and mechanistic studies (e.g. for understanding the onset and progression of human diseases, or for
detailing regulatory modules in cells or subcellular compartments).
Selected publications:
1.
Merico V, Zuccotti M, Carpi D, Baev D, Mulas F, Bellazzi R, Pastorelli R, Redi C A, Moratti R, Garagna S, Balduini A. The
genomic and proteomic blueprint of mouse megakaryocytes derived from embryonic stem cells. J. Thromb. Haemost. 2012,
10: 907-915.
2.
Brunelli L, Llansola M, Felipo V, Campagna R, Airoldi L, Fanelli R and Pastorelli R. Food-relevant non-dioxin like
polychlorinated biphenyls alter the proteome of cerebellar neurons in culture by different key functional networks. J.
Proteomics 2012, 75:2417-30.
3. Campagna R, Brunelli L, Airoldi L, Fanelli R, Hakansson H, Heimeier R. A, De Boever P, Boix J, Llansola M, Felipo V,
Pastorelli R. Cerebellum proteomics addressing the cognitive deficit of rats perinatally exposed to the food-relevant nondioxin like polychlorinated biphenyl PCB138. (2011) Toxicol Sci. 123, 170-9.
4. Mazzoletti M, Bortolin F, Brunelli L, Pastorelli R, Erba E, Ubezio P, Broggini M. Combination of PI3K/mTOR
inhibitors: in vitro and in vivo antitumor activity and molecular correlates. Cancer Res. 2011, 71, 4573-84.
5.
Carpi D, Korkalainen M, Airoldi L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R. Dioxinsensitive proteins in differentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci. 2009 108: 330-43.
6.
Pastorelli R, Carpi D, Campagna R, Airoldi L, Pohjanvirta R, Viluksela M, Hakansson H, Boutros P C, Moffat I D, Okey A B,
Fanelli R. Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance: correlation with
genomic and transcriptomic analyses. Mol Cell Proteomics 2006; 5: 882-894
Sara Castiglioni, Head of the Environmental Biomarkers Unit since 2012, Researcher 2008-2012, PostDoc Fellowship 2006-2008, Research Fellowship 2001-2006 at Mario Negri Institute.
Doctoral Degree in Biological Sciences (University of Insubria, Varese, 2000). Postdoctoral Degree in
Environmental Analysis, Management and Protection of Biodiversity (University of Insubria, Varese and
Mario Negri Institute, 2002-2006). Postdoctoral Fellowship at University of New South Wales, Sydney,
Australia (2004).
Research Areas: Sewage Epidemiology – use of wastewater analysis to study habits and consumption of
some selected substances (i.e. illicit drugs) in the population producing wastewater. Monitoring
occurrence and fate of several classes of emerging contaminants in the environment and evaluation of
their biological and environmental effects.
Selected publications:
1.
Castiglioni S., Thomas KV., Bijlsma L., Covaci A., Emke E., Hernández F., Karolak S., Reid M., Ort C., Thomas KV., van
Nuijs ALN., de Voog P., Zuccato E. (2012) Evaluation of uncertainties associated with the determination of community drug
use through the measurement of sewage drug biomarkers. Environmental Science and Technology. [Epub ahead of print].
2.
Thomas KV., Bijlsma L., Castiglioni S., Covaci A., Emke E., Grabic R., Hernández F., Karolak S., Kasprzyk-Hordern B.,.
Lindberg LH., Lopez de Alba M, Meierjohann A., Ort C., Pico Y., Quintana JB., Reid M., Rieckermann J., Terzic S., van
Nuijs ALN., de Voog P. (2012) Comparing illicit drug use in 19 European cities through sewage analysis. Science of The
Total Environment 432:432-9.
3.
Castiglioni, S; Bagnati, R.; Melis, M.; Panawennage, D.; Chiarelli, P.; Fanelli, R.; Zuccato E. (2011) Identification of cocaine
and its metabolites in urban wastewater and comparison with the human excretion profile in urine. Water Res. 45, 5141-5150.
4.
Zuccato, E; Castiglioni, S; Tettamanti, M; Olandese, R; Bagnati, R.; Melis, M.; Fanelli, R. (2011) Changes in illicit drug
consumption patterns in 2009 detected by wastewater analysis. Drug Alcohol Depend 118, 464-469.
5.
Castiglioni, S.; Zuccato, E.; Chiabrando, C.; Fanelli, R.; Bagnati, R. (2008) Mass spectrometry analysis of illicit drugs in
wastewater and surface water. Mass Spectrometry Reviews. 27, 378– 394.
6.
Castiglioni, S.; Zuccato, E.; Crisci, E.; Chiabrando, C.; Fanelli, R.; Bagnati, R. (2006) Identification and Measurement of
Illicit Drugs and Their Metabolites in Urban Wastewater by Liquid Chromatography-Tandem Mass Spectrometry. Anal.
Chem. 78, 8421-8429.
ACTIVITIES
The Department works to investigate environmental factors and their effects on human health.
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The main research lines focus on the survey of environmental contaminants, the assessment of
human exposure with related health risks, and toxicity mechanisms of pollutants.
The assessment of environmental contamination is carried out not only for well-known and
widespread compounds, like dioxins and PCBs, but also for new classes of "unconventional"
pollutants, e.g., endocrine disruptors, potentially toxic "natural" compounds, and drugs entering
the environment after human or veterinary use. The identification –for the first time– of illicit
drugs in urban waste and river waters, led to a new original tool for the evidence-based
monitoring of community drug abuse. For all these survey activities sophisticated analytical
methods based on advanced mass spectrometric techniques are developed.
The Department is active in the assessment of human exposure to toxic compounds in the
atmosphere and the diet, which is the main source of priority pollutants (PCBs, dioxins and
other endocrine disruptors). Assessment of the risk associated to contamination in real-life
scenarios has recently gained much importance. In order to respond to the growing demand for
information, the Department is more and more involved in toxicological and ecotoxicological
risk analysis, based on studies in field and predictive models of toxicity. The activities on
predictive models are done in collaboration with the US EPA, and public authorities of some
European countries, such as Italy and UK. This produced a platform, VEGA (Virtual models for
property Evaluation of chemicals within a Global Architecture), which is open to the public via
the internet, for the prediction of toxicological and environmental properties. The nanomaterials
have been also modeled with QSAR methods.
The toxic effects of environmental contaminants on neurodevelopmental mechanisms of
environmental contaminants are investigated in animal models in vivo and in vitro.
Molecular epidemiology studies are used to identify genetic and/or environmental factors
posing risks to human health. By this approach, we search for new useful “biological markers"
to identify susceptible subjects, in view of finding appropriate preventive strategies.
The Department has implemented an advanced technological proteomic platform, in order to
identify proteins differentially expressed in biological compartments in various experimental
and clinical conditions. This approach is particularly relevant in toxicology, since it can
contribute to find new biomarkers of toxicity or pathology, and to identify molecular targets and
toxic effect mechanisms of pollutants and drugs. To integrate our proteomic studies, we have
now introduced among our activities metabolomics, i.e., the study of small molecules, such as
amino acids, carbohydrates, lipids, hormones etc., the final products of protein expression and
activity which contribute to define the biochemical phenotype of a biological system.
Mass spectrometry (MS) is a central analytical technique at the Department, where a complete
set of state-of-the-art instrumentation is available, from GC-MS and LC-MS to MALDI-TOFMS. These instruments are provided with modern solutions for sample introduction (chip-based
nanoLC), sample ionization (ESI, DESI and MALDI), tandem MS (MSn) by triple quadrupole
and TOF-TOF instruments, high mass resolution analysis (hybrid ion trap/orbitrap).
FINDINGS/MAIN RESULTS
Untargeted and targeted metabolomics reveals perturbations in specific metabolic pathways
involved in outcome of cardiopulmonary resuscitation in experimental animal models of cardiac
arrest and thus potential mechanisms accounting for outcome of cardiac arrest.
Proteomic analysis of mouse brain in different ischemia models suggests metabolic downregulation as a general feature of ischemic preconditioning, playing a pivotal role in
neuroprotection.
Importance of NDL-PCBs as a risk factor in developmental neurotoxicity in laboratory rodents.
Evidence of brain proteome alterations with detrimental consequences on cognitive functions in
the offspring.
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Evidence of new molecular players in the effects of TCDD on bone development provided by
proteomics coupled to networks analysis.
Bone protein profile in a murine model of osteoporosis.
Identification of novel protein targets responsive to the effects of estrogens in bone.
TCDD's effect on the liver proteome profile of exposed rats. Determination of a subset of rat
hepatic proteins indicative of differences in dioxin susceptibility.
The presence of 4-aminobiphenyl-hemoglobin adducts may help identify nonsmokers at high
risk of cancers related to environmental tobacco smoke exposure.
Reference values of allele and genotype frequency of several metabolic genes in 15,000 control
subjects.
CYP1A1 polymorphism affects lung tumor risk.
Identification of CYP2C9 genetic polymorphism as a determinant of severe adverse reactions to
phenytoin.
On-line in silico models to predict ecotoxicity of pesticides for regulatory purposes.
New in silico models, freely available on-line, to predict toxicity and ecotoxicity of chemicals
for the REACH European legislation. The tools have been used to predict properties of 4
millions chemicals.
A tool to assess if a chemical is bioaccumualive, with a high rate of accuracy, avoiding the use
of the experimental fish model.
The VEGA models for mutagenicity resulted to be the most predictive, in a comparison among
8 different models, achieving accuracy similar ot that of the experimental methods.
There is almost one thousand of VEGA users world-wise.
A new index integrating risk assessment for human and ecotoxicity endpoints.
A method aimed at characterizing environmental odors to identify odor sources in complex
environments.
Proteomic/bioinformatic workflow for comparative secretome analysis in cancer cell lines.
Global proteomic profiles of secretomes (different pancreatic carcinoma cell lines; pancreatic
cell lines with or without oncogenic K-RAS transfection), with identification of perturbed
functional networks. Accurate quantitative evaluation of protein dysregulation in the secretome
by stable isotope labeling by amino acid in cell culture (SILAC) and mass spectrometry.
In depth structural characterization of gamma-conglutin, a bioactive legume seed glycoprotein
by a glycoproteomic approach based on mass spectrometry and bioinformatic tools.
Illicit drug residues and their metabolites were found in urban waste and river waters.
Environmental levels can be used as a new tool to estimate illicit drugs consumption in the
population.
In Milan, between 2008 and 2009 we observed a significant decrease of heroin and cocaine
consumption, and an increase of methamphetamine.
The distribution of dietary intake values of dioxins, dioxin-like PCBs and non dioxin-like PCBs
was characterized for the general Italian population.
The higher intake of PCBs due to consumption of farmed fish vs. wild fish is mainly due to the
higher fat content in farmed fish..
Development of novel mass spectrometric methods for odour carachterization in environmental
samples, for odour pollution and its toxicity.
We characterized the pro-inflammatory and neurotoxic effects (activation of glial cells, release
of inflammatory cytokines, and motor neurons death) mediated by the activation of TLR4 in
primary cultures from mouse spinal cord. Both in this in vitro setting and in an in vivo model of
spontaneous motor neuron degeneration (the Wobbler mouse), a TLR4 antagonist extracted
from cyanobacteria showed anti-inflammatory and neuroprotective properties.
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NATIONAL COLLABORATIONS
AMA Roma
ARPA Emilia Romagna
ARPA Veneto
ASL Bergamo
ASL Brescia
ASL Como
ASL Cremona
ASL Lecco
ASL Lodi
ASL Milano
ASL Milano 1
ASL Milano 2
ASL Monza Brianza
ASL Vallecamonica-Sebino
ASL Varese
Centro Reach Srl
CLIR Spa Lomellina
CNR – IRSA
Comune di Peschiera del Garda (BS)
Comune di Rosignano Marittimo (LI)
Comune di Sant’Urbano (PD)
CSRA-Asti
Dipartimento delle Politiche Antidroga, Presidenza del Consiglio dei Ministri
Federchimica
Fondazione 'S. Maugeri'
ISPO, Firenze
Istituto Clinico Humanitas, Milano
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano
Istituto Scientifico San Raffaele, Milano
Istituto Superiore di Sanità
I.Z.S.L.T - Istituto Zooprofilattico Sperimentale del Lazio e Toscana
Metropolitana Milanese
Mineracqua
Ministero dell'Ambiente
Ministero della Salute
Ministero dello Sviluppo Economico
Politecnico di Milano
Politecnico di Torino
Provincia di Vercelli
Provincia Pordenone
Rotary Club Sirmione (BS)
Stazione Sperimentale dei Combustibili, Milano
Università degli Studi del Piemonte Orientale
Università degli Studi di Cagliari
Università degli Studi di Genova
Università degli Studi di Milano
Università degli Studi di Napoli "Federico II"
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Università degli Studi di Palermo
Università degli Studi di Pavia
Università degli Studi di Perugia
Università degli Studi di Roma "La Sapienza"
Università degli Studi di Siena
Università degli Studi di Torino
Università dell’Insubria, Varese
Università degli Studi di Verona
INTERNATIONAL COLLABORATIONS
CEFIC, European Chemical Industry Council, Bruxelles, Belgio
Centre for Environmental Policy, Imperial College, Londra, Gran Bretagna
Danish Institute of Agricultural Sciences, Research Centre Foulum, Tjele, Danimarca
Department of Computer Science and Engineering, University of Galati, Romania
Department of Electrical and Computer Engineering, University of Patras, Grecia
Department of Environmental Science, Faculty of Science and Technology, Aarhus University,
Aarhus, Danimarca
Department of Inland Fisheries, Institute of Freshwater Ecology and Inland Fisheries, Berlino,
Germania
Department of Molecular Biology, University of Bergen, Bergen, Norvegia
Department of Organic Chemistry, Universidad de Cadiz, Cadice, Spagna
Environmental Chemistry, IIQAB-CSIC, Barcellona, Spagna
Environmental Hygiene and Chemistry Department, Institute of Environmental Medicine and
Hospital
Environmental Protection Agency, US EPA - National Risk Management Research Laboratory
(NRMRL), Cincinnati OH, USA
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbona, Portogallo
Food and Environment Research Agency, York, Gran Bretagna
Forschungzentrum Jülich Gmbh, Jülich, Germania
Helmholtz-Zentrum für Umweltforschung UFZ, Lipsia, Germania
Institute of Environmental Assessment and Water Research (IDAEA-CSIC) Barcellona, Spagna
Institute of Environmental Medicine, Karolinska Institute, Stoccolma, Svezia
Institute of Pharmaceutical Chemistry, University of Pécs, Pecs, Ungheria
Institute of Phytomedicine, Biological Control, Horticulture and Nematology, Vienna, Austria
Institute of Soil Science and Plant Cultivation, Pulawy, Polonia
Interdisciplinary Nanotoxicity Center, Department of Civil and Environmental Engineering,
Jackson State University, Jackson, Mississippi, USA
Istituto di Chimica di São Carlos, Università di São Paulo, Brasile
KnowledgeMiner Software, Berlino, Germania
KWR Water cycle Research Institute (KWR) Utrecht, Olanda
Laboratory of Neurobiology, Centro de Investigation Principe Felipe, Valencia, Spagna
Lithuanian Institute of Agricultrure, Vilnius, Lituania
Liverpool John Moores University, Liverpool, Gran Bretagna
National Institute of Chemistry, Kemijski Institut Ljubljana, Lubiana, Slovenia
Natural Resources Research Institute, University of Minnesota, Duluth, USA
National Institute for Public Health and the Environment (RIVM), Bilthoven, Olanda
Norwegian Institute for Water Research (NIVA), Oslo, Norvegia
Plant Protection Institute, Hungarian Academy of Sciences, Budapest, Ungheria
PublicSpace Ltd, Lancaster, Gran Bretagna
Research Institute for Pesticides and Water, University Jaume I Castellón, Spagna
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Rudjer Boskovic Institute, Zagabria, Croazia
School of Biomedical Sciences, University of Ulster, Coleraine, Gran Bretagna
SETAC Europe, Bruxelles, Belgio
Symlog, Parigi, Francia
Technische Universitaet Dresden, Dresda, Germania
TNO, Delft, Olanda
Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp, Anversa,
Belgio
Unit of Environmental Risk and Health, Flemish Institute for Technological Research,
Boeretang, Belgio
Universitat Politècnica de Catalunya, Barcellona, Spagna
Universitat Rovira i Virgili, Tarragona, Spagna
University of Bath, Bath, Gran Bretagna
University of Paris ‐ Sud 11, Parigi, Francia
University of Santiago de Compostela, Santiago de Compostela, Spagna
EDITORIAL BOARD MEMBERSHIP
Journal of Environmental Science and Health, Part B (Emilio Benfenati), Journal of
Environmental Science and Health, Part C (Emilio Benfenati), Chemistry Central Journal
(Emilio Benfenati), Frontiers (Emilio Benfenati), The Open Toxicology Journal (Emilio
Benfenati), The Open Biomarkers Journal (Luisa Airoldi), Journal of Waste Management
(Enrico Davoli).
PEER REVIEW ACTIVITIES
Addiction, Analytical Chemistry, Chemical Biology & Drug Design, Chemical Research
Toxicology, Chemometrics and Intelligent Laboratory Systems, CHEMOLAB, Chemosphere,
Clinical Biochemistry, Drug and Alcohol Dependence, Environment International,
Environmental Pollution, Environmental Modelling & Software, Environmental Science &
Technology, Journal of Cellular Biochemistry, Journal of Chemical Information and Modeling,
International Journal of Molecular Science, Journal Computer-Aided Molecular Design, Journal
of Hazardous Materials, Journal of Neuroscience Research, Molecular Diversity, Toxicology
Letters, Waste Management, Water Research, International Journal of Environmental Analytical
Chemistry, Molecular Nutrition and Food Research, Journal of Chromatography A, The Open
Biomarkers Journal, The Open Biomarkers Journal, Journal of Neurochemistry, Journal of
Proteome Research, Neurochemistry International, External review of the quality of the
scientific outputs of the European Food Safety Authority (EFSA).
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
CCPF - Commissione Consultiva Prodotti Fitosanitari (Ministero della Salute, Ministero
dell'Ambiente)
CEFIC - External Scientific Advisory Panel
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ECCO - European Commission Coordination
EFSA - European Food Safety Authority
IGQ - Environment and Energy Commission, Safety Commission
EVENT ORGANIZATION
Training Course on QSAR, Sao Paulo, Brazil, August 23-29, 2012.
ANTARES Workshop “Facts about QSAR and non-testing methods”, Istituto di Ricerche
Farmacologìche Mario Negri, Milan, Italy, November 21-22, 2012.
Workshop: The determination of illicit drug use in population through wastewater biomarker
analysis. 11-12 December 2012, Lisbon, Portugal.
CONFERENCE AND WORKSHOP CONTRIBUTIONS
Kick-off meeting: project CT.11.SDI.058 “Estimation of drug use in the population through
wastewater analysis” funded by EMCDDA. EMCDDA Lisbon, Portugal. 19 January 2012.
Course "Il metodo QSAR e le sue applicazioni pratiche nel Regolamento REACH", Milan,
Italy, March 6, 2012.
8ª Conferenza Sicurezza Prodotti - A che punto siamo con il REACH, Milan, Italy, March 8,
2012.
Campus Colloquia: Inquinanti emergenti nelle acque. Bologna, Italy, March 9, 2012.
Workshop: Drug prevention and information 2010 project. New methodological tools for policy
and programme evaluation JUST/2010/DPIP/AG/1410. Rome, Italy, 27-29 March 2012.
Seminar on alternative methods for cosmetics (Regolamento 1223/09: Nuove metodologie e
piattaforme informatiche), Milan, Italy, April 20, 2012.
SETAC 6th Word Congress 2012, SETAC Europe 22nd Annual Meeting, Berlin, Germany, 2024 May 2012.
60th American Society for Mass Spectrometry Conference, Vancouver, Canada May 20-24,
2012.
ESF Exploratory Workshop: Setting the future for water and health research. Barcelona, Spain.
May 21-22, 2012.
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Workshop: Studi di comparazione epidemiologica sull’utilizzo di sostanze dopanti da parte di
atleti dilettanti attraverso il monitoraggio delle acque reflue di impianti sportive. Cetraro (CS),
Italy, June 16, 2012.
QSAR2012, Tallinn, Estonia, June 18-22, 2012.
Workshop: Metodi (Q)SAR, REACH e il Gruppo di Lavoro Italiano, Rome, Italy, September
13, 2012.
Workshop: Drug prevention and information 2010 project. New methodological tools for policy
and programme evaluation JUST/2010/DPIP/AG/1410. Rome, Italy, 19-21 September 2012.
NOSE 2012 International Conference on Odour Monitoring and Control. Palermo, September
23-26, 2012.
Workshop: The effects of residues of cytostatics and other pharmaceuticals on non-target
organisms. Naples, Italy, 16-18 October 2012.
AMERICAN HEART ASSOCIATION. November 3-4, 2012. Los Angeles, CA, US, November
3-4, 2012.
NORMAN Mass Bank workshop. Amsterdam, The Netherlands. 27 November 2012.
NORMAN workshop. Amsterdam, The Netherlands. 29-30th November 2012.
High Resolution Mass Spectrometry in biomedical research. Milano, Italy, December 12, 2012.
Kick-off meeting Marie Curie ITN Project SEWPROF. Lisbon, Portugal. 14 December 2012.
GRANTS AND CONTRACTS
A2A Brescia
ACEGAS S.p.A, Trieste
AIDEPI (Associazione delle Industrie del Dolce e della Pasta Italiane)
AIIPA (Associazione Italiana Industrie Prodotti Alimentari)
AMA, Roma
Aprica S.p.A.
ASL Mantova
ASL Napoli 2
ASSOFOODTEC/UCIMAC (Costruttori Italiani Macchine per Caffè Espresso ed Attrezzature
per Bar)
BASF Italia S.r.l.
Bergamo Pulita S.r.l.
Bracco Imaging Spa
Cambrex, Paullo (MI)
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Catanzaro Costruzioni S.r.l.
Chemservice S.r.l.
CLIR S.p.A.
COOP Italia
CSRA
Comune di Gorla Maggiore (VA)
Comune di Lomello (PV)
Comune di Rosignano Marittimo (LI)
Consorzio Quadrifoglio S.p.A.
Dipartimento Politiche Antidroga, Presidenza del Consiglio dei Ministri
ECODECO S.r.l.
Ecoresearch S.r.l.
Eigenmann & Veronelli S.p.A.
Elior Ristorazione
European Commission, DG RTD (ORCHESTRA, RISKCYCLE, ToxBank, NanoBRIDGES)
European Commssion , DG Environment (ANTARES)
European Commission, DG Justice
European Commission, Marie Curie Action
Federchimica, Milano
FIAT Auto S.p.A.
F.I.S. - Fabbrica Italiana Sintetici S.p.A.
Fondazione Aqualab
Fondazione CARIPLO, Milano
Fondazione Italo Monzino, Milano
Gruppo CSA, S.p.a. Rimini (RN)
INDENA S.p.A.
Istituto Superiore di Sanità, Roma
Ministero dell'Ambiente, Italia
Ministero della Salute, Italia
Norwegian Institute for Water Research (NIVA)
Nufarm S.A.S., Francia
Oxon Italia S.p.A., Pero (MI)
Politecnico di Milano
Provincia di Pordenone
Regione Lombardia, Assessorato Sanità
SO.GE.NU.S. S.p.A.
Università degli Studi di Milano
Veolia Servizi Ambientali S.p.A.
SCIENTIFIC PUBLICATIONS (2012)
Scornavacca G, Gesuete R, Orsini F, Pastorelli R, Fanelli R, De Simoni M G, Airoldi L
Proteomic analysis of mouse brain cortex identifies metabolic down-regulation as a general feature of ischemic preconditioning
J Neurochem 122: 1219-1229(2012)
Merico V, Zuccotti M, Carpi D, Baev D, Mulas F, Sacchi L, Bellazzi R, Pastorelli R, Redi C A, Moratti R, Garagna
S, Balduini A
The genomic and proteomic blueprint of mouse megakaryocytes derived from embryonic stem cells
J Thromb Haemost 10: 907-915(2012)
Brunelli L, Campagna R, Airoldi L, Cauli O, Llansola M, Boix J, Felipo V, Pastorelli R
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Exploratory investigation on nitro- and phospho-proteome cerebellum changes in hyperammonemia and hepatic
encephalopathy rat models
Metab Brain Dis 27: 37-49(2012)
Brunelli L, Llansola M, Felipo V, Campagna R, Airoldi L, De Paola M, Fanelli R, Mariani Alessandro, Mazzoletti M,
Pastorelli R
Insight into the neuroproteomics effects of the food-contaminant non-dioxin like polychlorinated biphenyls
J Proteomics 75: 2417-2430(2012)
Toropova A P, Toropov A A, Martyanov S E, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
CORAL: QSAR modeling of toxicity of organic chemicals towards Daphnia magna
Chemometrics Intelligent Laboratory System 110: 177-181(2012)
Toropova A P, Toropov A A, Rasulev B, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
QSAR models for ACE-inhibitor activity of tri-peptides based on representation of the molecular structure by a graph
of atomic orbitals and SMILES
Structural Chemistry 23: 1873-1878(2012)
Fernández A, Lombardo A, Rallo R, Roncaglioni A, Giralt F, Benfenati E
Quantitative consensus of bioaccumulation models for integrated testing strategies
Environ Int 45: 51-58(2012)
Toropov A A, Toropova A P, Rasulev B, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
Coral: QSPR modeling of rate constants of reactions between organic aromatic pollutants and hydroxyl radical
J Comput Chem 33: 1902-1906(2012)
Maggioni S, Balaguer P, Chiozzotto C, Benfenati E
Screening of endocrine-disrupting phenols, herbicides, steroid estrogens, and estrogenicity in drinking water from the
waterworks of 35 Italian cities and from PET-bottled mineral water
Environ Sci Pollut Res Int E-pub: (2012)
Toropova A P, Toropov A A, Benfenati E, Gini G
QSAR models for toxicity of organic substances to Daphnia magna built up by using the CORAL freeware
Chem Biol Drug Des 79: 332-338(2012)
Toropova A P, Toropov A A, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
CORAL: Quantitative models for estimating bioconcentration factor of organic compounds
Chemometrics Intelligent Laboratory System 118: 70-73(2012)
Toropov A A, Toropova A P, Benfenati E, Gini G, Puzyn T, Leszczynska D, Leszczynksy J
Novel application of the CORAL software to model cytotoxicity of metal oxide nanoparticles to bacteria Escherichia
coli
Chemosphere 89: 1098-1102(2012)
Toropov A A, Toropova A P, Rasulev B, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
CORAL: Binary classifications (active/inactive) for liver-related adverse effects of drugs
Curr Drug Saf 7: 257-261(2012)
Toropova A P, Toropov A A, Lombardo A, Roncaglioni A, Benfenati E, Gini G
Coral: QSAR models for acute toxicity in fathead minnow (Pimephales promelas)
J Comput Chem 33: 1218-1223(2012)
Toropov A A, Toropova A P, Martyanov S E, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
CORAL: Predictions of rate constants of hydroxyl radical reaction using representation of the molecular structure
obtained by combination of SMILES and Graph approaches
Chemometrics Intelligent Laboratory System 112: 65-70(2012)
Toropov A A, Toropova A P, Lombardo A, Roncaglioni A, De Brita N, Stella G, Benfenati E
CORAL: the prediction of biodegradation of organic compounds with optimal SMILES-based descriptors
Central European Journal Chemistry 10: 1042-1048(2012)
Toropov A A, Toropova A P, Raska I Jr, Benfenati E, Gini G
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QSAR modeling of endpoints for peptides which is based on representation of the molecular structure by a sequence
of amino acids
Structural Chemistry 23: 1891-1904(2012)
Toropov A A, Toropova A P, Gonella Diaza R, Benfenati E, Gini G
SMILES-based optimal descriptors: QSAR modeling of estrogen receptor binding affinity by correlation balance
Structural Chemistry 23: 529-544(2012)
Toropova A P, Toropov A A, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
The average numbers of outliers over groups of various splits into training and test sets: A criterion of the reliability
of a QSPR? A case of water solubility
Chem Phys Lett 542: 134-137(2012)
Toropov A A, Nesmerak K
SMILES-based QSPR model for half-wave potentials of 1-phenyl-5-benzyl-sulfanyltetrazoles using CORAL
Chem Phys Lett 539-540: 204-208(2012)
Toropov A A, Toropova A P, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
Calculation of molecular features with apparent impact on both activity of mutagens and activity of anticancer agents
Anticancer Agents Med Chem 12: 807-817(2012)
Mays C, Benfenati E, Pardoe S
Use and perceived benefits and barriers of QSAR models for REACH: findings from a questionnaire to stakeholders
Chem Cent J 6: 159(2012)
Toropova A P, Toropov A A, Benfenati E, Gini G, Leszczynska D, Leszczynksy J
CORAL: Models of toxicity of binary mixtures
Chemometrics Intelligent Laboratory System 119: 39-43(2012)
Baderna D, Boriani E, Dalla Giovanna F, Benfenati E
Lubricants and additives: A point of view
Springer-Verlag, Berlin 109-132(2012)
De Paola M, Mariani Alessandro, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P, Castellaneta
V, Boldrin V, Rossetti C, Chiabrando C, Forloni G, Mennini T, Fanelli R
Neuroprotective effects of Toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor
neuron degeneration
Mol Med 18: 971-981(2012)
Capelli L, Sironi S, Del Rosso R, Bianchi G, Davoli E
Evaluating the dispersion of toxic odour emissions from complex sources
J Environ Sci Health A Tox Hazard Subst Environ Eng 47: 1113-1122(2012)
Davoli E, Zuccato E, Bianchi G, Palmiotto M, Il Grande M, Bonati S, Rossi A N
Dynamic olfactometry and potential sample toxicity. Guidelines for a safe occupational health approach
Chemical Engineering Transactions 30: 7-12(2012)
Capelli L, Sironi S, Del Rosso R, Bianchi G, Davoli E
Olfactory and toxic impact of industrial odour emissions
Water Sci Technol 66: 1399-1406(2012)
Zucchi S, Castiglioni S, Fent K
Progestins and antiprogestins affect gene expression in early development in Zebrafish (Danio rerio) at environmental
concentrations
Environ Sci Technol 46: 5183-5192(2012)
Thomas K V, Bijlsma L, Castiglioni S, Covaci A, Emke E, Grabic R, Hernandez F, Karolak S, Kasprzyk-Hordern B,
Lindberg R H, Lopez de Alda M J, Meierjohann A, Ort C, Pico Y, Quintana J B, Reid M, Rieckermann J, Terzic S,
Van Nuijs A L N, de Voogt P
Comparing illicit drug use in 19 European cities through sewage analysis
Sci Total Environ 432: 432-439(2012)
Paiano V, Fattore E, Carrà A, Generoso C, Fanelli R, Bagnati R
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Liquid chromatography-tandem mass spectrometry analysis of perfluorooctane sulfonate and perfluorooctanoic acid
in fish fillet samples
J Anal Methods Chem E-pub: (2012)
Bertoldi M, Borgini A, Tittarelli A, Fattore E, Cau A, Fanelli R, Crosignani P G
Health effects for the population living near a cement plant: An epidemiological assessment
Environ Int 41: 1-7(2012)
Magagnotti C, Bachi A, Zerbini G, Fattore E, Fermo I, Riba M, Previtali S C, Ferrari M, Andolfo A, Benedetti S
Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers
Biochim Biophys Acta Mol Basis Dis 1822: 970-979(2012)
Sulaiman G M, A'dhiah A H, Al Sammarrae K W, Bagnati R, Frapolli R, Bello E, Uboldi S, Romano M, Panini N,
Scanziani E, Pezzolato M, Erba E, D'Incalci M
Assessing the anti-tumour properties of Iraqi propolis in vitro and in vivo
Food Chem Toxicol 50: 1632-1641(2012)
LAY PRESS SELECTION (2012)
Ulaszewska M.M., Capri E., Zuccato E. Latte materno e inquinamento. Quali pericoli ? Il Pediatra Novembre 2012:
42-49.
Zuccato E., Castiglioni S. Consumi di sostanze stupefacenti nelle città europee. Ricerca e pratica 2012; 28: 252-60.
RESEARCH ACTIVITIES
Laboratory of Molecular Toxicology
Proteome Analysis
Proteome analysis includes protein separation by one- and two-dimensional gel electrophoresis,
protein excision from the gel, their digestion with proteolytic enzymes and their identification
by mass spectrometry (MALDI-TOF-MS, LC-ESI-MS/MS) coupled to the use of existing
databases. Alternatively, peptides resulting from the digestion of protein mixtures with specific
proteases are separated by two-dimensional liquid chromatography.
Relative and absolute quantitative analyses of proteins differentially expressed are performed
respectively by label-free mass spectrometry (e.g. Spectral counts), and Stable Isotope Labeling
AminoAcids in Culture (SILAC), or Selected Reaction Monitoring-Mass spectrometry (SRMMS).
Toxicoproteomics
Studies are ongoing on the characterization of changes in the proteome profile induced by
environmental toxic compounds, with the aim of obtaining protein biomarkers with the ability
to differentiate two or more biological states. Proteome changes in tissues and target organs of
animals, and cells treated with endocrine disruptors, estrogens, or environmental carcinogens,
are related to functional changes during toxicological processes.
Clinical Proteomics
Qualitative and quantitative proteome changes resulting from the exposure to environmental
toxic compounds or in pathological conditions are monitored in human biological plasma and
urine. Ongoing studies aim at the characterization of protein biomarkers for early diagnosis of
diseases and for the identification of therapeutic targets.
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Interactome
Identification and characterization of protein networks by combining SILAC (stable isotope
labeling by/with amino acids in cell culture) strategy coupled to mass-spectrometry as powerful
method to study in vitro protein-protein interaction.
Metabolomics
Metabolomics research focuses on the analysis of metabolites in biological fluids to link human
metabolic profile variations to endogenous or exogenous pathophysiological stimuli and to
genetic modifications. The study of small molecules (amino acids, carbohydrates, fatty acids,
hormones, etc), which contribute to define the biochemical phenotype of a biological system, is
addressed by two different basic mass spectrometry based approaches: (i) untargeted
metabolomics as the comprehensive analysis of all measurable metabolites in a sample without
any a priori knowledge of their chemical structure; (ii) targeted metabolomics as the
measurement of a defined group of chemically characterized metabolites. These techniques are
applied to human samples (biofluids) in different pathological conditions (e.g. cardiovascular
dysfunctions, cancer, rare diseases), and to in vivo or in vitro models.
The integration of proteomic and metabolomic studies will provide information that can help to
better understand disease development and to identify preventive interventions.
Pathways analysis
An integrated data-mining platform such as MetaCore (GeneGo Inc., USA) is used in order to
map the proteomics and/or metabolomics data into biological networks and for their functional
interpretation.
Molecular Epidemiology
The laboratory works mainly on the measurement of biological markers used to assess human
cancer risk or human exposure to environmental toxic compounds. Our most recent studies
include comprehensive mass spectrometry based analysis of plasma protein expression changes
in cancer patients, followed by semi-quantitative analysis of putative protein biomarkers of
cancer risk. Carcinogen plasma levels, DNA- and blood protein-adduct formation by several
environmental carcinogens are also studied, The laboratory participates in an international
cooperation study aimed at the collection of reference values on allele and genotype frequency
of the most common metabolic enzyme polymorphisms in control populations.
Laboratory of Analytical Biochemistry
Identification and characterization of proteins by mass spectrometry
Our laboratory is developing different analytical and instrumental techniques –based on mass
spectrometry– for the identification and characterization of proteins and peptides in biological
samples. This activity is mainly aimed at 1) global proteomic characterization and comparison
of secretomes from human cancer cell lines; 2) profiling proteins in biological fluids for
discovery and identification of biomarkers of physiopathological and toxicological relevance, 3)
identifying and characterizing endogenous degradation products of proteins, 4) identifying
proteins produced by cells in vitro in response to given stimuli, 5) identifying and characterizing
biologically relevant proteins isolated from biological samples by immunoaffinity-based
techniques.
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Proteomics in oncology
This activity is mainly aimed at discovering –among the proteins we find abnormally secreted
by human cancer cell lines or oncogene-transfected cell lines– new molecules of oncological
interest, and in particular novel candidate therapeutic targets or diagnostic/prognostic
biomarkers. The complex alterations observed in the cancer secretomes are rationalized and
interpreted by using “systems biology” tools that are able to highlight the functional networks
most significantly perturbed. Ongoing projects focus on pancreatic cancer, and in particular on
the perturbations induced by oncogenic K-Ras in the secretome of pancreatic ductal epithelial
cells.
Glycoproteomics
Glycoproteomic characterization (amino acid sequence, glycosylation site(s), and type of bound
saccharides) of plant proteins of pharmaceutical/nutraceutical interest by gel electrophoresis,
enzymatic degradation and mass spectrometry.
Inflammation and neurodegeneration induced by environmental agents
We are studying the neurotoxic effects of endotoxin (LPS) and other environmental
contaminants (PBDE e methylmercury) on neuronal cell primary cultures and in animal models.
The mechanisms leading to the activation of the inflammatory reaction are studied by
biochemical and immunochemical methods in vitro, and by histological and functional analysis
in vivo. Novel anti-inflammatory drugs of natural origin are tested in this model, with the aim of
evaluating their neuroprotective effects.
Laboratory of Environmental Chemistry and Toxicology
Development and use of analytical methods to evaluate contamination in
water bodies, soil, biota, human samples in exposed population
Analytical methods are developed to study environmental pollutants in water ecosystems,
landfills, contaminated sites. Qualitative and quantitative analyses of organic pollutants are done
by mass spectrometry (GC-MS, LC-MS, LC-MS/MS). Typical analyses include PCDD/F, PCB,
PAH, polybrominated diphenylethers, pesticides, endocrine disruptor chemicals, and industrial
pollutants.
Studies on environmental, toxicological and ecotoxicological properties
of chemicals
Research is carried out on pollutant properties, exploring a broad range of toxicological and
environmental properties in order to get safer chemicals. The use of computational models
allows processing millions of chemicals. This involves searching literature data, comparing and
evaluating different sources, and mainly developing predictive models to cope with the lack of
experimental data. Thus, we develop models starting merely from the chemical structure. The
research addresses the different kinds of chemical descriptors and chemical fragments, obtained
with different software. Then, we develop models using algorithms such as neural network,
fuzzy logic, genetic algorithms, classifiers, multivariate analysis, etc. Different methods are
compared and integrated within a structured ensemble. Standardized methods for pesticides
were developed and validated according to OECD guidelines. Innovative tools to evaluate the
applicability domain of the models have been developed, to get predictions useful for regulatory
purposes, such as REACH, biocide, pesticides, and other regulations.
Risk assessment of pollutants
Studies are aimed at assessing the risk of pollutants for human population and environment. For
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this we model transport and diffusion of pollutants, to obtain a predicted concentration on given
space and time scales. Such an activity is integrated with those above described on chemical
analyses and toxicity prediction, to achieve a continuous transfer of data and research.
Research on pollutants emitted in the atmosphere (Unit of Industrial and
Environmental Hygiene)
Studies address different aspects of atmospheric pollution. Research deals with: sampling areas
around the pollution source, chemical analyses, transport modeling depending on
meteorological conditions and orography, risk assessment for population and environment.
Qualitative and quantitative analyses are done by gas chromatography-mass spectrometry using
high resolution for PCDDs/PCDFs, and negative ion-chemical ionization for PCBs.
Laboratory of Mass Spectrometry
Mass Spectrometry Imaging
Mass spectrometry imaging is one of the latest, rapidly growing innovative technique in mass
spectrometry. It is used to visualize molecular distribution in a two dimensional space of a
sample. A mass spectrometry imaging protocol has been developed in collaboration with the
Analytical Instrumentation Unit, based on nano-particles assisted laser desorption-ionization,
that allows distribution studies of anticancer drug, in tumor tissues of mice, revealing
differences of drug penetration, related to the dosage-schedule.
Method development in environmental sciences
Methods, analytical methodologies, instrumentation and software for data acquisition and
reduction, are developed for environmental studies. High-sensitivity instrumentation, mainly
based on mass spectrometry, is developed for trace and ultra-trace analysis. Also, transportable
instrumentation is developed for field studies or continuous monitoring.
Characterization of environmental odor annoyance and its toxicity
Characterization of odors poses several analytical problems because they result from a complex
mixture of compounds (odorants) stimulating receptors in the nasal cavity. Most odorants are
volatile organic compounds (VOC) generated by bacterial degradation of organic matter. They
are often present at trace levels, while numerous sources can contribute to the total odor. Using
sampling techniques specifically developed for olfactometry, solid phase microextraction and
GC/MS analysis, we can detect traces (low ppb to high ppt) of a wide polarity/volatility range of
airborne VOC odorant compounds. With a chemometric approach, we can characterize the
sources of emissions, assess odor control methods, and identify emissions that contribute to
odors in ambient air.
Laboratory of Food Toxicology
Nutrition studies: Chemical contaminants in food. Nutrition and Health
We are studying human exposure to dietary PCBs and dioxins in Italy. In particular,
contaminants were measured in samples of human milk collected from mothers living in highly
contaminated areas. Further studies were aimed at measuring PCBs and dioxins in samples of
fish caught in Italy and in food items from an Italian area at high risk of contamination.
Other studies will investigate the relationship between dietary sodium in intake and health. In
particular this activity will set up and apply practical methodologies to reduce sodium content of
the daily diet in groups of volunteers.
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Therapeutic and illicit drugs in the environment
Pharmaceuticals are a class of emerging environmental pollutants. We have organized a
campaign to detect the presence of pharmaceuticals and their metabolites in Italian rivers and
sewage treatment plants and in samples of drinking water, with the aim of characterizing the
contamination and assessing related risks.
Further ongoing studies are aimed at investigating a possible relationship between antibiotic
occurrence and resistance in environmental bacteria.
The possible presence of illicit drugs in water samples from sewage treatment plants and rivers
was investigated, starting with cocaine and its metabolites. Their levels, used to estimate drug
abuse in the local population, revealed that cocaine consumption greatly exceeds official
estimates. This approach has been subsequently extended to include other common drugs of
abuse such as cannabis, opiates (heroin, morphine), and amphetamines (amphetamine,
methamphetamine, ecstasy). Our evidence-based method allows monitoring of patterns and
trends of drug abuse in local communities, and is able to detect qualitative and quantitative
consumption changes in real time. This tool can therefore complement survey methods in more
realistically describing the drug abuse phenomenon. Ongoing studies are focussed to assess
consumptions at national scale, in collaboration with the National Agency for Drug Policy, at
regional scale in collaboration with Regione Lombardia, and locally, in collaboration with
Metropolitana Milanese.
Further ongoing studies, carried out in collaboration with several research groups in Europe and
the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), are aimed to study
illicit drug consumption in Europe. We will simultaneously measure consumptions in 19 cities
in 14 different nations and will compare our results with consumptions estimated by traditional
epidemiological methods.
Unit of Environmental Pollutants Risk Assessment
Toxicological risk assessment
Starting from real cases of contamination, the unit aims to develop methods for the exposure
assessment also employing probabilistic approaches, and more refined statistical models. The
activities focus on risk assessment related to specific environmental conditions, or human
activities, which pose a risk for human health. These studies include risk assessments related to
contamination of water or soil, emissions of toxics pollutants from waste management
processes, including transfer of these compounds into the food chain. During 2012, studies
focused on health effects due to waste disposal into landfills, soil treatment with sludge and the
potential transfer of persistent organic pollutants across the food chain, and health effects due to
atmospheric pollution.
Research activities also include measurement of contaminants in environmental samples, and
assessment of human exposure. Specific research projects focus on analysis of polychlorinated
and polybrominated dioxins and furans (PCDD, PBDD, PCDF and PBDF), polychlorinated
biphenyls (PCBs), perfluorooctanoic acid (PFOA), and perfluorooctane sulphonate (PFOS), in
aquatic organisms at different levels of the food chain, and farmed fish coming from different
areas of the Mediterranean sea. The purpose is to estimate the exposure to these pollutants
trough fish consumption in the general Italian population.
Another study on-going during 2012 focuses on analysis and exposure assessment of
acetaldehyde as contaminant in beverage samples, in order to assess the risk of health effects for
consumers.
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Unit of Analytical Instrumentation
Development and application of analytical methods for compounds of
biological and environmental interest.
Biological fluids and environmental samples are analysed mainly using solid phase extraction
(SPE) and liquid chromatography - mass spectrometry (LC-ESI-MS/MS). Proteins and peptides
are also analysed by laser desorption ionization techniques. Tissue samples are directly analyzed
by using MALDI or PALDI Imaging (Matrix or nanoParticle Laser Desorption Ionization).
Available instruments include liquid chromatographs and mass spectrometers equipped with
different analyzers: time of flight (TOF), triple quadrupoles, ion traps and high resolution LTQOrbitrap, with conventional and nanoElectroSpray sources.
Substances of interest include proteins, peptides, steroids, hormones, pharmaceuticals, drugs of
abuse, and other environmental contaminants (pesticides, perfluorinated compounds).
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DEPARTMENT OF NEUROSCIENCE
STAFF
Head
Gianluigi FORLONI, Biol.Sci.D.
Laboratory of Biology of Neurodegenerative Disorders
Head
Gianluigi FORLONI, Biol.Sci.D.
Genetic of Neurodegenerative disorders Unit
Head
Diego ALBANI, Biol Sci. D.
Laboratory of Cell Death and Neuroprotection
Head
Tiziana BORSELLO, Biol.Sci.D.
Laboratory of Epidemiology and Social Psychiatry
Head
Barbara D’AVANZO, Philos.D.
Laboratory of Experimental Neurology
Head
Annamaria VEZZANI, Biol.Sci.D.
Physopathology of glia-neuron communication Unit
Teresa RAVIZZA, Biol. Sci.D
Head
Laboratory of Experimental Psychopharmacology
Head
Luigi CERVO, Ph.D.
Laboratory of Geriatric Neuropsychiatry
Head
Ugo LUCCA, MSc
Geriatric Epidemiology Unit
Head
Mauro TETTAMANTI, Biol.Sci.D.
Geriatric Pharmacology Unit
Head
Emma RIVA, M.D.
Laboratory of Inflammation and Nervous System Diseases
Head
Maria Grazia DE SIMONI, Biol.Sci.D
Cell therapy and Acute Brain Injury Unit
Head
Elisa Roncati Zanier
Laboratory of Molecular Neurobiology
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Head
Caterina BENDOTTI, Pharm.D.
Laboratory of Neurobiology of Prions
Head
Roberto CHIESA, Biol. Sci. D
Laboratory of Neurochemistry and Behavior
Head
Roberto William INVERNIZZI, Biol. Sci D
Pharmacology of Cognitive Behavior Unit
Head
Mirjana CARLI, Ph.D.
Laboratory of Neurological Disorders
Head
Ettore BEGHI, M.D.
Laboratory of Quality Assessment of Geriatric Services Unit
Head
Alessandro NOBILI, M.D.
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CURRICULA VITAE
Gianluigi Forloni, obtained the Degree of Biological Science at the University of Milan in 1985. After
two years of post doc at the Department of Neuroscience and Psychiatry at Johns Hopkins University in
Baltimore, USA, he came back to the Mario Negri Institute and between 1992 and 1996 he was the head
of the Neurobiology of Alzheimer's disease Unit; since 1996 he is the Head of the Biology of
Neurodegenerative Diseases Lab and since 2002 the Head of the Neuroscience Department. His scientific
interest is focused on the biological and genetic bases of aging-related disorders in particular Alzheimer’s
disease, Prion-related encephalopathies and Parkinson’s disease. He has been member of several
European committees for the examination of projects in the neuroscience field. He is now member of the
coordination group of the European IMI Consortium PharmaCog. He is President of the Italian
Association on Brain Aging Research (AIRIC) and member of the European Academy of Sciences. He is
the author of more than 230 peer-reviewed scientific articles and about 30 reviews or book chapters.
Selected publications

Forloni G., Angeretti N., Chiesa R., Monzani E., Salmona M., Bugiani O.,Tagliavini F. Neurotoxicity of a prion protein
fragment. Nature 362: 543-546 (1993)

Forloni, G., Tagliavini, F.,Bugiani, O. and Salmona, M. Amyloid in Alzheimer’s disease and prion-related
encephalopathies: Studies with synthetic peptides. Progr. Neurobiol. 49: 287- 315 (1996)

Forloni G. Iussich, S. Awan T. Colombo L. Angeretti, N. Girola, L. Bertani, I. Poli, G. Caramelli, M. Bruzzone,
MG.Farina, L. Limido, L. Rossi, G. Giaccone G. Ironside, JW. Bugiani, O.Salmona M. and Tagliavini, F. Tetracyclines
affect prion infectivity Proc. Natl. Acad. Sci . New York 99: 10849-10854 (2002)

Fioriti, L. Angeretti, N.. Colombo, L., De Luigi A., Manzoni, C., Colombo A., Morbin, M., Tagliavini, F., Salmona, M.
Chiesa, R. Forloni, G. Neurotoxic and gliotrophic activity of a synthetic peptide homologous to Gerstmann-SträusslerScheinker disease amyloid protein. J. Neurosci. 27: 576-83 (2007)

Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, Restelli E, Balducci C, Fiordaliso F, Salio M,
Bianchi S, Fioriti L, Morbin M, Pincherle A, Marcon G, Villani F, Carli M, Tagliavini F, Forloni G, Chiesa R. Mutant
prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model.
Neuron. 60: 598-609 (2008)

Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro
A, Forloni G. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused
by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem. 110:1445-56 (2009).

Balducci, C., Beeg, M., Stravalaci, M., Bastone, A.,, Sclip, A., Biasini, E., Tapelll., Colombo, L. Canzoni, C., Borsello,
T., Chiesa, R., Gobbi, M., Salmona M. Forloni, G., A oligomers impair memory independently of cellular prion potei
Proc. Natl. Acad. Sci USA, 107: 2295-2300 (2010)

Senatore, A., Colleoni, S., Verderio, C., Restelli, E., Morini, R., Codliffe, SB, Bertani, I., Mantovani, S., Canovi, M.
Micotti, E., Forloni, G., Dolphin AC., Matteoli, M., Gobbi, M., Chiesa R. Mutant Prion Protein Suppresses
Glutamatergic Neurotransmission in Cerebellar Granule Neurons by Impairing Membrane Delivery of Voltage-gated
Calcium Channel 2d -1 Subunit. Neuron 74: 300-313 (2012)
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Puoti, G., Bizzi, A., Forloni G., Safar JG.,Tagliavini, F., Gambetti, P. Sporadic human prion diseases: molecular
insights and diagnosis. Lancet Neurology 11: 618-28 (2012)
Ettore Beghi graduated in Medicine in 1972 and received his specialty in neurology in 1976 at the
University of Milan. He trained in epidemiology with a fellowship at the Department of statistics and
Epidemiology of the Mayo Clinic in Rochester, MN (USA). He is Head of the Laboratory of
Neurological Disorders at the Mario Negri Institute, Director of the Neurophysiology/Epilepsy Unit and
Professor of Neuroepidemiology at the University of Milano-Bicocca, Monza. He is member of the
editorial board of the journals Epilepsia, Neuroepidemiology, Inpharma, Drugs in R & D, Clinical Drug
Investigation, Neurological Sciences and is a referee of several national and international medical
journals. The main areas of interest and research include studies on the descriptive, analytic, and
experimental epidemiology in the field of epilepsy, peripheral neuropathies, headache, and amyotrophic
lateral sclerosis.
Selected publications

Nobile-Orazio E, Cocito D, Jann S, Uncini A, Beghi E, Messina P, Antonini G, Fazio R, Gallia F, Schenone A, Francia
A, Pareyson D, Santoro L, Tamburin S, Macchia R, Cavaletti G, Giannini F, Sabatelli M; for the IMC Trial Group.
Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating
polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012;11:493-502.
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Beghi E, D'Alessandro R, Beretta S, Consoli D, Crespi V, Delaj L, Gandolfo C, Greco G, La Neve A, Manfredi M,
Mattana F, Musolino R, Provinciali L, Santangelo M, Specchio LM, Zaccara G; On behalf of the Epistroke Group.
Incidence and predictors of acute symptomatic seizures after stroke. Neurology 2011; 77:1785-1793

E. Beghi, E. Pupillo, P. Messina, G. Giussani, A. Chio, S. Zoccolella, C. Moglia, M. Corbo, G. Logroscino, for the
EURALS Group. Coffee and Amyotrophic Lateral Sclerosis: A Possible Preventive Role. Am J. Epidemiol 2011; 174 :
1002-1008.

Leone MA, Vallalta R, Solari A, Beghi E, for the FIRST Group. Treatment of first tonic-clonic seizure does not affect
mortality: long-term follow-up of a randomised clinical trial. J Neurol Neurosurg Psychiatry 2011; 82(8):924-927.
A. Del Felice, E. Beghi, G. Boero, A. La Neve, G. Bogliun, A. De Palo, L.M. Specchio. Early versus late remission in a
cohort of patients with newly diagnosed epilepsy. Epilepsia 2010; 51: 37-42.
G. Logroscino, B.J. Traynor, O. Hardiman, A. Chiò, D. Mitchell, R.J. Swingler, A. Millul, E. Benn, E. Beghi. Incidence
of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 2010; 81: 385-390.
Leone MA, Solari A, Beghi E, for the FIRST Group. Treatment of the first tonic-clonic seizure does not affect long-term
remission of epilepsy. Neurology 2006; 67: 2227-2229
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Caterina Bendotti, got her degree in Pharmacy at the University of Milano in 1984; In 1986 -1988 she was
post doc at the Genetic developmental Lab, Dept. of Physiology of the Johns Hopkins University, Baltimore,
USA. In 1988 -1992 she was research fellow in the laboratory of Neuropharmacology and in the 1992, she
became head of the Molecular Neurobiology Unit in Institute, since 1998 she is head of laboratory. The
major research interest is the study of pathogenetic mechanisms of familial Amyotrophic Lateral Sclerosis..
Since 2002 she is a member of the editorial board of Journal of Neurochemistry. In 2002-2003 has been
Member of Scientific Committees of the International Symposia on ALS held in Milano, 17-19
Novembre,2003. In 2003-2007 has been member of the Italian Ministry of Health Committees for the
diagnosis, cure, care and assistance of patients with ALS. Since 2005 is member of the Board of Directors of
the Italian Society of Neuroscience. Since 2006 is member of the Research Advisory Panel of the MND
Association, UK. Scientific reviewer of 11 international scientific journals. In 2007 she has co-organised the
first international meeting on” Mutant SOD1 and familial ALS:from the molecule to man” held in
Milano(13-16 September). She is author and co-author of 135 articles with peer-review. Rapporteur of
many communications in national and international meetings.
Selected publications

Bendotti C, Marino M, Cheroni C, Fontana E, Crippa V, Poletti A, De Biasi S.. Dysfunction of constitutive and inducible
ubiquitin-proteasome system in amyotrophic lateral sclerosis: Implication for protein aggregation and immune response.
Prog Neurobiol. 2012 97:101-26

Nardo G, Pozzi S, Pignataro M, Lauranzano E, Spano G, Garbelli S, Mantovani S, Marinou K, Papetti L, Monteforte M,
Torri V, Paris L, Bazzoni G, Lunetta C, Corbo M, Mora G, Bendotti C, Bonetto V. Amyotrophic lateral sclerosis
multiprotein biomarkers in peripheral blood mononuclear cells. PLoS One. 2011;6(10):e25545.

Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S, Bendotti
C, De Biasi S, Poletti A. The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins
involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet. 19(17):3440-56, 2010

Peviani M, Caron I, Pizzasegola C, Gensano F, Tortarolo M, Bendotti C. Unraveling the complexity of amyotrophic
lateral sclerosis: Recent advances from the transgenic mutant SOD1 mice. CNS Neurol Disord Drug Targets. 9(4):491503, 2010

Ludolph AC, Bendotti C, Blaugrund E, Chio A, Greensmith L, Loeffler JP, Mead R, Niessen HG, Petri S, Pradat PF,
Robberecht W, Ruegg M, Schwalenstöcker B, Stiller D, van den Berg L, Vieira F, von Horsten S. Guidelines for
preclinical animal research in ALS/MND: A consensus meeting. Amyotroph Lateral Scler.11(1-2):38-45, 2010

Basso M, Samengo G, Nardo G, Massignan T, D'Alessandro G, Tartari S, Cantoni L, Marino M, Cheroni C, De Biasi S,
Giordana MT, Strong MJ, Estevez AG, Salmona M, Bendotti C, Bonetto V. Characterization of detergent-insoluble
proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis.PLoS One. 4(12):e8130.
2009

Bendotti C, Carrì MT. Amyotrophic lateral sclerosis: mechanisms and countermeasures. Antioxid Redox Signal.
11:1519-22, 2009

Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, Carrì MT, Bendotti C.Treatment with lithium carbonate does not
improve disease progression in two different strains of SOD1 mutant mice. Amyotroph Lateral Scler. 10(4):221-8, 2009

Nardo G, Pozzi S, Mantovani S, Garbelli S, Marinou K, Basso M, Mora G, Bendotti C, Bonetto V.Nitroproteomics of
peripheral blood mononuclear cells from patients and a rat model of ALS. Antioxid Redox Signal. 11:1559-67, 2009

Cheroni C, Marino M, Tortarolo M, Veglianese P, De Biasi S, Fontana E, Zuccarello LV, Maynard CJ, Dantuma NP,
Bendotti C.Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial
amyotrophic lateral sclerosis. Hum Mol Genet. 18(1):82-96, 2009

Carri MT, Grignaschi G, Bendotti C. Targets in ALS: designing multidrug therapies. Trends Pharmacol Sci. 27(5):26773, 2006

Bendotti C, Carri MT. Lessons from models of SOD1-linked familial ALS. Trends Mol Med. 10(8):393-400, 2004.
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Migheli A., Atzori C., Piva R., Tortarolo M., Girelli M., Schiffer D. and Bendotti C. Lack of apoptosis in mice with
ALS. Nature Medicine: 5, 966-967, 1999.
Tiziana Borsello got her Degree in Biological Science at the University of Torino in 1990 and she then
obtained a PhD in Neuroscience at the University of Turin Medical School. She won a 1 year fellowship
from the European Science Foundation to work at the Netherlands Research Institute of Amsterdam.
From 1997 to 1999 she was a Researcher at the Institute of Neurobiology, CNR, Rome Italy. In the period
1999-2003 she was Premier Assistant at the Département de Biologie Cellulaire et de Morphologie,
Université de Lausanne, Switzerland, and then became Maitre Assistant and group leader in the same
institute in 2004. In 2004 joined the Biol. Neurodeg. Disorders Lab at the "Mario Negri” Institute. In
2005 won the Prize of the Pfizer Foundation, Neuroscience and Diseases Nervous System. Since 2006 she
is the Head of the Unit: Neuronal Death and Neuroprotection. Her main scientific interests focus on
understanding the role of signalling pathways in neuronal death after different stress-stimuli and
neuroprotection. In particular, the present research is focused on the study of themechanisms leading to
excitotoxic stress, ischemia, Traumatic Brain Injury and cell death pathways in neurodegenerative
diseases such as Alzheimer, with the challenge to design more specific methods of neuroprotection.
Selected publications

Esposito S, Pristerà A, Maresca G, Cavallaro S, Felsani A, Florenzano F, Manni L, Ciotti MT, Pollegioni L, Borsello T,
Canu N. Contribution of serine racemase/d-serine pathway to neuronal apoptosis. Aging Cell. 2012; 11: 588-98.

Repici M, Chen X, Morel MP, Doulazmi M, Sclip A, Cannaya V, Veglianese P, Kraftsik R, Mariani J, Borsello T,
Dusart I. Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal
cord injury. Neurobiol Dis. 2012;46:710-21.

Feligioni M, Brambilla E, Camassa A, Sclip A, Arnaboldi A, Morelli F, Antoniou X, Borsello T. Crosstalk between JNK
and SUMO signalling pathways:deSUMOylation is protective agaist HO-induced cell injury. PLoS One. 2011;6
(12):e28185.

Sclip A, Antoniou X, Colombo A, Camici GG, Pozzi L, Cardinetti D, Feligioni M, Veglianese P, Bahlmann FH, Cervo
L, Balducci C, Costa C, Tozzi A, Calabresi P, Forloni G, Borsello T. c-jun N-terminal kinase regulates soluble Abeta
oligomers and cognitive impairment in AD mouse model . J Biol Chem. 2011 Dec 23;286(51):43871-80. Epub 2011 Oct
27.

Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, Canu N, Benussi L, Ghidoni R, Forloni G, Borsello
T.JNK plays a key role in Tau hyperphosporilation in Alzheimer diseases models. J Alzheimers Dis. 2011;26:315-29.

Antoniou X, Falconi M, Di Marino D, Borsello T. JNK3 as a therapeutic target for Neurodegenerative disease. J
Alzheimers Dis. 2010 Feb 24.

Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa
R, Gobbi M, Salmona M, Forloni G. Synthetic Amyloid-Beta Oligomers Impair Long-Term Memory Independently Of
Cellular Prion Protein. Proc Natl Acad Sci U S A. 2010; 107:2295-300

Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, Borsello T. JNK Regulates App Cleavage And
Degradation In A Model Of Alzheimer's Disease Neurobiol Dis, 2009; 33:518-25

Borsello T Ed “Neuroprotection: Methods In Molecular Biology” Published By Humana Press, Usa HYPERLINK
"http://www.humanapress.com/"Humana Press, USA, Methods in Molecular Biology, June 2007

Colombo A, Repici M, Pesaresi M, Santambrogio S, Forloni G, Borsello T. The Tat-Jnk Inhibitor Peptide Interferes With
Beta Amyloid Protein Stability Cell Death Differ. 2007, 14:1845-8.

Borsello T and Forloni G. JNK signalling: a possible target to prevent neurodegeneration. Current Pharmaceutical
Design 2007, 13, 1875-1886

Centeno C., Repici M., Chatton J. Y., Riederer B. M., Bonny C., Nicod P., Price M., Clarke P. G., Papa S., Franzoso G.
and Borsello T. Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. Cell Death Differ ,
2007, 14: 240-253.
Luigi Cervo, Ph.D. (Open University, Milton Keynes, U. K.), since 2006 is the head of the Experimental
Psychopharmacology Laboratory. From 1978 to 2001 he was a research fellow and then chief of the
Behavioural Pharmacology Unit in the Laboratory of Neuropharmacology and in 1981 he was awarded
the degree in Biochemical Research from the “M. Negri” Institute. Between 1981 and 1983 he spent two
years as a research fellow in the Department of Psychiatry at the Chicago University, Illinois, U.S.A
(Prof. Charles Robert Schuster). His main research interests concern drug dependence and drug craving,
depression, anxiety. Author and co-author of several peer-review articles, author of communications in
international meetings, he is reviewer of several international peer-reviewed scientific journals. He is
member of the Society for Neuroscience, European Behavioural Pharmacological Society, Italian Society
for Neuroscience and Italian Society of Neuropsychopharmacology.
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Selected publications
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Cervo L, Carnovali, F, Stark JA, Mennini T. Cocaine-seeking behavior in response to drug-associated stimuli in rats:
involvement of D3 and D2 dopamine receptors. Neuropsychopharmacology 2003; 28: 1150-1159.
Grignaschi G, Burbassi S, Zennaro E, Bendotti C, Cervo L. A single high dose of cocaine induces behavioural
sensitization and modifies mRNA encoding GluR1 and GAP-43 in rats. Eur J Neurosci 2004; 20: 2833-2837.
Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, Invernizzi R.
Deficits of serotonin synthesis cause resistance to antidepressants, J Neurosci 2005; 25: 8165-8172.
Cervo L, Cocco A, Petrella C, Heidbreder CA. Selective antagonism at dopamine D3 receptors attenuates cocaine
seeking behaviour in the rat. Int J Neuropsychopharmacol. 2007; 10: 167-181.
Burbassi S, Cervo L. Stimulation of serotonin(2C) receptors influences cocaine-seeking behavior in response to drugassociated stimuli in rats. Psychopharmacology (Berl). 2008; 196: 15-27.
Burattini C, Burbassi S, Aicardi G, Cervo L. Effects of naltrexone on cocaine- and sucrose-seeking behaviour in response
to associated stimuli in rats. Int J Neuropsychopharmacol. 2008; 11,: 103-109.
Fumagalli F, Franchi C, Caffino L, Racagni G, Riva MA, Cervo L. Single session of cocaine intravenous selfadministration shapes goal-oriented behaviours and up-regulates Arc mRNA levels in rat medial prefrontal cortex. Int J
Neuropsychopharmacol. 2009; 12: 423-429.
Watson J, Guzzetti S, Franchi C, Di Clemente A, Burbassi S, Emri Z, Leresche N, Parri HR, Crunelli V, Cervo L.
Gamma-hydroxybutyrate does not maintain self-administration but induces conditioned place preference when injected
in the ventral tegmental area. Int J Neuropsychopharmacol. 2010; 13:143-153.
Di Clemente A, Franchi C, Orrù A, Arnt J, Cervo L. Bifeprunox: a partial agonist at dopamine D2 and serotonin 1A
receptors, influences nicotine-seeking behaviour in response to drug-associated stimuli in rats. Addict Biol. 2012; 17:
274-286.
Cervo L, Torri V. Comment on: "Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related
responses in mice" (Magnani P, Conforti A, Zanolin E, Marzotto M and Bellavite P, Psychopharmacology, 2010).
Psychopharmacology (Berl). 2012; 220: 439-440.
Orrù A, Fujani D, Cassina C, Conti M, Di Clemente A, Cervo L. Operant, oral alcoholic beer self-administration by
C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABA(B) receptors. Psychopharmacology (Berl).
2012; 222: 685-700.
Fumagalli F, Moro F, Caffino L, Orrù A, Cassina C, Giannotti G, Di Clemente A, Racagni G, Riva MA, Cervo L.
Region-specific effects on BDNF expression after contingent or non-contingent cocaine i.v. self-administration in rats.
Int J Neuropsychopharmacol. 2012 Nov 20:1-6. [Epub ahead of print]
Roberto Chiesa graduated in Biological Sciences with major in Genetics at the University of Pavia in
1991, and obtained a Ph.D. in Pharmacology at the Mario Negri Institute for Pharmacological Research of
Milan in 1994. From 1996 through 2000 he was Research Associate at the Department of Cell Biology
and Physiology of Washington University in St. Louis, MO, USA. In 2001 Dr. Chiesa moved back to the
Mario Negri Institute where he is currently head of the Prion Neurobiology lab in the Department of
Neuroscience. He also holds an Associate Telethon Scientist position (Dulbecco Telethon Institute,
Telethon Foundation). The study of molecular mechanisms responsible of the neuronal dysfunction and
phenotype differences in the familial prion diseases. He received the James L. O’Leary Prize (1998) and
Bruno Ceccarelli Prize (2000) for the research in neuroscience area. He is member of editorial board of
PlosOne and Biochemical Journal
Selected publications
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Chiesa R, Piccardo P, Ghetti B, Harris DA Neurological illness in transgenic mice expressing a prion protein with
an insertional mutation. Neuron. 21:1339-51 (1998)
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Fioriti L, Dossena S, Stewart LR, Stewart RS, Harris DA, Forloni G, Chiesa R. Cytosolic prion protein (PrP) is
not toxic in N2a cells and primary neurons expressing pathogenic PrP mutations. J Biol Chem. 280:11320-8
(2005)
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Biasini E, Massignan T, Fioriti L, Rossi V, Dossena S, Salmona M, Forloni G, Bonetto V, Chiesa R Analysis of
the cerebellar proteome in a transgenic mouse model of inherited prion disease reveals preclinical alteration of
calcineurin activity. Proteomics. 6:2823-34 (2006)
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Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, Restelli E, Balducci C, Fiordaliso F, Salio M,
Bianchi S, Fioriti L, Morbin M, Pincherle A, Marcon G, Villani F, Carli M, Tagliavini F, Forloni G, Chiesa R.
Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic
mouse model. Neuron. 2008, 60:598-609 (2008).
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Biasini E., Tapella L., Mantovani S., Stravalaci M., Gobbi M., Harris D.A. and Chiesa R. (2009)
Immunopurification of pathological prion protein aggregates. PloS ONE, 4(11): e7816
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Massignan T. Stewart R.S., Biasini E. Solomon I.H., Bonetto V., Chiesa R. and Harris D.A. (2010) A novel,
drug-based, cellular assay for the activity of neurotoxic mutants of the prion protein. J. Biol. Chem. 285: 77527765
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Balducci C., Beeg M., Stravalaci M., Bastone A., Sclip A., Biasini E., Tapella L., Colombo L., Manzoni C.,
Borsello T., Chiesa R., Gobbi M., Salmona M., Forloni G. (2010) Ab oligomers impair memory independently of
cellular prion protein. Proc. Natl. Acad. Sci. 107: 2295-2300
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Massignan T., Biasini E., Lauranzano E., Veglianese P., Pignataro M., Fioriti L., Harris D.A., Salmona M., Chiesa
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R., and Bonetto V. (2010) Mutant prion protein expression is associated with an alteration of the Rab GDP
dissociation inhibitor alpha (GDI)/Rab11 pathway. Mol Cell Proteomics 9: 611-22
Biasini E., Tapella L., Restelli E., Pozzoli M., Massignan T., and Chiesa R. (2010) The hydrophobic core region
governs mutant prion protein aggregation and intracellular retention. Biochem Journal 430: 477-86
Restelli E., Fioriti L., Mantovani S., Airaghi S., Forloni G., and Chiesa R. (2010) Cell type-spcific neuroprotective
activity of untranslocated prion protein. PloS ONE, 5(10): e13725
Quaglio E., Restelli E., Garofoli A., Dossena S., De Luigi A., Tagliavacca L., Imperiale D., Migheli A., Salmona
M., Sitia R., Forloni G., and Chiesa R. (2011) Expression of mutant or cytosolic PrP in transgenic mice and cells
is not associated with endoplasmic reticulum stress or proteasome dysfunction. PloS ONE, 6(4): e19339
Senatore A., Colleoni S., Verderio C., Restelli E., Morini R., Condliffe S.B., Bertani I., Mantovani S., Canovi M,
Micotti E., Forloni G, Dolphin A.C., Matteoli M., Gobbi M., and Chiesa R. (2012) Mutant PrP suppresses
glutamatergic neurotransmission in cerebellar granule neurons by impairing membrane delivery of VGCC 2-1
subunit. Neuron, 74: 300-313
Barbara D’Avanzo obtained her master in philosophy at the University of Milan in 1989. Her main field
of interest is epidemiologic research in mental health and quality evaluation of the mental health services.
First involved in the analysis of the implementation of the psychiatric reform in Italy, then addressed the
quality and the role of residential facilities and treatment and continuity of care in the community services
network. She works at the effectiveness evaluation and implementation problems of the most common
psychosocial and psychological interventions for severe mental illness. More recently, she is
implementing a monitoring system of suicide attempts and self-harm episodes in various areas of Italy, in
the framework of suicide mortality monitoring and suicide prevention study and implementation, and is
also working on issues related to recovery-oriented services, consumers’ empowerment, methods of
consumers participation to service evaluation, and acknowledgment of the value of consumers’
knowledge and perspective about mental health services and treatments. She is head of the Laboratory of
Epidemiology and Social Psychiatry since 2011, and is member of the Scientific National Board of the
World Association for Psychosocial Rehabilitation.
Selected publications
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D'Avanzo B, Barbato A, Erzegovesi S, Lampertico L, Rapisarda F, Valsecchi L. Formal and informal help-seeking for
mental health problems. A survey of preferences of Italian students. Clin Pract Epidemiol Ment Health 2012; 8: 47-51.
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Parabiaghi A, D'Avanzo B, Tettamanti M, Barbato A, GISAS Study Group. The GiSAS study. Rationale and design of a
pragmatic randomized controlled trial on aripiprazole, olanzapine and haloperidol in the long-term treatment of
schizophrenia. Contemp Clin Trials 2011; 32:675-684.
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Barbato A, Parabiaghi A, Panicali F, Battino N, D'Avanzo B, De Girolamo G, Rucci P, Santone G, PROGRES-Acute
Group. Do patients improve after short psychiatric admission? A cohort study in Italy Nord J Psychiatry 2010; E-pub
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Campi R, Barbato A, D'Avanzo B, Guaiana G, Bonati M Suicide in Italian children and adolescents J Affect Disord
2009; 113:291-295.
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Barbato A, D'Avanzo B. Efficacy of couple therapy as a treatment for depression: a meta-analysis. Psychiatr Q 2008;
79:121-132.
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D'Avanzo B, Aliprandini E, Beghi M, Cornaggia C M, Erlicher A, Frova M, Mascarini A, Miragoli P, Righi A. Strutture
residenziali e semiresidenziali nei servizi di salute mentale. Dove sta la differenza? Epidemiologia e Psichiatria Sociale
2008; 17:57-64.
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Barbato A, D'Avanzo B. Marital therapy for depression. Cochrane Database Systematic Reviews 2006; Issue 2.
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Parabiaghi A, Barbato A, D'Avanzo B, Erlicher A, Lora A. Assessing reliable and clinically significant change on Health
of the Nation Outcome Scales: method for displaying longitudinal data. Aust N Z J Psychiatry 2005; 39:719-725.
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Barbato A, D'Avanzo B. Involuntary placement in Italy. Br J Psychiatry 2005; 186:542-543.
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Guaiana G, Andretta M, Corbari L, Mirandola M, Sorio A, D'Avanzo B, Barbui C. Antidepressant drug consumption and
public health indicators in Italy, 1955-2000. J Clinical Psychiatry 2005; 66:750-755.
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D'Avanzo B, Battino R N, Gallus S, Barbato A. Factors predicting discharge of patients from community residential
facilities: A longitudinal study from Italy. Aust N Z J Psychiatry 2004; 38:619-628.
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D'Avanzo B, Barbato A, Barbui C, Battino N, Civenti G, Frattura L. Discharges of patients from public psychiatric
hospitals in Italy between 1994 and 2000. Int J Social Psychiatry 2003; 49 27-3.
Maria Grazia De Simoni got the Doctoral Degree in Biological Sciences in 1977 at the University of
Milano, Italy. 1981: Research Specialist in Pharmacology (PhD), Mario Negri Institute, Milan, Italy.
1981-1982: European Community fellowship for "Advanced Professional Training", INSERM U 171,
Universitè Claude Bernard, Lyon, France; 1984 Department of Histology, Karolinska Institute,
Stockholm. Working experience:1987-1997: Chief of the Neurochemistry Unit, Mario Negri Institute,
Milano; 1998-present: Chief of the Laboratory of Inflammation and Nervous System Diseases, Mario
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Negri Institute. Scientific interests: pathogenesis of cerebral ischemia/reperfusion and traumatic brain
injury; inflammatory response and apoptotic mechanisms as targets of therapeutic strategies; animal
models and clinical studies. She is member of the board of “Master in Tecnologie Avanzate Applicate
alle Patologie Neurodegenerative", University of Milan and member of the board of “Associazione
Italiana per la Ricerca sull’Invecchiamento Cerebrale” (AIRIC).
Selected pubblications
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De Simoni MG, Storini C, Barba M, Catapano L, Arabia AM, Rossi E, Bergamaschini L. Neuroprotection by
complement (C1)-inhibitor in mouse transient brain ischemia. J Cereb Blood Flow Metab, 23: 232-239, 2003.
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De Simoni M G, Rossi E, Storini C, Pizzimenti S, Echart C, Bergamaschini L. The powerful neuroprotective action of
C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. Am J Pathol., 164: 1857-1863, 2004.
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Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, De Luigi A, Vergani C and De Simoni MG.
Peripheral treatment with enoxaparin, a low-molecular weight heparin, reduces plaques and -amyloid accumulation in a
mouse model of Alzheimer’s disease. J. Neurosci. 24: 4181-4186, 2004
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Troglio F, Echart C, Gobbi A, Pawson T, Pelicci PG, De Simoni MG & Pelicci G. The neuron-specific Rai (Shc C)
adaptor regulates the PI3K-Akt pathway in vivo and protects against cerebral ischemia. Proc Natl Acad Sci U S A
101(43): 15476-15481, 2004.
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Storini C, Bergamaschini L, Gesuete R, Rossi E, Maiocchi D, De Simoni MG. Selective inhibition of plasma kallikrein
protects brain from reperfusion injury. JPET 318: 849-854, 2006
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Capone C, Fabrizi C, Piovesan P, Principato MC, Marzorati C, Ghirardi O, Fumagalli L, Carminati P and De Simoni
MG. 2-Aminotetraline derivative protects from ischemia/reperfusion brain injury with a broad therapeutic window,
Neuropsychopharmacology, 32: 1302-1311, 2007
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Capone C, Frigerio S, Fumagalli S, Gelati M, Principato M C, Storini C, Montinaro M, Kraftsik R, De Curtis M, Parati
E, De Simoni MG. Neurosphere - derived cells exert a neuroprotective action by changing the ischemic
microenvironment. PLoS ONE 2 e373, 2007.
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Pastori C, Librizzi L, Breschi GL, Regondi C, Frassoni C, Panzica F, Frigerio S, Gelati M, Parati E, De Simoni MG, de
Curtis M.Arterially perfused neurosphere-derived cells distribute outside the ischemic core in a model of transient focal
ischemia and reperfusion in vitro.PLoS ONE. 3(7):e2754. 2008
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Orsini F, Villa P, Parrella S, Zangari R, Zanier E, Gesuete R, Stravalaci M, Ottria R, Reina JJ, Paladini A, Micotti
E,Ribeiro-Viana R, Rojo J, Pavlov VI, Stahl GL, Bernardi A, Gobbi M, andDe Simoni MG. Targeting mannose binding
lectin confers long lasting protection with a surprisingly wide therapeutic window in cerebral ischemia. Circulation 2012;
126: 1484-1494.
Scornavacca G, Gesuete R, Orsini F, Pastorelli R, Fanelli R, De Simoni MG, Airoldi L. Proteomic analysis of mouse
brain cortex identifies metabolic downregulation as a general feature of ischemic preconditioning. J Neurochem. 2012;
122: 1219-1229.
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Roberto W. Invernizzi started his career in the laboratory of Neuropharmacology of the “Istituto di
Ricerche Farmacologiche “Mario Negri” in 1976, where, at present, he heads the Laboratory of
Neurochemistry and Behavior. In 1986 he got his degree in Biological Sciences at the Università Statale di
Milano and in 1996 he was nominated head of the Intracerebral Microdialysis Unit. Of particular interest
to Invernizzi’s research team is the study of the neurochemical mechanisms and neuronal circuitries
involved in the pathology of the main psychiatric diseases, such as depression and schizophrenia and in
the mechanism of action of psychotropic drugs. Since 1987 he applied the intracerebral microdialysis
technique to study the in vivo release of monoamines. Using this technique, Invernizzi’s team first
contributed to clarifying the role of serotonergic and adrenergic autoreceptors in the effect of
antidepressant drugs suggesting new hypotheses on their mechanism of action. Currently, Invernizzi’s
laboratory is involved in two main collaborative projects aimed at clarifying the neurochemical
mechanisms involved in the “resistance” to antidepressant drugs and the role of glutamatergic and
serotonergic mechanisms in attentional processes. Reviewer for various international journals in the field
of pharmacology and neurochemistry. Author and co-author of more than 70 peer-reviewed articles.
Member of the Italian Society of Neuroscience and the Italian Society of Pharmacology.
Selected publications
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Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, Andre´ CB, Haenggi M, Miss M-T, Galley G, Norcross RD,
Invernizzi RW, Wettstein JG, Moreau J-L and Hoener MC. Brain-Specific Overexpression of Trace Amine-Associated
Receptor 1 Alters Monoaminergic Neurotransmission and Decreases Sensitivity to Amphetamine.
Neuropsychopharmacology 2012, 37: 2580-92.
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Baviera M, Invernizzi RW, Carli M. Haloperidol and clozapine have dissociable effects in a model of attentional
performance deficits Carli M, Calcagno E, Mainolfi P, Mainini E, Invernizzi RW. Effects of aripiprazole, olanzapine,
and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial
prefrontal cortex. Psychopharmacology (Berl). 2011;214:639-52.
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Carli M, Calcagno E, Mainini E, Arnt J, Invernizzi RW. Sertindole restores attentional performance and suppresses
glutamate release induced by the NMDA receptor antagonist CPP. Psychopharmacology (Berl). 2011;214(3):625-37
Pozzi L, Sacchetti G, Agnoli L, Mainolfi P, Invernizzi RW, Carli M. Distinct Changes in CREB Phosphorylation in
Frontal Cortex and Striatum During Contingent and Non-Contingent Performance of a Visual Attention Task. Front
Behav Neurosci. 2011;5:65.
Pozzi L, Baviera M, Sacchetti G, Calcagno E, Balducci C, Invernizzi RW, Carli M. Attention deficit induced by
blockade of N-methyl D-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and
cAMP response element binding protein phosphorylation: role of metabotropic glutamate receptors2/3. Neuroscience.
2011;176:336-48
Calcagno E, Invernizzi RW Strain-dependent serotonin neuron feedback control: role of serotonin receptors. J
Neurochem 2010 114: 1701-1710
Calcagno E, Guzzetti S, Canetta A, Fracasso C, Caccia S, Cervo L, Invernizzi RW. Enhancement of cortical extracellular
5-HT by 5-HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-responder
mice. Int J Neuropsychopharmacol 2009 12: 793-803
Calcagno E, Carli M, Baviera M, Invernizzi RW. Endogenous serotonin and serotonin2C receptors are involved in the
ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade. J Neurochem 2009 108
: 521-532
Baviera M, Invernizzi RW, Carli M. Haloperidol and clozapine have dissociable effects in a model of attentional
performance deficits induced by blockade of NMDA receptors in the mPFC. Psychopharmacology 2008; 196: 269-280.
Calcagno E, Canetta A, Guzzetti S, Cervo L, Invernizzi RW. Strain differences in basal and post-citalopram extracellular
5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan with tryptophan
hydroxylase-2 activity. J Neurochem 2007; 103 : 1111-1120
Invernizzi RW, Pierucci M, Calcagno E, Di Giovanni G, Di Matteo V, Benigno A, Esposito E. Selective activation of
5HT2C receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: a combined in vivo
electrophysiological and neurochemical study. Neuroscience 2007 144 : 1523-1535
Ugo Lucca got his Master of Science, University of Aberdeen - UK, 1999. At the Mario Negri Institute
he was investigator from 1986- 1995, head of the "Clinical Evaluation of Antidementia Drugs Unit"
(1995-1996) and, since 1996, head of the "Laboratory of Geriatric Neuropsychiatry". The main areas of
interests include epidemiology and clinic features of dementia; natural history of dementia;
neuropsychiatric disorders of the elderly; instruments for the screening diagnosis and clinical course
assessment of dementia; clinical evaluation of anti dementia treatments and CNS active drugs (phase I, II,
III, IV and observational studies).
Selected publications
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Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, et al. Long-term acetyl-L-carnitine
treatment in Alzheimer's disease. Neurology 1991; 41:1726-1732
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Lucca U, Comelli M, Tettamanti M, Tiraboschi P, Spagnoli A. Rate of progression and prognostic factors in Alzheimer’s
disease: a prospective study. J Am Geriats Society 1993; 41: 45-49.
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Lucca U, Tettamanti M, Forloni G, Spagnoli A. Nonsteroidal anti-inflammatory drug use in Alzheimer’s disease.
Biological Psychiatry 1994; 36: 854-856.
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Imbimbo BP, Martelli P, Troetel WM, Lucchelli F, Lucca U, Thal LJ, and the Eptastigmine Study Group. Efficacy and
safety of eptastigmine for the treatment of patients with Alzheimer’s disease. Neurology 1999; 52: 700-708.
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Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer’s disease and Vascular Dementia. Am J Clinical Nutr 2004; 80: 114-122.
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Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. New England Journal of
Medicine 2006; 355: 1390.
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Lucca U, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M,
Tempia P, Guala A, Fasolo G, Riva E.Association of mild anemia with cognitive, functional, mood and quality of life
outcomes in the elderly: the "Health and Anemia" study. PLoS ONE. 3(4):e1920 (2008)
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Merlo A, Zemp D, Zanda E, Rocchi S, Meroni F, Tettamanti M, Recchia A, Lucca U, Quadri P. Postural stability and
history of falls in cognitively able older adults: The Canton Ticino study. Gait Posture 2012; 36: 662-66.
Alessandro Nobili got his degree in Medicine (Milan, 1990). Master in Biotechonological Research,
Regione Lombardia, Milan 1988. International School of Pharmacology, 31° Course on: Drug
Epidemiology and Post-marketing Surveillance, Erice, September 1990. Course on: Methods in
Epidemiological Research, Milan, October 1990. Course: Long Term Clinical Trials, Cogne January
1991.
Main areas of interest Methodology of Randomized Clinical Trials; Pharmacoepidemiology and postmarketing surveillance research; Drug utilization studies; Quality assessment of geriatric services;
Qualitative studies on caregiver role in the care of patients with dementia; Methodological evaluation of
the Special Care Unit for Alzheimer Disease patients; Methodology of drug information. Employment
and research experience Chief of the Unit of Quality Assessment of Geriatric Services Chief of the Drug
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Information Services for the Elderly, Laboratory of Geriatric Neuropsychiatry, Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan. Editorial Board of the MICROMEDEX Inc., Englewood,
Colorado 80111-4740 USA. National Expert accredited by Italian Ministry of Health for The Italian
(AIFA) and European Agency for the Evaluation of Medicinal Products (EMEA). Head of the
Laboratory of the Quality Assessment of Geriatric Services at the Mario Negri Institute since 2007.
Selected publications
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Nobili A, Riva E, Tettamanti M, et al. The effect of a structured intervention on cergivers of patients with dementia and
problem behaviour: a randomized controlled pilot study. Alzheimer Dis Assoc Disord 2004; 18: 75-82.
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Nobili A, Piana I, Balossi L, Pasina L, Matucci M, Tarantola M, Trevisan S, Riva E, Lucca U, Tettamanti M. Alzheimer
special care units compared with traditional nursing home for dementia care: are there differences at admission and in
clinical outcomes? Alzheimer Dis Assoc Disord. 2008; 22: 352-61.
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A. Nobili, L. Pasina, M. Tettamanti, U. Lucca, E. Riva, I. Marzona, L. Monesi, R. Cucchiani, A. Bortolotti, I. Fortino, L.
Merlino, G. Walter Locatelli, G. Giuliani. Potentially severe drug interactions in elderly outpatients: results of an
observational study of an administrative prescription database. Journal of Clinical Pharmacology and Therapeutics 2009;
34: 377-386.
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Marengoni A, Bonometti F, Nobili A, Tettamanti M, Salerno F, Corrao S, Iorio A, Marcucci M, Mannucci PM; Italian
Society of Internal Medicine (SIMI) Investigators. In-hospital death and adverse clinical events in elderly patients
according to disease clustering: the REPOSI study. Rejuvenation Res. 2010; 13:469-77.
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Nobili A, Licata G, Salerno F, Pasina L, Tettamanti M, Franchi C, De Vittorio L, Marengoni A, Corrao S, Iorio A,
Marcucci M, Mannucci P M, SIMI Investigators. Polypharmacy, length of hospital stay, and in-hospital mortality among
elderly patients in internal medicine wards. The REPOSI study. Eur J Clin Pharmacol 2011;67:507-519.
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Nobili A, Marengoni A, Tettamanti M, Salerno F, Pasina L, Franchi C, Iorio A, Marcucci M, Corrao S, Licata G,
Mannucci P M. Association between clusters of diseases and polypharmacy in hospitalized elderly patients: Results from
the REPOSI study. Eur J Intern Med 2011;22:597-602.
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Franchi C, Tettamanti M, Marengoni A, Bonometti F, Pasina L, Cortesi L, Fortino I, Bortolotti A, Merlino L, Lucca U,
Riva E, Nobili A. Changes in trend of antipsychotics prescription in patients treated with cholinesterase inhibitors after
warnings from Italian Medicines Agency. Results from the EPIFARM-Elderly Project. Eur Neuropsychopharmacol
2012 ; 22 : 569-577
Mannucci P M, Nobili A. Internal and geriatric medicine: An alliance for the challenges of the elderly. Eur J Intern Med
2012 ; 23 : 479-482
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Annamaria Vezzani got her Degree in Biological Science at the University of Milan in 1978 and she
specialized in Neuropharmacology at the Mario Negri Institute in 1982. She spent her post-doctoral
period in Baltimore at the University of Maryland in 1983-1984 working on the mechanisms of
epileptogenesis in experimental models of epilepsy. She spent additional post-doctoral periods at the
University of Stockholm and at the Karolinska Institute between 1985 and 1999. She was on sabbatical
at the Albert Einstein College of Medicine in 2002 in the laboratory of Developmental Epilepsy. She is
involved in studies on the biochemical and molecular mechanisms involved in the etiopathogenesis of
seizures disorders using experimental models of epilepsy. The present research is focused on the
functional role of neuroactive peptides and inflammatory mediators in the modulation of neuronal
excitability and seizure-related neurodegeneration. Focus of the research is also on the mechanisms of
pharmacoresistance. Since 1997 she is the Head of the Laboratory of Experimental Neurology at the
Mario Negri Institute. She is member of the Editorial Board of various scientific journals and
Associate Editor for basic science of Epilepsia, the official journal of the International League Against
Epilepsy (ILAE). She has been appointed of the Chair of the Commission on Neurobiology of ILAE
which is promoting initiatives for improving translational research in epilepsy. She has been awarded
of the prestigeous Epilepsy Research Recognition Award for translational research in 2009 by the
American Epilepsy Society
Selected publications
Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoni MG. Interleukin-1beta immunoreactivity
and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of
electrographic seizures.(1999) J Neurosci.19:5054-65.
Vezzani A., Moneta D., Conti M., Richichi C., Ravizza T., De Luigi A., De Simoni M.G., Sperk, Andell-Jonsson S.,
Lundkvist J., Iverfeldt K. and Bartfai T. Powerful anticonvulsant action of IL-1 receptor antagonist upon intracerebral
injection and astrocytic overexpression in mice (2000) Proc Natl Acad Sci USA, 97: 11534
Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, Aliprandi M, Bagnati R, Fanelli R, D'Incalci M, Samanin R,
Vezzani A. Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance (2002) J
Neurosci, 22: 5833
Balosso S, Ravizza T, Perego C, Peschon J, Campbell I, De Simoni MG, Vezzani A. TNF-alpha inhibits kainic acidinduced seizures in mice via p75 receptors (2005) Ann Neurol, 57: 804-12
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Ravizza T, Gagliardi B, Noè F, Boer K, Aronica E and Vezzani A. Innate and adaptive immunity during epiletogenesis and
spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy (2008) Neurobiol Dis, 29:
142
Noè F, Pool AH, Nissinen J, Gobbi M, Bland R, Rizzi M, Balducci C, Ferraguti F, Sperk G, During MJ, Pitkänen A,
Vezzani A. Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe epilepsy
(2008) Brain, 131:1506
Balosso S, Maroso M, Sanchez-Alavez M, Ravizza T, Frasca A, Bartfai T, Vezzani A. A novel non-transcriptional pathway
mediates the proconvulsive effects of interleukin-1beta. (2008) Brain, 131:3256
Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer A, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA, Bianchi
ME and Vezzani A. Toll-Like Receptor 4 (TLR4) and High Mobility Group Box 1 (HMGB1)are involved in ictogenesis
and can be targeted to reduce seizures (2010) Nature Medicine, 16:413-9.
Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. (2011) Nat Rev Neurol, 7: 31-40.
Vezzani A Before epilepsy unfolds: finding the epileptogenesis switch. (2012) Nat Med, 18:1626
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Diego Albani graduated in Biological Sciences in 1996 with full marks and he has been working at
“Mario Negri” Institute since 2002, after a 3-year post-doc experience in the laboratory of Prof Renato
Dulbecco, CNR-ITBA in Milan, Italy. His is head of the Unit of Genetics of Neurodegenerative Disorders
since 2011. His present interests deal with the biological basis of neurodegenerative disorders including
Alzheimer’s (AD) and Parkinson’s disease (PD), with a particular focus on genetics, oxidative stress and
recombinant proteins as innovative drugs. Dr Albani is actively involved in ongoing research projects
focused on pharmacogenomics of AD, the genetic basis of aging and the activation of neuronal enzymes
(sirtuins) by natural phytoproducts as novel strategy against AD and PD. He is currently member of the
Editorial Board of three international journals.
Selected publications
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Zucchi I, Bini L, Valaperta R, Ginestra A, Albani D, Susani L, Sanchez JC, Liberatori S, Magi B, Raggiaschi R,
Hochstrasser DF, Pallini V, Vezzoni P, Dulbecco R (2001) “Proteomic dissection of dome formation in a mammary cell
line: role of tropomyosin–5b and maspin Proc Natl Acad Sci USA, 98, 5608-5613
Albani D, Zucchi I, Bini L, Valaperta R, Liberatori S, Montagna C, Susani L, Barbieri O, Pallini V, Vezzoni P, Dulbecco
R(2002) “Dome formation in cell cultures as expression of an early stage of lactogenic differentiation of the mammary
gland “ Proc Natl Acad Sci USA, 99, 8660-5
Albani D, Peverelli E, Rametta R, Batelli S, Veschini L, Negro A, Forloni G (2004): “Protective effect of TAT-delivered
-synuclein: relevance of the C-terminal domain and involvement of HSP70” FASEB J, 18, 1713-1715
Albani D, Roiter I, Artuso V, Batelli S, Prato F, Pesaresi M, Galimberti D, Scarpini E, Bruni A, Franceschi M, Piras MR,
Confaloni A, Forloni G (2007) “Presenilin-1 mutation E318G and familial Alzheimer's disease in the italian population”.
Neurobiol Aging, 28, 1682-8.
Albani D., Polito L., Batelli S., De Mauro S., Fracasso C., Martelli G., Colombo L., Manzoni C., Salmona M., Caccia S.,
Negro A., Forloni G (2009) The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against
toxicity caused by α-synuclein or amyloid-β (1-42) peptide. J Neurochem, 110,1445-56
Albani D, Polito L, Forloni G. Sirtuins as Novel Targets for Alzheimer's Disease and Other Neurodegenerative
Disorders: Experimental and Genetic Evidence (2010) J Alzheimer’s Disease, 19, 11-26
Albani D, Tettamanti M, Batelli S, Polito L, Dusi S, Ateri E, Forloni G, Lucca U (2011) Interleukin-1, Interleukin-1
and Tumor Necrosis Factor-genetic variants and risk of dementia in the very old: evidence from the “Monzino 80-plus”
prospective study. Age, Apr 21. [Epub ahead of print]
Batelli S, Peverelli E, Rodilossi S, Forloni G, Albani D (2011). Macroautophagy and the proteasome are differently
involved in the degradation of alpha-synuclein wild type and mutated A30P in an in vitro inducible model
(PC12/TetOn). Neuroscience, 195, 128-37
Albani D, Tettamanti M, Batelli S, Polito L, Dusi S, Ateri E, Forloni G, Lucca U. Interleukin-1α, interleukin-1β and
tumor necrosis factor-α genetic variants and risk of dementia in the very old: evidence from the "Monzino 80-plus"
prospective study. Age (Dordr). 2012 Apr;34(2):519-26
Mirjana Carli started his scientific career in the laboratory of Neuropharmacology of the “Istituto di
Ricerche Farmacologiche Mario Negri” Milan in 1977, where, at present, she is head of the
Pharmacology of Cognitive Behaviour Unit. She spent a few years in the laboratory of Cognitive
Neuroscience, Dept. of Experimental Psychology, University of Cambridge (UK) directed by Prof.
Trevor W. Robbins. Here she took interest in the role of brain monoamines in attention, and for this
purpose developed several behavioral tests for rats. In 1986 she returned to the laboratory of
Neuropharmacology of the “Istituto di Ricerche Farmacologiche Mario Negri”. Here she devoted her
efforts to the study of the role played by neuronal mechanisms in cognitive processes such as memory,
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attention and executive functions. Her work has improved the knowledge of the role played by some
serotonin receptors in cognitive processes.
Selected publications
Agnoli L and Carli M Dorsal-striatal 5-HT2A and 5-HT2C receptors control impulsivity and perseverative responding in
the 5-choice serial reaction time task. Psychopharmacology 2012, 219: 633-45
Carli M, Calcagno E, Mainolfi P, Mainini E, Invernizzi RW. Effects of aripiprazole, olanzapine, and haloperidol in a
model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex.
Psychopharmacology (Berl). 2011;214: :639-52.
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Carli M, Calcagno E, Mainini E, Arnt J, Invernizzi RW. Sertindole restores attentional performance and suppresses
glutamate release induced by the NMDA receptor antagonist CPP. Psychopharmacology (Berl). 2011;214:625-37
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Pozzi L, Sacchetti G, Agnoli L, Mainolfi P, Invernizzi RW, Carli M. Distinct Changes in CREB Phosphorylation in
Frontal Cortex and Striatum During Contingent and Non-Contingent Performance of a Visual Attention Task. Front
Behav Neurosci. 2011;5:65.
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Pozzi L, Baviera M, Sacchetti G, Calcagno E, Balducci C, Invernizzi RW, Carli M. Attention deficit induced by
blockade of N-methyl D-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and
cAMP response element binding protein phosphorylation: role of metabotropic glutamate receptors2/3. Neuroscience.
2011;176:336-48
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Pozzi L, Greco B, Sacchetti G, Leoni G, Invernizzi RW, Carli M. Blockade of serotonin 2A receptors prevents PCPinduced attentional performance deficit and CREB phosphorylation in the dorsal striatum of DBA/2 mice.
Psychopharmacology (Berl). 2010; 208:387-99.
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Noe F, Vaghi V, Balducci C, Fitzsimons H, Bland R, Zardoni D, Sperk G, Carli M, During MJ, Vezzani A.
Anticonvulsant effects and behavioural outcomes of rAAV serotype 1 vector-mediated neuropeptide Y overexpression
in rat hippocampus. Gene Ther. 2010 17::643-52.
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Calcagno E, Carli M, Baviera M, Invernizzi RW. Endogenous serotonin and serotonin2C receptors are involved in the
ability of M100907 to suppress cortical glutamate release induced by NMDA receptor blockade. J Neurochem. 2009;
108:521-32.
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Noè F, Frasca A, Balducci C, Carli M, Sperk G, Ferraguti F, Pitkonen A, Bland R, Fitzsimons H, During M, Vezzani
A. Neuropeptide Y overexpression using recombinant adeno-associated viral vectors. Neurotherapeutics. 2009; 6:300-6.
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Baviera M, Invernizzi RW, Carli M. Haloperidol and clozapine have dissociable effects in a model of attentional
performance deficits induced by blockade of NMDA receptors in the mPFC. Psychopharmacology (Berl). 2008
196:269-80.
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Sorensen AT, Kanter-Schlifke I, Carli M, Balducci C, Noe F, During MJ, Mezzani A, Kokaia M. NPY gene transfer in
the hippocampus attenuates synaptic plasticity and learning. Hippocampus. 2008;18:564-74.
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Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, Restelli E, Balducci C, Fiordaliso F, Salio M,
Bianchi S, Fioriti L, Morbin M, Pincherle A, Marcon G, Villani F, Carli M, Tagliavini F, Forloni G, Chiesa R. Mutant
prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model.
Neuron. 2008; 60:598-609
Teresa Ravizza got her Doctoral Degree in Biological Sciences in 1996 at the University of Milano.
Then she got a Master in “Research Specialist in Pharmacology” at Mario Negri Institute in 2000. She
spent her post-doc training at the Albert Einstein College of Medicine of New York in 2000-2001, where
she studied the mechanisms underlying epileptogenesis in experimental models of pediatric epilepsy. She
spent additional post-doc periods at the Academic Medical Center of Amsterdam and at University of
Irvine (UCI), California (USA) between 2005 and 2009. Since 2010, she is the head of the Unit of
Pathophysiology of Neuron-Glia Communication. Her scientific interest is to characterize changes in the
expression of molecules produced by astrocytes and microglia in various pathological conditions, such as
epilepsy, trauma, excitotoxicity and inflammation. A special focus is given to the pro- and antiinflammatory molecules, and to the role played by these mediators in mediating functional and
biochemical alteration in the brain (neuronal cell loss, neuronal excitability, alteration in blood-brain
barrier permeability).
Selected pubblications
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Ravizza T, Boer K, Redeker S, Spliet WGM, van Rijen PC, Troost D, Vezzani A, Aronica E. (2006) The IL-1 system in
epilepsy-associated malformations of cortical development. Neurobiol Dis, 24, 128
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Ravizza T, Lucas SM, Balosso S, Bernardino L, Ku G, Noè F, Malva J, Randle JC, Allan S, Vezzani A. (2006)
Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia, 47, 1160
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Ravizza T, Gagliardi B, Noè F, Boer K, Aronica E, Vezzani A. (2008) Innate and adaptive immunità during
epiletogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy.
Neurobiol Dis, 29, 142
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Ravizza T, Noé F, Zardoni D, Vaghi V, Sifringer M, Vezzani A. Interleukin converting enzyme inhibition impairs
kindling development in rats by blocking astrocytic IL-1 production (2008) Neurobiol Dis, 31, 327
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Marcon J, Gagliardi B, Noé F, Morin M, Lerner-Natoli M, Vezzani A, Ravizza T. Age-dependent vascular changes
induced by status epilepticus in rat forebrain: implication for epileptogenesis (2009) Neurobiol Dis, 34, 121
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Balosso S, Ravizza T, Pierucci M, Calcagno E, Invernizzi R, Di Giovanni G, Esposito E, Vezzani A. Molecular and
functional interactions between TNF-alpha receptors and the glutamatergic system in the mouse hippocampus:
implications for seizure susceptibility (2009) Neuroscience, 161, 293
Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA,
Bianchi ME, Vezzani A. Toll-like receptor 4 (TLR4) and High Mobility Group Box 1 (HMGB1) are involved in
ictogenesis and can be targeted to reduce seizures (2010) Nature Medicine, 16, 413
Dubé C, Ravizza T, Hamamura T, Zha Q, Keebaugh A, Fok K, Andres A, Nalcioglu O, Obenaus A, Vezzani, Baram TZ.
Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers (2010) J Neurosci,
30, 7484
Ravizza T, Balosso S, Vezzani A Inflammation and prevention of epileptogenesis. Neurosci Lett. 2011; 497:223-30
Akin D, Ravizza T, Maroso M, Carcak N, Eryigit T, Vanzulli I, Aker RG, Vezzani A, Onat FY.IL-1β is induced in
reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave
discharges, and contributes to their occurrence. Neurobiol Dis. 2011; 44:259-69
Librizzi L, Noè F, Vezzani A, de Curtis M, Ravizza T.Seizure-induced brain-borne inflammation sustains seizure
recurrence and blood-brain barrier damage. Ann Neurol. 2012; 72: 82-90
Emma Riva, Medical Doctor degree in 1984 University of Milan, PhD in 1990 in Cardiovascular
Pathophysiology at the University of London (UK) Training: Research Assistant, Department of
Pharmacology, Medical School, University of Ottawa, Canada; Internship in Internal Medicine, Ospedale
Luigi Sacco, Milan; Cardiac Fellow, St Thomas' Hospital, London, UK. Field of interest: Prevalence and
effects of anemia on cognitive, functional and clinical variables in the elderly; Problem behaviors in
dementia; Burden for care-givers of Alzheimer Disease patients; End of life care. Present and past roles
in Institute Head of the Geriatric Pharmacology Unit, Istituto "Mario Negri", Milan; Scientific Director
of the hospice “Via di Natale Franco Gallini”, Aviano, Italy; Consultant Istituto Geriatrico “Pio Albergo
Trivulzio”, Milan: Project member of PREDICT (Policy Review and Evaluation of Dementia and
Institutional Care Trends): a Transnational Comparison.
Selected publications
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Riva E, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M,
Tempia P, Guala A, Fasolo G, Lucca U. Association of mild anemia with hospitalization and mortality in the Elderly:
The Health and Anaemia Population-based Study. Haematologica 2009;94:22-28
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Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone MV, Detoma P, Giacomin A,
Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta MG, Riva E. Prevalence, incidence and types of mild
anemia in the elderly: the "Health and Anemia" population-based study. Haematologica. 2010;95(11):1849-1956
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Lucca U, Garrì MT, Recchia A, Logroscino G, Tiraboschi P, Franceschi M, Bertinotti C, Biotti A, Gargantini E,
Maragna M, Nobili A, Pasina L, Franchi C, Riva E, Tettamanti M. A population-based study of dementia in the oldest
old: The Monzino 80-plus. Study design, methodological challenges, and population characteristics. BMC Neurology
2011;11:54 DOI:10.1186/1471-2377-11-54
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Avanzini F, Marelli G, Donzelli W, Busi G,Carbone S, Bellato L, Colombo EL, Foschi R, Riva E, Roncaglioni MC, De
Martini. Conversion from intravenous to subcutaneous insulin therapy: effectiveness and safety of a standardized
protocol and predictors of transition outcome. Diabetes Care 2011
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Monesi L, Baviera M, Marzona I, Avanzini F, Monesi G, Nobili A, Tettamanti M, Cortesi L, Riva E, Fortino I, Bortolotti
A, Fontana G, Merlino L, Roncaglioni MC. Prevalence, incidence and mortality of diagnosed diabetes: evidence from an
Italian population-based study: Diabetic Medicine 2012; 29: 385-92.
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Baviera M, Monesi L, Garzona I, Avanzino F, Monesi G, Nobili A, Tettamanti M, Riva E, Cortesi L, Bortolotti A,
Fortino I, Merlino L, Fontana G, Roncaglioni MC. Trends in drug prescriptions to diabetic patients from 2000 to 2008 in
Italy's Lombardy Region: a large population-based study. Diabetes Research and Clinical Practice 2011 DOI:
10.1016/j.diabres.2011.05.004
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Franchi C, Lucca U, Tettamanti M, Riva E, Fortino I, Bortolotti A, Merlino L, Pasina L, Nobili A. Cholinesterasi
inhibitor use in Alzheimer’s disease: the PEIFARM-Elderly Project. Pharmacoepidemiology and Drug Safety, 2011
DOI:10.1002/pds.2124
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Nobil i A, Franchi C, Pasina L, Tettamanti M, Baviera M, Monesi L, Roncaglioni C, Riva E, Lucca U, Bortolotti A,
Fortino, I Merlino L. Drug utilization and polypharmacy in an Italian elderly population: the EPIFARM-Elderly Project.
Pharmacoepidemiology and Drug Safety, 2011 DOI: 10.1002/pds.2108
Mauro Tettamanti got his Biology Degree at the Università degli Studi di Milano in 1986, and the
specialisation in Epidemiology and Medical Statistics in 1993, at the Università degli Studi di Pavia.
Teaching experience Introduction course to statistics, Master in Ergonomy, Politecnico di Milano, years
2001-2004 Areas of interest: Planning, conduction and analysis of clinical trials and epidemiologic
researches in the geriatric field: Phase I, II, III and observational studies on the efficacy of drugs on
neurologic disorders, with special emphasis on dementia; Effects of multi-disciplinary interventions on
geriatric/dementia patients; Epidemiology and risk factors of dementia; Care of patients with terminal
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illness; Association of anemia with prevalence of diseases and cognitive problems Scholarship between
1989 and 1998, Senior Researcher since 1999 and Head of the Unit of Geriatric Epidemiology at the
Mario Negri Institute since 2001.
Selected publications
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Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004; 80: 114-122
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Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch Neurol
2006; 63:154-155
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Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. N Engl J Med 2006; 355:1390
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Tettamanti M, Garri' M T, Nobili A, Riva E, Lucca U. Low folate and the risk of cognitive and functional deficits in the
very old: The Monzino 80-plus study. J Am Coll Nutr 2006; 25: 502-508
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Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, et al. Prevalence, incidence and types of mild
anemia in the elderly: the "Health and Anemia" population-based study. Haematologica 2010; 95:1849-56
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Nobili A, Franchi C, Pasina L, Tettamanti M, Baviera M, Monesi L, et al. Drug utilization and polypharmacy in an
Italian elderly population: the EPIFARM-elderly project. Pharmacoepidemiol Drug Saf 2011; 20:488-496.
Elisa R Zanier. 1998, Medical Doctor degree (110/110) at the University of Milano, Italy. 1998/2001:
Residency in Anesthesiology and Critical Care Medicine at the University of Milano. 2 years Postdoctoral fellowship at the Neurotrauma Laboratory-Neurosurgery Division, University of Los Angeles,
California (UCLA), USA. 2003-2008 Assistant physician in the Neurosurgical Intensive Care Unit,
Department of Anesthesia and Critical Care Medicine, Fondazione IRCCS Ospedale Maggiore
Policlinico, Milano. Since 2007: Teaching assignment into postgraduate school of Critical Care Medicine
and Anesthesiology, University of Milano. Since 2008: Associate researcher at the Laboratory of
Inflammation and Nervous System Diseases, Mario Negri Institute. Since 2012 Head of the Unit of Cell
Therapy and Acute Brain Injury, Mario Negri Institute, Milano. Present interests include: experimental
models: traumatic brain injury and stroke. Scientific fields: pathophysiology of brain
ischemia/reperfusion injury and traumatic brain injury; inflammation as target of therapeutic strategies;
the protective mechanisms of stem cells. Publications in PubMed: 32.
Selected Publications:
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Orsini F, Villa P, Parrella S, Zangari R, Zanier ER, Gesuete R, Stravalaci M, Fumagalli S, Ottria R, Reina JJ, Paladini A,
Micotti E, Ribeiro-Viana R, Rojo J, Pavlov VI, Stahl GL, Bernardi A, Gobbi M, De Simoni MG. Mannose binding
lectin, a novel target for stroke. Circulation. 2012, 18;126:1484-94
Zanier ER, Montinaro M, Viganò M, Villa P, Fumagalli S, Pischiutta F, Longhi L, Leoni ML, Rebulla P, Stocchetti N,
Lazzari L, De Simoni MG. Human umbilical cord blood mesenchymal stem cells protect mice brain after trauma. Crit
Care Med. 2011; 39(11):2501-2510.
Zanier ER, Brandi G, Peri G, Longhi L, ZoerleT, Tettamanti M, Garlanda C, Sigurtà A, Valaperta S, Mantovani A, De
Simoni MG, Stocchetti N. Cerebrospinal fluid pentraxin 3 early after subarachnoid hemorrhage is associated with
vasospasm. Intensive Care Med. 2011 Feb;37(2):302-9. Epub 2010 Nov 12.
Gesuete R. Storini C. Fantin A., Stravalaci M., Zanier ER, Orsini F, Vietsch H., Mannesse M. L. M., Ziere B., Gobbi M.
and De Simoni M.G. “Recombinant C1-inhibitor in Brain Ischemic Injury” Ann Neurology, 66:332-342, 2009.
Stocchetti N, Colombo A, Ortolano F, Videtta W, Marchesi R, Longhi L, Zanier ER. Time course of intracranial
hypertension after traumatic brain injury. J Neurotrauma. 24(8): 1339-46, 2007.
Zanier ER, Ortolano F, Ghisoni L, Losappio S, Colombo A, Stocchetti N. Intracranial pressure monitoring in intensive
care: clinical advantages of a computerized system over manual recording. Crit Care 11(1): R7, 2007.
Stocchetti N, Protti A, Lattuada M, Magnoni S, Longhi L, Ghisoni L, Egidi M, Zanier ER: Impact of pyrexia on
neurochemistry and cerebral oxygenation after acute brain injury. J Neurol Neurosurg Psychiatry 76 : 1135-1139, 2005.
Longhi L, Zanier ER, Royo N, Stocchetti N, McIntosh TK. Stem cell transplantation as a therapeutic strategy for
traumatic brain injury. Transplant Immunology 15, 143–148, 2005.
Zanier ER, Lee S, Vespa P, Giza C, Hovda D: Increased hippocampal CA3 vulnerability to low-level kainic acid
following lateral fluid percussion injury. J Neurotrauma 20: 409-420, 2003.
Ip EY, Zanier ER, Moore AH, Lee SM, Hovda DA: Metabolic, Neurochemical, and Histologic Responses to Vibrissa
Motor Cortex Stimulation After Traumatic Brain Injury. J Cereb Blood Flow Metab. 23(8): 900-910, 2003.
Rossi S, Zanier ER, Mauri I, Colombo A, Stocchetti N: Brain temperature, body core temperature, and intracranial
pressure in acute cerebral damage. J Neurol Neurosurg Psychiatry 71: 448-454, 2001.
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ACTIVITIES
The Department of Neuroscience is formed by twelve Laboratories; the activities of research are
devoted to the study of neurological and psychiatric diseases, evaluated by the biological point
of view, clinical and epidemiological aspects and the quality of care. Together with these
activities, in the Department other more general expertise are present, drug information service
and preparation of protocols for clinical trial and epidemiological studies are activities in charge
of the Neuroscience Department. Traditionally part of the Department was devoted to the
creation of experimental models for the pharmacological, neurochemical and pathogenetic
studies in Alzheimer or prion's diseases, epilepsy, depression and cognitive impairment. More
recently, consolidated expertise were created in the pathogenesis of amyotrophic lateral
sclerosis (ALS), cerebral stroke and drug abuse. Some of these disorders, like epilepsy, ALS
and Alzheimer's disease are investigated from the clinical and epidemiological points of view
for the evaluation of drug and care efficacy. The activities of the Department are aimed to an
integration of the different expertise to develop multidisciplinary approaches. The purpose is to
address at different levels, knowledge, therapy and clinical practice to the numerous questions,
largely
unresolved,
proposed
by
the
disorders
of
nervous
system.
MAIN FINDINGS
The intracerebral application of synthetic  amyloid 1-40 e 1-42 in oligomeric form is
associated with a cognitive damage that does not occur when the pepetides are applied in
monomeric form of fibrils species, the effect is partially due to inflammatory mechanism
mediated by non-neuronal cells
The comparative MRI analysis of different experimental models of Alzheimer’s disease (AD)
showed similar reduction of brain regions volume associated to aging, only partially
superimposable at the AD condition. At the striatal level the reduction of volume is particulary
relevant and it has been associated to a synaptic loss
Doxycycline, a tetracycline that pass the blood brain barrier with anti-amyloidogenic activity
not only reduced the  amyloid aggregates but also antagonize the neuronal dysfunction induced
by  amyloid oligomers
A polyphorphism in the gene coding for SIRT-2, a protein member of the sirtuin family,
proteins with deacetylase activity, has been associated with development of chronic diseases in
elderly,
A cell permeable peptide able to block JNK-PSD-95 interaction and prevent PSD-95
phosphorylation. The application of this peptide in vitro was able to stabilize PSD-95 in the
PSD and prevent Aβ oligomer-induced synaptopathy.
It has been shown as it is possible to distinguish the pathological and the physiological role of
JNK in cellular homeostasis condion. The complete activation of JNK is induced by two other
kinases upstream the signal cascade, MKK4 and MKK7, but only the second one is responsible
of the JNK activation following the stress stimuli as exitotoxicity
Studies in different cell models have shown that activation of endoplasmic reticulum stress or
alterations in the proteasome are not responsible for the neurodegeneration in prion diseases of
genetic origin.
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The PrP molecules carrying deletions encompassing the conserved central region (PrP CR) are
strongly neurotoxic this toxicity is inhibited by the wild-type form of PrP. we found that while
CR-dependent toxicity is cell-autonomous, the rescuing activity of wild-type PrP can be
exerted in trans from nearby cells.
Mutated PrP interacts with the voltage-gated calcium channel 2-1 subunit which promotes the
anterograde trafficking of the channel. Owing to ER retention of mutant PrP, 2-1 accumulates
intracellularly, impairing delivery of the channel complex to the cell surface
In a prospective population-based study in the oldest old (Monzino 80-plus Study), higher
baseline BMI was associated with a reduced risk of dementia suggesting that the relationship
between BMI and dementia may change over time. Underweight could represent a marker of
disease severity from the prodromal phase of dementia.
In the same prospective population-based study (Monzino 80-plus Study), though the average
daily coffee intake tended to decrease from midlife, coffee consumption remained common in
the very old. In this prospective, observational study in the oldest old, long-term consumption of
coffee was associated with a 30% decreased risk of developing dementia.
In a prospective ambulatory population of cognitively normal or mildly cognitively impaired
elderly seen consecutively at the Memory Clinic of the Ospedali Regionali of Mendrisio and
Lugano, Switzerland (Canton Ticino Study), the ability to control balance while standing with
eyes open on a compliant surface showed a highdegree of association with the fall-history of
older people with no or mild cognitive impairment.
The long-term extentension (5 years from the initial visit) of the study on the association
between mild anemia and mortality in the elderly residents of Biella municipality (Health and
Anemia Study) showed a persistent negative effect of mild anemia on survival also after
controlling for many potential confounders. This unfavorable prognosis was mainly associated
with mild anemia due to chronic disease, renal insufficiency and low plasma concentrations of
vitamin B12 and/or folate: Mortality associated with thalassemia trait or iron deficiency was
similar to that of non-anemic elderly persons.
In the Creutzfeldt-Jakob disease study 55 patients were randomized and followed up in the
Italian part of the study. The data from these patients were pooled with 66 patients of a similar
study performed in France. Analyses for the efficacy and safety of doxycycline are on-going and
will be published in 2013.
The prevalence of patients who received a prescription of the atypical antipsychotics risperidone
and olanzapine was significantly reduced in year following the warning issued by the Italian
Drug Agency on their relation with incidence of cerebrovascular accidents. In the same period
other ontipsychotics showed an increase in prevalence.
We have examined some determinants of admission to the “via di Natale” Hospice, in Aviano
(Italy) during its first ten years. We analyzed 2,217 interviews with relatives of terminally ill
patients at the time of the request for admission, from 2000 to 2009. About half the patients
(51.4%) have been admitted after the interviews. Age and previous place of care differed
significantly for patients admitted and not admitted to the hospice. The low income of patients
and their families, or being alone, were the main determinants of admission. The proportions of
patients who received information about the disease, as well as the number of relatives fully
aware of the advanced stage of the illness rose during the ten years of activity.
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Patients with dementia resident in Alzheimer’s special care units (ASCU) had a lower rate of
hospitalisation and use of physical restraints than those in traditional nursing homes.
In ASCU 60% of patients with dementia were taking at least one antipsychotic, 49% typical and
51% atypical. More than 50% of patients exposed to antipsychotics at baseline, were still taking
the drug after 18 months of follow-up. The use of antipsychotic agents was strongly related to
the presence of agitation, irritability, delusions, anxiety, night-time behaviour and aberrant
motor behaviour.
In the Lecco Local Health Authority 16% of elderly patients were exposed to potential severe
drug-drug interactions; age and number of chronic drugs were associated with an increasing risk
of DDIs. Since physicians still have some difficulty in managing this topic, it is essential to
provide them with adequate information on which factors raise the risk of DDIs.
Age, local health unit (LHU) of residence, number of drugs and co-prescribed PIDs were
predictors of hospitalization for hemorrhage.
During 2005 in Lombardy Region, 76% of the elderly aged 65 years ore more (76% women and
75% men) received at least one chronic drug, 46% were exposed to polypharmacy (46% women
and 45% men) and 20% to chronic polypharmacy (18% women and 22% men). Elderly in the
age groups of 75-79, 80-84 and 85-89 years had the highest risk to be exposed to chronic
polypharmacy (OR 2.25; 95%CI: 2.23-2.27, OR 2.68; 95%CI: 2.65-2.71, and OR 2.84; 95%CI:
2.79-2.89 respectively).
During 2005, 34 % of the population living in Lombardy Region received at least one antibiotic
drug prescription. The highest prescription prevalence was observed in the 0-17 and 80 or more
year age ranges (41.6% and 41.9%, respectively). Patients aged <18 years (OR= 1.73; 95% CI
1.73, 1.74), aged 65 or older (OR= 1.64; 95% CI 1.63, 1.65), and those that live in Brescia (OR
1.66, 95% CI 1.65, 1.66) had a statistically significant higher risk of antibiotic drug exposure.
In a large population sample of subject living in Lomabrdy Region, the use of paroxetine and
fluoxetine peaked in 2002 and then decreased. The prescripition rates of mirtazapine gradually
increased all through the study period: from 0.07% in 2000 to 0.13% in 2006. On the contrary,
the prescription rates of reboxetine showed a different trend and progressively decreased from
0.20 in 2000 to 0.04 in 2006.
In a sample of 38 internal medicine and geriatric wards, at hospital admission 52% of 1332
elderly patients aged 65 years or older taken five or more different drugs (polypharmacy) and
were in the ward for a mean of 11 days. At hospital discharge there was an increase in the rate
of patient with polypharamacy (+13%) and with multiple disease (+16%).
Among elderly patients admitted with a diagnosis of AFF to internal medicine wards, an
appropriate antithrombotic prophylaxis was taken by less than 50%, with an underuse of VKAs
prescription independently of the level of cardio-embolic risk. Hospitalization did not improve
the adherence to guidelines.
After multiadjustment, the diagnosis of dementia was associated with in-hospital death (OR =
2.1; 95% CI = 1.0 - 4.5). Having dementia and at least one adverse clinical event during
hospitalization showed an additive effect on in-hospital mortality (OR = 20.7 ;95% CI = 6.9 –
61.9).
The strongest association between clusters of diseases and polypharmacy was found for diabetes
mellitus plus CHD plus CVD, diabetes plus CHD, and HF plus atrial fibrillation (AF).
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The prescription of typical antipsychotics has been associated with an increased risk of CVEs.
After stratification, persons prescribed with AChEI did not show any association with CVEs.
Nineteen percent of patients admitted to internal medicine and geriatric hospital wards are rehospitalized at least once within 3 month after discharge. Adevrse events during hospitalization,
previous hospital admission, and vascular and liver diseases were significantly associated with
likelihood of readmission.
We found a significant association with an increased risk of mortality at 3 months follow in
patients exposed to at least 2 potentially severe DDIs (OR=2.62; 95% CI, 1.00-6.68; p=0.05).
Hospitalization was associated to an increase in potentially severe DDIs. Careful monitoring for
potentially severe DDIs, especially for those created at discharge or recently generated, is
important to minimize the risk of associated harm.
We found that there were geographical differences in the prevalence of elderly people with
chronic polypharmacy, only partly explained by health indicators. These findings highlight the
need for targeted efforts on prescription practice to reduce polypharmacy
In the participatory research project evaluating quality of the Pistoia mental health services,
change between the first and second surveys were limited to waiting time for the visits at the
mental health service. Critical issues remained: choice of professionals, information, length of
waiting, medication side effects, self-help groups
In a survey study involving all the Emergencies of the Province of Trento monitoring of selfharm and suicide attempts was found that with exeption of the age ranging 35-39 years old, the
incidence of suicide was higher in female population: The risk was higher in divorced and
single males. 26% had high risk profile of intention and lethality, while in 18% there was not
intentionality to attempt suicide. In the 45% of cases the people were in contact with the local
mental health service.
The prevalence rates per 10.000 of lithium users in Lombardy in 2000 and in 2010 were stable.
In females, they went from 16.7, in 2000, to 17.0, in 2010 and in males from 13.7 to 14.4. Also
incidence rates showed no significant changes: they went from 4.28 to 3.9 in females, and from
4.2 to 3.5 in males.
According to the survey conducted in the schools in the city of Como, 30% students said they
had tried cannabis at least once, and more frequently males and older subjects did so. 25% said
they had used cannabis in the last six months and 16% in the last month. Among the 235
cannabis users, 80% used it in the last six months and 56% in the last month. Males consistently
used cannabis more than females.
There is a direct correlation between ALS and mechanical trauma as a result of the following
observations: The risk of ALS increases with the number of traumatic events and the severity of
injuries. There is an inverse correlation between ALS and coffee intake. The prevalence of
extrapyramidal signs in patients with ALS is higher than that expected in the general population.
Early onset differs from late onset ALS for the higher exposure to lead, solvents,
electromagnetic fields, and professional physical activity.
There is an inverse correlation between physical exercise and ALS. However, among affected
individuals the disease tends to occur at a younger age is the patient practiced physical exercise.
Data on the 10-year mortality of ALS show a 13% survival rate; however, the disease diagnosis
was confirmed only in 5.5% of survivors.
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L-acetylcarnitine associated to riluzole is more effective than riluzole alone in patients with
ALS. Patients receiving the drug present slowing of functional impairment and reduction of
short-term mortality In patients with traumatic spinal cord injury erythropoietin was not found
to be unequivocally superior to metylprednisolone in terms of efficacy and tolerability;
however, some results favored the experimental treatment.
The study on medication overuse headache supports the efficacy and safety of sodium valproate
vs. placebo. A comprehensive rehabilitation program does not reduce the risk of falls in
Parkinson disease when compared to usual care.
In patients with epilepsy, an active monitoring of adverse events and drug interactions reduce
significantly these events without addictive monetary costs. Treatment of chronic inflammatory
demyelinating polyradiculoneuropathy with immunoglobulins for 6 months is less frequently
discontinued because of inefficacy, adverse events, and/or intolerance than treatment with
intravenous methylprednisolone
The attitudes of Italian specialists toward epilepsy surgery are heterogeneous and reflect the
cultural background and the number of surgical candidates commonly seen.
The administrative records have high sensitivity and specificity, but they tend to slightly
overestimate the frequency of the disease.
The faster course of ALS in mice with SOD1 mutation depends on a greater accumulation of
protein aggregates due to dysfunction of the proteasome. Acting on this system could therefore
lead to a significant slowing of the disease.
The motoneurons damaged in models of familial ALS trigger early defense mechanisms
through the activation of molecules that are part of the immune response. This may opens up
new perspectives in the study and in the control of the disease.
Treatment with GCSF or with coenzyme Q10 from onset of symptoms in mice SOD1G93A has
not confirmed the positive result on the course of the disease observed in previous studies on the
same animals treated before symptoms. Because these treatments resulted ineffective also in
clinical trials of ALS patients, our results highlight the importance of a preclinical experimental
approach more suitable to promote therapeutic interventions effective in patients.
The human cord blood mononuclear cells injected into the cerebral ventricle significantly slow
down the disease progression in two mouse models of motor neuron degneration. Their effect is
not due to cell replacement but is rather associated with the production and release of circulating
protective factors which may act both at the central and/or peripheral level.
We have demonstrated the crucial involvement of some pro- and anti-inflammatory cytokines in
seizures using experimental models of epilepsy in rodents, thus describing a new
etiopathological mechanism which may be relevant for human epilepsy.
We have demonstrated that membrane-bound drug transport proteins are functionally activated
by seizures and have a significant role in decreasing the brain concentrations of antiepileptic
drugs in experimental models. Pharmacological intervention to block the activity of these
proteins may contribute to reverse multidrug resistance in epilepsy.
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Gene therapy studies highlight the possibility to significantly reduce spontaneous seizure that
are refractory to anticonvulsant drugs opening the perspective of using gene therapy in
pharmacoresistant forms of epilepsy.
The complement system is a relevant target in acute brain injury:
-
Recombinant complement inhibitor (rhC1-INH) has a powerful neuroprotective action
and a wide therapeutic window in brain ischemia/reperfusion injury
-
Targeting mannose-binding lectin (MBL), an activator of the lectin complement
pathway, leads to neuroprotection with a wide therapeutic window
-
In subarachnoid hemorrage (SAH) patients ficolin-3, an activator of the lectin
complement pathway is associated to clinical and structural parameters of severity.
Mesenchymal stem cells drive protective microglia polarization in in vitro and in vivo injury.
Microglia is associated to protective actions in the injured brain
Long term efficacy of human bone marrow mesenchymal stem cells in traumatized mice brain is
not affected by immunosuppressive treatment.
Deficits of executive functions dependent on prefrontal cortex are counteracted by intrastriatal
administration of D1-like and D2-like receptor antagonista
TAAR1 modulates brain monoamines transmission and reduce the sensitivity to amphetamine
Truncation of mecp2 gene models motor deficits of Rett sindrome
A single session of cocaine self-administration is sufficient to shape rat behaviour towards goaldirected behaviours and selectively up-regulate Arc expression in mPFC. This is the first
evidence that the mPFC's function is already profoundly influenced by the first voluntary
cocaine exposure.
The use and the early phases of cocaine abstinence induce a finely tuned modulation of BDNF
expression in the NAc and in the mPFC.
Environmental stimuli associated to drug self-administration induce drug-seeking behaviour
when presented to rodents after a long period of abstinence.
Bifeprunox, a partial agonist at DA D2 and 5-HT1A receptors, influences nicotine-seeking
behaviour in response to drug-associated stimuli in rats.
Operant oral alcoholic beer self-administration by C57BL/6J mice is a useful experimental
procedure to induce lasting consumption of pharmacologically relevant amounts of ethanol.
The positive allosteric modulators of GABAB receptors may represent potential candidate
compounds for the management of alcohol addiction.
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NATIONAL COLLABORATIONS
Agenzia di Sanità Pubblica del Lazio, Roma
Associazione Familiari Insonnia Familiare Fatale malattie da prioni, Treviso
Associazione Italiana GIST A.I.G.
Associazione Mondiale di Riabilitazione Psicosociale, Sezione Italiana, Milano
Associazione per la Ricerca Neurogenetica, Lamezia Terme (CS) e ASL 6, Regione Calabria
Agenzia di Sanità Pubblica del Lazio, Roma
Assessorato alla Salute, Comune di Milano
Azienda Ospedaliera Ospedali Riuniti di Bergamo
Azienda Sanitaria Locale di Bergamo
Azienda ULS TO2, Torino
Bracco Imaging, Milano
Catholic University of Sacro Cuore, Roma
Cell Factory, Fondazione IRCCS Ospedale Maggiore Policlinico, Milano
CEND, Centro Eccellenza per le Malattie Neurodegenerative, Università di Milano
Centro di Terapie per l’Adolescenza, Milano
Centro Fatebenefratelli San Giovanni di Dio, Cernusco sul Naviglio
Centro di Neurofarmacologia, Dipartimento di Scienze Farmacologiche, Università di Milano
Centro Parkinson-Istituti Clinici di Perfezionamento
Centro Studi in Psichiatra, ASL 2, Torino
Centro di Terapie per l’Adolescenza, Milano
Clinica IRCSS S. Maria Nascente, Milano
Clinica Neurologica III Università di Milano, Azienda Ospedaliera S. Paolo, Milano
Clinica Neurologica, Università di Perugia, Ospedale S. Maria della Misericordia, Perugia
Clinica Psichiatrica, Università Milano Bicocca
Clinica Psichiatrica, Università di Parma
Clinica Psichiatrica, Università di L’Aquila
Clinica Psichiatrica Università degli Studi di Genova
Consorzio Ricerche Luigi Amaducci, CRIC, Arcugnano (Vc)
Consorzio MIA, Milano
Department of Quantitative Methods for Business Economic Sciences, Facoltà di Statistica,
Università Bicocca, Milano
Dept of Biomedical Sciences & Biotechnologies, University of Brescia
DIBIT, San Raffaele Scientific Insitute, Milano
Dipartimento di Biologia Funzionale e Strutturale Università dell’Insubria
Dipartimento di Biologia, Biologia Struttutale Universita Tor Vergata di Roma
Dipartimento di Chimica Biologica, Università di Padova
Dipartimento di Chimica, Università degli Studi di Firenze
Dipartimento di Chimica, Università degli Studi di Milano
Dipartimento di Chirurgia "P. Valdoni" - Lab., Ricerca Center for Research in Neurobiology
"Daniel Bovet" (CRiN), "Sapienza" Università di Roma
Dipartimento Dipendenze ASL di Como
Dipartimento Endocrinologia, Università di Milano
Dipartimento Farmaco Chimico Tecnologico, Università di Siena
Dipartimento di Farmacologia Medica, Università di Milano
Dipartimento di Fisiologia Umana, Facoltà di Medicina, Università di Milano
Dipartimento di Medicina e Sanità Pubblica, Sezione di Psichiatria e Psicologia Clinica,
Università di Verona
Dip. di Morfofisiologia, Scuola di medicina Veterinaria, Università di Torino, Grugliasco (TO).
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Dipartimento di Neurologia, Seconda Università di Napoli
Dip. Neurologia, IRCCS Fondazione Maugeri, Pavia
Dipartimento Neurologia, Ospedale Molinette, Torino
Dipartimento di Neurologia Università di Milano, Ospedale Luigi Sacco.
Dipartimento di Neuroscienze, Università di Parma, Parma
Dipartimento di Neuroscienze e Organi di Senso, Università di Bari, Bari.
Dipartimento di Neuroscienze, Oftalmologia e Genetica, Unità di Neuroimmunologia,Università
di Genova
Dipartimento di Salute Mentale, Azienda Provinciale per i Servizi Sanitari di Trento, Trento
Dipartimento di Salute Mentale di Niguarda, Milano
Dipartimento di Salute Mentale ASL 3 ”Genovese”, Genova
Dipartimento di Salute Mentale San Carlo, Milano
Dipartimento di Salute Mentale della Ulss 5 Ovest Vicentino
Dipartimento di Scienze Biomediche e Cliniche Università di Milano, Milano
Dip. di Scienze Biomolecolari e Biotecnologie, Università di Milano
Dipartimento di Scienze Fisiologiche Università di Pavia, Pavia
Dipartimento Scienze Neurologiche, Università di Genova, Genova
Dipartimento Scienze Neurologiche, Ospedale Maggiore Policlinico di Milano
Direzione Generale Famiglia e Solidarietà Sociale, Regione Lombardia, Milano
Direzione Generale Sanità, Regione Lombardia, Milano
Direzione Regionale Sanità e Servizi Sociali, Regione Umbria
Divisione di Ematologia, Università di Pavia Fondazione IRCCS Policlinico S. Matteo, Pavia
Divisione Neurologica, Università di Bologna
EPAPSY, Scientific Association for Regional Development and Mental Health, Athens, Greece
Evidentia Medica, Grottaferrata, Roma
Facoltà di Statistica, Università Bicocca, Milano
Federazione Alzheimer Italia, Milano
Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti, FADOI
Federazione Italiana dei Medici di Medicina Generale
Franco Calori Cell Factory, Centro Trasfusionale e di Immunologia dei Trapianti, IRCCS
Ospedale Maggiore, Milano
Fondazione Casa della carità “Angelo Abriani”, Milano
Fondazione Clelio Angelino
Fondazione Cecchini Pace, Milano
Fondo Edo Tempia
Golgi Cenci Foundation, Abbiategrasso (Mi)
Hospice “Franco Gallini”, Aviano (PN)
IRCSS "Casa Sollievo della Sofferenza", San Giovanni Rotondo
IRCCS Istituto Auxologico Italiano, Milano
Istituto di Ricovero e Cura a Carattere Scientifico IRCCS (I.N.R.C.A.), Ancona
IRCSS Fatebenefratelli di Brescia
IRCSS "San Raffaele", Milano
IRCCS “Santa Maria Nascente”, Milano
I.S.B. - Ion Source & Biotechnologies
Istituto Europeo di Oncologia, IRCCS, Milano
Istituto di Farmacologia e Farmacognosia, Università di Urbino
Istituto di Farmacologia, Università di Milano
Istituto di Fisiologia Umana II Università degli Studi di Milano, Milano
Istituto “G. Ronzoni”, Milano
Istituto Italiano di Tecnologia, Genova
Istituto Nazionale Neurologico “Carlo Besta”, Milano
Istituto Scientifico Humanitas
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Istituto di Scienze e Tecnologie della Cognizione, CNR, Roma
Istituto "Stella Maris", IRCCS, Calambrone (PI)
Istituto Superiore di Sanità, Roma
Istituto Zooprofilattico Piemonte Liguria Val D'Aosta,Torino
Laboratorio di Epidemiologia e Neuroimaging e U.O. Alzheimer, IRCCS Fatebenefratelli,
Brescia.
Laboratorio di Immunopatologia Renale, Ospedale San Carlo, Milano
Laboratorio di Neuroscienze, Centro Dino Ferrari, Università di Milano
Laboratory for Cell Therapy “Stefano Verri”, Paediatric Department, University of MilanoBicocca, San Gerardo Hospital, Monza, Italy
Lega Italiana per la Lotta contro i Tumori
Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova
Nico, Neuroscience Institute Cavalieri Ottolenghi, Torino
Oncologia Medica, IRCCS Fondazione Salvatore Maugeri, Pavia
Ospedale del Bambin Gesu’, Roma
Ospedale Regionale Ca Fondello, Treviso
Ospedale "Molinette", Torino
Polo Oncologico, ASL 12, Biella
Polo Tecnologico, IRCCS S. Maria Nascente, Fondazione Don Carlo Gnocchi Onlus, Milano
Provincia Lombardo-Veneta Ordine Ospedaliero San Giovanni di Dio, Fatebenefratelli di
Cernusco sul Naviglio
Progetto Itaca, associazione Volontari per la Salute Mentale – ONLUS, Milano
Scuola Normale Superiore, Laboratorio NEST: National Enterprise for nanoScience and
nanoTechnology, Pisa
Scuola di Specializzazione in Psicoterapia IRIS-Insegnamento e Ricerca Individuo e Sistemi,
Milano
Scuola di Terapia Cognitiva “Studi Cognitivi”, Milano
Società Italiana Medicina Interna, Roma
Società Italiana di Geriatria e Gerontologia, SIGG
Società Italiana Geriatri Ospedalieri, SIGOs
Società INFORMA
Terzo Dipartimento di Medicina Interna, Medicine Operative, Unità Oderzo − ASL 9 Treviso
Unione Nazionale delle Associazioni per la Salute Mentale (UNASAM), Milano
Unità di Geriatria, Ospedale Maggiore IRCCS, Università di MilanoUnità Operativa di
Neurologia, Casa di Cura S. Maria (Multimedica), Castellanza (VA).
Unità Operativa di Neurologia Riabilitativa , Centro S. Maria Nascente, Fondazione Don Carlo
Gnocchi Onlus, Milano.
Unità di Patologia Umana e Istologia, Dip. Sciense mediche di Base, Università di Bari
Unità di Patologia e Medicina Orale, Dipartimento di Scienze Chirurgiche Ricostruttive e
Diagnostiche, Università degli Studi di Milano
Unità Operativa di Psichiatria, Azienda Ospedaliera Luigi Sacco di Milano, Milano
Unità Operativa di Psichiatria, Azienda Ospedaliera San Gerardo di Monza, Monza, Unità
Operativa di Psichiatria di Garbagnate, Azienda Ospedaliere Salvini di Garbagnate, Garbagnate
Milanese
Unità Operativa di Psichiatria, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli
e Regina Elena di Milano, Milano
Unità di Post-Genomica, Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti
University of Milan
Università of Foggia
University of Pavia
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University of’Insubria, Varese
University of Piemonte Orientale, Novara
University of Milano, IRCCS Ospedale Maggiore, Milano
UniversityMilano-Bicocca, Monza
University La Sapienza, Roma
U.O. Neurologia, Clinica S. Maria, IRCCS, Castellanza (VA).
UNASAM, Unione Nazionale delle Associazioni per la Salute Mentale
Unità Operativa di Psichiatria, Azienda Ospedaliera Luigi Sacco di Milano, Milano
Web Medica, Grottaferrata, Roma
INTERNATIONAL COLLABORATIONS
Albert Eistein College of Medicine, Bronx, NY, USA
Atomic Energy Commission, Service de Neurovirologie, Fontenay-aux-Roses, Francia
Beaumont Hospital, Dublin, Irlanda
Brain Repair Centre, University of Cambridge, Cambridge, UK
Cambridge Centre for Brain Repair, University of Cambridge, UK
Centre for Neuroscience Research and Division of Biomolecular Sciences, GKT School, King’s
College, London, UK
Centre National de la Recherche Scientifique, Paris. Francia
Clinica Neurologica dell’Università di Tirana, Albania
Chorley & South Ribble General Hospital, Chorley,
Cochrane Schizophrenia Group, Università di Nottingham, Nottingham, UK
Cochrane Collaboration Depression Anxiety Neurotics Disorders, UK
Columbia Univ, Haverstraw, NY, USA
Department of Anatomy and Physiology, Laval University, Quebec, Canada
Department of Biochemistry, Boston University, Boston USA
Department of Cell Biology, Washington University, St Louis, USA
Department of Chemistry,The Australian National University, Canberra City, Australia
Department of Experimental Psychology, University of Cambridge, UK
Department of Metabolic Diseases, Ospedali Regionali Lugano and Mendrisio, Svizzera
Departiment of Neuroscience, Physiology & Pharmacology University College London, , UK
Department (Neuro) Pathology, Academisch Medisch Centrum ,Amsterdam,The Netherlands
Department of Pathology and Infectious Diseases Royal Veterinary College, Herts, UK
Department of Psychiatry, Geneva University Hospitals, Ginevra, Svizzera
Department of Psychiatry, Medical Center University of Mississippi, Jackson, USA
Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Germany
Department of Psychiatry, University of Cambridge, Cambridge
Department of Psychiatry, University of Oxford, United Kingdom
Department of Psychiatry, University of Oslo, Norway
Directorate General for the Health and Consumer Protection, European Commission,
Luxembourg
Division of Medical Genetics, CHUV Lausanne, Switzerland
Divisione di Geriatria, Ospedali Regionali di Lugano e Mendrisio, Switzerland
EPAPSY, Scientific Association for Regional Development and Mental Health, Athens, Greece
European Union of Family Associations of People with Mental Illness (EUFAMI)
Fundació Privada Clinic per a la Recerca Biomèdica, Hospital Clinic i Provincial, Barcelona,
Spain
Georg August University Goettingen, Goettingen, Germany.
GH Pitié Salpêtrière, Paris, France
Harvard Institute of Medicine, Boston, MA, USA
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Hoffmann-La Roche AG, Svizzera
HSPH Harvard University, Boston, USA
IBCM, University of Lausanne, Lausanne, Switzerland
Imperial college London, UK
INSERM U 751, Marseille, Francia
Institut de Génétique Humaine du CNRS, Montpellier, France
Institut National de la Santé et de la Recherche Médicale, Paris, France
Jefferson Med Coll, Philadelphia, USA
Karolinska Institutet, Stockholm, Sweden
King’s College Hospital, London, UK
Lancaster University, Lancaster, UK.
Lexicon Pharmaceuticals Texas, USA
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
MPRC, Univ Baltimore, Baltimore, MD, USA
National Insitute on Aging, NIH, Baltimore, USA
Neurobiologie des processus adaptative, Paris-6 Universite France
Neuroprion, Network of Excellence, WP VI, EC
Neurological Department of the University of Tirana, Albania
Neurology, GlaxoSmithKline, New Frontiers Science Park North, Harlow UK
Ninewells Hospital and Medical School, Dundee, Scotland, UK
Northern Illinois University, DeKalb, IL, USA
Novartis Pharma, Basel, Switzerland
NYU, NY, USA
Observatoire National Santé mentale et Précarité, Région Rhône-Alpes, Lione, France
Ohio State Univ, Columbus, Ohio, USA
Robarts Research Institute, London, Ontario, Canada
Royal Manchester Children's Hospital, Manchester, UK
Royal Preston Hospital, Preston, UK
Sergievsky Center, Columbia University, New York, NY, USA
Servizio di Geriatria, Ospedale della Beata Vergine, Mendrisio, Switzerland
Sheffield Care and Research Centre for Motor Neuron Disorders, University of Sheffield, UK
Strathclyde University, Glasgow, UK
The London School of Medicine and Dentistry, Whitechapel, London, UK
The Scripps Research Institute, Jupiter, Florida, USA
Technology Park of Bizkaia, Bizkaia, Spagna
Toxicology Unit MRC, Leicester, UK
Trinity College Dublin e Memory Clinic del St. James’s Hospital di Dublin, Ireland
Université de la Méditerranée -Hôpital de la Timone Marseille, France
University of Alberta, Canada
University of Bristol, Frenchay Hospital, Frenchay, Bristol, UK
University of Bristol, School of Medical Sciences, UK
Univ of California at Irvine, Irvine, CA, USA
University of Cardiff, UK
University of Chicago, Chicago, IL, USA
Univ of Colorado, Denver, USA
University of Copenhagen, Denmark
University Hospital, London, ON, Canada
Univ of Innsbruck, Innsbruck, Austria
University of Lausanne, Lausanne Switzerland
Univ of Maryland, Baltimore, USA
University of Maastricht, The Netherlands
University of Rijeka Medical School, Rijeka, Croazia
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University of Szeged, Ungheria
University of Utrecht, the Netherlands
Université Victor Segalen, Bordeaux, France
Unit of Molecular Genetics, CHUV Lausanne, Switzerland
Virtanen Institute for Molecular Sciences, University of Kuopio, Finland
Vrije Universiteit Medical Center, Amsterdam, The Netherlands
Walton Hospital, Liverpool, UK
WAPR (World Association for Psychosocial Rehabilitation)
Washington University, St Louis, MI,USA
Weill Cornell Medical College, New York, USA
World Mental Health, Department of Mental Health and Substance Abuse, Geneva, Switzerland
World Association for Psychosocial Rehabilitation
World Health Organization, Disability and Rehabilitation Team
EDITORIAL BOARD MEMBERSHIP
Amyotrophic Lateral Sclerosis (Beghi)
Annals Pharmacotherapy (Nobili)
Biochemical Journal (Chiesa)
Clinical Drug Investigation (Beghi)
Clinical Neurology and Neurosurgery (Beghi)
CNS & Neurological Disorders - Drug Targets (Bendotti)
Cochrane Collaboration, Epilessia (Beghi)
Dialogo sui Farmaci (Nobili)
Drugs in the R&D (Beghi)
Early Intervention in Psychiatry (Barbato)
Educazione Sanitaria e Promozione della Salute (Barbato)
Epidemiologia e Prevenzione (Lucca)
Epigenetic of Neurodegenerative diseases (Forloni)
Epilepsia (Beghi, Vezzani, assistant editor)
Epilepsy Current (Vezzani)
Epilepsy Research (Vezzani)
Frontiers in Immunology: Frontiers in Molecular Innate Immunity (De Simoni)
Inpharma (Beghi)
Intensive Care Medicine Experimental (De Simoni)
International Journal of Mental Health (Barbato)
International Journal of Molecular Epidemiology and Genetics (Forloni, senior, Albani
associate)
ISRN Vascular Medicine (De Simoni)
Journal of Alzhiemer’s disease (Albani, Forloni, Borsello)
Journal of Neurochemistry (Bendotti)
Journal of Neuroscience Online (Forloni)
MAP Kinase (Borsello)
Neurological Sciences (Beghi)
Neuroepidemiology (Beghi)
Neuroscience (Vezzani)
Open Aging Journal (Forloni)
Open Geriatric Medicine Journal (Forloni)
PlosOne (Forloni, Chiesa, Accademic editors)
Pharmacoepidemiology and Drug Safety (Nobili)
ANNUAL REPORT
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IRFMN
Psychiatric Rehabilitation Journal (Barbato)
Quality of Life Research (Barbato)
Ricerca & Pratica (Nobili)
Stroke (De Simoni, Associate editor)
Sistema Salute (Barbato)
The Open Pathology Journal (De Simoni)
PEER REVIEW ACTIVITIES
Acta Neurologica Scandinavica
Acta Psychiatrica Scandinava
Addiction Biology
Age and Aging
Alzheimer's & Dementia
Alzheimer Disease and Associated Disorders
American Journal of Clinical Nutrition
American Journal of Hematology
American Journal of Human Genetics
American Journal of Pathology
American Journal of Physiology
Amyotrophic Lateral Sclerosis
Annals of Neurology
Annals of Pharmacotherapy
Archives of Internal Medicine
Arthritis Research & Therapy
Behavioural Brain Research
Behavioural Neuroscience
Behavioural Pharmacology
Biochimica et Biophysica Acta
Biochemical Journal
Biochemistry
BioMed Central Neurology
Biological Psychiatry
BMC Psychiatry
BMC Public Health
Brain Research
Brain Research Bulletin
Brain Research Review
Clinical Drug Investigation
Clinical Neurology and Neurosurgery
Clin Pharm Therapy
CNS Drugs
Chronobioly International
Drugs
Epidemiologia e Psichiatria Sociale
Epidemiology and Psychiatric Sciences
Epilepsia
Epilepsy & Behavior
Epilepsy Research
European Journal of Clinical Pharmacology
ANNUAL REPORT
119
2012
IRFMN
European Journal of Immunology
European Journal of Internal Medicine
European Journal of Neuroscience
European Journal of Pharmacology
European Journal of Public Health
Experimental Neurology
European Neuropsychopharmacology
Expert Opinion on Pharmacotherapy
FASEB Journal
FEBS letters
Fundamental Clinical Psychopharmacology
Future Drugs
Giornale di Neuropsichiatria dell’Età Evolutiva
Glia
Health and Quality of Life Outcomes
Human Molecular Genetics
International Journal of Mental Health Systems
International Journal of Neuropsychopharmacology
Journal of Alzhiemer’s disease
JAMA
Journal of the American Board of Family Practice
Journal of Biological Chemistry
Journal of Cell. Biology
Journal of Cell Physiology
Journal of Cerebral Blood Flow and Metabolism
Journal of Chemical Neuroanatomy
Journal of Geriatric Psychiatry and Neurology
Journal of Gerontology
Journal of Headache and Pain
Journal of Histochemistry and Cytochemistry
Journal of Immunology
Journal of Internal Medicine
Journal of Neurochemistry
Journal of Neuroimmunology
Journal of Neurology, Neurosurgery and Psychiatry
Journal of Neuroscience
Journal of Pharmacology and Experimental Therapeutics
Journal of Pharmacy and Pharmacology
Journal of Psychopharmacology
Journal of Psychosomatic Research
Journal of Structural Biology
Journal of Virology
Life Sciences
Lancet
Lancet Neurology
Molecular Brain Research
Molecular and Cellular Neuroscience
Molecular Therapy
Nature Neuroscience
Nature Biotechnology
ANNUAL REPORT
120
2012
IRFMN
Neuroepidemiology
Neurology
Neurological Sciences
Neurobiology of Learning and Memory
Nerobiology of Aging
Neurobiology of Diseases
Neuropharmacology
Neuropsychopharmacology
Neuroscience
Neuroscience Letters
Neurotherapeutics
Neurotoxicity Research
N.S. Archives Pharmacology
Parkinsonism & Related Disorders
Pharmacological Reports
Pharmacological Research
Pharmacoepidemiology and Drug Safety
Pharmacology Biochemistry & Behavior
PloS Biology
PloS One
PloS Pathogens
Proc Natl Acad Sci, USA
Progress in Neuro-Psychopharmacology & Biological Research
Psychopharmacology
Schizophrenia Research
Social Psychiatry and Psychiatric Epidemiology
Synapse
Trends Molecular Medicine
The International Journal of Neuropsychopharmacology
Vaccine
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
Agenzia Europea di Valutazione dei Medicinali (EMEA)
Agenzia Italiana per il Farmaco (AIFA)
Associazione Italiana di Neuroepidemiologia (Presidente uscente)
Associazione Italiana per la Ricerca sull’Invecchiamento Cerebrale (AIRIC, President)
Associazione Italiana di Neuroepidemiologia (Presidente uscente)
Board of "Master in Advanced Technologies for the Study of Neurodegenerative Diseases",
Milan University
Board Assessorato alle Politiche Sociali e Cultura della Salute, Comune di Milano
Comitato di coordinamento internazionale del progetto europeo”Quelles professionnalités en
santé mentale. Perspectives croisées, usagers, élus professionnels”.
Commissione di Epidemiologia dell’ILAE (Co-Chair)
Commissione sulla Health Care Policy della Lega Internazionale contro l’Epilessia (ILAE)
Comitato Ordinatore del Master in "Tecnologie Avanzate Applicate alle Patologie
Neurodegenerative", Università di Milano
Committee for Proprietary Medicinal Products (CPMP) presso L’EMEA
Consiglio di amministrazione, Fondazione Cecchini Pace, Milano
ANNUAL REPORT
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2012
IRFMN
Consiglio Direttivo AIRIC
Coordination Group IMI-PharmaCog project
Direttivo della Lega Italiana contro l’Epilessia (LICE)
Editorial Committee, Guidelines of community based rehabilitation, World Health
Organization.
Esperto Nazionale, accreditato dall’AIFA (Agenzia Italiana del Farmaco), per l’EMEA (Esperto
per il Medical Research Council (MRC), UK
Gruppo di Approfondimento Tecnico per lo sviluppo dell’area ‘Promozione della salute
mentale’, Regione Lombardia
Gruppo di lavoro sull'epilessia dell'Organizzazione Mondiale della Sanità
Gruppo di Studio sull’Epilessia della Società Italiana di Neurologia (SIN)
Gruppo di Studio sulla Qualità della Vita della Società Italiana di Neurologia (SIN)
Gruppo di Studio sulla Sclerosi Laterale Amiotrofica della Società Italiana di Neurologia (SIN)
Medical Research Council Strategic Grant Application, UK
Mental Health Working Party, gruppo di lavoro nominato dal Direttorato Generale per la
Protezione del Consumatore della Commissione Europea (DG-SANCO), Bruxelles
Gruppo di coordinamento Neuroprion NoE, EU
International Committee su “Epilepsy and the Law”
International Organizing Committee e coordinator della segreteria al Global Forum for
Community Mental Health, istituito dal Department of Mental Health della World Health
Organization.
International Subcommittee della American Academy of Neurology
International Steering Committee dell’European Network on mental health promotion and
mental disorder prevention (EMHPA).
International Subcommittee dell’American Academy of Neurology
National Institutes of Health of the USA and World Health Organization supported project on
The Future of Psychiatric Diagnosis: Refining the Research Agenda.
Neurobiology Commission of the International League Against Epilepsy
Neuroepidemiology Section of the American Academy of Neurology (Chair uscente)
Research Advisory Panel, MND Association, UK
Task Force sull’epidemiologia dell’epilessia della ILAE
Scientific Advisory Board of Sheffield Institute Foundation for MND
Scientific Advisory Board del Thierry Latran Foundation, Francia
Working Group on Epilepsy della World Health Organization (WHO)
EVENT ORGANIZATION
10a Giornata di studio sulla malattia di Alzheimer:
La diagnosi di mild cognitive impairment, malattia di Alzheimer e demenze non-Alzheimer alla
luce dei nuovi criteri diagnostici proposti Il trattamento delle demenze: approcci attuali e
strategie futur. 17 March 2012, Istituto Veneto di Scienze Lettere ed Arti, Venezia
Brain Ischemia and Stroke, Rome, December 10-12, 2012
XI International Meeting of the World Association for Psychosocial Rehabilitation, Milano
November 10-13 2012.
Convegno: Gestione della complessità clinica e terapeutica del paziente anziano ospedalizzato: il
contributo del Registro REPOSI. Fondazione IRCCS Cà Granda Ospedale Maggiore
Policlinico. Milano, Sepetember 26, 2012
ANNUAL REPORT
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GRANTS AND CONTRACTS
Abbott GmbH & Co. KG
ADDF,USA
AFM, France
Agenzia di Sanità Pubblica del Lazio
AIFA
AiRett
AISLA
Alzheimer's Association
Amgen, Milano
AriSLA
ASL 2 Piemonte.
ASL TO1 Torino
Assessorato alla Salute, Comune di Milano
Association pour la recherché sur la SLA, France
Auris medical
Azienda USL 3 Pistoia e Valdinievole
Bristol-Myers Squibb
Boehringer Ingelheim
Centro Studi in Psichiatria ASL TO2, Torino
CPADs EU grant
CURE
Czech Science Foundation
EISAI
Epilepsy
European Research Area Board – ERAB
Dana Foundation
Dipartimento di Salute Mentale, Azienda Ospedaliera Niguarda Ca’ Granda, Milano
Dipartimento di Salute Mentale di Pistoia e Valdinievole Evidentia Medica, Grottaferrata (Roma)
Fondazione Cariplo, Milano
Fondazione Mariani, Milano
Fondazione Italo Monzino, Milano
Fondazione Vialli e Mauro per la Ricerca
FP6, European Union
Glaxo-SmithKline, Italy
Grünenthal, Germany
Hospice "via di Natale Franco Gallini", Aviano (PN)
Human Frontiers Scientific Programme
IMPHA II, DG-SANCO, Public Health and Consumers' Protection (Directorate General
Istituto Comprensivo Statale "G.D. Romagnosi", Carate Brianza (MI)
Istituto Regionale Lombardo di Formazione per l’Amministrazione Pubblica – IREF
I.R.I.S
Istituto San Paolo; Torino
Istituto Superiore di Sanità
Janssen-Cilag
H. Lundbeck A/S, Danimark
Hoffmann-La Roche AG, Svizzera
Metis, Società Scientifica FIMMG
Ministero della Ricerca Scientifica
Ministero della Salute
MND Association, UK
ANNUAL REPORT
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2012
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Newron
Ospedale “Casa Sollievo” di San Giovanni Rotondo
Pharming
Provincia Autonoma di Trento
Progetto Itaca, Milano
Regione Lombardia, Assessorato alla Famiglia e Solidarietà Sociale e Assessorato alla Sanità,
Milano
Rimoldi e Bergamini
Rotary Clubs Gruppo 1, Milano
Rotary Clubs Milano Naviglio Grande San Carlo, Milano Scala, Inner Wheel Milano San Carlo
Rotta-Pharm, Italy
Sanofi-Aventis
San Paolo Foundation
SELECTA MEDICA, Pavia
Servier Laboratories, Parigi
Sienabiotech
Sigma Tau
Sinthopharm
Thierry Latran Foundation, France
Telethon
Unione Nazionale Associazioni per la Salute Mentale – UNASAM
Vertex
WebMedica, Grottaferrata (Roma).
World Health Organisation
SCIENTIFIC PUBLICATIONS (2012)
Agnoli L, Mainolfi P, Invernizzi RW and Carli M. Dopamine D1-Like and D2-Like Receptors in
the Dorsal Striatum Control Different Aspects of Attentional Performance in the Five-Choice
Serial Reaction TimeTask Under a Condition of Increased Activity of Corticostriatal Inputs.
Neuropsychopharmacology doi: 10.1038/npp.2012.236
Agnoli L and Carli M Dorsal-striatal 5-HT2A and 5-HT2C receptors control impulsivity and
perseverative responding in the 5-choice serial reaction time task. Psychopharmacology 2012,
219: 633-45
Albani D, Tettamanti M, Batelli S, Polito L, Dusi S, Ateri E, Forloni G, Lucca U.
Interleukin-1, interleukin-1 an tumor necrosis factor- genetic variants and risk of
dementia in the very old: evidence from the “Monzino 80-plu” prospective study. AGE
2012; 34: 519-26.
Albani D, Martinelli Boneschi F, Biella G, Giacalone G, Lupoli S, Clerici F, Benussi L,
Ghidoni R, Galimberti D, Squitti R, Mariani S, Confaloni A, Bruno G, Mariani C,
Scarpini E, Binetti G, Magnani G, Franceschi M, Forloni G Replication study to confirm
the role of CYP2D6 polymorphism rs1080985 on donepezil efficacy in Alzheimer's
disease patients. J Alzheimers Dis. 2012;30:745-9.
Antoniou X, Borsello T. The JNK signalling transduction pathway in the brain. Front Biosci
(Elite Ed). 2012 Jan 1;4:2110-20. Review.
ANNUAL REPORT
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Barbato A, Bossini L, Calugi S, D'Avanzo B, Fagiolini A, Koukouna D, Parabiaghi A,
Rapisarda F, Rucci P, Vallarino M, ENBREC Group. Validation of the Italian version of the
Functioning Assessment Short Test (FAST) for bipolar disorder. Epidemiol Psychiatr Sci 2012
E-pub.
Beghi E, Messina P, Pupillo E, Crichiutti G, Baglietto MG, Veggiotti P, Zamponi N, Casellato
S, Margari L, Cianchetti C; the TASCA study group. Satisfaction with antiepileptic drugs in
children and adolescents with newly diagnosed and chronic epilepsy. Epilepsy Res
2012;100:142-151
Bendotti C, Marino M, Cheroni C, Fontana E, Crippa V, Poletti A, De Biasi S.. Dysfunction of
constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis:
Implication for protein aggregation and immune response. Prog Neurobiol. 97:101-26, 2012
Bersano A, Debette S, Zanier E R, Lanfranconi S, De Simoni MG, Zuffardi O, Micieli G. The
genetics of small-vessel disease. Curr Med Chem 2012; 19: 4124-41.
Biasini E., Turnbaugh J.A., Massignan T., Veglianese P., Forloni G., Bonetto V., Chiesa R., and
Harris D.A. (2012) The toxicity of a mutant prion protein is cell-autonomous, and can be
suppressed by wild-type prion protein on adjacent cells. PloS ONE, 7(3): e33472
Bigini P, Diana V, Barbera S, Fumagalli E, Micotti E, Sitia L, Paladini A, Bisighini C, De
Grada L, Coloca L, Colombo L, Manca P, Bossolasco P, Malvestiti F, Fiordaliso F, Forloni G,
Morbidelli M, Salmona M, Giardino D, Mennini T, Moscatelli D, Silani V, Cova
L.Longitudinal tracking of human fetal cells labeled with super paramagnetic iron oxide
nanoparticles in the brain of mice with motor neuron disease. PLoS One. 2012;7(2):e32326.
Bilotta C, Franchi C, Nobili A, Nicolini P, Djade CD, Tettamanti M, Fortino I, Bortolotti A,
Merlino L, Vergani C. New prescriptions of spironolactone associated with angiotensinconverting-enzyme inhibitors and/or angiotensin receptor blockers and their laboratory
monitoring from 2001 to 2008: a population study on older people living in the community in
Italy. Eur J Clin Pharmacol 2012 Sep 21.
Cervo L, Torri V. Comment on: "Dose-effect study of Gelsemium sempervirens in high
dilutions on anxiety-related responses in mice" (Magnani P, Conforti A, Zanolin E, Marzotto M
and Bellavite P, Psychopharmacology, 2010). Psychopharmacology (Berl). 2012; 220: 439-440.
Caccia S, Pasina L, Nobili A. Critical appraisal of lurasidone in the management of
schizophrenia. Neuropsychiatr Dis Treat 2012 ; 8 : 155-168
Caccia S, Pasina L, Nobili A. How pre-marketing data can be used for predicting the weight of
drug interactions in clinical practice. Eur J Intern Med 2012 ; E-pub :
Capitanio D, Vasso M, Ratti A, Grignaschi G, Volta M, Moriggi M, Daleno C, Bendotti C,
Silani V, Gelfi C. Molecular signatures of amyotrophic lateral sclerosis disease progression in
hind and forelimb muscles of an SOD1(G93A) mouse model. Antioxid Redox Signal. 17:133350, 2012.
D'Avanzo B, Barbato A, Erzegovesi S, Lampertico L, Rapisarda F, Valsecchi L. Formal and
informal help-seeking for mental health problems. A survey of preferences of Italian students
Clin Pract Epidemiol Ment Health 2012; 8: 47-51.
De Paola M, Mariani A, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P,
Castellaneta V, Boldrin V, Rossetti C, Chiabrando C, Forloni G, Mennini T, Fanelli R.
Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse
model of motor neuron degeneration. Mol Med. 18: 971-81, 2012
ANNUAL REPORT
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Di Clemente A, Franchi C, Orrù A, Arnt J, Cervo L. Bifeprunox: a partial agonist at dopamine
D2 and serotonin 1A receptors, influences nicotine-seeking behaviour in response to drugassociated stimuli in rats. Addict Biol. 2012; 17: 274-286.
Di Santo R, Costi R, Cuzzucoli Crucitti G, Pescatori L, Rosi F, Scipione L, Celona D, Vertechy
M, Ghirardi O, Piovesan P, Marzi M, Caccia S, Guiso G, Giorgi F, Minetti P Design, synthesis
and structure-activity relationship of N-Arylnaphthylamine derivatives as amyloid aggregation
inhibitors. J Med Chem 2012 ; 55 : 8538-8548
Erba G, L. Moja, Beghi E, Messina P, Pupillo E. Barriers towards epilepsy surgery. A survey
among practicing neurologists. Epilepsia 2012;53:35-43
Erba G. Messina P, Pupillo E, Beghi E. Acceptance of epilepsy surgery among adults with
epilepsy – What do patient think? Epilepsy & Behavior 2012;24:352-358
Esposito S, Pristerà A, Maresca G, Cavallaro S, Felsani A, Florenzano F, Manni L, Ciotti MT,
Pollegioni L, Borsello T, Canu N. Contribution of serine racemase/d-serine pathway to neuronal
apoptosis. Aging Cell. 2012 11: 588-98.
Errede M, Girolamo F, Ferrara G, Strippoli M, Morando S, Boldrin V, Rizzi M, Uccelli A,
Perris R, Bendotti C, Salmona M, Roncali L, Virgintino D. Blood-brain barrier alterations in the
cerebral cortex in experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol.
71:840-54, 2012.
Filibian M, Frasca A, Maggioni D, Micotti E, Vezzani A, Ravizza T. In vivo imaging of glia
activation using 1H-magnetic resonance spectroscopy to detect putative biomarkers of tissue
epileptogenicity (2012) Epilepsia, 53:1907-16.
Franchi C, Tettamanti M, Marengoni A, Bonometti F, Pasina L, Cortesi L, Fortino I, Bortolotti
A, Merlino L, Lucca U, Riva E, Nobili A. Changes in trend of antipsychotics prescription in
patients treated with cholinesterase inhibitors after warnings from Italian Medicines Agency.
Results from the EPIFARM-Elderly Project. Eur Neuropsychopharmacol 2012; 22: 569-77.
Fumagalli F, Moro F, Caffino L, Orrù A, Cassina C, Giannotti G, Di Clemente A, Racagni G,
Riva MA, Cervo L. Region-specific effects on BDNF expression after contingent or noncontingent cocaine i.v. self-administration in rats. Int J Neuropsychopharmacol. 2012 Nov 20:16. [Epub ahead of print]
Frigerio F, Frasca A, Weissberg I, Parrella S, Friedman A, Vezzani A, Noé FM. Long-lasting
pro-ictogenic effects induced in vivo by rat brain exposure to serum albumin in the absence of
concomitant pathology (2012) Epilepsia, 53:1887-97.
Galbiati M, Onesto E, Zito A, Crippa V, Rusmini P, Mariotti R, Bentivoglio M, Bendotti C,
Poletti A. The anabolic/androgenic steroid nandrolone exacerbates gene expression
modifications induced by mutant SOD1 in muscles of mice models of amyotrophic lateral
sclerosis. Pharmacol Res. 65:221-30, 2012
Gemma S, Camodeca C, Sanna Coccone S, Joshi B P , Bernetti M, Moretti V, Brogi S, Bonache
de Marcos M C, Savini L, Taramelli D, Basilico N, Parapini S, Rottmann M, Brun R, Lamponi
S, Caccia S, Guiso G, Summers R L, Martin R, Saponara S, Gorelli B, Novellino E, Campiani
G, Butini S. Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: further
structure-activity relationships, in vivo studies, and preliminary toxicity profiling. J Med Chem
2012 ; 55 : 6948-6967
Gianni M, Peviani M, Bruck N, Rambaldi A, Borleri G, Terao M, Kurosaki M, Paroni G,
Rochette-Egly C, Garattini E p38αMAPK interacts with and inhibits RARα: suppression of the
kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells..Leukemia.
26:1850-61,2012
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Gustafson DR, Mazzuco S, Ongaro F, Antuono P, Forloni G, Albani D, Gajo GB, Durante E,
Caberlotto L, Zanardo A, Siculi M, Gallucci M. Body mass index, cognition, disability, APOE
genotype, and mortality: the "Treviso Longeva" Study. Am J Geriatr Psychiatry. 2012; 20:594602.
Kruja J, Beghi E, Zerbi D, Dobi D, Kuqo A, Zekja I, Mijo S, Kapisyzi M, Messina P. High
Prevalence of major neurological disorders in two Albanian communities: Results of a door-todoor survey. Neuroepidemiology 2012;38:138-147
Librizzi L, Noè F, Vezzani A, de Curtis M, Ravizza T. Seizure-induced brain-borne
inflammation sustains seizure recurrence and blood-brain barrier damage (2012). Ann Neurol.
72:82-90.
Lora A, Barbato A, Cerati G, Erlicher A, Percudani M. The Mental Health System in
Lombardy, Italy. Access to services and patterns of care. Soc Psychiatry Psychiatr Epidemiol.
2012; 47: 447-454.
Mannucci P M, Nobili A, Garattini S. New drugs for thromboprophylaxis in atrial fibrillation.
Eur J Intern Med 2012 ; 23 : 1-5
Mannucci P M, Nobili A. Internal and geriatric medicine: An alliance for the challenges of the
elderly. Eur J Intern Med 2012 ; 23 : 479-482
Marengoni A, Bianchi G, Nobili A, Tettamanti M, Pasina L, Corrao S, Salerno F, Iorio A,
Marcucci M, Mannucci P M, SIMI Investigators. Prevalence and characteristics of
antidepressant drug prescriptions in older Italian patients. Int Psychogeriatr 2012 ; 24 : 606-613
Marengoni A, Nobili A, Romano V, Tettamanti M, Pasina L, Djade S, Corrao S, Salerno F,
Iorio A, Marcucci M, Mannucci PM; SIMI Investigators. Adverse Clinical Events and Mortality
During Hospitalization and 3 Months After Discharge in Cognitively Impaired Elderly Patients.
J Gerontol A Biol Sci Med Sci 2012 Sep 12.
Mengozzi M, Cervellini I, Villa P, Erbayraktar Z, Gökmen N, Yilmaz O, Erbayraktar S,
Manohasandra M, Van Hummelen P, Vandenabeele P, Chernajovsky Y, Annenkov A, Ghezzi
P. Erythropoietin-induced changes in brain gene expression reveal induction of synaptic
plasticity genes in experimental stroke. PNAS, 2012; 109: 9617-22.
Merlo A, Zemp D, Zanda E, Rocchi S, Meroni F, Tettamanti M, Recchia A, Lucca U, Quadri P.
Postural stability and history of falls in cognitively able older adults: The Canton Ticino study.
Gait Posture 2012; 36: 662-66. SIAMOC Best Clinical Paper Award.
Messina P, Beghi E. Modeling drop-outs in amyotrophic lateral sclerosis. Contemporary
Clinical Trials 2012;33:218-222
Monesi L, Baviera M, Marzona I, Avanzini F, Monesi G, Nobili A, Tettamanti M, Cortesi L,
Riva E, Fortino I, Bortolotti A, Fontana G, Merlino L, Roncaglioni M C. Prevalence, incidence
and mortality of diagnosed diabetes: evidence from an Italian population-based study. Diabet
Med 2012 ; 29 : 385-392
Nobile-Orazio E, Cocito D, Jann S, Uncini A, Beghi E, Messina P, Antonini G, Fazio R, Gallia
F, Schenone A, Francia A, Pareyson D, Santoro L, Tamburin S, Macchia R, Cavaletti G,
Giannini F, Sabatelli M; for the IMC Trial Group. Intravenous immunoglobulin versus
intravenous
methylprednisolone
for
chronic
inflammatory
demyelinating
polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol 2012;11:493-502.
Obreli Neto PR, Nobili A, de Lyra DP Jr, Pilger D, Guidoni CM, de Oliveira Baldoni A,
Cruciol-Souza JM, de Carvalho Freitas AL, Tettamanti M, Gaeti WP, Nakamura Cuman RK.
Incidence and predictors of adverse drug reactions caused by drug-drug interactions in elderly
outpatients: a prospective cohort study. J Pharm Pharm Sci 2012 15: 332-343.
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Obreli Neto P R, Nobili A, de Oliveira Baldoni A, Guidoni C M, de Lyra Jùnior D P, Pilger D,
Duzanski J, Tettamanti M, Cruciol-Souza J M, Gaeti W P, Kenji R, Cuman R K N. Adverse
drug reactions caused by drug-drug interactions in elderly outpatients: a prospective cohort
study. Eur J Pharmacol 2012 ; 68 : 1667-1676
Orrù A, Fujani D, Cassina C, Conti M, Di Clemente A, Cervo L. Operant, oral alcoholic beer
self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of
GABA(B) receptors. Psychopharmacology (Berl). 2012; 222: 685-700.
Orsini F, Villa P, Parrella S, Zangari R, Zanier E, Gesuete R, Stravalaci M, Ottria R, Reina JJ,
Paladini A, Micotti E,Ribeiro-Viana R, Rojo J, Pavlov VI, Stahl GL, Bernardi A, Gobbi M, and
De Simoni MG. Targeting mannose binding lectin confers long lasting protection with a
surprisingly wide therapeutic window in cerebral ischemia. Circulation 2012; 126: 1484-1494
Olgiati P, Politis A, Albani D, Rodilossi S, Polito L, Ateri E, Zisaki A, Piperi C, Liappas I,
Stamouli E, Mailis A, Atti AR, Ferrari B, Morini V, Moretti F, Biella G, Forloni G,
Papadimitriou GN, Ronchi DD, Kalofoutis A, Serretti A. Association of SORL1 alleles with
late-onset Alzheimer's disease. findings from the GIGAS_LOAD study and mega-analysis. Curr
Alzheimer Res. 2012; 9:491-9.
Parabiaghi A, Franchi C, Tettamanti M, Barbato A, D'Avanzo B, Fortino I, Bortolotti A,
Merlino L, Nobili A. The declining use of reboxetine in years 2000 to 2006: a
pharmacoepidemiological comparative study. J Clin Psychopharmacol 2012; 32: 303-305.
Pasina L, Djade CD, Lucca U, Nobili A, Tettamanti M, Franchi C, Salerno F, Corrao S,
Marengoni A, Iorio A, Marcucci M, Violi F, Mannucci PM. Association of Anticholinergic
Burden with Cognitive and Functional Status in a Cohort of Hospitalized Elderly: Comparison
of the Anticholinergic Cognitive Burden Scale and Anticholinergic Risk Scale : Results from
the REPOSI Study. Drugs Aging 2012 Dec 14. [Epub ahead of print]
Perale G, Rossi F, Santoro M, Peviani M, Papa S, Llupi D, Torriani P, Micotti E, Previdi S,
Cervo L, Sundström E, Boccaccini AR, Masi M, Forloni G, Veglianese P. Multiple drug
delivery hydrogel system for spinal cord injury repair strategies. J Control Release. 2012; 159:
271-280.
Peviani M, Kurosaki M, Terao M, Lidonnici D, Gensano F, Battaglia E, Tortarolo M, Piva R,
Bendotti C.Lentiviral vectors carrying enhancer elements of Hb9 promoter drive selective
transgene expression in mouse spinal cord motor neurons. J Neurosci Methods. 205:139-47;
2012
Polito L, Kehoe PG, Davin A, Benussi L, Ghidoni R, Binetti G, Quadri P, Lucca U, Tettamanti
M, Clerici F, Bagnoli S, Galimberti D, Nacmias B, Sorbi S, Guaita A, Scarpini E, Mariani C,
Forloni G, Albani D. The SIRT2 polymorphism rs10410544 and risk of Alzheimer's disease in
two Caucasian case-control cohorts. Alzheimers Dement 2012 May 30. [Epub ahead of print
Puoti G, Bizzi A, Forloni G, Safar JG, Tagliavini F, Gambetti P.Sporadic human prion diseases:
molecular insights and diagnosis. Lancet Neurol. 2012; 11:618-28.
Pupillo E, Messina P, Logroscino G, Zoccolella S, Chiò A, Calvo A, Corbo M, Lunetta C,
Micheli A, Millul A, Vitelli E, Beghi E; EURALS Consortium. Trauma and amyotrophic lateral
sclerosis: a case-control study from a population-based registry. Eur J Neurol 2012; 19: 15091517.
Repici M, Chen X, Morel MP, Doulazmi M, Sclip A, Cannaya V, Veglianese P, Kraftsik R,
Mariani J, Borsello T, Dusart I. Specific inhibition of the JNK pathway promotes locomotor
recovery and neuroprotection after mouse spinal cord injury. Neurobiol Dis. 2012; 46:710-21.
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Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, Andre´ CB, Haenggi M, Miss M-T,
Galley G, Norcross RD, Invernizzi RW, Wettstein JG, Moreau J-L and Hoener MC. BrainSpecific Overexpression of Trace Amine-Associated Receptor 1 Alters Monoaminergic
Neurotransmission and Decreases Sensitivity to Amphetamine. Neuropsychopharmacology
2012, 37: 2580-92.
Ristagno G, Fumagalli F, Porretta-Serapiglia C, Orrù A, Cassina C, Pesaresi M, Masson S,
Villanova L, Merendino A, Villanova A, Cervo L, Lauria G, Latini R, Bianchi R.
Hydroxytyrosol Attenuates Peripheral Neuropathy in Streptozotocin-Induced Diabetes in Rats. J
Agric Food Chem. 2012 May 31. [Epub ahead of print]
Senatore A., Colleoni S., Verderio C., Restelli E., Morini R., Condliffe S.B., Bertani I.,
Mantovani S., Canovi M, Micotti E., Forloni G, Dolphin A.C., Matteoli M., Gobbi M., and
Chiesa R. (2012) Mutant PrP suppresses glutamatergic neurotransmission in cerebellar granule
neurons by impairing membrane delivery of VGCC 2-1 subunit. Neuron, 74: 300-313
Stravalaci M., Bastone A., Beeg M., Cagnotto A., Colombo L., Di Fede G., Tagliavini F, Cantù
L., Del Favero E., Mazzanti M., Chiesa R., Salmona M, Diomede L., and Gobbi M. (2012)
Specific recognition of biologically active amyloid-β oligomers by a new Surface Plasmon
Resonance-based immunoassay and an in vivo assay in Caenorhabditis elegans. J. Biol. Chem.,
87: 27796–27805
Traina G, Bigini P, Federighi G, Sitia L, Paroni G, Fiordaliso F, Salio M, Bendotti C, Brunelli
M. Lipofuscin accumulation and gene expression in different tissues of mnd mice. Mol
Neurobiol. 45:247-57, 2012
Vezzani A Before epilepsy unfolds: finding the epileptogenesis switch. Nat Med, 18:1626, 2012
Vidale S, Verrengia E, Gerardi F, Arnaboldi M, Bezzi G, Bono G, Guidotti M, Grampa G,
Perrone P, Zarcone D, Zoli A, Beghi E, Agostoni E, Porazzi D, Landriscina M. Stroke
management in northern Lombardy: organization of an emergency-urgency network and
development of a connection between prehospital and in-hospital settings. International Journal
of Stroke 2012;7:527-533.
Zenoni D, Priori C, Bellan C and Invernizzi RW. Stability of diluted epinephrine in prefilled
syringes for use in neonatology. European Journal of Hospital Pharmacy
doi:10.1136/ejhpharm-2012-000068
LAY PRESS SELECTION (2012)
Barbato A. L'approccio basato sulle evidenze in salute mentale: navigazione a vista tra
entusiasmo e scetticismo. Sistema Salute 2012; 56: 170-176.
Caccia S, Pasina L, Nobili A. Citocromo P450: polimorfismo genetico e variabilità
farmacologica. Ricerca & Pratica 2012 ; n. 164 : 60-71
Franchi C, Arosio F, Djade C D, Salvini Porro G, Nobili A. Valutazione della percezione
dell'efficacia dei trattamenti antidemenza in Italia. Ricerca & Pratica 2012 ; n. 166 : 149-159
Monesi L, Baviera M, Cortesi L, Marzona I, Avanzini F, Monesi G, Nobili A, Tettamanti M,
Riva E, Fortino I, Bortolotti A, Fontana G, Merlino L, Roncaglioni M C. Dalla lettura dei
database amministrativi: l'epidemiologia e il trattamento del diabete in Regione Lombradia dal
2000 al 2007. Giornale Italiano Diabetologia Metabolismo: GIDM 2012 ; 32 : 70-78
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Nobili A, Pasina L, Mangiagalli A, Marchetti A R, Frau S, Zimol R. Farmaci e anziani. Metodi
per gestire l'inappropriatezza prescrittiva. Dialogo sui Farmaci 2012 ; n. 3 : 112-120
Riva E, Coppa A, Tettamanti M, Lucca U, Garattini S, Gallini C, Marson R. Dieci anni di
esperienze dell’Hospice “via di Natale”. Rivista Italiana di Cure Palliative 2012; 14 (1): 19-25.
RESEARCH ACTIVITIES
Laboratory of Biology of Neurodegenerative Disorders
Alzheimer's disease: genetic studies and clinical investigations
In collaboration with different neurological centers and the laboratory of Geriatric
Neuropsychiatry it has been created a bank of blood samples for DNA of patients with
Alzheimer’s disease (AD), in familial (FAD) or sporadic form (SAD), and patients with
vascular dementia (VD). In all subjects the diagnosis of dementia is performed according to the
international guidelines. Since 2005 we started also the collection of blood samples from
subjects with front-temporal dementia. The genetic studies are aimed to the identification of
causal factors in FAD and risk factors in SAD. Mutations on genes encoding proteins involved
in the physiopathology of AD were investigated. The pathogenic role of these mutations is
under investigation using fibroblasts obtained from skin biopsy. Furthermore, we continued the
screening of FAD samples for the genes encoding for presenilin 1 and 2 (PS-1 and PS-2) and
APP, missense mutations in these three genes were associated with AD.
Alzheimer's disease: preclinical studies
The formation of  amyloid (A) deposits in brain parenchyma and on the wall of cerebral blood
vessels is an early event in AD and there are now numerous genetic, biochemical and
neuropathological studies pointing to a causal role of A in the pathogenesis of AD. Thus,
prevention the formation of A aggregates or their elimination once formed is a potential
therapeutic approach to the disease. This aim is strongly persecuted with different strategies
including the regulation of enzymes responsible of the synthesis and degradation of A and the
enzymes influencing the metabolism of amyloid precursor protein (APP). In the lab, we developed
the idea to interfere directly with the A deposits formation using anti-amyloidogenic drugs. The
experimental studies have shown the potential therapeutic activity of these drugs in AD, and now
they will be tested in a clinical setting.
Alzheimer’s disease: Translational studies
In the frame of the European Consortium IMI-PharmaCog have been set up several protocols
for the MRI analysis in various transgenic mice models of Alzheimer’s disease (AD). The
PharmaCog project focused on the optimization of the translational studies to facilitate the
therapeutic approaches considering in experimental models and in the clinical studies the same
parameters, behaviorally, biochemically and of imaging. In this contest it will be analyzed
longitudinally in single, carrying human amyloid precursor protein mutated (APP) associated to
AD, double carrying APP and mutated PS1 transgene, and triple transgenic mice carrying APP,
PS2 and mutated tau transgene. We performed the MRI analysis in the same animals at 4, 8,
12, 18 and 24 months, the analysis has been structural, functional and spettroscopical. The
strumental parameters (ROI, T2, DTI) have been harmonized with the partners deveoping
similar approaches in humans. The structural results confirm some common features in the three
animal models: the progressively reduction with aging of volume of specific regions like
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hippocampus and striatum and a reduction of the entorhinal cortex thickness, while the olfactory
bulbs are preserved.
The role of oligomers in the Alzheimer pathogenesis
Recent data have shown the essential role plays by oligomers, small and soluble aggregates of
Ain the Alzheimer pathogenesis and in particular in the cognitive decline associated to the
disease. In collaboration with the Department of Biochemistry an Molecular Pharamacology we
developed some in vivo models to analyze the neuronal dysfunction induced by Abut
not in monomeric or fibrillar species. The intracerebral application of these different forms
confirmed that Aoligomers induced behavioral impairment while monomeric or fibrillar forms
of Adid not affect the cognitive behavior.
Sirtuins and aging
The sirtuins are a family of conserved proteins with de-acetylation activity. In human the
sirtuins are coded by 7 different genes and are localized in the citosol, within the nuclei and in
the cellular mitochondria. SIRT-1, the better known sirtuin, is involved in the aging physiology
and energetic metabolism, its activation induced beneficial effects in Alzheimer and Parkinson
experimental models. We studied sirtuins from different points of view, genetic, cellular and
behaviorally. The genetic studies are devoted to identify alterations associated to AD in Italian
populations. During the screening of all sirtuin genes, we found several single nucleic
polymorphisms that now are investigated in larger population (560 AD subjects). The cellular
studies are focused on the role of SIRT-1 and SIRT-2 in the cell death mechanisms and
oxidative stress in cellular models of AD. Since sirtuins have been involved in the energetic
metabolism, and mental as well as physical exercise exert protective effect in AD, we are
evaluating in AD animal models if sirtuins are able to mediate the beneficial effects of physical
exercise and environmental stimulation.
Genetics of aging
In collaboration with Geriatric Neuropsychiatry Lab for the Monzino 80-plus study and with dr.
Maurizio Gallucci from the ARGel Association in Treviso for Trelong study we collected a
large number of blood samples from subjects over seventy. In these samples we are performing
a genetic analysis to identify genetic profiles associate to the longevity and /or to the agingassociated pathologies with specific attention to the dementias. The aim is to cross the
genotype/phenotype profile with pathologies and environmental aspects including style of life,
diet and economical conditions to identify risks and protective factors. Initially the subjects
were genotypized for ApoE, whom allele E4 is a well-known risk factor for Alzheimer’s disease
and several other disorders and sirt-1 a gene codified for protein member of a enzymatic family
of sirtuins associated to the longevity in several experimental models. The results are interesting
but before drawing any conclusion we need to consider the numerous other parameters collected
in our database.
Parkinson’s Disease: genetic studies
Parkinson’s disease (PD) is the second more diffuse neurodegenerative disorder with an
unknown pathogenesis, however for PD several therapies are available and, although at the
symptomatic level, their efficacies is well-established. In the etiological studies on PD the
genetic component has been traditionally considered with scarce interest whereas the
environmental causes were carefully evaluated. This orientation was based on the evidence that
the exposure to several toxins can mimic the PD pathology. However the genetic studies in the
last few years have completely changed the perspective with the identification of mutations on
two genes, encoding for alpha-synuclein and parkin, associated to the juvenile forms of the
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disease. A mutation on alpha synuclein gene is an event extremely rare, only three mutations
identified until now, the parkin mutations are numerous ether in puntiform or in deletion form.
The mutations on alpha-synuclein gene are dominant while the parkin mutations are associated
with PD in recessive form. We collected, in collaboration with several neurological centers,
blood samples from PD subjects and the screening of the samples involved genes like alphasynuclein, parkin, DJ-1 and other factors potentially involved in PD.
Parkinson’s disease: in vitro studies
The identification of the mutations associated to Parkinson’s disease (PD) gave a substantial
contribute to understand the disease and allowed the development of cellular models to
investigate the pathogenesis of the disease. In past we showed the potential neurotoxic activity
of alpha-sinuclein using the synthetic peptide homologous to the fibrillogenic fragment 61-95
(NAC) of the protein. Successively with help of dr. Negro at the Department of Biochemistry at
the University of Padova we prepared cDNA vectors including the sequence of wild type and
mutated alpha-synuclein Their transfection to the PC12 cells induced in specific conditions a
cellular damage. More recently alpha-synuclein was associated to a TAT sequence capable to
transport inside the cells the protein. With this method the intracellular concentration of alphasinuclein was better controlled. In a micromolar range alpha-synuclein was toxic, but in
nanomolar range, it exerted neuroprotective effect against oxidative stress induced by hydrogen
peroxide. This double effect dose-dependent was confirmed in an “inducible” model. More
recently again in collaboration with Dr. Negro (Padua University), we obtained the recombinant
form of DJ-1 associated with TAT (TAT-DJ-1). This protein is similar to alpha-synuclein,
mutations of its sequence has been associated to PD. TAT-DJ-1 silencing by small interference
RNA (siRNAi) were used to study the interaction between DJ-1 and alpha synuclein..
Laboratory of Cell Death and Neuroprotection
Synaptic Dysfunction
Nowadays it is assumed that AD is a synapse-related pathology (synaptopathy) in which Aβ
oligomers accumulate in the brain parenchyma and lead to synaptic dysfunction and loss, a
phenomenon that precedes extensive amyloid deposition in the brain. However, the relationship
between A and synapses loss remains unclear. We set up a new in vitro model to study the
cellular and molecular alterations that lead to AD synaptopathy. In this model we demonstrated
that JNK plays a key role in the onset of AD synaptopathy. JNK in fact is activated in the
postsynaptic compartment following Aβ oligomers exposure and it contributes to synaptic
dysfunction acting on two main postsynaptic targets: caspase-3, which has been already
described to be involved in AD synaptopathy and PSD-95. In particular JNK-mediated
phosphorylation of PSD-95 promotes its removal from the PSD and consequently spine
shrinkage and loss. We generated a cell permeable peptide able to block JNK-PSD-95
interaction and prevent PSD-95 phosphorylation. The application of this peptide in vitro was
able to stabilize PSD-95 in the PSD and prevent Aβ oligomer-induced synaptopathy. This study
can potentially be a breakthrough in the comprehension of AD pathogenesis and will help in
developing effective and preventive therapeutic strategies in order to counteract or nullify the
degenerative processes activated by A.
The cargo strategy as a key tool in neuroprotection
Studying the role of JNK in the mechanisms underlying synaptic plasticity, we observed that it
is extensively expressed in the presynaptic compartment, where it controls the release of
glutamate into the synaptic cleft. JNK inhibition through D-JNKI1 in fact is able to reduce the
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neurotransmitter release. In the presynaptic compartment JNK immunoprecipitates with
syntaxin-2, a membrane protein participating in the exocytosis of presynaptic vescicles. JNK
binding to syntaxin2 is inhibited by D-JNKI1, suggesting that this interaction is involved in the
regulation of glutamate release. These results allow to better understand the mechanisms
regulating synaptic plasticity and set the basis for the development of new molecules able to
modulate the release of glutamate.
Design and synthesis of new peptides cell-permeable inhibitors of
MKK7(MKK7s)
It is possible to distinguish the JNK pathological role from the physiological one that the kinase
performs under condition of cellular homeostasis. The complete activation of JNK is induced by
two MKK that are at the two upstream kinases, MKK4 and MKK7, but only the second is
responsible for JNK activation after condition of cellular stress like excitotoxicity, event at the
base of different acute and chronic CNS pathologies. In fact the MKK7 is phosphorylated by
NMDA, while MKK4 is not activated. Thank to molecular modelling studies, we synthetized a
selective inhibitor of MKK7 designed on the interaction of the kinase with GADD45B, a protein
modulated by NFkB and able to inhibit the activity of MKK7. Using two different sequences
involved in the interaction, we have synthetized two new cell-permeable peptides (MKK7I):
Gadd45 (69-86) that only contains the region of the binding site to MKK7, and another longer
Gadd45 (60-86) that contains the binding site and also another essential region for the activation
of MKK7. These peptides do not cause toxicity in primary cultures of cortical neurons and
protect against neuronal death induced by excitotoxic (NMDA 100um) and hypoxic treatment.
Our data clearly show that the addition of peptides at a concentration of 20 mM results in a
strong inhibition of the phosphorylation of MKK7, without interfering with the phosphorylation
of MKK4. Therefore, the two designed peptides act speficically on MKK7 and present a
neuroprotective
effect
against
stress:
NMDA-toxicity
and
anoxia.
In addition, preliminary experiments in an animal model of cerebral ischemia, subjected to
treatment with the peptide MKK7I 1h before damage, showed an encouraging reduction of the
infarcted area, equal to 50% when compared to controls treated with vehicle. MKK7Is
neuroprotettive effect are currently under investigation against cerebral ischemia, in two
models: a transient and permanent ischemia. The preliminary results are encouraging; we are
currently trying to identify the therapeutic window of intervention post-ischemia of the peptide
MKK7I.
SIMBA2
We decided to design a peptide able to inhibit JNK3, that unlike JNK1 and JNK2 is specifically
expressed in the brain and is activated after acute and chronic cellular stress. The new cellpermeable peptide, SIMBA2, designed through molecular modeling studies based on the
interaction with B-arrestin-2, has proven effective in Alzheimer’s disease. To demonstrate the
peptide specificity, we performed a cell-free protein kinase assays, that demonstrated SIMBA2
ability to inhibit JNK3 without interacting with JNK1, sharing more then with 90% of
homology. Then we tested SIMBA2 efficacy in blocking APP phosphorilation at Thr668, the
most important site for the amyloidogenic cleavage of the protein. SIMBA2 prevented the
phosphorylation of APP and also of c-Jun, the elective JNK target. The peptide was also
neuroprotective against neuronal death induced by soluble Aβ oligomers and was able to
prevent the synaptic dysfunction induced by sub-lethal doses of Aβ oligomers, that precedes the
neurodegeneration. We observed as SIMBA2 is able to rescue the levels of PSD proteins like of
NMDA and AMPA receptors subunits and of the scaffold protein PSD-95, reduced by oligomer
treatment. Finally, SIMBA2, has been tested in an animal model of AD (mice TgCRND8) in an
advanced-state of the disease; the peptide doesn’t exert toxicity in mice and was able to confirm
in vitro data. In fact the peptide reduced APP phosphorilation at Thr668 and protected from
synaptic degeneration.
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Laboratory of Experimental Neurology
Role of inflammatory molecules in ictogenesis and epileptogenesis
We are studying the role of IL-1beta and HMGB1 systems in the genesis and propagation of
seizures and in the associated neurodegenerative phenomena. We have demonstrated that
epileptic activity induces the synthesis of these pro-inflammatory molecules, danger signals and
their specific receptors. In particular, IL-1beta and HMGB1 have proconvulsive actions while
their receptor antagonists (IL-1Ra, Box-A, Toll-like receptors inhibitors) or IL-1beta synthesis
inhibitors, have anticonvulsant activities. We are actively studying the role of these molecules in
epilepsy models with the intent of promoting their clinical applications in drug-resistant
epileptic patients. This possibility is encouraged by the clinical use of some of these molecules
(e.g. anakinra, the IL-1R antagonist) in chronic inflammatory and autoimmune diseases in
humans. We are studying pharmacological approaches to block IL-1beta- and HMGB1signaling involved in the proconvulsive effects of these molecules.
Role of Toll-like receptor signaling in seizures and neurological sequelae
Infection and fever, which are concomitant with increased levels of pro-inflammatory molecules
not only in the periphery but also in the brain, can be precipitating events of seizures; moreover,
a causal link between CNS infection and epilepsy has been proposed. In the context of
convergence of brain infection and the epileptic process, an obvious candidate is represented by
the Toll-like receptor (TLRs) family. These receptors are pivotal for activation of innate
immunity and inflammation following both infections or epileptogenic brain injuries. Moreover,
we recently described that HMGB1 released from neurons and glia exposed to pro-convulsant
stimuli lowers threshold to seizures by activating TLR4. The aims of the project is two-fold: (1)
to characterize TLR2 and TLR3 inflammatory signaling in the brain of rodents exposed to
infection-like challenges; (2) to investigate whether TLR2 and TLR3 signaling contribute to
seizure threshold and cognitive dysfunctions. We propose to focus on novel targets, to develop
new treatments for prevention of drug resistant epilepsy and associated comorbidities, since
these are unmet clinical need.
In vivo MRI to determine glia activation and blood-brain barrier damage
This study is focused on in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS)
techniques to evaluate the role of glia activation and blood-brain barrier damage in the epileptic
process. Our intention is to explore whether these two phenomena can be used as biomarkes of
epileptogenesis. This information may provide a clinically applicable method for predicting the
development of spontaneous seizures in individual at risk, thus permitting to envisage
preventive strategies.
miRNA and inflammation: new opportunities for therapy in epilepsy
associated pathologies
Increasing evidence supports the critical role of microRNAs (miRNAs) in post-transcriptional
gene regulation in several biological processes of the central nervous system. Specific miRNAs
are considered to represent a new class of modulators of the inflammatory response. In
particular, the miRNA-146a has been specifically associated with the regulation of the Toll-like
and interleukin-1 receptors (TIRs) signaling, which represents a major pro-epileptogenic
pathway activated in both experimental and human epilepsy. Interestingly, this miRNA has
been shown to be upregulated in experimental models of epilepsy, as well as in human TLE.
The overall goal of the project is to evaluate the role of miRNAs, with a special focus on
miRNA-146a, in regulating inflammatory pathways and to study their role in ictogenesis and in
epileptogenesis.
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Identifying key regulators of the immune/inflammatory response for
developing anticonvulsive/antiepileptogenic approaches
A key role of the brain immune response to pathogens or injuries is to activate homeostatic
programmes in competent cells for tissue defense or repair. This task is achieved by inducing
release of soluble inflammatory mediators acting as effector molecules on target cells.
Resolution of inflammation is a highly coordinated and active process that is controlled by
endogenous pro-resolving mediators and is instrumental to switch off inflammation after its
onset. If this mechanism fails then inflammation might perpetuate resulting in varying degree of
tissue injury or dysfunction. A crucial question is how microglia and astrocytes, or leukocytes,
balance these tissue demands after injury, and how their behavior can be modified to ameliorate
inflammation outcomes. Our hypothesis is that the brain immune response triggered by
ictogenic or epileptogenic injuries is inefficiently controlled by pro-resolving endogenous
molecules and their cognate receptors, thus resulting in chronic inflammation. Using
experimental models of seizures and post-injury epilepsy, we will study the role of key proresolving molecules governing the post-injury inflammatory response. The final goal of the
project is to demonstrate that incrementing the brain ability to activate efficiently pro-resolving
mechanisms of inflammation represents a promising target for developing therapeutic strategies
in epilepsy.
Time-lapse single-cell Ca2+ imaging in cell cultures
This project investigates whether astroglia-mediated inflammatory pathways can affect neuronal
activity, by analyzing changes in intracellular Ca2+ neuronal signals. This is a well established
read-out measure of cell activation following physiopathologic stimuli. Using time-lapse singlecell Ca2+ imaging in primary cultures of mouse hippocamapl neurons, we study whether cell
responses evoked by proinflammatory stimuli or activation of glutamate receptors are modified.
In particular, the effects will be tested on the augmentation of the NMDA-mediated Ca2+
response provoked in neurons by cytokines and danger signals which are inflammatory
mediators released by glial cells in diseased tissues.
Blood-brain barrier and epileptogenesis
We are studying BBB permeability and microvasculature changes induced in the brain by
seizures or by neurotrauma or infection and how these modifications may affect the process of
epileptogenesis. Experimental models of symptomatic epilepsy are used.
New therapeutic approaches of in vivo gene transfer
This study concerns the use of viral vectors to introduce genes with therapeutic potential in the
brain, thus increasing the synthesis of specific proteins to produce long-lasting anticonvulsant
effects. We have demonstrated that adeno-associated viral vector carrying the human
neuropeptide Y gene, significantly increases the brain concentration of this peptide after its
intrahippocampal injection for a prolonged time (at least up to 5 months after a single
intracerebral injection). The rats overexpressing this peptide are less susceptible to seizures.
Future development of this study concerns the optimization of the transgene transfer technology
to envisage a possible clinical application.unctional changes in cultured neurons and astrocytes
from mouse forebrain.
Laboratory of Geriatric Neuropsychiatry
Population study on the prevalence of dementias in the older-old
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Parallel to the progressive increase of individuals aged 80 years or older within the elderly
population (65+), the number of demented patients of 80 years or older makes up an ever
increasing fraction of the total population affected by dementia. As very often happens,
the exclusion from studies of subjects in the oldest age classes tends to inevitably
underestimate the total number of individuals affected by dementia present in the
population. To fill this gap, a door-to-door population study on the prevalence, incidence,
risk factors and evolution of dementias and age-associated cognitive deficits has been set
up in an elderly population aged 80 years or older living in eight small towns of Varese
Province. The survey was subsequently extended to all registered individuals aged 100 or
older residing in the province of Varese. The study is funded by a grant from the
Fondazione Italo Monzino, Milano.
Health and Anemia in the elderly population
A large survey in old residents of Biella (65 years or older) has been conducted in
collaboration with the Local Health Authority of Biella (ASL 12) and with the Division of
Hematology, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, Pavia, to
estimate the prevalence and incidence of anemia (mild, moderate and severe) in the
elderly population and to investigate whether low hemoglobin concentration associated to
alteration of CBC such as mean corpuscular volume, leukocytes and/or platatelet cell
counts could predict or were associated with myelodysplastic syndrome in the elderly.
Evaluating risk profiles in ambulatory and hospitalised elderly
subjects
In collaboration with the Geriatric Division of the Ospedali Regionali of Lugano and
Mendrisio, Switzerland, hospitalized and ambulatory patients are evaluated from a
neuropsychological, functional and mobility point of view to estimate the impact of these
factors on heath-related outcomes and disease progression (Canton Ticino Study).
Longitudinal follow-up of individuals with mild cognitive impairment
(MCI)
In collaboration with the Geriatric Unit of Ospedali Regionali of Lugano and Mendrisio,
Switzerland, the follow-up study of all Mild Cognitive Impairment or Questionable
Dementia (CDR 0.5) patients seen at the Memory Clinic of the Hospitals is continuing to
estimate the rate of conversion to dementia and to evaluate the possible risk factors
associated with conversion (Canton Ticino Study).
A European Multicentre Double-Blind Placebo Controlled trial of
Nilvadipine in Mild to Moderate Alzheimer’s disease (NILVAD Project European Union FP7 Program)
In collaboration with the Trinity College Dublin and St. James’s Hospital Dublin together
with other ten centres from eight European countries participating in the NILVAD
Project. The study employs a randomized double-blind placebo controlled parallel design.
The objectives of this study are to investigate the efficacy and safety of Nilvadipine (8 mg
once a day) as a disease course modifying treatment for mild to moderate Alzheimer’s
disease in a phase III double-blind placebo-controlled study. The primary efficacy
outcome measures in this study is the change from baseline to week 78 in cognitive
function, as assessed by the Alzheimer’s -Disease Assessment Scale (ADAS -Cog 12). A
total of 500 subjects over age 50 years with mild to moderate Alzheimer’s disease
(NINCDS-ADRDA criteria); 250 in the nilvadipine group and 250 in the placebo group.
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The total study duration will be 82 weeks. Patients will receive study medication for 78
weeks.
A randomized, double-blind study versus placebo for the evaluation
of efficacy and tolerability of doxycycline administered by oral route
in patients affected by Creutzfeldt-Jakob disease
The primary objective of this study is to evaluate the effects of doxycycline, compared
with the effects of placebo, in increasing survival time of patients with Creutzfeldt-Jakob
disease. The secondary objective is the evaluation of the effects of doxycycline treatment
on the rate of disease progression as assessed by functional scales and neurological
examination. Safety of treatment is assessed for all subjects.
Fatal Familial Insomnia (FFI): preventive treatment with doxycycline
of at risk individuals
Department of Neuroscience, in collaboration with 3nd Department of Internal Medicine,
Medicine Operative, Unit Oderzo − ASL 9 Treviso and with Fondazione IRCCS Istituto
Neurologico "Carlo Besta". The objective of this study is to test whether the chronic
administration of 100 mg of doxycycline can prevent (or postpone) the onset of FFI in
members of a family carrying the genetic mutation of the prion protein. Survival of the
treated individuals will be evaluated after 11 years.
Analyses of health data taken from linked administrative databases
Following the establishment of administrative databases to monitor medical expenditure
reimbursed by the National Health Service, a new field was open to study health using
indirect data coming from these sources. We collaborated in analysing data on old
subjects and patients with dementia related problems will be evaluated
Quality of care of terminally ill oncological subjects
In 2000 we started a collaborative programme with the hospice “via di Natale Franco
Gallini” in Aviano (PN). The present aim of the collaborative research project is to
investigate both the clinical and sociodemographic determinants associated with
awareness of illness severity in a cohort of terminal cancer patients (n=1080) at the time
of admission to the hospice, from 2001 to 2011
Laboratory of Inflammation and Nervous System
Diseases
The complement system in stroke and traumatic brain injury experimental
models
Previous studies of ours have indicated that the complement system may represent a novel
target for reducing damage following acute brain injury. We have shown that C1-INH, an
endogenous inhibitor of the complement system, protects against brain injury. Notably it has a
wide therapeutic window, being effective also when administered up to 18 h after ischemia. Our
data strongly suggest that this remarkable property of C1-INH is due to its ability to bind
mannose-binding lectin (MBL), a key protein of the complement lectin pathway. Thus, we have
recently focussed our attention on MBL as a novel target for brain injury. Our data show that
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MBL is deposited on the ischemic endothelium and we have hypothesized that this may
represent a key pathogenetic event leading to brain damage. Based on these results, we have
developed different strategies aimed at inhibiting MBL functions and all of them lead to
neuroprotection with a wide time window of efficacy. In particular, we have identified a newly
synthesized MBL-binding molecule (Polyman2) and we have demonstrated that it is effective in
reducing neurological deficits and anatomical damage also when administered up to 24 h from
the onset of brain ischemia in mice. Ongoing studies are aimed at understanding the
pathogenetic mechanism by which MBL exert its toxic effect on the activated endothelium,
elucidating this aspect provides an opportunity to identify new neuroprotective strategies.
Another goal of this project is to evaluate the involvement of this protein in traumatic brain
injury that we model in mice. Detailed analysis of the MBL gene in humans has revealed that a
surprisingly high percentage of individuals (10-15% depending on the population considered)
carries a genetic deficiency in MBL which leads to low circulating levels of MBL. In order to
confirm the relevance of this protein also in humans, another part of this project is aimed at
defining whether MBL deficiency in stroke patients limits the progression of the injury.
Stem cells as a therapeutic approach in stroke and traumatic brain injury
We have previously demonstrated a beneficial effect of neural stem cells after transient brain
ischemia. Ethical issues involved in stem cell research and the limited availability of most adult
stem cells outline the need to look for other cell populations. We have thus focussed on
mesenchymal stem cells (MSC) obtained from cord blood (CB-MSC) or bone marrow (BMMSC) that are available sources of progenitors with multilineage capacity and can represent
ideal candidates for cell-based therapy after acute brain injury. We have assessed the
effectivness of CB-MSC (provided by Cell Factory, Ospedale Maggiore Policlinico, Milano) in
reducing ischemic and traumatic brain injury (TBI) and investigated the mechanisms triggered
by their infusion in the injured brain. We have provided evidence that the beneficial role of stem
cells is related to the ability to induce a switch from a “hostile” to an “instructive” status in the
inflammatory cells present in the injured tissue including microglia/macrophage phenotypical
switch, glial scar inhibition and activation of trophic events that promote healing and
regeneration. More recently we have defined successful protocols of MSC infusion obtained
from human donors (provided by the Laboratory for Cell Therapy “Stefano Verri, Ospedale San
Gerardo, Monza) in the immunocompetent injured brain in mice. Since immunosuppression in
acute brain injured patients could lead to deleterious infective complications and not be
tolerated, these results represent a further step towards translation to clinical practice. Presently
we are working on other crucial aspects that need to be fully clarified before proceeding safely
to clinical application, namely: 1) the common/differential contribution to the therapeutic effect
of MSC obtained from different sources (BM versus CB or aminion) has never been directly
determined and needs to be addressed in order select the most effective cell population and to
develop a successful therapeutic protocol; 2) there is evidence that MSC may interact with
brain cells by direct cell-cell communication and/or by indirect secretion of factors and thereby
promote functional and structural recovery, however which are the specific factors produced by
MSC driving the beneficial effects and which is the cell type more prone to respond to MSC is
still unknown; 3) assessment of the long term efficacy and safety issue of MSC.
In vivo real time imaging in ischemic mouse brain by two-photon
microscopy
Ischemic stroke triggers local inflammation-related events, including blood brain barrier
damage, leukocyte/monocyte recruitment and microglia activation, all contributing to ischemic
damage progression after the acute event, thus being potential therapeutic targets. In vivo
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imaging of the brain at cellular resolution in 3D provides an ideal tool to get an insight into
these dynamic events. We have recently established an original approach by means of twophoton microscopy (2-PM) that allows the visualisation and measurement of dynamic events
taking place in the brain. Two-photon microscope benefits from high-energy electronic
transition in a fluorescent molecule due to the cooperation of two low-energy photons, thus
enabling imaging over long periods in living animals.
We have applied 2-PM to obtain highly detailed imaging and quantification of immune cell
behavior within the ischemic territory. In particular, we have focused on the tracking of
infiltrated lymphocytes (in collaboration with the Centre For Biophotonics at the Strathclyde
University of Glasgow) and of activated microglia. As regards the analysis of lymphocytes, we
collected data as number of infiltrated lymphocytes, their track velocity, displacement rate and
meandering index thus providing a comprehensive description of lymphocyte behaviour in the
brain. We found that, after ischemia, lymphocytes split into two different patterns of motility
behavior and move along the perivascular space prior to brain tissue invasion. Microglia were
analyzed by assessing their motility (displacement rate) and morphological features (Sholl
analysis). We found that, following focal ischemia, microglia were stationary, but highly
dynamic in modifying their shape, being able to develop their ameboid morphology within 24h
after ischemia. In mice deficient for the receptor of fractalkine, a chemokine involved in the
control of microglia activation, ameboid transformation was prevented with significant
reduction in ischemic volume.
Ongoing studies are aimed at elucidating the dynamism of other immune cells associated with
the evolution of ischemic damage over time. Thus our studies will provide the basis of a
rationale manipulation of the immune response for therapeutic purpose in brain ischemia
Temporal
pattern
of
expression
and
colocalization
microglia/macrophage phenotype markers following acute brain injury
of
Microglia, the major cellular contributors to post-injury inflammation, have the potential to act
as markers of disease onset and progression and to contribute to neurological outcome of brain
trauma and stroke. After acute injury, these resident cells are rapidly activated and undergo
dramatic morphological and phenotypic changes. This intrinsic response is associated to
recruitment of blood-born macrophages which migrate into the injured brain parenchyma.
Activated microglia and recruited macrophages (M/M), can affect neuronal function and
promote neurotoxicity through the release of several harmful components such as inflammatory
cytokines, proteases and reactive oxygen and nitrogen species. On the other hand they also
possess protective qualities and promote neurogenesis and lesion repair, an action that we have
previously documented. These different activation states are characterized by a specific pattern
of phenotypic markers, whose expression depends on the temporal evolution of the brain lesion.
Our ongoing studies aim at getting insight on previously unexplored aspects of M/M phenotype
changes induced by acute brain injury, namely, the presence of specific phenotype markers,
their temporal expression, whether or not there are concomitantly expressed by the same
subpopulation, whether they are expressed at distinct phases or locations in relation to the
lesion. Laboratory of Molecular Neurobiology
Study on pathogenic mechanisms of Amyotrophic Lateral Sclerosis
Comparative analysis of gene expression and proteome profiling of two mouse models of
familial ALS with phenotypic differences of disease.
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Recently, we observed that two genetically distinct strains of mice (C57 and 129Sv), but
carriers of the same number of copies of the transgene for human SOD1 with G93A mutation,
develop a different phenotype of ALS as regard the age of onset and illness duration. The
genetic variability is probably a reason for differences in age of onset and severity of disease in
patients with both familial and sporadic ALS. Hence our interest was focused on the study of
two strains of mice and patients C57/G93A and 129Sv/G93A the behavioral, biochemical and
histopathological order to understand the mechanisms responsible for the different development
of the disease.
In collaboration with the group of Prof. Pamela Shaw of the University of Sheffield (UK) we
made a comparison between the two strains of the gene expression profile in motoneurones
laser-dissected. This analysis showed that in motoneurons of mice with a disorder phenotype
less aggressive there is the activation of genes mainly related to an immune response complex,
an effect which could reflect a defense mechanisms. On the contrary, the mice with a faster
disease progression show evident abnormalities of mitochondria and especially a greater
accumulation of protein aggregates in the spinal cord. During this year we validated some of
these differences, even under the protein profile by immunohistochemical analysis and
immunoblotting quantities. We have also shown through the analysis of some molecules known
for their protective role, as angiogenin and Nrf2, which this experimental approach is useful to
identify new mechanisms associated with a slowing of the disease to be studied as possible
therapeutic targets. These results are reported in two manuscripts under submission (project
funded by MNDA U. K. and EUROMOTOR FP7 program
Study on the mechanisms of neuroimmunity in the pathogenesis of ALS
Growing evidence indicates that infiltration of blood-derived immune cells in the central
nervous system is to be considered not as an event secondary to the progressive
neurodegeneration but as a causative phenomenon in the pathogenesis of ALS. Indications of a
dialogue between motoneurons and cells of both innate and adaptive immunity are emerging
although the mechanisms underlying this connection renain elusive. We have clear evidences
suggesting that motoneurons are active player in the immunomodulation in ALS.
In fact, we have observed that the immunoproteasoma responsible for the production of antigens
for the response of histocompatibility MHCI is strongly activated in motoneurons of mice
SOD1G93A at very eraly stages in the development of the disease. During this year we have
demonstrated that other proteins involved in the MHCI response are strongly activated in the
motoneurons at the symptoms onse. We are trying to understand whether this response
contribute to the degenerative process or encompass protective value to motoneurons. We have
also shown that some modifications that are found in the monocytes of patients with sporadic
ALS, as the reduction of receptors CCR2 that serve for the mobilization of these cells, are also
characteristics features of SOD1G93A mice. We are now analyzing which role have these
modifications on the development and progression of the disease.These results could open new
frontiers in the development of effective therapies for the ALS. (Project funded by AriSLA)
In vitro and in vivo studies on the role of TNFalpha-MAPK pathway in the
ALS pathogenesis.
The study on the role of receptors for TNF alpha in the degeneration of motor neurons has led to
the conclusion that the receptor TNFR2 is that most responsible for the cellular damage. In fact,
in vitro study shows that motoneurones carrying the SOD1G93A mutation are fully protected by
the absence of the receptor TNFR2. This can also be observed in vivo in SOD1G93A mice that
lack of TNFR2 receptor however, this protection is not accompanied by an improvement in the
motor impairment and survival of these mice. We are now trying to understand the reason for
this discrepancy. However, this result underlines the importance of considering not only the
protection of the motoneurons but also targeted interventions to other districts involved in the
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disease as the muscles and probably the immune system in order to obtain an effective
therapy.(Project funded by the Regione Lombardia,project Nepente).
Therapeutical interventions in mouse model of ALS
Induction and mobilization of bone marrow hematopoietic stem cells (HSC) by G-CSF
(granulocyte colony stimulating factor) in SOD1G93A mice.
Several experimental studies indicate that stem cells from bone marrow induced by G-CSF in
particular the type more immature (CD34+) are able to play a neuroprotective action in different
models of neurodegeneration.
A recent study showed that even in mice SOD1G93A a continuous infusion of GCSF given
before the onset of symptoms is able to improve the course of the disease. Unfortunately, this
positive effect was not found in our ALS mice when the drug was administered from the onset
of symptoms. Moreover, treatment with a higher dose of GCSF for a shorter period has
accelerated the disease progression and this effect was associated with an increase of
proliferating cells in the spinal cord. We are trying to identify these cells and to verify if they
are toxic rather than protective through the analysis of specific markers capable of recognizing
the two cell types. In addition, to understand if this toxic effect may depend on the presence of
mutant SOD in the cells mobilised by GCSF, we have isolated stem cells from the bone marrow
of mice that do not express SOD1G93A, but only a fluorescent protein (GFP). These cells have
been administered to SOD1G93A mice
immunosuppressed by treatment with
cyclophosphamide.The results of this study will be important to understand if interventions with
GCSF should be limited to patients SLA sporadic, and to identify the mechanism of action of
these cells both positive and negative.
(Supported by Thierry Latran Foundation, AISLA and Ministry of Health)
Effect of coenzyme Q10 and its reduced form ubiquinol in mice SOD1G93A
In collaboration with the Laboratory of Pharmacodynamics and Pharmacokinetics of the
Department of Biochemistry, we evaluated the effect of treatment with coenzyme Q10 in
comparison to ubiquinol on the disease course in SOD1G93A mice. The treatment was
administered to the symptoms onset which is a condition closer to that applicable to patients.
Unfortunately, none of the two treatments has ameliorated the motor impairment or the survival
of the mice confirming the failure shown recently in a clinical trial with coenzyme Q10 in ALS
patients. Because in a previous study the coenzyme Q10 had shown a significant effect, albeit
modest, to increase the survival of mice SOD1G93A when administered before the onset of
symptoms, our results underly the importance of considering for the pre-clinical study protocols
more suitable for a potential clinical application.
Studies aimed to identify biomarkers for the diagnosis and progression of
the ALS.
In collaboration with the laboratory of translational Proteomics of the Department of
Biochemistry we are continuing the study for the identification of specific biomarkers of ALS.
In particular, we have validated in samples of cerebrospinal fluid of ALS patients in comparison
with those with other disease, the specificity of some of the protein abnormalities previously
observed in cells of the peripheral blood. The study is still in progress. The samples of spinal
fluid obtained with informed consent of the patient, come from the Department of Neurology of
the second University of Naples.
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Use of Magnetic Resonance Imaging (MRI) to study disease progression
in ALS animal models
During this year has been completed the analysis of Magnetic Resonance to monitor in vivo the
progression of the disease in mice SOD1 G93A. The results have clearly shown that this
technique allow to detect the degeneration of principal cranial motor nuclei well before the
onset of motor symptoms. Indeed the degeneration of motoneurons causes an increase in T2
signal in correspondence to these nuclei. This signal is correlated to the formation of vacuoles
around degenerated cells that precedes the loss of motoneurons. MRI is therefore able to detect
in vivo the nuclei degeneration before the death of motoneurons. Use of the technique of the
MRI is very important because it can be directly translated to the clinic, as a marker of disease
progression in patients
Laboratory of Experimental Psychopharmacology
Drug Abuse: Neural basis of drug self-administration
To separate the direct pharmacological effects of cocaine from those associated with active drug
self-administration we employed a yoked control-operant paradigm and investigated the
expression of well established markers of the rapid action of cocaine, i.e. the inducible early
genes, such as Activity-Regulated Cytoskeletal-associated protein (Arc), and trophic factors,
such as Brain Derived Neurotrophic Factor (BDNF), in rats after a single intravenous (i.v.)
cocaine self-administration session. Animals self-administering cocaine (SA) did more active
lever-presses than yoked-cocaine (YC) and yoked-vehicle (YV) animals. This goal-oriented
behaviour was accompanied by a selective increase in Arc mRNA levels in the medial
prefrontal cortex (mPFC). These findings demonstrate that a single session of cocaine i.v. selfadministration is sufficient to shape rat behaviour towards goal-directed behaviours and
selectively up-regulate Arc expression in mPFC (of SA animals), providing the first evidence
that the mPFC's function is already profoundly influenced by the first voluntary cocaine
exposure. Ongoing studies are evaluating whether this effect is peculiar to cocaine or common
to other drugs of abuse.
BDNF dynamic changes were investigated in the nucleus accumbens (NAc) and mPFC during
use and the early phases of cocaine abstinence after chronic exposure by employing a “yoked
control-operant paradigm”. The effect on BDNF was region-specific and dependent on the
withdrawal time. In the NAc, BDNF protein levels increased immediately after the last selfadministration session, with a larger increase in passively cocaine-exposed rats. In the mPFC,
BDNF expression was elevated 24 hours after the last self-administration session, independently
of how the drug was encountered. No changes were found in NAc and mPFC 7 days after the
last self-administration session. Analysis of transcript levels in the mPFC indicated that action
on exon I might contribute to BDNF's cortical induction.
Neural basis of “drug craving” and “relapse” in the drug abuse
assumption
Drug craving, defined as the desire to experience the effect(s) of a previously experienced
psychoactive substance is a cardinal feature of drug addiction and is clinically significant
because of its potential link to relapse. To provide useful indications to the development of
novel therapeutic approaches to prevent the use and abuse and the relapse of drug assumption
following the outcome of craving, we elaborated experimental models of self-administration
and relapse induced by cocaine, nicotine and alcohol-associated cues, after a period of
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abstinence. Ongoing studies are evaluating the role of several neurochemical mechanisms
potentially involved in the drug-seeking behaviour
Search for pharmacological agents modulating drug craving and relapse
Environmental stimuli associated with the intake of psychotropic substances of abuse may have
the ability to induce the craving that often preludes to relapse in formally detoxified patients.
Studying nicotine in an experimental model of extinction-reinstatement induced by the
presentation of environmental stimuli associated with self-administration of psychotropic
substance of abuse, it was found that bifeprunox, a high-affinity partial agonist of dopamine
(DA) D2 receptors and serotonin1A (5-HT1A) receptors, preferentially reduced nicotine-seeking
behaviour in response to drug-associated stimuli in rats after a long period of abstinence.
Operant oral alcoholic beer self-administration by C57BL/6J mice: a new model
for study alcohol dependence
Alcohol abuse is recognized worldwide as one of the main risk factors for health.One of the
most serious alcohol-related diseases is addiction, a chronic, progressive and relapsing disease
that often has a fatal outcome, and against which there is currently no appropriate cure. To study
this disease we developed an experimental procedure in which C57BL/6J mice self-administer
voluntary alcoholic beer (ethanol content 9% v/v) in daily sessions of 30 minutes. Using this
procedure mice that normally avoid consuming elevated amount of alcoholic beverages, selfadminister high amounts of alcoholic beer to the point of intoxication, displaying moderate
ataxia and increased locomotor activity.This procedure has proved effective in identifying new
drugs with potential therapeutic activity such as BHF177, a positive allosteric modulator of
GABAB receptors.
Chronic neurophatic and oncologic pain
Experimental models to study the emotional components of chronic pain
We have developed in rodents experimental models to study the emotional components of
chronic pain. In particular we have in our Laboratory a model of neurophatic pain by chronic
constriction of the sciatic nerve. Ongoing studies are evaluating whether this model of chronic
pain is also useful to model the emotional components that often accompanies this pathology in
humans, such as anxiety and depression.
Laboratory of Epidemiology and Social Psychiatry
Randomised controlled trial of the Italian Group for the Study of the
Second Generation Antipsychotics – GiSAS
The study aims at evaluating efficacy and safety of three antipsychotic drugs - aripiprazole,
olanzapine and haloperidol – by a pragmatic design and involving a large sample of patients
with schizophrenia treated in community psychiatric services across Italy. A total of 35 centres
has recruited at least one patient. Recruitment was closed in March 2011, with a total of 296
subjects recruited, among whom 166 completed the one-year follow-up.
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A tool to increase share and participation in mental health care. The
Shared Care Paths
The Shared Care Pathways (SCP) are developed in the mental health service of Trento, Italy, to
accompany and shape the mainstream clinical activity in a way that enhances sharing, reciprocal
collaboration and equality among users, family members, psychiatrists, non-medical
professionals in agreement with recovery and empowerment values. They consisted of five
contracts: 1. relationship as respect, listening, sincerity and openness; 2. individual treatment
plan: aims carefully defined according to shared procedures; 3. drugs: adequate information and
communication, increased attention to side effects; 4. crisis prevention: signs awareness, actions
useful to prevent the crisis or reduce the impact; 5. crisis management according to user’s
wishes. The group revised the accomplishments every six months, confirming or modifying
aims and reciprocal commitments. Quantitative and qualitative analyses of the 148 SCP have
been conducting to assess group characteristics of the most and least successful SCP; different
points of view of the actors about the usefulness and most appreciated contracts, users’ and
family members’ wellbeing improvement, impact on professionals’ role and identity were
studies with questioinnaires and qualitative interviews
Monitoring of self-harm and suicide attempts
Data collection is active in all Emergencies of the Province of Trento, covering a total of
530.000 inhabitants. Between July 2009 and November 2012 a total of 596 events attributable
to 507 individuals were registred.
European Network of Bipolar Research Export Centres - ENBREC
ENBREC is an EU-wide network of expert centres specialised in research and care on bipolar
disorders, aiming at integrate research efforts on the mechanism of disease, and optimize
diagnosis and treatment. The final product was the ENBREC Toolkit for clinical assessment of
bipolar disorders and a standardized battery of tests for assessment of cognitive functioning in
bipolar disorders.
Quality Evaluation of a Department of Mental Health with the participation
of users
The study investigates the quality of assistance offered to patients with severe mental illnesses
and intensively cared by the mental health services, through an instrument developed with
substantial contribution of users according to a participatory research model. Valid
questionnaires at the first survey were 199 and 197 at the second.
HoNOS-5 Study: towards the development of a clinically oriented
informative system
Using the HoNOS (Health of the Nation Outcome Scales) database, including repeated assessments of
more than 6500 mental health service users, we developed two different models for the identification of
reliable and clinically significant change in routine outcome assessment.To compute clinical significance,
longitudinal hierarchical linear models (HLMs) and reliable and clinically significant change (RCSC)
were combined and aspplied to a prevalence sample of 842 outpatients of four Italian community mental
health services.
Reliability and validity of the Italian version of the Beck Cognitive Insight
Scale (BCIS)
The aims were to assess reliability and validity of the Italian version of the scale; to study
structure and score differences between clinical and control subjects; to define the relationship
between BCIS and other tools for psychotic symptoms and severity of illness; to evaluate
usefulness in outcome measurement.
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Survey and ecological study of drug abuse in the area of Como
Waste waters are analysed in order to quantify use of specific drugs in the population served by
a specific waste water area. In order to attribute the detected consumption to specific population
groups, a general population survey and a survey in a randomised sample of schools have been
conducted in the area of Como, where a waste water analysis was conducted. A total of 800
subjects aged 14-18 from 41 randomised classes distributed in 13 schools have been
investigated by means of a questionnaire specifically developed.
Laboratory of Neurobiology of Prions
Prion's disease
Prion diseases, also known as transmissible spongiform encephalopathies, are progressive and
invariably fatal degenerative disorders of the central nervous system that affect humans and
other animals. Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS)
syndrome, and fatal familial insomnia (FFI) are the most common forms in humans; scrapie of
the goat and sheep, bovine spongiform encephalopathy (“mad cow disease”), and chronic
wasting disease of deer and elk are the best-known examples of prion zoonoses. These diseases
result from the conformational change of a cellular protein of unclear function (denominated
prion protein, PrP) into a self-propagating pathogenic isoform that accumulates in the brain of
the patients and causes neuronal dysfunction and degeneration through an unknown mechanism.
Three different manifestations of prion diseases are recognized: sporadic, infectious and genetic.
Genetic prion diseases display autosomal dominant inheritance and are linked to insertional and
point mutations in the PrP gene, on chromosome 20. These mutations are presumed to favor the
conformational conversion of PrP into a pathogenic isoform. Interestingly, different mutations
are associated with different types of prion disease (CJD, GSS or FFI).The research activity in
the laboratory of Prion Neurobiology is focused on two main questions: 1) What causes
neuronal dysfunction in inherited prion diseases? 2) How do different PrP mutations cause
different diseases? We have developed a research program to tackle these questions, using
transfected cells, transgenic mice and primary neuronal cultures for complementary exploration
of responses to mutant prion proteins. These experimental models are being analyzed with a
wide range of molecular and cell biology techniques, as well as protein chemistry and
proteomics.The major achievements of the laboratory are the development of the first transgenic
mouse model of Creutzfeldt-Jakob disease that recapitulates the cognitive, motor and
neurophysiological abnormalities of the human disorder (Dossena et al., Neuron, 2008), and the
discovery of the molecular mechanism by which mutant PrP induces neuronal dysfunction
(Senatore et al., Neuron, 2012).
Molecular mechanisms of synaptic dysfunction in genetic prion diseases
How mutant PrP leads to neurological dysfunction in genetic prion diseases is unknown.
Tg(PG14) mice synthesize a misfolded mutant PrP which is partially retained in the neuronal
endoplasmic reticulum (ER). As these mice age, they develop ataxia and massive degeneration
of cerebellar granule neurons. We found that motor behavioral deficits in Tg(PG14) mice
emerge before neurodegeneration and are associated with defective glutamate exocytosis from
granule neurons due to impaired calcium dynamics. We then discovered that PrP interacts with
the voltage-gated calcium channel 2-1 subunit which promotes the anterograde trafficking of
the channel. Owing to ER retention of mutant PrP, 2-1 accumulates intracellularly, impairing
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delivery of the channel complex to the cell surface. Thus mutant PrP disrupts cerebellar
glutamatergic neurotransmission by reducing the number of functional channels in cerebellar
granule neurons. These results link intracellular PrP retention to synaptic dysfunction, indicating
new modalities of neurotoxicity and potential therapeutic strategies.
Mechanism of toxicity of deleted form of prion protein
Insight into the normal function of PrP, and how it can be subverted to produce neurotoxic effects,
is provided by PrP molecules carrying deletions encompassing the conserved central region. The
most neurotoxic of these mutants carries a short deletion in the central core of the molecule (called
CR). This mutant produces a spontaneous neurodegenerative illness when expressed in
transgenic mice, and this phenotype can be dose-dependently suppressed by co-expression of wildtype PrP. Whether the toxic activity of CR PrP and the protective activity or wild-type PrP are
cell-autonomous, or can be exerted on neighboring cells, is unknown. To investigate this question,
we have utilized co-cultures of differentiated neural stem cells derived from mice expressing CR
or wild-type PrP. Using this system, we found that while CR-dependent toxicity is cellautonomous, the rescuing activity of wild-type PrP can be exerted in trans from nearby cells.
These results provided important insights into how CR PrP subverts a normal physiological
function of PrP, and the cellular mechanisms underlying the rescuing process.
A new method for detecting toxic amyloid-β oligomers involved in
Alzheimer’s disease
Soluble oligomers of the amyloid- peptide play a key role in the pathogenesis of Alzheimer’s
disease, but their elusive nature makes their detection challenging. We have developed a new
immunoassay based on surface plasmon resonance (SPR) that specifically recognizes
biologically active amyloid- oligomers. This assay allows specific recognition of oligomeric
intermediates, discriminating them from monomers and higher order aggregates. The species
recognized by SPR generate ionic currents in artificial lipid bilayers and inhibit the
physiological pharyngeal contractions in the nematode Caenorhabditis elegans, a new method
for testing the toxic potential of amyloid- oligomers. With these assays we found that the
formation of toxic oligomers is inhibited by epigallocatechin gallate and increased by a
mutation linked to early onset dementia. The SPR-based immunoassay provides new
opportunities for detection of toxic amyloid- oligomers in biological samples and could be
adapted to study misfolding proteins in other neurodegenerative disorders.
Laboratory of Neurochemistry and Behavior
Executive functions dependent on prefrontal cortex are modulated by
striatal D1-like and D2-like receptors
The cognitive deficit is a core symptom of schizophrenia and is common to other psychiatric
and neurological conditions. The cognitive deficit of schizophrenia was modelled in rats by
using a test of attention such as the 5-choice serial reaction time task (5-CSRTT) and injections
of glutamate NMDA receptor antagonists into the medial prefrontal cortex. This model makes
clear links with psychopathology as dysfunctional glutamate neurotransmission in the mPFC
has been implicated in cognitive deficits of schizophrenia and the 5-CSRTT is the rat analogue
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of the continuous performance test used to assess attention and vigilance in schizophrenic
patients. Blockade of NMDA receptors of the medial prefrontal cortex caused a cognitive
deficits characterized by attention deficit, impulsivity and compulsivity. We used this model to
investigate the role of D1-like and D2-like receptors in attention deficit caused be cortical
glutamatergic dysfunction. We found that cortical information important for input selection
process can be restored by blockade of striatal D1-like receptors while blockade of D2 receptors
rescued behavioural flexibility i.e. the ability to switch from one response to the next in a
complex motor sequence.
Trace amine-associated receptor1 modulates brain monoamines
transmission and reduce the sensitivity to psychostimulants
Trace amine-associated receptor1 (TAAR1) has been recently identified in the central nervous
system. Its physiological role is not clear because only in the last few years suitable tools, such
as selective TAAR1 agonists and antagonists and TAAR1 knockout and transgenic animal,
become available. In collaboration with Hoffmann-La Roche researchers, who generated
TAAR1 transgenic mice we found that overexpression of TAAR1 caused an alteration of brain
dopamine, noradrenaline and serotonin release under basal conditions and reduced response to
amphetamine, a psychostimulant with pharmacological properties and a well known recreational
drug. These results indicate that TAAR1 represents a novel mechanism for controlling
monoaminergic transmission and a potential target for the development of novel drugs.
Experimental model of Rett syndrome
Rett syndrome is a X-linked genetic disorder predominantly caused by the loss-of-function of
the mecp2 gene. Females are predominantly affected. After a normal development until 6-18
months, a regression phase begins and patients start to show a spectrum of abnormalities
including neurological symptoms such as ataxia, aphasia and apraxia, abnormal motor functions
irregular breath, disruption of the sleep/wake pattern, autistic symptoms, repetitive hand
movements (hands-wringing), convulsions back deformities and feding abnormalities.
Experimental models are fundamental for investigating the biological bases of the disease and is
necessary for the development of potential therapies. With this aim and the support of the Italian
Rett Syndrome Associaton (AIRETT), we characterize the behaviour of mecp2308-/- homozygous
female mice, which carry a truncated gene. Differently from conventional knockout mice that
survive for few weeks, gene truncation is associated with a milder phenotype and prolonged
survival (>10 months), which allows the investigation of motor and cognitive functions and
behavior at different ages. Mecp2308-/- mice showed early onset motor deficits (motor
performance and coordination), tremors, clasping and kiphosis worsening over time. Cognitive
performance as well as emotional and social behavior were apparently not affected.
Laboratory of Neurological Disorders
Epidemiological studies on amyotrophic lateral sclerosis (ALS)
Included are studies on the incidence, risk factors and mortality of ALS. The data are obtained
from a regional registry of the disease activated in 1998 and including all patients with newly
diagnosed ALS identified in the Lombardy region. Using similar study protocols, the same data
are collected in three additional regional registries (from Piemonte, Liguria and Puglia) included
in a network with the Lombard registry. Information obtained from patients enrolled in the
Lombard registry and from cases examined by members of the Italian ALS Study Group has
been used to assess the validity and reliability of diagnostic criteria for ALS and selected
disability scales. Based on the data recorded, the annual incidence of ALS is comparable to that
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obtained in other Western countries where ALS registries have been activated, and is among the
highest ever published (1.9 per 100,000). Mortality of ALS has been found to be comparable to
that of studies from similar populations studied with the same protocol. The study on the
validation of the current diagnostic criteria for ALS (the El Escorial criteria) showed that to be
considered valid and reliable, the criteria should be used after proper training of the
investigators.
In October 2004, the Laboratory of Neurological Disorders has started a European collaborative
group for the ALS registries (EURALS) with the intent to create a common database
(completed in the year 2005) with the participation of the existing regional and national disease
registries. With the collaboration of the UK and Irish groups participating in the EURALS
collaboration, a scientific report has been published on a meta-analysis of the incidence of ALS,
performed by pooling data from the 1998-99 cohorts of patients enrolled in the populationbased registries. Two studies have been recently concluded: 1. A case-control study on trauma
and risk of ALS (in collaboration with the Italian registries); 2. A survey of the prevalence of
cognitive impairment and extrapyramidal signs in patients with newly diagnosed ALS (Italian
registries); 3. A study on the correlation between ALS and coffee intake; 4. A comparative
study of the genotype and phenotype of early onset and late onset ALS; 5. A case-control study
of sport, physical activity, and trauma and risk of ALS (in collaboration with partners of the
EURALS group). The following investigations are still in progress: 1- A study on the mortality
of ALS in a population-based incident cohort 1998-2002, aimed to assess long-term survival
and verify the correctness of the diagnosis; 2. A study comparing cognitive impairment and
extrapyramidal signs in a sample of ALS patients and in a matched control population in
Lombardy; 3. An observational study to identify environmental and and genetic risk factors in
some European populations. 4. A survey on dietary factors in patients with ALS and healthy
controls to investigate the effects of alimentary habits on the disease risk.
Therapeutic trials in neurological disorders
During the year 2010 seven therapeutic trials sponsored by the Italian Drug Agency (AIFA) and
a therapeutic trial sponsored by the Italian Ministry of Health were ongoing. Included are: 1. A
randomized double-blind parallel-group placebo-controlled trial on the efficacy and tolerability
of L-acetylcarnitine in ALS; 2. A randomized open-label parallel-group trial comparing
Erythropoietin to Methyl-prednisolone in patients with acute spinal cord injury; 3. A
randomized double-blind parallel-group placebo-controlled trial on the efficacy and safety of
valproate in medication-overuse headache; 4. A randomized open-label trial of the efficacy of a
comprehensive rehabilitation program for the prevention of falls in Parkinson’s disease; 5. A
randomized open-label trial on the efficacy of an active monitoring of the adverse effects of
antiepileptic drugs and of relevant drug interactions; 6. A randomized open-label trial on the
efficacy of an educational program for physicians working in nursing homes. 7. A multicenter,
randomized, double-blind, placebo controlled, parallel-group trialof intravenous
immunoglobulin svc. methylprednisolone in patients with chronic inflammatory demyelinating
polyradiculoneuropathy The first trial aims at finding a potentially effective drug in a clinical
condition for which there is only one product (Riluzole) with at best modest efficacy on
survival. L-acetylcarnitine has been found to improve survival in experimental models of motor
neuron disease. The second trial intends to verify the efficacy of erythropoietin, a drug shown to
mitigate the effects of traumatic spinal shock and accelerate recovery in experimental animals.
The drug chosen for comparison (methylprednisolone at high doses) has been selected for being
the present gold standard in clinical practice. The third trial aims at verifying whether valproate
(a drug commonly used for the prophylaxis of migraine) abates symptoms occurring in drugoveruse headache, a common and frequently invalidating variety of chronic idiopathic
headache. The fourth trial aims at assessing whether a comprehensive rehabilitation program
compared to usual care is followed by a reduction in the incidence of falls in patients with
Parkinson’s disease at risk of falls. The fifth trial aims at verifying the added value of an active
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monitoring of adverse drug interactions compared to usual care in patients receiving
antiepileptic drugs associated to other compounds. The sixth trial aims to verify the added value
of a web-based educational program in reducing the number of inappropriate prescriptions
compared to usual care. The seventh trial aims at evaluate the comparative efficacy and
tolerance of IVIg or corticosteroids over a 6 month period, which remains unclear.
The laboratory of neurological disorders is the coordinator of the first trial and a partner in the
other trials, where the main tasks include protocol and CRF preparation, statistical analysis, and
preparation of the final scientific report.
Public knowledge and attitudes towards epilepsy
Two national population-based surveys have been conducted to assess the knowledge and
attitudes of the Italian population towards epilepsy. The first study was a telephone interview of
819 women and 737 men aged 18 or older to verify the basic knowledge of the frequency,
causes and characteristics of the disease and their attitudes towards the affected individuals. The
answers were compared to those of a previous interview performed 25 years before. The
interviewees showed satisfactory basic knowledge, with few exception, and an overall
improvement in the acquired notions and the attitudes when compared to the responders in the
antecedent survey. However, about half of them still considered epilepsy a psychiatric disorder
and a source of important limitations in everyday life. Knowledge and attitudes varied with age,
gender and education. A second telephone survey involved 600 primary and secondary school
teachers. As with the previous interview, respondents showed a satisfactory basic knowledge
but some negative attitudes towards epilepsy and several of them declared being unable to
manage an epileptic seizure.
Barriers toward epilepsy surgery
Epilepsy surgery is a valuable therapeutic option in patients who do not respond to the available
drugs. Knowledge and attitudes toward epilepsy surgery have been tested through a
questionnaire survey in a sample of 183 neurologists and child neurologists in Italy and then to
patients (adults and adolescents) and their relatives. The responses to the first investigation
(only neurologists) were compared to those of a group of epilepsy experts. The study showed a
significant heterogeneity of responses, two thirds of them non-aligned to those of epilepsy
experts who were largely in favor of surgery. The only variables associated with negative
attitudes were the small number of surgical candidates among their patients and the region of
specialty attainment. The second survey was conducted in 228 adults patients with epilepsy in
tertiary referral centers in Lombardy. The responses showed that patients, even those who were
possible candidates for surgery, had received insufficient information and were therefore
unwilling to accept the treatment. Their opinion changed when detailed information on the risks
and benefits of surgery was given.
Prevalence and incidence of epilepsy in northern Italy
The study aim was to calculate the prevalence and incidence of epilepsy in a well-defined area
of Lombardy, using administrative data for the period 2000-2008 provided by the regional
database. Included were patients fulfilling the ICD 9 code for epilepsy and seizures and/or the
disability exemption code for epilepsy, the presence of EEG, and antiepileptic drugs
prescriptions in variable combinations. The validity of the diagnostic criteria was ossessed
examining a sample of patients with epilepsy through their caring physicians.
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Laboratory of Quality Assessment of Geriatric Services
Utilisation, integration and implementation of administrative database for
the assessment of prescribing appropriateness and in-hospital and
community therapeutical continuity
The availability of computerized system for the management and care of community-dwelling
and in-hospital patients represents an opportunity for developing and implementing new
strategy in the field of the evaluation, monitoring and implementation for the appropriateness of
drug prescription and the continuity of care. A collaborative study has been set up with the
Health Directorate of Lombardy Region, the Bergamo Local Health Unit and the hospital
“Azienda Ospedali Riuniti” of Bergamo with the goal to test in some critical prescribing fields
the effectiveness of multidisciplinary integrated interventions and educational events in
improving the prescribing practice and to implement the utilisation of generic drugs.
In the Working Group on the appropriateness prescribing in the elderly an interactive databse
has been done for the evaluation of prescription drugs with the aims of:
- identifying of drug interactions
- identifying of inappropriate prescribing
- Analysing the anticholinergic effects
- assessing the appropriate dosage in case of impaired renal function.
Drug interactions in elderly patients
In a collaborative study with Lombardy Region we analysed all prescriptions dispensed from
January 1, 2003 to December 31, 2003 to individuals aged 65 or more registered under the
Local Health Authority of Lecco, a northern Italian province with a population of almost
330,000 persons. Elderly who received at least two co-administered prescriptions were selected
to assess the presence of DDIs. 9115 elderly (16%) were exposed to potentially severe drugdrug interactions and 61% were women. A total of 13.520 severe drug interactions were
recognized, mainly involving cardiovascular drugs (56.8% of the cases). The prevalence of
potentially severe DDI increased at rising of the patient’s age and of the number of chronic
drugs prescribed. At univariate and multivariate analysis age and number of chronic drugs were
associated with an increasing risk of DDIs. Elderly constitute a population at high risk of DDIs.
Since physicians still have some difficulty in managing this topic, it is essential to provide them
with adequate information on which factors raise the risk of DDIs.
Drug utilisation in elderly patients
In a collaborative study with the Health Directorate of the Lombardy Region, a drug utilization
study aimed to investigate the overall drug prescription rate, the prescribing pattern of chronic
therapies and polypharmacy in relation to gender and different age groups of communitydwelling elderly people has been set up. All prescription for elderly aged 65 years or older (n=1
767 239), reimbursed by the National Health Service (NHS) and dispensed by retail pharmacies
of the 15 local health units (LHU) in the Lombardy Region between 1 January and 31
December 2005 were analyzed. During the year of the study, 1555142 elderly (88% of the
elderly population) received at least one drug prescription (89% women and 87% men). The
overall prescription prevalence rate was slightly higher in women than in men (OR 1.20; 95%
CI: 1.19-1.21), and increased up to 75 years of age in both sexes, reaching a plateau which
persisted until 85 years. Each treated elderly received an average of 5 drugs (active substances)
(median 4, interquartile range 2-7), without any difference between genders; 76% of the elderly
(76% women and 75% men) received at least one chronic drug, 46% were exposed to
polypharmacy (46% women and 45% men) and 20% to chronic polypharmacy (18% women
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and 22% men). Age and LHU of residence were predictors for chronic polypharmacy exposure
and at multivariate analysis, elderly in age groups of 75-79, 80-84 and 85-89 years had the
highest risk to be exposed to chronic polypharmacy (OR 2.25; 95%CI: 2.23-2.27, OR 2.68;
95%CI: 2.65-2.71, and OR 2.84; 95%CI: 2.79-2.89 respectively).
Quality assessment of services on dementia
A sample of Lombardy Region Alzheimer Special Care Units (ASCU) was compared with
traditional nursing homes to assess their effects on main clinical outcome in a sample of 450
residents followed for 18 months. Patients admitted at ASCU had a lower risk of hospitalisation,
use of physical restraints, and a higher probability of withdrawing antipsychotics than patients
admitted to NH. No difference was reported on overall mortality and falls.
Census and quality assessment of the Lombardy Region Alzheimer
Evaluation Unit (AEU)
A collaborative study with the Italian Alzheimer Association (Federazione Alzheimr Italia) was
organised with the aim to assess the quality of Lombardy Region AEU. After a census of the 81
AEU active in the Lombardy Region, a random sample of 18 AEU was selected for the quality
evaluation by specific indicators that covered all the three axes of quality (structure, process and
outcome). The overall quantitative score for each of the three axes was nearly 50% of the
available score. The comparison of the 18 AEU sowed some differences in all the three quality
axes, in particular the process axis. The results of the study highlight the need to improve the
standard of these services in order to better meet the needs of families and patients with
Alzheimer Disease.
Antipsychotic use in a sample of Italian Alzheimer Special Care Units
An observational prospective study was set up to evaluate the frequency of antipsychotic use
and their association with BPSD in institutionalised patients with dementia in northern Italian
Alzheimer’s special care units (ASCU). Sixty percent of 319 patients were taking at least one
antipsychotic, 49% typical and 51% atypical. Forty five percent were exposed to one
antipsychotic, 14% two and 1% three. Risperidone was the most frequently prescribed
antipsychotic followed by promazine, olanzapine and haloperidol. In 40% of the cases, another
hypnotic or sedative drug was simultaneously administered. Antipsychotics were significantly
associated with female sex, older age and higher NPI score, but did not significantly influence
mortality, hospitalisation, falls or use of physical restraint at follow-up.
Antipsychotic use and mortality in the “very old” with dementia: the
Monzino 80-plus study
To investigate the association between the use of antipsychotic drugs and the risk of death in the
very old general population affected by dementia we analysed the data of The Monzino 80-plus
study. This is an ongoing, prospective population-based study of all eighty years or older
residents in eight municipalities of Varese province, Italy. The diagnosis of dementia was based
on DSM-IV criteria. Information on drug use at baseline was obtained from participants and/or
caregivers. At baseline, 33.6% of the elderly participants (n1/4618) were found to be affected by
dementia. The use of antipsychotics was much more common among demented than non
demented elderly (19.1% vs 2.3%, p<0.0001). Frequency of antipsychotic drug use was similar
among demented persons living at home and those institutionalized (18.8% vs 20.0%,
p1/40.73). After a follow-up period of 1, 2, 3, or 4 years, no significant differences (p>0.33) in
death rate were found between demented elderly taking antipsychotics (29.7%, 48.3%, 61.9%,
64.4%) and those not taking antipsychotics (34.4%, 49.0%, 60.6%, 67.2%). The difference
remarne not significantly different also when potential confounders (age, sex education,
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smoking history, BMI, stroke, diabetes, hypertension, myocardial infarction, heart failure,
COPD) were entered into a logistic regression model (p 1/4 0.46).
Rationalization of drug prescribing in patients resident in the Bergamo
Local Health Authority
In a study aimed to improve the quality of drug prescribing of general practitioners (GPs) in
selected therapeutic areas (non-steroidal anti-inflammatory drugs, proton pump inhibitors,
antibiotics, and antihypertensive agents, conducted among 160 GPs of the Bergamo Local
Health Authority, we found a reduction of inappropriate prescribing of nearly 3% in all the
indicatos of drug utilization and cost analyzed.
The REPOSI Study
The REgistro POliterapie SImi (REPOSI) study is a collaborative effort between the Italian
Society of Internal Medicine (SIMI-Società Italiani Medicina Interna) and the Mario Negri
Institute for Pharmacological Research. It was designed with the purpose to set up a network of
internal medicine and geriatric wards in order to investigate patients aged 65 years or older
affected by multiple diseases and prescribed with polypharmacy. Participation to the network
was on a voluntary basis. During a period of four weeks, three months apart each from the
other, the 38 wards involved in the study, recruited 1332 elderly patients (aged 65 years or
older). The main results from the analyses of this cohort of hospitalized elderly patients are the
following:
1. at hospital admission 52% of patients taken five or more different drugs (polypharmacy)
and were in the ward for a mean of 11 days.
2. The comparison discharge-admission showed an increasing rate of patient with
polypahramacy (+13%) and with multiple disease (+16%).
3. No difference emerged in terms of in-hospital mortality between patients with
polypharmacy and the other ones.
4. At multivariate analysis the in-hospital mortality and hospital stay were positively
associated with age, adverse clinical events, and comorbidity (Charlson Index).
Furthermore, with aim of recognizing clusters of diseases among the hospitalized elderly, and of
identifying groups of patients at risk of in-hospital death and adverse clinical events according
to disease clustering, a regression analysis was done. Patients affected by the clusters including
heart failure (HF) and either chronic renal failure (CRF), or chronic obstructive pulmonary
disease had a significant association with in-hospital death (OR=4.2;95%CI=1.6-11.4;
OR=2.9;95%CI=1.1-8.1, respectively), as well as patients affected by CRF and anaemia
(OR=6.0;95%CI=2.3-16.2). The cluster including HF and CRF was also associated with adverse
clinical events (OR=3.5;95%CI=1.5-7.7). The effect of both HF and CRF and CRF and anaemia
on in-hospital death was additive.
Another analysis was done with the aims to evaluate the rate of prescriptions of drugs for peptic
ulcer or gastro-oesophageal reflux disease (GERD) in elderly patients at admission and
discharge in a sample of internal medicine wards, and to analyze their appropriateness of use in
relation to the evidence-based indications. The appropriateness of drug prescriptions for peptic
ulcer and GERD were retrospectively evaluated taking into account the presence of conditions
requiring their use or the use of gastro-toxic drugs combination. Among 1155 patients eligible
for the analyses, elderly treated with drugs for the treatment of GERD or peptic ulcer were 466
(40.3%) at hospital admission and 647 (56.0%) at discharge. 65.2% of patients receiving a drug
for peptic ulcer or GERD at admission and 64.1% at discharge were inappropriately treated.
Among patients inappropriately treated the number of other drugs prescribed was associated
with an increased use of drugs for peptic ulcer or GERD, also after adjustment for age, sex and
number of diagnoses at admission (OR 95%CI=1.25 (1.18-1.34), p=.0001) or discharge (OR
95%CI= 1.11 (1.05-1.18), p=0.0003).
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With the aim to evaluate the association between the presence of bacterial or communityacquired pneumonia (CAP) and the use of drugs inhibiting gastric acid secretion such as proton
pump inhibitors (PPIs) and antagonists H2-receptor (anti-H2) was conducted logistic regression
analysis. A statistically significant association between the presence of bacterial infection and
use of PPI was found. This association was greater in elderly receiving the drug for more than
14 days and even after adjusting results for age, sex and comorbidity.
To evaluate the adherence to current guidelines on cardio-embolic prophylaxis in elderly (>65
years old) patients admitted with an established diagnosis of AFF to the Italian internal
medicinewards participating in REPOSI registry project, we retrospectively analyzed registry
data collected from January to December 2008. At admission, CHADS2 score was ≥ 2 in 68.4%
of patients, at discharge in 75.9%. Among patients with AFF 26.5% at admission and 32.8% at
discharge were not on antithrombotic therapy, and 43.7% at admission and 40.9% at discharge
were not taking an appropriate therapy according to the CHADS2 score. Among elderly patients
admitted with a diagnosis of AFF to internal medicine wards, an appropriate antithrombotic
prophylaxis was taken by less than 50%, with an underuse of VKAs prescription independently
of the level of cardio-embolic risk. Hospitalization did not improve the adherence to
guidelines.To explore the association of dementia with in-hospital death in acutely ill medical
patients, we analzed data on 1332 in-patients aged 65 years or older enrolled in the REPOSI
study.
After multiadjustment, the diagnosis of dementia was associated with in-hospital death (OR =
2.1; 95% CI = 1.0 - 4.5). Having dementia and at least one adverse clinical event during
hospitalization showed an additive effect on in-hospital mortality (OR = 20.7 ;95% CI = 6.9 –
61.9). Acutely ill elderly patients affected by dementia are more likely to die shortly after
hospital admission. Having dementia and adverse clinical events during hospital stay increases
the risk of death.
We assessed which clusters of diseases are associated with polypharmacy in acute-care elderly
inpatients. Among clusters of diseases, the highest mean number of drugs (N=8) was found in
patients affected by heart failure (HF) plus chronic obstructive pulmonary disease (COPD), HF
plus chronic renal failure (CRF), COPD plus coronary heart disease (CHD), diabetes mellitus
plus CRF, and diabetesmellitus plus CHD plus cerebrovascular disease (CVD). The strongest
association between clusters of diseases and polypharmacy was found for diabetes mellitus plus
CHD plus CVD, diabetes plus CHD, and HF plus atrial fibrillation (AF).We evaluate the
prevalence of antidepressant prescription and related factors in elderly in-patients, as well as the
consistency between prescription of antidepressants and specific diagnoses requiring these
medications. The number of patients treated with antidepressant medication at hospital
admission was 115 (9.9%) and at discharge 119 (10.3%). In a multivariate analysis, a higher
number of drugs (OR = 1.2; 95% CI = 1.1–1.3), use of anxiolytic drugs (OR = 2.1; 95% CI =
1.2–3.6 and OR = 3.8; 95% CI = 2.1–6.8), and a diagnosis of dementia (OR = 6.1; 95% CI =
3.1–11.8 and OR = 5.8; 95% CI = 3.3–10.3, respectively, at admission and discharge) were
independently associated with antidepressant prescription. A specific diagnosis requiring the use
of antidepressants was present only in 66 (57.4%) patients at admission and 76 (66.1%) at
discharge.
Prevalence and appropriateness of antidepressant use in the elderly.
The objectives of the present study were to investigate the prevalence and the appropriateness of
antidepressant (AD) use in the elderly population living in three Local Health Unit of Lombardy
Region by using a population-based prescription dataset. Changes in the patterns of
antidepressant prescribing from 2000 to 2007 were investigated and put into relation with the
rates of depressive disorders in Lombardy. The 1-year prevalence of “AD use” increased
dramatically from 2000 to 2007. The greatest shift occurred between 2000 and 2003 when the
global prescription almost doubled increasing from 5.5% to 9.9%. The most pronounced
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increase was seen in females who in 2007 reached a 1-year prevalence of AD use of 13.8%. The
prescription of TCAs and other ADs remained stable across the years, thus the observed
changes were mainly attributable to SSRIs. The SSRIs accounted for 44.8% of “AD use” in
2000 and rose to 75.7% in 2007. The most prescribed antidepressant was citalopram: its 1-year
prevalence increased about sixfold and, in 2007, peaked at 3.3%. Citalopram was followed by
two SSRI: paroxetine (2.2%) and sertraline (1.9%).
Pattern of Cholinesterase Inhibitors Use in Alzheimer’s disease: Results
of the EPIFARM-Elderly Project.
This study was aimed to examine the trend of cholinesterase inhibitors (ChEIs) use during
2002-2007 and to estimate the rate of Alzheimer’s disease (AD) patients treated with ChEIs.
Individuals aged 65 years or older who received at least one prescription of ChEIs between
January 1, 2002 and December 31, 2007 were included in the study. ChEIs utilization was
estimated using prescription data of drugs reimbursed by the Italian National Health Service
between January 1, 2004 and December 31, 2007 in three provinces of the Lombardy region
(Milan, Lecco and Brescia), Italy. The rate of elderly who received at least one prescription of
ChEIs increased from 0.5% in 2002 to 0.7% in 2004 and then remained unchanged until to
2007. The percentage of mild to moderate AD cases taking ChEIs was rather low (19-20%), and
fairly stable overtime in the less treated oldest age groups (80+), while decreased in the
youngest (65-79 years). In incident AD cases, the percentage of newly treated patients
decreased overtime in the overall group (from 11.7% in 2004 to 8.0% in 2007) as well as in
each age class. In the cohort of incident AD cases who started the treatment during 2004, nearly
40% were also in treatment three years later.
The declining use of reboxetine in years 2000-2006
To compare the use of reboxetine with that of fluoxetine and paroxetine in a large population
sample of subject living in Lomabrdy Region, and to compare reboxetine prescribing trends
with those of mirtazapine. As expected, the use of paroxetine and fluoxetine peaked in 2002 and
then decreased. The prescripition rates of mirtazapine gradually increased all through the study
period: from 0.07% in 2000 to 0.13% in 2006. On the contrary, the prescription rates of
reboxetine showed a different trend and progressively decreased from 0.20 in 2000 to 0.04 in
2006. The annual rates of the prolonged use of paroxetine and fluoxetine significantly increased
over time: from 58% in 2000 to 63% in 2006 (p<0.001) and were characterised by a highly
significant heterogeneity (p<0.001). Also reboxetine prolonged use showed a statistically
significant growth: from 33% in 2000 to 52% in 2006 (p<0.001). It increased by 4% per year
with no significant heterogeneity. The overall proportion of prolonged use, however, was
significantly lower for reboxetine (42%) than for paroxetine (57%; OR: 0.55, 95% IC: 0.530.57, p<0.001) and fluoxetine (58%; OR: 0.53, 95% IC: 0.51-0.55, p<0.001).
Across the study period the annual rates of persistence ranged 21-27% for reboxetine, 28%-43%
for paroxetine and 30%-46% for fluoxetine. There was a certain fluctuation in annual rates and
no significant time trends were evident. The overall proportion of persistence was significantly
lower for reboxetine (23%) than for paroxetine (34%; OR: 1.67, 95% IC: 1.56-1.79, p<0.001)
and fluoxetine (36%; OR:1.89, 95% IC: 1.76-2.03).
Within region differences in outpatient antibiotic prescription
To assessed antibiotic patterns of use and geographical distribution of prevalence and
consumption by age in 15 Local Health Units (LHUs) of Italy’s Lombardy region, we
retrospectively analysed administrative claims for the community-dwelling population in 2005.
A total of 3 120 851 people (34 % of the population) received at least one antibiotic drug
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prescription. The highest prescription prevalence was observed in the 0-17 and 80 or more year
age ranges (41.6% and 41.9%, respectively). Large differences were found in prevalence rates
between different LHUs (ranging from 28.7% in Milan to 39.4% in Brescia) and in DIDs
(ranging from 12.2 DID in Sondrio to 19.8 DID in Brescia). The age and residence of the
population were the main determinants of drug exposure. In particular, patients aged <18 years
(OR= 1.73; 95% CI 1.73, 1.74), aged 65 or older (OR= 1.64; 95% CI 1.63, 1.65), and those that
live in Brescia (OR 1.66, 95% CI 1.65, 1.66) had a statistically significant higher risk of
antibiotic drug exposure. A careful monitoring should be carried out to reduce antibiotic
resistance and improve the rational use of drugs.
Changes in co-prescribing warfarin and potentially interacting drugs and
risk of major bleeding in community-dwelling elderly people
To analyze the rate and trend of co-prescribing warfarin and potentially interacting drugs (PIDs)
and the risk of hospitalization for major bleeding in communitydwelling elderly people, a cohort
of community-dwelling elderly people (aged 65 years or more) who received at least one
prescription for warfarin during the period 2001-2007 was drawn from Lombardy Region
administrative database (northern Italy) was analysed. Age, local health unit (LHU) of
residence, number of drugs and co-prescribed PIDs were predictors of hospitalization for
hemorrhage, but the risk decreased during the study period (OR 0.94; 95% CI, 0.89-0.99).
Compared with prescribing warfarin alone, coprescribing antibacterial drugs, calcium
antagonists, allopurinol, omeprazole and ranitidine increased the risk of hospitalization for
major bleeds. Over time, the rate of users warfarin of alone increased, and the percentage of
those co-prescribed of PIDs fell slightly (χ2 trend: 3.74; p<0.001). No differences were found in
the interaction between the co-prescription of warfarin with PID and years of prescription.
Effect of an integrated e-learning intervention, focused on
“Comprehensive Geriatric Assessment” to improve the quality of drug
prescribing in hospitalized elderly patients. The ELICADHE-AIFA Project
Health care systems are increasingly challenged by the complex management of geriatric
patients with multiple chronic conditions that receive multiple drugs. The traditional clinical
assessment does not provide thorough information on all the needs of these patients.
Comprehensive Geriatric Assessment (CGA) provides such information, offers a more specific
and sensible care plan for each patient, and may improve the quality of prescribing. With the
aim to evaluate whether an integrated e-learning program of medical education, focused on
teaching and implementing CGA added to geriatric pharmacological notions (GPNs)
(intervention) is superior to delivering only GPNs (control) in reducing the prescription of
potentially inappropriate drugs (PID) or potential drug-drug interactions (PDDI) in hospitalized
elderly, a cluster randomized single-blind controlled study was set up in a sample of elderly
patients (aged 75 years or more) consecutively admitted to 20 geriatric and internal medicine
hospital wards, and randomized to study intervention or control group.
Secondary aims are to assess the clinical impact of the integrated e-learning intervention on the
length of hospitalization, in-hospital and overall mortality, re-hospitalization, institutionalization
and persistence of the effect of improving quality of drug prescribing during a follow-up of 12
months.
The results of this project should help to provide National Health Service with indications on
the clinical impact of a e-learning intervention in improving pharmacological use in hospitalized
elderly patients.
The results of the pilot study indicate that 26% of patients in the intervention group and 18% in
the control group were treated on admission with at least one inappropriate medication
according to the Beers criteria. These percentages drop respectively to 21% and 16% at
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discharge. 56% of patients in the intervention group and 77% in the control group were taking
medications at admission with the risk of potential interactions (12% and 15% of patients
respectively were at the risk of drug interactions whose clinical significance was considered as a
major). Regarding the use of inappropriate drugs or duplicate emerges a reduction in both
groups, while in relation to drug interactions, there is a drop for those classified with greater
clinical relevance.
Co-prescription of antipsychotics in patients treated with cholinesterase
inhibitors: the EPIFARM-Elderly Project
The objective of the study was to assess co-prescribing of antipsychotics in elderly taking
cholinesterase inhibitors (ChEIs) from 2002 to 2008 and the changes subsequent to two main
official warnings issued by the Italian Medicines Agency to restrict their use. Elderly patients
aged 65-94 years who received at least one prescription of ChEIs between 1 January 2002 and
31 December 2008 were selected. Co-prescribing of atypical antipsychotics in patients exposed
to ChEIs declined from 21.0% in 2002 to 14.6% in 2008 (OR 0.92; 95%CI:0.90, 0.94; p<0.001),
while the prescribing prevalence of typicals slightly increased (OR 1.08; 95%CI:1.03, 1.13;
p=0.001). In relation to the two warnings, the prevalence of patients who received a coprescription of antipsychotics was significantly lower in 2005 than 2004 (23.1% vs. 28.0%; OR
0.79; 95%CI:0.73-0.86; p<0.001) and in 2007 than 2006 (19.4% vs. 23.0%; OR 0.79;
95%CI:0.73-0.86; p<0.001). After the first safety warning the prevalence of prescriptions for
risperidone and olanzapine dropped significantly, and there was a significant increase for
quetiapine. Haloperidol prescriptions increased, especially after the second warning. Despite
regulatory warnings issued to discourage the use of antipsychotics, they are still frequently
prescribed to patients taking ChEIs. Awaiting further studies to clarify their therapeutic role,
physicians should prescribe antipsychotics very cautiously and only after careful risk-benefit
assessment.
Antipsychotics use and cerebrovascular events in Italian adult and older
persons;
subgroup
analysis
of
persons
prescribed
with
acetilcholinesterase inhibitors
Our aims were to evaluate the association of antipsychotics use with CVEs amongst Italian
adults and elderly, to compare the effect of typical and atypical antipsychotics on CVEs, and to
investigate a possible interaction between antipsychotics and acetilcholinesterase inhibitors
(AChEI). Administrative claims from community-dwelling people aged 50 to 94 years living in
Northern Italy were analysed using a retrospective case-control design, from 2003 to 2005. The
primary outcome measure was hospital discharge diagnosis of CVEs during 2005. We identified
4413 cases of CVEs matched with 17652 controls. The mean age was 76.4 years and 51% of the
samples were females. The crude OR for CVEs due to any antipsychotic was 1.48
(95%CI=1.21–1.81), due to atypical antipsychotics 1.39 (95%CI=1.07-1.79) and due to typical
antipsychotics 1.91 (95%CI=1.38-2.63). In multi-adjusted models the association remained
significant only for typical antipsychotics (OR=1.62;95%CI=1.17-2.25). Amongst the 223
persons prescribed with AChEI, 72 cases of CVEs were identified; of these, subjects taking
antipsychotics did not have an increased risk of CVEs (OR=0.62;95%CI=0.30-1.25). In
conclusion, typical antipsychotics prescription was associated with an increased odd of CVEs.
After stratification, persons prescribed with AChEI did not show any association with CVEs.
Drug information service for the elderly
A daily free of charge telephone service for drug and clinical information is available for
physicians and elderly. Nearly 600 questions are answered each year.
ANNUAL REPORT
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DEPARTMENT OF CARDIOVASCULAR
RESEARCH
STAFF
Head
Maria Grazia FRANZOSI, Biol.Sci.D.
Laboratory of Cardiovascular Clinical Pharmacology
Head
Roberto LATINI, M.D.
Bio-imaging Unit
Head
Fabio FIORDALISO, Biol.Sci.D.
Cardiovascular Endocrine Unit
Head
Serge MASSON, Ph.D.
Tissue Culture Unit
Head
Giovanna BALCONI, BSc.
Laboratory of Clinical Drug Evaluation
Head
Maria Grazia FRANZOSI, Biol.Sci.D.
Bioinformatics Unit
Head
Enrico NICOLIS
Laboratory of General Practice Research
Head
Maria Carla RONCAGLIONI, Biol.Sci.D.
Laboratory of Medical Statistics
Head
Simona BARLERA, Dr.Sci.Pol., MSc.
Laboratory of Clinical Pharmacology
Head
Gianni TOGNONI, M.D.
Nursing Research Unit
ANNUAL REPORT
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IRFMN
Head
Paola DI GIULIO, R.N., MSc
ANNUAL REPORT
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CURRICULA VITAE
Maria Grazia Franzosi got her Biological Science degree in 1972 at the University of Milan.
Education
1972
1978
Doctoral degree in Biological Sciences, University of Milan, Italy
Postdoctoral degree in Pharmacological Research, Istituto di Ricerche Farmacologiche "Mario
Negri” di Milano, Italy
Main fields of activity
Coordination of multicentric randomised clinical trials. Relationship between genetic and environmental risk
factors in coronary events. Pharmacogenetics. Cardiovascular genetic epidemiology. Pharmacoeconomics.
Drug Epidemiology and Post-Marketing Surveillance.
Position
from 2002
from 2005
from 2004
from 2001
from 1998
from 1997
from 1996
1994-1996
from 1993
from 2002
from 1989
1985-1988
from 1984
1975-1984
Director of the Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
"Mario Negri", Milano, Italy
Member of the Coordinating Committee of Master course in Clinical Research – University of
Milano
Member of Steering Committee, Studio GISSI-AF Study, Milano, Italy
Member of Steering Committee, Studio GISSI-HF Study, Milano, Italy
Member of Steering Committee of the PROCARDIS Research Programme - A genome-wide
strategy to identify susceptibility loci in precocious coronary artery disease - University of
Oxford, UK
Member of “Antithrombotic Trialists’ Collaboration”, Oxford, UK
Member of Steering Committee e National Coordinator for Italy of the Organization to
Assess Strategies for Ischemic Syndromes (OASIS-2, OASIS-4 CURE, Michelangelo
OASIS-5 e OASIS 6, CURRENT OASIS-7, FUTURA OASIS-8), INTER-HEART,
ACTIVE, RE-LY, AVERROES, RIVAL studies and of RE-LY Registry, Population Health
Research Institue, McMaster University, Hamilton, Canada
Director of European Coordinating Centre and Member of Steering Committee, Collaborative
Organization for RheothRx Evaluation (CORE), McMaster University, Hamilton, Canada
Member of Steering Committee, Studio GISSI-Prevenzione, Milano, Italy
Member of “Fibrinolytic Therapy Trialists’s Collaboration”, Oxford, UK e del “Collaborative
Group on Angiotensin Converting Enzyme Inhibitors Trials”, National Institutes of Health,
Bethesda, Washington, USA
Head of the Laboratory of Clinical Drug Evaluation, Istituto di Ricerche Farmacologiche "Mario
Negri"
Head of the Clinical Drug Evaluation Unit of the Laboratory of Clinical Pharmacology, Istituto
di Ricerche Farmacologiche "Mario Negri"
Member of the Scientific and Organising Secretariat, Gruppo Italiano per lo Studio della
Sopravvivenza nell'Infarto Miocardico (GISSI-1, GISSI-2, GISSI-3 studies) Milano, Italy
Researcher at the Laboratory of Clinical Pharmacology, Istituto di Ricerche Farmacologiche
"Mario Negri" and at the Regional Center for Drug Information of the Lombardy Region
Selected publications

GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,
Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of n-3 polyunsaturated fatty acids in patients with chronic heart
failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223-1230

Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D,
Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R,
Watkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and
coronary disease. N Engl J Med 2009; 361: 2518-2528

GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni
AP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;
360: 1606-1617

The FUTURA/OASIS-8 Trial Group. Low-Dose vs standard-dose unfractionated heparin for percutaneous coronary
intervention in acute coronary syndromes treated with fondaparinux: The FUTURA/OASIS-8 Randomized Trial. JAMA
2010; 304: 1339-1349

Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J,
Pogue J, Reilly PA, Yang S, Connolly SJ, on behalf of the RE-LY investigators. Efficacy and safety of dabigatran
compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial
fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975-983

Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians
identifies five new loci for coronary artery disease Nat Genet 2011; 43: 339-344
ANNUAL REPORT
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Barbati E, Specchia C, Villella M, Rossi ML, Barlera S, Bottazzi B, Crociati L, d'Arienzo C, Fanelli R, Garlanda C, Gori
F, Mango R, Mantovani A, Merla G, Nicolis EB, Pietri S, Presbitero P, Sudo Y, Villella A, Franzosi MG. Influence of
pentraxin 3 (PTX3) genetic variants on myocardial Infarction risk and PTX3 plasma levels. PLoS One 2012; 7: e53030
Simona Barlera got her degree in Political Science, area Statistics at the “Università degli Studi di
Milano” in Milano in 1992, followed by a master in Medical Statistics at the London School of Hygiene
and Tropical Medicine, “University of London” in 1998.
Education and training
1987-1992
Degree in Political Sciences, course of studies Statistics, Università degli Studi di Milano,
Milano (Italy)
1993-1995
Post-degree Specialization in Pharmacological Research. School of Specialization in
Pharmacological Research of Lombardy Region, Milan
1997-1998
Master of Science in Medical Statistics at the London School of Hygiene and Tropical
Medicine, University of London, London.
1998-1999
Visiting Scientist in the Department of Statistical Genetics, Wellcome Trust Centre for
Human Genetics, University of Oxford (UK).
Main fields of activity
Methodology of Clinical Trials in the cardiovascular field. Preparation and viewing of research protocols,
planning and conduct of statistical analyses and the reporting of findings on scientific journals.
Genetic epidemiology: genome-wide strategies (linkage analysis) to identify susceptibility genes in
coronary artery disease; case-control studies in order to identify candidate genes involved in the
cardiovascular pathology.
Position Held
from Oct 2006 Head of the Laboratory of Medical Statistics, Department of Cardiovascular Research,
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
1999 -2006
Head of the Medical Statistics Unit, Department of Cardiovascular Research, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano, Italy
1992-1997
Researcher in the Unit of Applied Statistics and Information Technology, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano, Italy
Selected publications

GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,
Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of n-3 polyunsaturated fatty acids in patients with chronic heart
failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223-1230

Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D,
Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R,
Watkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) Lipoprotein Level and
Coronary Disease. N Engl J Med 2009; 361: 2518-2528

GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni
AP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;
360: 1606-1617

Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians
identifies five new loci for coronary artery disease. Nat Genet 2011; 43: 339-344

Holliday EG, Maguire JM, Evans TJ, Koblar SA, Jannes J, Sturm JW, Hankey GJ, Baker R, Golledge J, Parsons MW,
Malik R, McEvoy M, Biros E, Lewis MD, Lincz LF, Peel R, Oldmeadow C, Smith W, Moscato P, Barlera S, Bevan S,
Bis JC, Boerwinkle E, Boncoraglio GB, Brott TG, Brown RD Jr, Cheng YC, Cole JW, Cotlarciuc I, Devan WJ, Fornage
M, Furie KL, Grétarsdóttir S, Gschwendtner A, Ikram MA, Longstreth WT Jr, Meschia JF, Mitchell BD, Mosley TH,
Nalls MA, Parati EA, Psaty BM, Sharma P, Stefansson K, Thorleifsson G, Thorsteinsdottir U, Traylor M, Verhaaren BF,
Wiggins KL, Worrall BB; The Australian Stroke Genetics Collaborative; The International Stroke Genetics Consortium;
The Wellcome Trust Case Control Consortium 2, Sudlow C, Rothwell PM, Farrall M, Dichgans M, Rosand J, Markus
HS, Scott RJ, Levi C, Attia J. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat
Genet 2012; 44: 1147-1151

Masson S, Anand I S, Favero C, Barlera S, Vago T, Bertocchi F, Maggioni AP, Tavazzi L, Tognoni G, Cohn JN, Latini
R, Val-HeFT Investigators, GISSI-HF Investigators. Serial measurement of cardiac troponin T using a highly sensitive
assay in patients with chronic heart failure. Data from two large randomized clinical trials. Circulation 2012; 125: 280288
Roberto Latini got his Medical Doctor degree in 1978 at the University of Milan.
Education
1970-1978
University of Milan School of Medicine, degree in Medicine
1981-1983
Merck Sharp & Dohme International Fellow in Clinical Pharmacology
ANNUAL REPORT
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Main fields of activity
Mechanisms of cardiac damage following ischemia, with focus on neurohumoral activation. Use of stem
cells for cardiac repair. Biohumoral investigations within large scale clinical trials in heart failure and
atrial fibrillation.
Positions
from 1990
Head of the Cardiovascular Clinical Pharmacology Laboratory (Department of
Cardiovascular Research) Istituto di Ricerche Farmacologiche “Mario Negri”, Milan,
Italy
from 2001
Member of the GISSI-HF Steering Committee
from 2004
Member of the GISSI-AF Steering Committee
from 2005
Member of the CandHeart Steering Committee
1999-2009
Visiting Professor Dept of Medicine, New York Medical College, Valhalla, NY, USA
1981-1983
Cardiology Fellow (Dr. R. E. Kates, Laboratory) Stanford University Medical Center,
CA, USA
1976-1981
Member of the Sub-Group RMs for Drugs (Community Bureau of Reference,
Commission of the European Communities)
1973-1990
Fellow at the Laboratory of Clinical Pharmacology of the Istituto di Ricerche
Farmacologiche "Mario Negri", Milano, Italy
Selected publications

GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni
AP, Lucci D, Di Pasquale G, Tognoni G), Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;
360: 1606-1617

Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, Caspani L, Raimondi F, Bordone G, Iapichino G,
Mancebo J, Guerin C, Ayzac L, Blanch L, Fumagalli R, Tognoni G, Gattinoni L, for the Prone-Supine II Study Group.
Prone positioning in patients with moderate and severe acute respiratory distress syndrome. A randomized controlled
trial. JAMA 2009; 302: 1977-1984

Damman K, Masson S, Hillege HL, Maggioni AP, Voors AA, Opasich C, van Veldhuisen DJ, Montagna L, Cosmi F,
Tognoni G, Tavazzi L, Latini R. Clinical outcome of renal tubular damage in chronic heart failure. Eur Heart J 2011; 32:
2705–2712

Latini R, Masson S, Pirelli S, Barlera S, Pulitano' G, Carbonieri E, Gulizia M, Vago T, Favero C, Zdunek D, Struck J,
Staszewsky L, Maggioni AP, Franzosi MG, Disertori M, GISSI-AF Investigators. Circulating cardiovascular biomarkers
in recurrent atrial fibrillation: data from the GISSI-Atrial Fibrillation Trial. J Intern Med 2011; 269: 160-171

Latini R, Gullestad L, Masson S, Nymo SH , Ueland T, Cuccovillo I, Vårdal M , Bottazzi B, Mantovani A, Lucci D,
Masuda N, Sudo Y, Wikstrand J, Tognoni G, Aukrust P, Tavazzi L, on behalf of the Investigators of the Controlled
Rosuvastatin Multinational Trial in Heart Failure (CORONA) and GISSI-Heart Failure (GISSI-HF) trial. Pentraxin-3 in
chronic heart failure: the CORONA and GISSI-HF trials. Eur J Heart Fail 2012; 14. 992-999

Masson S, Anand I S, Favero C, Barlera S, Vago T, Bertocchi F, Maggioni AP, Tavazzi L, Tognoni G, Cohn JN, Latini
R, Val-HeFT Investigators, GISSI-HF Investigators. Serial measurement of cardiac troponin T using a highly sensitive
assay in patients with chronic heart failure. Data from two large randomized clinical trials. Circulation 2012; 125: 280288
Maria Carla Roncaglioni got her Biological Science degree in 1987 at the University of Milan.
Education
1987
Doctoral degree in Biological Sciences, University of Milan, Italy
1982-1983 “Research Fellow” at the Dept. of Biochemistry, Faculty of Medicine, Rijksuniversiteit of
Limburg, Maastricht , The Netherland (Prof. C.Hemker);
1998-1999 “Visiting Scientist” at the Cardiovascular Research Unit, Hammersmith Hospital, London,
UK (Prof. A. Maseri)
Main fields of activity
Coordination of multicenter clinical trials and observational studies in different cardiovascular areas
(neurological, angiological, cardiological). Coordination of a network of more than 1000 GPs actively
involved in epidemiological and experimental studies in the prevention of cardiovascular diseases.
Position
from 2001 Head of the Laboratory for General Practice Research, Istituto di Ricerche Farmacologiche
"Mario Negri", Milano, Italy
from 1989 Senior Researcher in the Clinical Pharmacology Laboratory, Istituto di Ricerche
Farmacologiche "Mario Negri", Milano, Italy
from 1974 Researcher in the Laboratory for the Study of Haemostasis and Thrombosis, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano, Italy
ANNUAL REPORT
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2012
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Selected publications

Tognoni G, Avanzini F, Pangrazzi J, Roncaglioni M C, Bertele V, de Gaetano G, Caimi V, Tombesi M, Colombo Fabio,
Barlera S, PPP - Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: A
randomized trial in general practice. Lancet 2001; 357: 89-95

Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi J, Tognoni G, Brown DL. Aspirin for the primary prevention of
cardiovascular events in women and men: A sex-specific meta-analysis of randomized controlled trials. JAMA 2006;
295: 306-313

Montalvo G, Avanzini F, Anselmi M, Prandi R, Ibarra S, Marquez M, Armani D, Moreira J M, Caicedo C, Roncaglioni
MC, Colombo Fabio, Camisasca P, Milani V, Quimi' S, Gonzabay F, Tognoni G. Diagnostic evaluation of people with
hypertension in low income country: cohort study of &quot;essential&quot; method of risk stratification. BMJ 2008;
337: a1387

Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease:
collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860

Rischio and Prevenzione Investigators. Efficacy of n-3 polyunsaturated fatty acids and feasibility of optimizing
preventive strategies in patients at high cardiovascular risk: rationale, design and baseline characteristics of the Rischio
and Prevenzione study, a large randomised trial in general practice. Trials 2010; 11: 68

Rothwell PM, Price JF, Fowkes FGR , Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JFF, Wilson M, Mehta
Z, Meade TW. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the
time course of risks and benefits in 51 randomised controlled trials. Lancet 2012; 379: 1602-1612
Gianni Tognoni got his Medical Doctor degree in 1970, University of Milan.
Main areas of methodology
Randomized clinical trials; outcomes studies; pharmacoepidemiology; pharmacoeconomics;
epidemiological monitoring and assessment of health care systems, drug policy; genetic epidemiology;
community epidemiology; transfer of technology; health and human rights.
Main clinical areas
Acute and chronic CV diseases; psychiatry; aging; intensive care; neurodegenerative disordes; hematooncology.
Position
2004-2010 Member, Commission of Human Experimentation of the Italian Drug Agency (AIFA)
2001-2003 Member, Commissione Unica del Farmaco (CUF), Ministry of Health
from 2002 Director, Consorzio Mario Negri Sud, S. Maria Imbaro, Chieti.
1996-2002 Coordinator, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
"Mario Negri", Milano
from 1990 Co-Director, Scuola Superiore di Ricerca in Medicina Generale (CSeRMEG)
from 1976 Founding member of the International Society of Drug Bulletins (ISDB)
Coordinator, Commission of Human Experimentation, Regione Lombardia
from 1983 Founder and in the Editorial Board of the nursing research Journal Rivista
dell'Infermiere/Assistenza Infermieristica e Ricerca
from 1977 Consultant to WHO and other UN agencies for drug selection and policy; training in
methods of clinical and epidemiological research in developing countries mainly in Latin
America and Africa
1976-1999 Head, Laboratory of Clinical Pharmacology of the Istituto di Ricerche Farmacologiche
"Mario Negri", Milano
from 1975 Head, Regional Centre for Drug Information (CRIF), Regione Lombardia, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano
1969-1974 Research Assistant, Laboratory of Clinical Pharmacology, Istituto di Ricerche
Farmacologiche "Mario Negri", Milano
Selected publications
 Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Tonelli M, Garg AX, Pellegrini F, Ravani P, Jardine M, Perkovic
V, Graziano G, McGee R, Nicolucci A, Tognoni G, Strippoli GF. Meta-analysis: erythropoiesis-stimulating agents in
patients with chronic kidney disease. Ann Intern Med 2010; 153: 23-33
 Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SRK, McMurray JJ, Freeman DJ, Jukema
JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM,
Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR,
Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of
randomised statin trials. Lancet 2010; 375: 735-742
 Sud S, Friedrich JO, Taccone P, Polli F, Adhikari NKJ, Latini R, Pesenti A, Guérin C, Mancebo J, Curley MAQ,
Fernandez R, Chan M-C, Beuret P, Voggenreiter G, Sud M, Tognoni G, Gattinoni L. Prone ventilation reduces mortality
in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med
ANNUAL REPORT
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

2010; 36: 585-599
The NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J
Med 2010; 362: 1463-1476
Finzi AA, Latini R, Barlera S, Rossi MG, Ruggeri A, Mezzani A, Favero C, Franzosi MG, Serra D, Lucci D, Bianchini F,
Bernasconi R, Maggioni AP, Nicolosi GL, Porcu M, Tognoni G, Tavazzi L, Marchioli R. Effects of n-3 polyunsaturated
fatty acids on malignant ventricular arrhythmias in patients with chronic heart failure and implantable cardioverterdefibrillators: A substudy of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSIHF) trial Am Heart J 2011; 161: 338-343.e1
Mozaffarian D, Marchioli R, Macchia A, Silletta MG, Ferrazzi P, Gardner TJ, Latini R, Libby P, Lombardi F, O'Gara PT,
Page RL, Tavazzi L, Tognoni G, for the OPERA Investigators. Fish oil and postoperative atrial fibrillation: the Omega-3
Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA 2012; 308: 2001-2011
Giovanna Balconi got her degree at the School for Technicians of Biomedical Institutes of the
University of Milan, with a specialisation in Histology in the Pathological Anatomy Laboratory of the
same University (1968).
Main fields of interest
Isolation, culture and characterization of peripheral blood circulating progenitor cells of patients with
heart failure.
“In vitro” culture and characterization of stem cells for repair of myocardial infarction in experimental
animal models.
Management of biobanks in clinical studies.
Positions
from July 2005
Head of Tissue Culture Unit, Cardiovascular Clinical Pharmacology Laboratory,
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Oct 1995 - June 2005 Head of Tissue Culture Unit, Vascular Biology Laboratory, Istituto di Ricerche
Farmacologiche "Mario Negri", Milano, Italy
Dec 1983 - Oct 1995 Head of Tissue Culture Unit, Anticancer Chemotherapy Laboratory, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano, Italy
Oct 1968 - Nov 1983 Researcher, Anticancer Chemotherapy Laboratory, Istituto di Ricerche
Farmacologiche "Mario Negri", Milano, Italy
Selected publications

Cusella De Angelis MG, Balconi G, Bernasconi S, Zanetta L, Boratto R, Galli D, Dejana E, Cossu G. Skeletal myogenic
progenitors in the endothelium of lung and yolk sac. Exp Cell Res 2003; 290: 207-216

Galli D, Innocenzi A, Staszewsky L, Zanetta L, Sampaolesi M, Bai A, Martinoli E, Carlo E, Balconi G, Fiordaliso F,
Chimenti S, Cusella G, Dejana E, Cossu G, Latini R. Mesoangioblasts, vessel-associated multipotent stem cells, repair
the infarcted heart by multiple cellular mechanisms. A comparison with bone marrow progenitors, fibroblasts, and
endothelial cells. Arterioscler Thromb Vasc Biol 2005; 25: 692-697

Sarto P, Balducci E, Balconi G, Fiordaliso F, Merlo L, Tuzzato G, Pappagallo GL, Frigato N, Zanocco A, Forestieri C,
Azzarello G, Mazzucco A, Valenti M T, Alborino F, Noventa D, Vinante O, Pascotto P, Sartore S, Dejana E, Latini R.
Effects of exercise training on endothelial progenitor cells in patients with chronic heart failure. J Card Fail 2007; 13:
701-708

Galvez BG, Sampaolesi M, Barbuti A, Crespi A, Covarello D, Brunelli S, Dellavalle A, Crippa S, Balconi G, Cuccovillo
I, Molla F, Staszewsky L, Latini R, DiFrancesco D, Cossu G. Cardiac mesoangioblasts are committed, self-renewable
progenitors, associated with small vessels of juvenile mouse ventricle. Cell Death Differ 2008; 15: 1417-1428

Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, Angelici L,
Masson S, Mohammed SAA, Dejana E, Gorini M, Zeiher AM, Latini R, GISSI-HF Investigators. Levels of circulating
pro-angiogenic cells predict cardiovascular outcomes in patients with chronic heart failure. J Cardiac Fail 2009; 15: 747755

Raimondi M T, Balconi G, Boschetti F, Di Metri A, Mohammed SAA, Quaglini V, Araneo L, Galvez BG, Lupi M,
Latini R, Remuzzi A. An opto-structural methods to estimate the stress-strain field induced by cell contraction on
substrates of controlled stiffness in vitro. J Appl Biomater Function Mater published online 07-11-2012;
DOI:10.5301/JABFM.2012.9773
Paola Di Giulio got her Nursing Diploma at the Nursing School of Istituto Nazionale dei Tumori in
Milano and her Master in Oncology Nursing at Guildford University (UK) in 1995.
Main fields of activity
Coordination of multicentre and observational studies in cardiology and palliative care. Coordination of
nursing networks.
Position
from March 2001 Associated professor at the Turin University. Coordinator of the Editorial Board of
“Assistenza
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from 1997
from 1995
from 1989
Infermieristica e Ricerca”
Responsible of the Nursing Research Unit
Senior researcher of the Cardiovascular Research Department
Consultant of the Clinical Phrmacology Laboratory
Selected publications

Di Giulio P, Toscani F, Villani D, Brunelli C, Gentile S, Spadin P. Dying with advanced dementia in long-term care
geriatric institutions: a retrospective study. J Palliat Med 2008; 11: 1023-1028

Amodeo R, De Ponti A, Sorbara L, Avanzini F, Di Giulio P, De Martini M. Come aumentare le conoscenze dei pazienti
con cardiopatia ischemica sulla loro malattia? Utilità di un incontro educazionale tenuto da infermieri. G Ital Cardiol
2009; 10: 249-255

Di Giulio P, Pera C, Scarano M, Ferri B, Lepore V, Miani D, Tognoni G. Rapporto finale dello studio QDF (Qualità di
vita, Depressione e Funzioni cognitive) nei pazienti con scompenso cardiaco. Assistenza Infermieristica e Ricerca 2009;
28: 5-38

Gouchon S, Gregori D, Picotto A, Patrucco G, Nangeroni M, Di Giulio P. Skin-to-Skin contact after cesarean delivery:
an experimental study. Nurs Res 2010; 59: 78-84

Baldi I, Gouchon SM, Di Giulio P, Buja A, Gregori D. Group sequential and adaptive designs: a novel, promising tool
for nursing research. J Adv Nurs 2011; 67: 1824-1833.

Avanzini F, Di Giulio P, Amodeo R, Baldo S, Bergna ML, Busi G, Carlino L, Colombo F, Cotza R, De Ponti A, Di
Rocco E, Marigliani C, Negri E, Roncaglioni MC, Saltarel I, Sorbara L, Tavani A, De Martini M. Efficacia di un
intervento educativo infermieristico in pazienti ricoverati per una sindrome coronarica acuta. Assistenza Infermieristica e
Ricerca 2011; 30: 16-23
Fabio Fiordaliso got his Biological Science degree in 1995 at the University of Milan.
Education
1998
Postdoctoral degree in Pharmacological Research, Istituto di Ricerche Farmacologiche
“Mario Negri”, Milan, Italy
1995
Doctoral degree in Biological Sciences, University of Milan, Italy
Main fields of activity
Therapeutical potential of stem cell and antioxidant treatments in experimental model of diabetic
cardiomyopathy and in primary myocyte cultures exposed to hyperglycemia.
Morphological and structrural analysis of cells and tissue by optical, confocal and electron microscopy.
Positions
from 2007 Head of Bio-imaging Unit, Department of Cardiovascular Research, Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan
from 2006 Member of the Heart Failure Association (HFA) of the European Society of Cardiology
from 2005 Member of the Working group on myocardial function (WG 4) of the European Society of
Cardiology
from 2005 Member of the steering committee of the Consorzio of Microscopy and Image Analysis
(MIA)
from 2001 Senior Research Scientist, Laboratory of Cardiovascular Clinical Pharmacology
(Department of Cardiovascular Research), Istituto di Ricerche Farmacologiche “Mario
Negri”, Milan
1997-2001 Post-Doctoral Research Fellow at Cardiovascular Research Institute (Department of
Medicine), New York Medical College, Valhalla, New York
1994-1997 Research Fellow, Laboratory of Cardiovascular Clinical Pharmacology (Department of
Cardiovascular Research), Istituto di Ricerche Farmacologiche “Mario Negri”, Milan
1992-1994 Research training, Institute of General Pathology, University of Milan (Italy)
Selected publications

Fiordaliso F, Cuccovillo I, Bianchi R, Bai A, Doni M, Salio M, De Angelis N, Ghezzi P, Latini R, Masson S.
Cardiovascular oxidative stress is reduced by an ACE inhibitor in a rat model of streptozotocin-induced diabetes. Life Sci
2006; 79: 121-129

Fiordaliso F, De Angelis N, Cuccovillo I, Bai A, Salio M, Serra DM, Bianchi R, Razzetti R, Latini R, Masson S. Effect
of β-adrenergic and renin-angiotensin system blockade on myocyte apoptosis and oxidative stress in diabetic
hypertensive rats. Life Sci 2007; 81: 951-959

Latini R, Brines M, Fiordaliso F. Do non-hemopoietic effects of erythropoietin play a beneficial role in heart failure?
Heart Fail Rev 2008; 13: 415-423

Neri T, Merico V, Fiordaliso F, Salio M, Rebuzzini P, Sacchi L, Bellazzi R, Redi CA, Zuccotti M, Garagna S. The
differentiation of cardiomyocytes from mouse embryonic stem cells is altered by dioxin. Toxicol Lett 2011; 202: 226236
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

Zoja C, Cattaneo S, Fiordaliso F, Lionetti V, Zambelli V, Salio M, Corna D, Pagani C, Rottoli D, Bisighini C, Remuzzi
G, Benigni A. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2
diabetes. Am J Physiol - Renal Physiology 2011; 301: F1114-F1123
Traina G, Bigini P, Federighi G, Sitia L, Paroni G, Fiordaliso F, Salio M, Bendotti C, Brunelli M. Lipofuscin
accumulation and gene expression in different tissues of mnd mice. Mol Neurobiol 2012; 45: 247-257
Serge Masson obtained his doctorate (PhD) in Biochemistry and Cellular Biology in 1990 at the
University of Marseilles (France), followed by a postdoctoral stay at the Panum Institute in Copenhagen
(Denmark).
Education
1988-1990 Doctorate fellow, Faculty of Medicine, University of Aix-Marseilles, France
1990-1993 Post-doctoral Researcher, Panum Institute and Assistant Lecturer, University of
Copenhagen, Denmark
1993
Research Scientist, NMR Laboratory, Hospital “San Raffaele”, Milan, Italy
from 1994 Research Scientist, Department of Cardiovascular Research, Istituto di Ricerche
Farmacologiche "Mario Negri", Milano, Italy
Main fields of activity
Physiopathology, diagnostic and prognostic role of the activation of neuroendocrine systems in
cardiovascular disease
Position
from 2002 Head of the Cardiovascular Endocrine Unit, responsible for Quality Assurance for the
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario
Negri", Milano, Italy
from 2011 Thesis Examiner for PhD of the Open Univerisity of London, UK
from 2002 Tutor of fellows of the School of Specialists in Pharmacological Research, Istituto di
Ricerche Farmacologiche "Mario Negri", Milano, Italy
from 2002 Fellows of the American Heart Association (Basic Council) and the Working Group on
Myocardial Function of the European Society of Cardiology
Selected publications

Masson S, Latini L, Milani V, Moretti L, Rossi M G, Carbonieri E, Frisinghelli A, Minneci C, Valisi M, Maggioni A P,
Marchioli R, Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators. Prevalence and prognostic value of
elevated urinary albumin excretion in patients with chronic HF. Data from the GISSI-Heart Failure (GISSI-HF) trial.
Circ Heart Fail 2010; 3: 65-72

Masson S, Latini R, Carbonieri E, Moretti L, Rossi MG, Ciricugno S, Milani V, Marchioli R, Struck J, Bergmann A,
Maggioni AP, Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators. The predictive value of stable precursor
fragments of vasoactive peptides in patients with chronic heart failure:data from the GISSI-heart failure (GISSI-HF) trial.
Eur J Heart Fail 2010; 12 : 338-347

Damman K, Masson S, Hillege HL, Maggioni AP, Voors AA, Opasich C, van Veldhuisen DJ, Montagna L, Cosmi F,
Tognoni G, Tavazzi L, Latini R. Clinical outcome of renal tubular damage in chronic heart failure. Eur Heart J 2011; 32:
2705–2712

Latini R, Masson S, Pirelli S, Barlera S, Pulitano' G, Carbonieri E, Gulizia M, Vago T, Favero C, Zdunek D, Struck J,
Staszewsky L, Maggioni AP, Franzosi MG, Disertori M, GISSI-AF Investigators. Circulating cardiovascular biomarkers
in recurrent atrial fibrillation: data from the GISSI-Atrial Fibrillation Trial. J Intern Med 2011; 269: 160-171

Latini R, Gullestad L, Masson S, Nymo SH , Ueland T, Cuccovillo I, Vårdal M , Bottazzi B, Mantovani A, Lucci D,
Masuda N, Sudo Y, Wikstrand J, Tognoni G, Aukrust P, Tavazzi L, on behalf of the Investigators of the Controlled
Rosuvastatin Multinational Trial in Heart Failure (CORONA) and GISSI-Heart Failure (GISSI-HF) trial. Pentraxin-3 in
chronic heart failure: the CORONA and GISSI-HF trials. Eur J Heart Fail 2012; 14. 992-999

Masson S, Anand I S, Favero C, Barlera S, Vago T, Bertocchi F, Maggioni AP, Tavazzi L, Tognoni G, Cohn JN, Latini
R, Val-HeFT Investigators, GISSI-HF Investigators. Serial measurement of cardiac troponin T using a highly sensitive
assay in patients with chronic heart failure. Data from two large randomized clinical trials. Circulation 2012; 125: 280288
Enrico Bjørn Nicolis has attended the courses in Computer Science at the University of Milan.
Education
1991-1999 “Research fellow”, Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Main fields of activity
Data management and analysis of randomized clinical trials. Developing of database and tools for studies
of population genetics, particularly for linkage analysis.
Position
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from 2001
from 1999
from 1997
from 1991
Head of the Bioinformatics Unit, Istituto di Ricerche Farmacologiche "Mario Negri",
Milano, Italy
Research fellow of the Laboratory of Clinical Drugs Evaluation
System administrator at the EDP center, Istituto di Ricerche Farmacologiche "Mario Negri",
Milano, Italy
Research fellow at the Medical Informatics and Applied Statistics Unit, Istituto di Ricerche
Farmacologiche "Mario Negri", Milano, Italy
Selected publications

Nobili A, Gebru F, Rossetti A, Schettino F, Zahn R W, Nicolis E, Macario G, Celani L, Acik V O, Farina ML, Naldi L.
Doctorline: A private toll-free telephone medical information service. Five years of activity: Old problems and new
perspectives. Ann Pharmacother 1998; 32: 120-125

Santoro E, Nicolis E, Franzosi MG.Telecommunication technology for the management of large scale clinical trials: The
GISSI experience. Comput Methods Programs Biomed 1999; 60: 215-223

Tognoni G, Franzosi MG, Nicolis E, Barlera S, Specchia C, Chiodini B, Crociati L, Ferrario L, PROCARDIS
Consortium. A trio family study showing association of the lymphotoxin-alfa N26 (804A) allele with coronary artery
disease. Eur J Hum Genet 2004; 12: 770-774

Specchia C, Barlera S, Chiodini BD, Nicolis EB, Farrall M, Peden J, Collins R, Watkins H, Tognoni G, Franzosi MG,
PROCARDIS Consortium. Quantitative trait genetic linkage analysis of body-mass index in familial coronary artery
disease. Hum Hered 2008; 66: 19-24

Disertori M, Latini R, Maggioni AP, Barlera S, Di Pasquale G, Franzosi MG, Lucci D, Staszewsky L, Masson S, Baviera
M, Nicolis E, Tognoni G, GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med
2009; 360: 1606-1617

Barbati E, Specchia C, Villella M, Rossi ML, Barlera S, Bottazzi B, Crociati L, d'Arienzo C, Fanelli R, Garlanda C, Gori
F, Mango R, Mantovani A, Merla G, Nicolis EB, Pietri S, Presbitero P, Sudo Y, Villella A, Franzosi MG. Influence of
pentraxin 3 (PTX3) genetic variants on myocardial Infarction risk and PTX3 plasma levels. PLoS One 2012; 7: e53030
ACTIVITIES
The areas of interest of the Department of Cardiovascular Research include the experimental,
clinical, genetic, epidemiological aspects of acute myocardial infarction, cardiac failure, cardiac
arrhythmias, as well as the clinical and epidemiological investigation of cardiovascular
prevention, hypertension and stroke. Following the successful experience of the GISSI-trials
(Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto), the activation of large
collaborative networks in the setting of the National Health Service hospitals and in general
practice has become a key characteristics of the Department, which can now rely on the
permanent collaboration of over 300 clinical groups and of several hundred general
practitioners. Over the years, firm links have also been established with international leading
research groups.
The activity in experimental research includes the pathophysiology, the pharmacological
modulation and the prognostic role of the activation of the renin-angiotensin-aldosterone
system, as well as other neurohormonal systems, in myocardial infarction and heart failure, the
pathophysiology, the pharmacological modulation and prognostic role of the activation of the
inflammatory processes in myocardial infarction and heart failure; a more recent research topic
is cell therapy of experimental myocardial infarction. A model of cardiac arrest and
cardiopulmonary resuscitation in rats and pigs has been recently set up and is being used for
assessing the role of inflammation in cardiac and brain injury after cardiac arrest.
The activity in clinical research includes the clinical assessment of therapeutic strategies and of
biomarkers of cardiovascular risk with large scale clinical trials in the field of acute coronary
syndromes, congestive heart failure and atrial fibrillation. Several studies have been conducted
in the area of clinical epidemiology and risk factors assessment of myocardial infarction. A
recently developing area is the genetic epidemiology of myocardial infarction and heart failure.
The collaboration with an european genetic network has allowed the participation to large
GWAS (genome wide association studies) on coronary disease, myocardial infarction and
stroke.
The collaboration with a large network of General Practitioners in the area of cardiovascular
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prevention allowed to test new hypotheses through large scale clinical trials and to evaluate the
actual transferability of evidence based interventions in the every day practice through
epidemiological or outcome research studies. Among the different activities, the Cardiovascluar
Research Department contributed to the accreditation of the Institute as a Contract Research
Organization (CRO) for the conduction of clinical trials, mainly academic. The Department is
able to arrange monitoring activities (counting on certified monitoring personnel) and it is also
attested by Eudravigilance for the sumbission of online Safety Reports.
Pharmacoepidemiological studies through the analysis of a large sample of Local Health Units
drug prescriptions were also performed. A research network of nurses has been developed with
the main focus on the assessment of health-related quality of life of patients and on the
epidemiology of nursing interventions and their implications for patients' well being and
outcomes.
MAIN FINDINGS
A subgroup analysis of patients enrolled in the GISSI-AF trial has shown that the risk of
incident atrial fibrillation is predicted by circulating cardiac markers (natriuretic peptides and
troponin T) and by left atrial function as assessed by echocardiography in patients in sinus
rhythm. Predictors of atrial fibrillation could help in treating or even preventing this arrhythmia
which has a prevalence of 5-6% in the elderly and is associated with a 10-fold increase in risk of
stroke.
A recent analysis on 7000 patients with chronic heart failure enrolled in the GISSI-HF trial has
shown that an unintentional decrease in body weight of at least 2 kg over the first year after
enrollmet is a relevant risk factor. The body weight loss (cachexia) is independent from other
risk factors. Studies are ongoing to better understand the mechanisms of this weight loss and
how possibly it could be attenuated.
Experiments are ongoing on the cardio- and neuro-protective effects of the noble gas argon,
administered after cardiac arrest. Preliminary results of experiments in the pig suggest that
ventilation with argon 70% in oxygen started with the resuscitation maoeuvers improves the
recovery of neurologic functions and reduces histological injury in the brain and in the heart.
The PROCARDIS is part of the Coronary Artery Disease Genetics Consortium (C4D), that has
reported a meta-analysis of genome-wide association studies for coronary artery disease (CAD)
in discovery and replication cohorts including both European and South Asian studies. Five loci
newly associated with CAD have been identified. This study showed that the effect sizes of
previously unidentified CAD-associated genes discovered by GWAS (gemome wide association
studies) have become progressively smaller, suggesting that there may not be large-effect
common variants remaining to be discovered, but rather that a large number of common variants
of small effect may contribute to CAD risk.
Greater understanding of the genetic variants underlying CAD, and particularly the pathways
involved, may lead to development of new therapeutic approaches to help address the world’s
leading cause of death.
The Department has contributed to largest GWAS study of ischemic stroke conducted to date,
as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). A new association with
the HDAC9 gene region has been identified in large vessel stroke with an estimated effect size
that is at the larger end for GWAS loci (OR = 1.38, 95% CI = 1.22–1.57, from replication data).
The GWAS also replicated known associations with three other loci and showed genetic
heterogeneity across subtypes of the disease for all four stroke loci. This genetic heterogeneity
seems likely to reflect heterogeneity in the underlying pathogenic mechanisms and reinforces
the need for the consideration of stroke subtypes separately in research and clinical contexts.
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NATIONAL COLLABORATIONS
AMD (Associazione Medici Diabetologi) - Lombardia
ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri)
AREU - Azienda Regionale Emergenza Urgenza - Lombardia
Azienda Ospedaliera CTO/Maria Adelaide, Torino
Centro Cardiologico Monzino IRCCS, Milano
Centro Emofilia e Trombosi Angelo Bianchi Bonomi, Fondazione Ca' Granda - Ospedale
Maggiore Policlinico, Milano
CINECA (Consorzio Interuniversitario per il Calcolo Automatico dell'Italia Nord-Orientale)
CSeRMEG (Centro Studi e Ricerche in Medicina Generale)
Dipartimento Cardio-Vascolare ed Endocrino-Metabolico, Ospedale Casa Sollievo della
Sofferenza IRCCS, San Giovanni Rotondo
Dipartimento Cardiologico “A. De Gasperis” - Struttura Complessa di Cardiologia 2 Insufficienza Cardiaca e Trapianto, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda,
Milano
Dipartimento di Cardiologia e UTIC, Istituto Clinico Humanitas IRCCS, Milano
Dipartimento di Immunologia, Istituto Clinico Humanitas IRCCS, Milano
Ematologia, Ospedale Sant’Anna, Torino
Fondazione Don Gnocchi IRCCS, Milano
Fondazione Istituto Neurologico “Carlo Besta”, Milano
Fondazione per il Tuo Cuore - Heart Care Foundation - ONLUS, Firenze
Fondazione Sestini, Bergamo
Gruppi organizzati di MMG (FIMMG, CoS, Ass.Cu.M.I., AMISI)
IEO – Istituto Europeo di Oncologia
IFOM-FIRC, Milano
ISMETT Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo
Istituto di Anestesiologia e Rianimazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli,
Regina Elena, Milano
Istituto di Anestesia e Rianimazione, Ospedale San Gerardo, Monza
Istituto di Ricerca in Cure palliative Lino Maestroni, Cremona
Istituto Ortopedico Galeazzi, Milano
Istituto Ortopedico Rizzoli, Bologna
Laboratorio di Endocrinologia, Ospedale Luigi Sacco, Milano
PoliMi Politecnico, Milano
Regione Lombardia
Regione Emilia Romagna
Servizio Farmaceutico, USSL 20, Verona
SIBioC (Società Italiana di Biochimica Clinica e Biologia Molecolare)
SIFO (Società Italiana di Farmacia Ospedaliera)
Unità Operativa Semplice di Neuroanestesia e Neurorianimazione, Dipartimento di Medicina
Perioperatoria e Terapie Intensive, Ospedale San Gerardo, Monza
Università degli Studi di Milano, Dipartimento di Medicina Interna
Università degli Studi di Milano Bicocca, Dipartimento di Biotecnologie e Bioscienze
Università degli Studi di Milano Bicocca, Dipartimento di Scienze della Salute, Centro di
Biostatistica per l’Epidemiologia Clinica
Università degli Studi di Catania, Dipartimento di Anestesia e Terapia Intensiva
Università degli Studi di Catania, Dipartimento di Scienze del Farmaco, Sezione di Biochimica
Università degli Studi di Milano, Dipartimento di Scienze Farmacologiche
Università degli Studi di Torino, Dipartimento di Anatomia, Farmacologia e Medicina Forense
Università degli Studi di Torino, Dipartimento di Sanità Pubblica e Microbiologia
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Università degli Studi di Verona, Dipartimento di Sanità Pubblica
Università degli Studi di Verona, Istituto di Anatomia Umana
INTERNATIONAL COLLABORATIONS
Cecomet (Centro de Epidemiologia comunitaria y Medicina tropical, Esmeraldas) Ecuador
Cochrane Collaboration, Oxford, UK
Clinical Trial Research Unit, Auckland University, Nuova Zelanda
CNIC Centro Nacional de Investigaciones Cardiovasculares, Madrid , Spain
CTSU (Clinical Trial Service Unit) /ISIS (International Studies on Infarct Survival), Oxford,
UK
Department of Cardiology, Italian Hospital of Buenos Aires, Argentina
Department of Epidemiology, Harvard School of Public Health, Boston, USA
DSAN SUPSI (Scuola Universitaria Professioni Sanitarie), Lugano, Switzerland
ECLA (Estudios Cardiologicos de Latino-America)
ECRIN (European Clinical Research Infrastructures Network)
Helsingborg Hospital, Sweden
Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, Vandoeuvre-les-Nancy, France
Karolinska Institutet, Stockholm, Sweden
Laerdal Foundation for Acute Medicine, Stavanger, Norway
Mayo Clinic, Cardiorenal Research Lab, Rochester, MN, USA
PHRI (Population Health Research Institute), McMaster University, Hamilton, Ontario, Canada
The Third Military University, Chong Qing, China
University of Cambridge, UK
University of Aachen, Germany
University of Helsinki, Central Hospital, Finland
University of Manchester, Medicine/Cardiology Manchester Royal Infirmary, UK
University of Minnesota, Minneapolis, USA
University of Oslo, Norvegia
University Medical Center, Groningen, The Netherlands
Wellcome Trust Centre for Human Genetics, University of Oxford, UK
WONCA (World Organization of Family Doctors)
EDITORIAL BOARD MEMBERSHIP
Current Controlled Trials, Global Heart (Maria Grazia Franzosi)
Journal of Cardiac Failure, Journal of Cardiovascular Medicine (Roberto Latini)
The Scientific World Journal, Resuscitation (Giuseppe Ristagno)
European Heart Journal, International Journal of Health Services, Journal of Cardiovascular
Medicine (Gianni Tognoni)
Assistenza Infermieristica e Ricerca, European Journal of Oncology Nursing, International
Journal of Practice Development (Paola Di Giulio)
PEER REVIEW ACTIVITIES
American Heart Journal, American Journal of Cardiology, American Journal of Medicine,
Archives of Medical Research, Atherosclerosis Thrombosis and Vascular Biology, Biomarkers
in Medicine, Canadian Medical Association Journal, Cardiovascular Drugs and Therapy,
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Cardiovascular Research, Cardiology, Circulation, Clinical Biochemistry, Clinical
Pharmacology and Therapeutics, Critical Care Medicine, Diabetes Research and Clinical
Practice, European Heart Journal, European Journal of Cardiovascular Nursing, European
Journal of Oncology Nursing, Free Radical Biology & Medicine, Health and Quality of Life,
Heart, Heart Vessels, International Journal of Cardiology, International Journal Diabetes in
Developing Countries, ISRN Nursing (International Scholarly Research Network), International
Journal of Obesity, Intensive Care Medicine, Journal of American College of Cardiology,
Journal of Cardiac Failure, Journal of Clinical Laboratory Analysis, Journal of Cardiovascular
Medicine, Journal of Critical Care, Journal of Internal Medicine, The Lancet, Life Sciences,
Metabolism, Nursing Research, PLoS Medicine, PharmacoEconomics, Pharmacological
Research, Postgraduate Medical Journal, Recent Patents in Endocrinology Metabolism Immune
Drug Discovery, Redox Report, Resuscitation.
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
Comitato Etico ASL di Milano
Comitato Etico della Provincia di Trento
Comitato Etico OIRM Sant’Anna di Torino
Comissione Regione Emilia Romagna, Programma di Ricerca Regione - Università 2010-2012,
Agenzia Sanitaria e Sociale Regionale
Comitato Scientifico IRC - Italian Resuscitation Council, Bologna
Gruppo di Studio SIAARTI - Società Italiana Anestesia Analgesia Rianimazione Terapia
Intensiva
Working Group Basic Life Support, European Resuscitation Council
EVENT ORGANIZATION
Riunione per presentazione dello studio ICOS-ONE (International CardioOncology SocietyONE Trial)
27/01/12, Istituto Europeo di Oncologia, Milano
Investigator's Meeting - FOCUS Fixed dose combination drug for secondary cardiovascular
prevention. European Community - Sevent Framework Programme – Health
07/03/12, Aula Guasti Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Investigator's Meeting – Riunione sullo stato di avanzamento dello studio BeTACTIC - Best
Therapy After Cardiac Transplantation, the Italian Challenge
03/05/12, Aula E, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Investigator's Meeting – Riunione sullo stato di avanzamento dello studio REGIA - Rischio
Emorragico GInocchio e Anca
Studio osservazionale prospettico di coorte sull’incidenza degli eventi emorragici nei pazienti
sottoposti ad interventi di sostituzione protesica di ginocchio ed anca
13/06/12, Aula E, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Seminar - Caren G. Solomon: Publishing Your Paper – Perspective of an Editor
15/06/12, Aula A, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Conference - WEIL CONFERENCE - Cardiac arrest, shock and trauma
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08-09/09/12, Aula A, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Seminar - Mauro Giacca: Searching for novel genes and microRNAs inducing myocardial
protection and regeneration
13/09/12, Aula Guasti, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
Master di I° Livello in Ricerca Clinica dell’Università degli Studi di Milano, Facoltà di
Medicina e Chirurgia, Dipartimento di Medicina Interna (Anno Accademico 2012-2013)
07/11/12 Introduzione al corso
La ricerca clinica oggi: stato attuale e obiettivi futuri
Corso di introduzione alla statistica medica
08/11/12 Elementi di statistica descrittiva
Il disegno dello studio in epidemiologia
09/11/12 La variabilità dei fenomeni biologici
12/11/12 Misure di rischio in epidemiologia
Inferenza statistica
13/11/12 Legislazione sulla sperimentazione clinica e ruolo dei Comitati Etici
Analisi della Sopravvivenza
14/11/12 Il disegno degli studi clinici
Esercitazione di Inferenza Statistica
15/11/12 Test diagnostici
Esercitazioni di statistica finale
19/11/12 Utilizzo di biomarker come endpoint surrogati, fattori prognostici e predittivi
20/11/12 Farmacovigilanza
Gestione della ricerca clinica in un IRCCS
21/11/12 Le interazioni tra farmaci
Monitoraggio degli studi clinici no-profit
22/11/12 Trial di non-inferiorità
Ricerca clinica nel campo dell'epilessia. Ricerca clinica nell'ictus
26/11/12 Ricerca Traslazionale
Outcome Research
27/11/12 Monitoraggio degli studi clinici profit & report delle reazioni avverse
La farmacovigilanza degli studi no profit: nuove direttive e prospettive future
28/11/12 Dalla preclinica alla clinica: sviluppo di nuovi farmaci cardiovascolari
La ricerca bibliografica oggi
Internet e le nuove tecnologie per l'aggiornamento medico-scientifico
29/11/12 Problemi aperti nella scoperta e nello sviluppo di farmaci
Ricerca in medicina generale
Gestione della ricerca clinica in Azienda
03/12/12 Il "discorso etico": dalla linearità dei buoni principi alla provocazione del reale
Revisioni sistematiche e metaanalisi
Istituto di Ricerche Farmacologiche “Mario Negri”, Milano
CONFERENCE AND WORKSHOP CONTRIBUTIONS
SICOA Società Italiana Cardiologia Ospedalità Accreditata. Il malato protagonista della sua
cura. Il cardiopatico esce dall’ospedale e desidera riprendere una vita normale; come aiutarlo?
14/01/12, Palazzo D’Aronco, Sala Ajace, Udine, Italy
ANNUAL REPORT
171
2012
IRFMN
- News dal Congresso Europeo di Cardiologia 2011: una corretta assunzione di vino ha un
impatto positivo sulla prognosi del paziente scompensato cronico
NEUROMED IRCCS Istituto Neurologico Mediterraneo. IInd Cardionetwork Meeting. 23/02/12, Camerelle Pozzilli (IS), Italy
- Study of the effect of hPTX3 administration in a model of chronic heart failure after
permanent coronary artery ligation
Università dell’Insubria, Università degli Studi di Brescia. MASTER di II° Livello in
Elettrofisiologia ed Elettrostimolazione Cardiaca, IV Edizione. 08/02/12, Ospedale di Circolo e
Fondazione Macchi, Varese
- Basi farmacocinetiche e farmacodinamiche
- Elementi di farmacocinetica – dosi ripetute
Casa di Cura Candela, ISMETT Istituto Mediterraneo per i Trapianti e Terapie ad Alta
Specializzazione. VII Congresso, Approccio multidisciplinare allo scompenso cardiaco. 1011/02/12, Hotel Palace di Mondello, Palermo
- Uso e abuso dei biomarker
Università dell’Insubria, Università degli Studi di Brescia. MASTER di II° Livello in
Elettrofisiologia ed Elettrostimolazione Cardiaca, IV Edizione. 15/02/12, Ospedale di Circolo e
Fondazione Macchi, Varese
- Farmacocinetica clinica
Fondazione per il tuo Cuore ONLUS - Heart Care Foundation, Associazione Nazionale Medici
Cardiologi Ospedalieri (ANMCO). Corso avanzato di formazione su metodologia, strategie e
tecniche della Ricerca Clinica. Edizione 2011-2012. 19-21/03/12, Learning Centre ANMCO,
Firenze
- Lo studio CYCLE (CYCLosporinE A in reperfused acute myocardial infarction)
ANMCO Associazione Nazionale Medici Cardiologi Ospedalieri - ANMCO SICILIA.
CARDIONURSING Congresso Regionale 2012. 20-21/04/12, Hilton Giardini Naxos, Messina,
Italy
- Progetti collaborativi e reti di ricerca regionali: un’opzione possibile?
European Society of Cardiology - ESC Working Group on Cardiovascular Pharmacology and
Drug Therapy. Biomarkers for Innovative Medicine in Heart Failure - Biomarker Strategies to
Improve Clinical Outcomes. Sevent Annual Meeting: Transatlantic Heart Failure Biomarker
Working Group. 21-22/04/12, Cannes, France
- Emerging heart failure biomarkers
University of Basel (Department of Bomedicine) – University of Bern (Department of Clinical
Research) – University of Lousanne (Department of Medicine). Cardiac pathways of
differentiation, metabolism and contraction. 22-26/04/12, Ascona, Switzerland
- CyP, a toll-like receptor 4 antagonist, protects the heart from ischemia/reperfusione injury
IRCCS Multimedica - Università degli Studi di Milano - Università degli Studi di Firenze. The
culprit atrium. Twelfth International Symposium, Heart Failure & Co. 27-28/04/12, Milano,
Italy
- Atrial neurohormonal properties and cardiovascular physiology implications
ANNUAL REPORT
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2012
IRFMN
SMART-Organizing and Scientific Committee. 23° SMART – Simposio Mostra Anestesia,
Rianimazione e Terapia Intensiva. 09-11/05/12, MiCo–Milano Congressi Ala Nord, Milano,
Italy
- CPR 2012
- Plasma high-sensitivity cardiac troponin T and post resuscitation myocardial dysfunctin in a
rat model of cardiac arrest
- Specific metabolic pathways involved in outcome of cardiopulmonary resuscitation: a pilot
plasma metabolomic study in a rat model of cardiac arrest and CPR
- Pentraxin 3 (PTX3) and inflammation cells in broncho-alveolar lavage fluids of patients with
suspected pneumonia
- Biomarkers of cardiopulmonary function
ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione) - UPMC
(University Pierre and Marie Curie). Dalla clinica alla ricerca: un percorso metodologico.
22/05/12, Palermo, Italy
- Come si scrive un articolo scientifico
SID - Società Italiana di Diabetologia. 24° Congresso Nazionale SID. Il diabete. 23-26/05/12,
Torino, Italy
- Iperglicemia in corso di sindrome coronarica acuta. Efficacia e sicurezza di un protocollo di
influsione endovenosa di insulina target 140-180
Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione per il tuo cuore - Heart
Care Foundation. Uniti nella ricerca per le cure di qualità, 43° Congresso Nazionale di
Cardiologia ANMCO. 30/05-02/06/12, Fortezza da Basso, Firenze, Italy
- Caratterizzazione bioumorale in pazienti con aterosclerosi coronarica diffusa a dispetto di
un basso profilo di rischio. Risultati preliminari dello studio CAPIRE
- Caratterizzazione non invasiva dell’aterosclerosi coronarica e dei biomarcatori circolanti in
pazienti con opposti profili di fattori di rischio. I risultati prelimari dello studio CAPIRE
- Correlazione tra i fattori di rischio tradizionali e aterosclerosi coronarica valutata con
tomografia computerizzata multistrato in pazienti senza precedenti di cardiopatia ischemica.
Risultati preliminari sulla prevalenza di “outliers”
- Determinanti clinico-anamnestici dello scompenso cardiaco e della disfunzione ventricolare
sinistra negli anziani. Risultati dello studio PREDICTOR
- Efficacia e sicurezza di un nuovo protocollo di infusione endovenosa di insulina a gestione
infermieristica (DDD 140-180) per il controllo della glicemia in corso di sindrome
coronarica acuta
ICGEB International Centre for Genetic Engineering and Biotechnology - The Arturo Falaschi
Conference Series on Molecular Medicine. Frontiers in Cardiac and Vascular Regeneration.
30/05-02/06/12, Trieste, Italy
- Cardiac effect of modified embryonic mesoangioblasts expressing PIGF, MMP9 or borth
after myocardial infarction in the mouse
Azienda Servizi Sanitari N° 1 di Trieste. Nuove metodologie per il trattamento dell’arresto
cardiaco. 15/06/12, Trieste, Italy
- CPR Novità linee guida
- Compressione manuale; compressione automatica; qualità delle compressioni toraciche;
compressioni toraciche da sole vs compressioni toraciche e ventilazione
- La defibrillazione: onde, energie e nuovi defibrillatori
ANNUAL REPORT
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2012
IRFMN
Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. The 4th Guangzhou Conference on
CPR. 22-24/06/12, Guangzhou, China
- Clinical and humoral biomarkers during and after CPR
The Third Military University Chong Qing. Lecture. 26/06/12, Chong Qing, China
- Advances in CPR 2012
College of Biomedical Engineering & Medical Imaging of TMU, The Third Military University
Chong Qing. Lecture. 27/06/12 Chong Qing, China
- The past, the present and the future of critical care medicine
Fondazione per il tuo Cuore ONLUS - Heart Care Foundation, Associazione Nazionale Medici
Cardiologi Ospedalieri (ANMCO). Corso avanzato di formazione su metodologia, strategie e
tecniche della Ricerca Clinica. Edizione 2011-2012, Modulo 5. 02-04/07/12, Learning Centre
ANMCO, Firenze
- Biomarkers in cardiologia
WONCA Europe. The art & science of general practice - 18th WONCA Europe Conference. 0407/07/12, Vienna, Austria
- Annual systematic review and plan, an effective strategy for improving cardiovascular
prevention. Results of a real life five-year experiment in general practice on 12505
individual at high cardiovascolar risk
WEIL CONFERENCE. Cardiac arrest, shock and trauma. 08-09/09/12, Istituto Mario Negri,
Milano
- Priorities of intervention and predictors of success of defibrillatiion
- Researching new biomarkers predictive of outcome of cardiac arrest. The kynurenine
pathway activation.
An experimental and clinical investigation
Ludwig Boltzmann Institut fur Translationale Herzinsuffizienzforschung. L.B.I. HF
Symposium, Heart Failure - From Pathophysiology to Therapy. 13-15/10/12, Medizinischen
Universität Graz, Austria
- Pathophysiology and epidemiology of heart failure
IRCCS Istituto Auxologico Italiano. Ipertensione arteriosa e patologia cardiovascolare. Dalla
fisiopatologia alla pratica, Ospedale San Luca, Sala Convegni. 15-17/10/12, Milano, Italy
- Atrio, proprietà neuro ormonali e fisiopatologia
European Resuscitation Council. Resuscitation 2012 – Annual meeting. Working together to
save lives. 18-20/10/12, Vienna, Austria
- Amplitude spectrum area to predict defibrillation outcome after recurrent and defibrillation
resistant ventricular fibrillation during pre-hospital cardiopulmonary resuscitation
- Rapid decreases in amplitude spectrum area after interruption of chest compression in outof-hospital cardiac arrest patients
- Advantages and disadvantages of rodents in CPR models
SIAARTI - Società Italiana Anestesia Analgesia Rianimazione Terapia Intensiva. 66°
Congresso Nazionale SIAARTI. 24-27/10/12, Napoli, Italy
- Sindrome post-rianimazione e sepsi. Quali affinità?
- Qualità delle compressioni e successo della rianimazione
ANNUAL REPORT
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2012
IRFMN
American Heart Association. AHA Scientific Session 2012. 03-07/11/12, Los Angeles, USA
- Ranolazine ameloriates postresuscitation hemodynamic instability and improves survival
with good neurological recovery
- Amplitude spectrum area-based defibrillation decision during prehospital cardiopulmonary
resuscitation in Lombardia, Italy
- Proinfiammatory cytokines and catecholamine release during selective head cooling in a
porcine model of cardiac arrest
- Comparison of outcome after cardiac arrest and cardiopulmonary resuscitation in obese and
lean rats
- Kynurenine pathway activation following resuscitation from cardiac arrest: an experimental
and clinical investigation - from a rat and a pig model to a preliminary clinical validation
- Amplitude spectrum area based defibrillation decision greatly improves shock success rate
and accuracy during prehospital cardiopulmonary resuscitation
- Elevated circulating levels of growth-differentiation factor-15 in elderly subjects with
preclinical left ventricular alterations
- Secreted frizzled related protein 3, an inhibitor of Wnt-signaling, is upregulated in clinical
and experimental heart failure
SITI - Società Italiana di Terapia Intensiva. 25° Congresso Nazionale SITI. 09-10/11/12, Roma,
Italy
- Focus on arresto cardiaco “Nuove strategie di defibrillazione”
IRCCS Azienda Ospedaliera Universitaria San Martino, IST - Istituto Nazionale per la Ricerca
sul Cancro. Congresso Nazionale, Hypothermia 2012 - The cardiac arrest and post resuscitation
care. 15-16/11/12, Genova, Italy
- Defibrillators and the predictors of success
Società Italiana di Genetica Umana. XV Congresso Nazionale. 21-23/11/12, Centro Congressi
Hilton Sorrento Palace, Sorrento (NA), Italy
- Influence of pentraxin 3 (PTX3) genetic variants on myocardial infarction risk and PTX3
plasma levels
WORKSHOP. La drug utiization attraverso i database amministrativi. 27/11/12, Istituto Mario
Negri, Milano
- La popolazione con diabete in Regione Lombardia: analisi dei database amministrativi
APICE Anaesthesia Pharmacology Intensive Care and Emergency - APICE Masterclass 2012,
25th Annual International Meeting. 30/11-02/12/12, Catania, Italy
- Pathophysiology, clinical assessment and management in ICU - Cardiovascular risk
stratification
- Looking for biomarkers predictive of outcome
- Defibrillation
GRANTS AND CONTRACTS
AIFA (Agenzia Italiana del Farmaco), Azienda Ospedaliera Ospedale Niguarda Ca’ Granda
Milano, Azienda Ospedaliera San Gerardo Monza, Brigham and Women's Hospital, Boston,
Bluegreen Biotech Srl, Boehringer Ingelheim Italia Spa, Chiesi Farmaceutici, Centro Nacional
de Investigaciones Cardiovasculares (CNIC) Madrid, Comunità Europea, Consorzio Mario
Negri Sud Santa Maria Imbaro, Elior Ristorazione SpA, Fondazione CARIPLO, Fondazione
ANNUAL REPORT
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2012
IRFMN
San Raffaele del Monte Tabor Milano, Fondazione Humanitas per la Ricerca Rozzano,
Fondazione per il Tuo Cuore - Heart Care Foundation - ONLUS, Firenze, Fondazione Sestini
Bergamo, Fondazione Veronesi, Helsinki University - Central Hospital, Helsingborg Hospital,
International Biomedical System SpA, Istituto Dermopatico dell’Immacolata IRCCS Roma,
Istituto Europeo di Oncologia IRCCS Milano, Laerdal Foundation for Acute Medicine
Stavanger, Ministero della Salute, Mitsubishi Chemical Europe, Novartis Pharma SpA,
Population Health Research Institute-Mc Master University, Regione Lombardia, ROCHE
Diagnostics GmBH, Sigma Tau SpA, SPA Società Prodotti Antibiotici SpA, Università degli
Studi di Milano, Università degli Studi Milano Bicocca, University of Manchester, UK
SCIENTIFIC PUBLICATIONS (2012)
Aleksova A, Masson S, Maggioni AP, Lucci D, Urso R, Staszewsky L, Ciaffoni S, Cacciatore G, Misuraca G, Gulizia
M, Mos L, Proietti G, Minneci C, Latini R, Sinagra G, CandHeart Investigators
Effects of candesartan on left ventricular function, aldosterone and BNP in chronic heart failure
Cardiovasc Drugs Ther 2012; 26: 131-143
Avalli L, Maggioni E, Formica F, Redaelli G, Migliari M, Scanziani M, Celotti S, Coppo A, Caruso R, Ristagno G,
Fumagalli R
Favourable survival of in-hospital compared to out-of-hospital refractory cardiac arrest patients treated with
extracorporeal membrane oxygenation: An Italian tertiary care centre experience
Resuscitation 2012; 83: 579– 583
Avanzini F, Bertele' V, Pistotti V, Mannucci PM, Garattini S
Solicited self-referencing undermines the credibility of researchers and journals
J Thromb Haemost 2012; 10: 481-482
Barbati E, Specchia C, Villella M, Rossi ML, Barlera S, Bottazzi B, Crociati L, d'Arienzo C, Fanelli R, Garlanda C,
Gori F, Mango R, Mantovani A, Merla G, Nicolis EB, Pietri S, Presbitero P, Sudo Y, Villella A, Franzosi MG
influence of pentraxin 3 (PTX3) genetic variants on myocardial Infarction risk and PTX3 plasma levels
PLoS One 2012; 7: e53030
Bernal A, San Martin N, Fernández M, Covarello D, Molla F, Soldo A, Latini R, Cossu G, Galvez BG
L-selectin and SDF-1 enhance the migration of mouse and human cardiac mesoangioblasts
Cell Death Differ 2012; 19: 345-355
Bigini P, Diana V, Barbera S, Fumagalli E, Micotti E, Sitia L, Paladini A, Bisighini C, De Grada L, Coloca L, Colombo
L, Manca P, Bossolasco P, Malvestiti F, Fiordaliso F, Forloni G, Morbidelli M, Salmona M, Giardino D, Mennini T,
Moscatelli D, Silani V, Cova L
Longitudinal tracking of human fetal cells labeled with super paramagnetic iron oxide nanoparticles in the brain of
mice with motor neuron disease
PLoS One 2012; 7: e32326
Chen B, Yin C, Ristagno G, Quan W, Tan Q, Gary Freeman G, Li Y
Retrospective evaluation of current-based impedance compensation defibrillation in out-of-hospital cardiac arrest
Resuscitation 2012; Epub
Cheng YC, Anderson CD, Bione S, Keene K, Maguire JM, Nalls M, Rasheed A, Zeginigg M, Attia J, Baker R,
Barlera S, Biffi A, Bookman E, Brott TG, Brown RD Jr, Chen F, Chen WM, Ciusani E, Cole JW, Cortellini L,
Danesh J, Doheny K, Ferrucci L, Franzosi MG, Frossard P, Furie KL, Golledge J, Hankey GJ, Hernandez D,
Holliday EG, Hsu FC, Jannes J, Kamal A, Khan MS, Kittner SJ, Koblar SA, Lewis M, Lincz L, Lisa A, Matarin M,
Moscato P, Mychaleckyj JC, Parati EA, Parolo S, Pugh E, Rost NS, Schallert M, Schmidt H, Scott RJ, Sturm JW,
Yadav S, Zaidi M, Boncoraglio GB, Levi CR, Meschia JF, Rosand J, Sale M, Saleheen D, Schmidt R, Sharma P,
Worrall B, Mitchell BD; GARNET Collaborative Research Group; GENEVA Consortium; on behalf of the
International Stroke Genetics Consortium
Are myocardial infarction–associated single-nucleotide polymorphisms associated with ischemic stroke?
Stroke 2012; 43: 980-986
Cholesterol Treatment Trialists' (CTT) Collaboration
ANNUAL REPORT
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2012
IRFMN
Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27
randomised trials of statin therapy
PLoS One 2012; 7: e29849
Cholesterol Treatment Trialists' (CTT) Collaborators
The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of
individual data from 27 randomised trials
Lancet 2012; 380: 581-590
Citerio G, Pesenti A, Latini R, Masson S, Barlera S, Gaspari F, Franzosi MG, NeuroMorfeo Study Group
A multicentre, randomised, open-label, controlled trial evaluating equivalence of inhalational and intravenous
anaesthesia during elective craniotomy
Eur J Anaesthesiol 2012; 29: 371-379
Dastani Z, Hivert MF, Timpson N, Perry JR, Yuan X, Scott RA, Henneman P, Heid IM, Kizer JR, Lyytikäinen LP,
Fuchsberger C, Tanaka T, Morris AP, Small K, Isaacs A, Beekman M, Coassin S, Lohman K, Qi L, Kanoni S,
Pankow JS, Uh HW, Wu Y, Bidulescu A, Rasmussen-Torvik LJ, Greenwood CM, Ladouceur M, Grimsby J,
Manning AK, Liu CT, Kooner J, Mooser VE, Vollenweider P, Kapur KA, Chambers J, Wareham NJ, Langenberg C,
Frants R, Willems-Vandijk K, Oostra BA, Willems SM, Lamina C, Winkler TW, Psaty BM, Tracy RP, Brody J,
Chen I, Viikari J, Kähönen M, Pramstaller PP, Evans DM, St Pourcain B, Sattar N, Wood AR, Bandinelli S, Carlson
OD, Egan JM, Böhringer S, van Heemst D, Kedenko L, Kristiansson K, Nuotio ML, Loo BM, Harris T, Garcia M,
Kanaya A, Haun M, Klopp N, Wichmann HE, Deloukas P, Katsareli E, Couper DJ, Duncan BB, Kloppenburg M,
Adair LS, Borja JB; DIAGRAM Consortium; MAGIC Consortium; GLGC Investigators; MuTHER Consortium,
Wilson JG, Musani S, Guo X, Johnson T, Semple R, Teslovich TM, Allison MA, Redline S, Buxbaum SG, Mohlke
KL, Meulenbelt I, Ballantyne CM, Dedoussis GV, Hu FB, Liu Y, Paulweber B, Spector TD, Slagboom PE, Ferrucci
L, Jula A, Perola M, Raitakari O, Florez JC, Salomaa V, Eriksson JG, Frayling TM, Hicks AA, Lehtimäki T, Smith
GD, Siscovick DS, Kronenberg F, van Duijn C, Loos RJ, Waterworth DM, Meigs JB, Dupuis J, Richards JB, Voight
BF, Scott LJ, Steinthorsdottir V, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch
LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Hofmann OM, Segrè AV, van
Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL,
Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Crawford G, Doney AS,
Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves
CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Kong
A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell
K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Petersen AK, Platou C, Proença C, Prokopenko I,
Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P,
Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam
RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J,
Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter
DJ, Hveem K, Laakso M, Morris AD, Palmer CN, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A,
Walker M, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Pedersen O, Barroso I,
Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D,
Boehnke M, McCarthy MI, Soranzo N, Wheeler E, Glazer NL, Bouatia-Naji N, Mägi R, Randall J, Elliott P, Rybin
D, Dehghan A, Hottenga JJ, Song K, Goel A, Lajunen T, Doney A, Cavalcanti-Proença C, Kumari M, Timpson NJ,
Zabena C, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Roccasecca RM, Pattou F, Sethupathy P,
Ariyurek Y, Barter P, Beilby JP, Ben-Shlomo Y, Bergmann S, Bochud M, Bonnefond A, Borch-Johnsen K, Böttcher
Y, Brunner E, Bumpstead SJ, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Crisponi L, Day IN, de Geus EJ,
Delplanque J, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Franzosi MG, Galan P, Goodarzi MO, Graessler J,
Grundy S, Gwilliam R, Hallmans G, Hammond N, Han X, Hartikainen AL, Hayward C, Heath SC, Hercberg S,
Hillman DR, Hingorani AD, Hui J, Hung J, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen
S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Mahley R, Mangino M,
Martínez-Larrad MT, McAteer JB, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Mukherjee S,
Naitza S, Neville MJ, Orrù M, Pakyz R, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Pfeiffer AF,
Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Rayner NW, Rice K, Ripatti S, Rivadeneira F,
Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Seedorf U, Sharp SJ, Shields B, Sigurðsson G,
Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tönjes A,
Uitterlinden AG, van Dijk KW, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley
A, Ward KL, Watkins H, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zelenika D, Zethelius B, Zhai G, Zhao
JH, Zillikens MC; DIAGRAM Consortium; GIANT Consortium; Global B Pgen Consortium, Borecki IB, Meneton
P, Magnusson PK, Nathan DM, Williams GH, Silander K, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner
AR, Cooper C, Serrano-Ríos M, Lind L, Palmer LJ, Hu FB 1st, Franks PW, Ebrahim S, Marmot M, Kao WH,
Pramstaller PP, Wright AF, Stumvoll M, Hamsten A; Procardis Consortium, Buchanan TA, Valle TT, Rotter JI,
Penninx BW, Boomsma DI, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Peltonen L,
ANNUAL REPORT
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2012
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Mooser V, Sladek R; MAGIC investigators; GLGC Consortium, Musunuru K, Smith AV, Edmondson AC, Stylianou
IM, Koseki M, Pirruccello JP, Chasman DI, Johansen CT, Fouchier SW, Peloso GM, Barbalic M, Ricketts SL, Bis
JC, Feitosa MF, Orho-Melander M, Melander O, Li X, Li M, Cho YS, Go MJ, Kim YJ, Lee JY, Park T, Kim K, Sim
X, Ong RT, Croteau-Chonka DC, Lange LA, Smith JD, Ziegler A, Zhang W, Zee RY, Whitfield JB, Thompson JR,
Surakka I, Spector TD, Smit JH, Sinisalo J, Scott J, Saharinen J, Sabatti C, Rose LM, Roberts R, Rieder M, Parker
AN, Pare G, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, McArdle W, Masson D, Martin NG,
Marroni F, Lucas G, Luben R, Lokki ML, Lettre G, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, König IR,
Khaw KT, Kaplan LM, Johansson Å, Janssens AC, Igl W, Hovingh GK, Hengstenberg C, Havulinna AS, Hastie ND,
Harris TB, Haritunians T, Hall AS, Groop LC, Gonzalez E, Freimer NB, Erdmann J, Ejebe KG, Döring A,
Dominiczak AF, Demissie S, Deloukas P, de Faire U, Crawford G, Chen YD, Caulfield MJ, Boekholdt SM, Assimes
TL, Quertermous T, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Taylor HA Jr, Gabriel SB, Holm H,
Gudnason V, Krauss RM, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE,
Strachan DP, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, Kathiresan S.
Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic metaanalysis of 45,891 individuals
PLoS Genet 2012; 8: e1002607
Diener H-C, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, O'Donnell M, Hohnloser SH, Hankey GJ,
Shestakovska O, Yusuf S, for the AVERROES Steering Committee and Investigators
Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a
predefined subgroup analysis from AVERROES, a randomised trial
Lancet Neurol 2012; 11: 225-231
Disertori M, Barlera S, Staszewsky L, Latini R, Quintarelli S, Franzosi MG
Systematic review and meta-analysis: Renin-angiotensin system inhibitors in the prevention of atrial fibrillation
recurrences. An unfulfilled hope
Cardiovasc Drugs Ther 2012; 26: 47–54
Eikelboom JW, Connolly SJ, Healey JS, Yang S, Yusuf S, Wallentin L, Oldgren J, Ezekowitz M, Alings M, Kaatz S,
Hohnloser SH, Diener HC, Franzosi MG, Huber K, Reilly P, Varrone J
Reply to Letters Regarding Article, "Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and
younger patients with atrial fibrillation: An analysis of the Randomized Evaluation of Long-Term Anticoagulant
Therapy (RE-LY) Trial"
Circulation 2012; 125: e293-e294
Ferratini M, Ripamonti V, Masson S, Grati P, Racca V, Cuccovillo I, Raimondi E, Capomolla S, Macchi C, Coruzzi
P, Vago T, Calvo M, Mantovani A, Latini R
Pentraxin-3 predicts functional recovery and 1-year major adverse cardiovascular events after rehabilitation of
cardiac surgery patients
J Cardiopulm Rehabil Prev 2012; 32: 17-24
Fox CS, Liu Y, White CC, Feitosa M, Smith AV, Heard-Costa N, Lohman K; GIANT Consortium; MAGIC
Consortium; GLGC Consortium, Johnson AD, Foster MC, Greenawalt DM, Griffin P, Ding J, Newman AB,
Tylavsky F, Miljkovic I, Kritchevsky SB, Launer L, Garcia M, Eiriksdottir G, Carr JJ, Gudnason V, Harris TB,
Cupples LA, Borecki IB, Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E,
Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Mägi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D,
Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song
K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparsø T, Doney A, Voight BF, Stringham HM, Li M, Kanoni
S, Shrader P, Cavalcanti-Proença C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, Ingelsson E,
An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Payne F, Roccasecca RM, Pattou F, Sethupathy P, Ardlie K,
Ariyurek Y, Balkau B, Barter P, Beilby JP, Ben-Shlomo Y, Benediktsson R, Bennett AJ, Bergmann S, Bochud M,
Boerwinkle E, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Charpentier
G, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Cornelis M, Crawford G, Crisponi L, Day IN, de Geus EJ,
Delplanque J, Dina C, Erdos MR, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Fox CS, Frants R, Franzosi MG,
Galan P, Goodarzi MO, Graessler J, Groves CJ, Grundy S, Gwilliam R, Gyllensten U, Hadjadj S, Hallmans G,
Hammond N, Han X, Hartikainen AL, Hassanali N, Hayward C, Heath SC, Hercberg S, Herder C, Hicks AA,
Hillman DR, Hingorani AD, Hofman A, Hui J, Hung J, Isomaa B, Johnson PR, Jørgensen T, Jula A, Kaakinen M,
Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le
Bacquer O, Lecoeur C, Li Y, Lyssenko V, Mahley R, Mangino M, Manning AK, Martínez-Larrad MT, McAteer JB,
McCulloch LJ, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Morken MA, Mukherjee S, Naitza S,
Narisu N, Neville MJ, Oostra BA, Orrù M, Pakyz R, Palmer CN, Paolisso G, Pattaro C, Pearson D, Peden JF,
Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM,
Rathmann W, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Roden M, Rolandsson O, Sandbaek A, Sandhu M,
ANNUAL REPORT
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2012
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Sanna S, Sayer AA, Scheet P, Scott LJ, Seedorf U, Sharp SJ, Shields B, Sigurðsson G, Sijbrands EJ, Silveira A,
Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Thorand B, Tichet J,
Tönjes A, Tuomi T, Uitterlinden AG, van Dijk KW, van Hoek M, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs
N, Waeber G, Wagner PJ, Walley A, Walters GB, Ward KL, Watkins H, Weedon MN, Wild SH, Willemsen G,
Witteman JC, Yarnell JW, Zeggini E, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ,
Meneton P, Magnusson PK, Nathan DM, Williams GH, Hattersley AT, Silander K, Salomaa V, Smith GD, Bornstein
SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Ríos M, Morris AD, Lind L,
Palmer LJ, Hu FB, Franks PW, Ebrahim S, Marmot M, Kao WH, Pankow JS, Sampson MJ, Kuusisto J, Laakso M,
Hansen T, Pedersen O, Pramstaller PP, Wichmann HE, Illig T, Rudan I, Wright AF, Stumvoll M, Campbell H,
Wilson JF, Hamsten A, Bergman RN, Buchanan TA, Collins FS, Mohlke KL, Tuomilehto J, Valle TT, Altshuler D,
Rotter JI, Siscovick DS, Penninx BW, Boomsma ID, Deloukas P, Spector TD, Frayling TM, Ferrucci L, Kong A,
Thorsteinsdottir U, Stefansson K, van Duijn CM, Aulchenko YS, Cao A, Scuteri A, Schlessinger D, Uda M,
Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Abecasis RG, Wareham NJ,
Sladek R, Froguel P, Watanabe RM, Meigs JB, Groop L, Boehnke M, McCarthy MI, Florez JC, Barroso I.
Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in
women
PLoS Genet 2012; 8: e1002695
Franchi C, Tettamanti M, Marengoni A, Bonometti F, Pasina L, Cortesi L, Fortino I, Bortolotti A, Merlino L, Lucca U,
Riva E, Nobili A
Changes in trend of antipsychotics prescription in patients treated with cholinesterase inhibitors after warnings from
Italian Medicines Agency. Results from the EPIFARM-Elderly Project
Eur Neuropsychopharmacol 2012; 22: 569-577
Franzosi MG, Latini R
Beta-adrenoceptor antagonists and antianginal drugs. Chapter 18
In: Aronson JK, Side Effects of Drugs. Annual 34
Elsevier, Amsterdam 2012, 303-310.
Gertow K, Sennblad B, Strawbridge RJ, Ohrvik J, Zabaneh D, Shah S, Veglia F, Fava C, Kavousi M, McLachlan S,
Kivimäki M, Bolton JL, Folkersen L, Gigante B, Leander K, Vikström M, Larsson M, Silveira A, Deanfield J, Voight
BF, Fontanillas P, Sabater-Lleal M, Colombo GI, Kumari M, Langenberg C, Wareham NJ, Uitterlinden AG,
Gabrielsen A, Hedin U, Franco-Cereceda A, Nyyssönen K, Rauramaa R, Tuomainen TP, Savonen K, Smit AJ, Giral
P, Mannarino E, Robertson CM, Talmud PJ, Hedblad B, Hofman A, Erdmann J, Reilly MP, O'Donnell CJ, Farrall M,
Clarke R, Franzosi MG, Seedorf U, Syvänen AC, Hansson GK, Eriksson P, Samani NJ, Watkins H, Price JF,
Hingorani AD, Melander O, Witteman JC, Baldassarre D, Tremoli E, de Faire U, Humphries SE, Hamsten A.
Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and
coronary artery disease risk.
Circ Cardiovasc Genet 2012; 5: 656-665
Holliday EG, Maguire JM, Evans TJ, Koblar SA, Jannes J, Sturm JW, Hankey GJ, Baker R, Golledge J, Parsons
MW, Malik R, McEvoy M, Biros E, Lewis MD, Lincz LF, Peel R, Oldmeadow C, Smith W, Moscato P, Barlera S,
Bevan S, Bis JC, Boerwinkle E, Boncoraglio GB, Brott TG, Brown RD Jr, Cheng YC, Cole JW, Cotlarciuc I, Devan
WJ, Fornage M, Furie KL, Grétarsdóttir S, Gschwendtner A, Ikram MA, Longstreth WT Jr, Meschia JF, Mitchell
BD, Mosley TH, Nalls MA, Parati EA, Psaty BM, Sharma P, Stefansson K, Thorleifsson G, Thorsteinsdottir U,
Traylor M, Verhaaren BF, Wiggins KL, Worrall BB; The Australian Stroke Genetics Collaborative; The International
Stroke Genetics Consortium; The Wellcome Trust Case Control Consortium 2, Sudlow C, Rothwell PM, Farrall M,
Dichgans M, Rosand J, Markus HS, Scott RJ, Levi C, Attia J
Common variants at 6p21.1 are associated with large artery atherosclerotic stroke
Nat Genet 2012; 44: 1147-1151
Huang J, Sabater-Lleal M, Asselbergs FW, Tregouet D, Shin SY, Ding J, Baumert J, Oudot-Mellakh T, Folkersen L,
Johnson AD, Smith NL, Williams SM, Ikram MA, Kleber ME, Becker DM, Truong V, Mychaleckyj JC, Tang W,
Yang Q, Sennblad B, Moore JH, Williams FM, Dehghan A, Silbernagel G, Schrijvers EM, Smith S, Karakas M,
Tofler GH, Silveira A, Navis GJ, Lohman K, Chen MH, Peters A, Goel A, Hopewell JC, Chambers JC, Saleheen D,
Lundmark P, Psaty BM, Strawbridge RJ, Boehm BO, Carter AM, Meisinger C, Peden JF, Bis JC, McKnight B,
Ohrvik J, Taylor K, Franzosi MG, Seedorf U, Collins R, Franco-Cereceda A, Syvänen AC, Goodall AH, Yanek LR,
Cushman M, Müller-Nurasyid M, Folsom AR, Basu S, Matijevic N, van Gilst WH, Kooner JS, Hofman A, Danesh J,
Clarke R, Meigs JB, Consortium D, Kathiresan S, Reilly MP, Consortium C, Klopp N, Harris TB, Winkelmann BR,
Grant PJ, Hillege HL, Watkins H, Consortium CF, Spector TD, Becker LC, Tracy RP, März W, Uitterlinden AG,
Eriksson P, Cambien F, Consortium C, Morange PE, Koenig W, Soranzo N, van der Harst P, Liu Y, O'Donnell CJ,
Hamsten A
Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation
ANNUAL REPORT
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2012
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Blood 2012; 120: 4873-4881
International Stroke Genetics Consortium (ISGC), Wellcome Trust Case Control Consortium (WTCCC2)
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
Nat Genet 2012; 44: 328-333
La Rovere MT, Pinna GD, Maestri R, Barlera S, Bernardinangeli M, Veniani M, Nicolosi GL, Marchioli R, Tavazzi
L, for the GISSI-HF Investigators
Autonomic markers and cardiovascular and arrhythmic events in heart failure patients: still a place in
prognostication? Data from the GISSI-HF trial
Eur J Heart Fail 2012; 14: 1410-1419
La Rovere MT, Staszewsky L, Barlera S, Mezzani A, Midi P, Marchioli R, Maggioni AP, Tognoni G, Tavazzi L,
Latini R, on behalf of the GISSI-HF Investigators
n-3PUFA and holter-derived autonomic variables in heart failure patients: Data from the Gruppo Italiano per lo
Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) Holter Substudy
Heart Rhythm 2012; Epub
Latini R, Gullestad L, Masson S, Nymo SH , Ueland T, Cuccovillo I, Vårdal M , Bottazzi B, Mantovani A, Lucci D,
Masuda N, Sudo Y, Wikstrand J, Tognoni G, Aukrust P, Tavazzi L, on behalf of the Investigators of the Controlled
Rosuvastatin Multinational Trial in Heart Failure (CORONA) and GISSI-Heart Failure (GISSI-HF) trial
Pentraxin-3 in chronic heart failure: the CORONA and GISSI-HF trials
Eur J Heart Fail 2012; 14: 992-999
Levantesi G, Marfisi R M, Franzosi M G, Maggioni AP, Nicolosi G L, Schweiger C, Silletta MG, Tavazzi L, Tognoni
G, Marchioli R
Uric acid: A cardiovascular risk factor in patients with recent myocardial infarction
Int J Cardiol 2012; Epub
Li Y, Ristagno G, Guan J, Barbut D, Bisera J, Weil MH, Tang W
Preserved heart rate variability during therapeutic hypothermia correlated to 96 hours neurological outcomes and
survival in a pig model of cardiac arrest
Crit Care Med 2012; 40: 580-586
Manning AK, Hivert M, Scott RA, Grimsby JL, Bouatia-Naji N, Chen H, Rybin D, Liu CT, Bielak LF, Prokopenko I,
Amin N, Barnes D, Cadby G, Hottenga JJ, Ingelsson E, Jackson AU, Johnson T, Kanoni S, Ladenvall C, Lagou V,
Lahti J, Lecoeur C, Liu Y, Martinez-Larrad MT, Montasser ME, Navarro P, Perry JR, Rasmussen-Torvik LJ, Salo P,
Sattar N, Shungin D, Strawbridge RJ, Tanaka T, van Duijn CM, An P, de Andrade M, Andrews JS, Aspelund T,
Atalay M, Aulchenko Y, Balkau B, Bandinelli S, Beckmann JS, Beilby JP, Bellis C, Bergman RN, Blangero J, Boban
M, Boehnke M, Boerwinkle E, Bonnycastle LL, Boomsma DI, Borecki IB, Böttcher Y, Bouchard C, Brunner E,
Budimir D, Campbell H, Carlson O, Chines PS, Clarke R, Collins FS, Corbatón-Anchuelo A, Couper D, de Faire U,
Dedoussis GV, Deloukas P, Dimitriou M, Egan JM, Eiriksdottir G, Erdos MR, Eriksson JG, Eury E, Ferrucci L, Ford
I, Forouhi NG, Fox CS, Franzosi MG, Franks PW, Frayling TM, Froguel P, Galan P, de Geus E, Gigante B, Glazer
NL, Goel A, Groop L, Gudnason V, Hallmans G, Hamsten A, Hansson O, Harris TB, Hayward C, Heath S, Hercberg
S, Hicks AA, Hingorani A, Hofman A, Hui J, Hung J, Jarvelin MR, Jhun MA, Johnson PC, Jukema JW, Jula A, Kao
WH, Kaprio J, Kardia SL, Keinanen-Kiukaanniemi S, Kivimaki M, Kolcic I, Kovacs P, Kumari M, Kuusisto J, Kyvik
KO, Laakso M, Lakka T, Lannfelt L, Lathrop GM, Launer LJ, Leander K, Li G, Lind L, Lindstrom J, Lobbens S,
Loos RJ, Luan J, Lyssenko V, Mägi R, Magnusson PK, Marmot M, Meneton P, Mohlke KL, Mooser V, Morken MA,
Miljkovic I, Narisu N, O'Connell J, Ong KK, Oostra BA, Palmer LJ, Palotie A, Pankow JS, Peden JF, Pedersen NL,
Pehlic M, Peltonen L, Penninx B, Pericic M, Perola M, Perusse L, Peyser PA, Polasek O, Pramstaller PP, Province
MA, Räikkönen K, Rauramaa R, Rehnberg E, Rice K, Rotter JI, Rudan I, Ruokonen A, Saaristo T, Sabater-Lleal M,
Salomaa V, Savage DB, Saxena R, Schwarz P, Seedorf U, Sennblad B, Serrano-Rios M, Shuldiner AR, Sijbrands EJ,
Siscovick DS, Smit JH, Small KS, Smith NL, Smith AV, Stančáková A, Stirrups K, Stumvoll M, Sun YV, Swift AJ,
Tönjes A, Tuomilehto J, Trompet S, Uitterlinden AG, Uusitupa M, Vikström M, Vitart V, Vohl MC, Voight BF,
Vollenweider P, Waeber G, Waterworth DM, Watkins H, Wheeler E, Widen E, Wild SH, Willems SM, Willemsen G,
Wilson JF, Witteman JC, Wright AF, Yaghootkar H, Zelenika D, Zemunik T, Zgaga L; DIAbetes Genetics
Replication And Meta-analysis (DIAGRAM) Consortium; The Multiple Tissue Human Expression Resource
(MUTHER) Consortium, Wareham NJ, McCarthy MI, Barroso I, Watanabe RM, Florez JC, Dupuis J, Meigs JB,
Langenberg C.
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic
traits and insulin resistance
Nat Genet 2012; 44: 659-669
ANNUAL REPORT
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2012
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Marzona I, O'Donnell M, Teo K, Gao P, Anderson C, Bosch J, Yusuf S
Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and
TRANSCEND studies
CMAJ 2012; 184: E329-E336
Masson S, Anand I S, Favero C, Barlera S, Vago T, Bertocchi F, Maggioni AP, Tavazzi L, Tognoni G, Cohn JN,
Latini R, on behalf of the Valsartan Heart Failure Trial (Val-HeFT) and Gruppo Italiano per lo Studio della
Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure ( GISSI-HF) Investigators
Serial measurement of cardiac troponin T using a highly sensitive assay in patients with chronic heart failure. Data
from 2 large randomized clinical trials
Circulation 2012; 125: 280-288
Masson S, Latini R, Mureddu GF, Agabiti N, Miceli M, Cesaroni G, Forastiere F, Wienhues-Thelen U-H, Block D,
Zaugg C, Vago T, Boccanelli R, on behalf of the Investigators of the PREDICTOR study
High-sensitivity cardiac troponin T for detect subtle abnormalities of cardiac phenotype in a general
population of elderly individuals
J Inter Med 2012; Epub
Meda C, Molla F, De Pizzol M, Regano D, Maione F, Capano S, Locati M, Mantovani A, Latini R, Bussolino F,
Giraudo E
Semaphorin 4A exerts a proangiogenic effect by enhancing vascular endothelial growth factor-A expression in
macrophages
J Immunol 2012; 188: 4081-4092
Monesi L, Baviera M, Marzona I, Avanzini F, Monesi G, Nobili A, Tettamanti M, Cortesi L, Riva E, Fortino I,
Bortolotti A, Fontana G, Merlino L, Roncaglioni MC
Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study
Diabet Med 2012; 29: 385–392
Monesi L, Baviera M, Cortesi L, Marzona I, Tettamanti M
Reply to Brinks and Rathmann: Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian
population-based study
Diabet Med 2012; 29: 1085
Mozaffarian D, Marchioli R, Macchia A, Silletta MG, Ferrazzi P, Gardner TJ, Latini R, Libby P, Lombardi F, O'Gara
PT, Page RL, Tavazzi L, Tognoni G, for the OPERA Investigators.
Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial
Fibrillation (OPERA) randomized trial
JAMA 2012; 308: 2001-2011
Mureddu GF, Agabiti N, Rizzello V, Forastiere F, Latini R, Cesaroni G, Masson S, Cacciatore G, Colivicchi F,
Uguccioni M, Perucci CA, Boccanelli A, on behalf of the PREDICTOR Study Group
Prevalence of preclinical and clinical heart failure in the elderly. A population-based study in Central Italy
Eur J Heart Fail 2012; 14: 718-729
Orsenigo F, Giampietro C, Ferrari A, Corada M, Galaup A, Sigismund S, Ristagno G, Maddaluno L, Young Koh G,
Franco D, Kurtcuoglu V, Poulikakos D, Baluk P, McDonald D, Lampugnani MG, Dejana E.
Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular
permeability in vivo.
Nat Commun 2012; 3: 1208
Palmer ND, McDonough CW, Hicks PJ, Roh BH, Wing MR, An SS, Hester JM, Cooke JN, Bostrom MA, Rudock
ME, Talbert ME, Lewis JP; DIAGRAM Consortium; MAGIC Investigators, Ferrara A, Lu L, Ziegler JT, Sale MM,
Divers J, Shriner D, Adeyemo A, Rotimi CN, Ng MC, Langefeld CD, Freedman BI, Bowden DW, Voight BF, Scott
LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch
LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM,
Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R,
Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS,
Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M,
Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B,
Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse
A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR,
Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR,
ANNUAL REPORT
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2012
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Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K,
Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van
Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS,
Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke
KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker
M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB,
Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U,
Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI, Soranzo N,
Wheeler E, Glazer NL, Bouatia-Naji N, Mägi R, Randall J, Johnson T, Elliott P, Rybin D, Henneman P, Dehghan A,
Hottenga JJ, Song K, Goel A, Egan JM, Lajunen T, Doney A, Kanoni S, Cavalcanti-Proença C, Kumari M, Timpson
NJ, Zabena C, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Roccasecca RM, Pattou F,
Sethupathy P, Ariyurek Y, Barter P, Beilby JP, Ben-Shlomo Y, Bergmann S, Bochud M, Bonnefond A, BorchJohnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Crisponi L,
Day IN, de Geus EJ, Delplanque J, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Frants R, Franzosi MG, Galan P,
Goodarzi MO, Graessler J, Grundy S, Gwilliam R, Hallmans G, Hammond N, Han X, Hartikainen AL, Hayward C,
Heath SC, Hercberg S, Hicks AA, Hillman DR, Hingorani AD, Hui J, Hung J, Jula A, Kaakinen M, Kaprio J,
Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O,
Lecoeur C, Li Y, Mahley R, Mangino M, Manning AK, Martínez-Larrad MT, McAteer JB, McPherson R, Meisinger
C, Melzer D, Meyre D, Mitchell BD, Mukherjee S, Naitza S, Neville MJ, Oostra BA, Orrù M, Pakyz R, Paolisso G,
Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC,
Pouta A, Province MA, Psaty BM, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Rolandsson O, Sandbaek A,
Sandhu M, Sanna S, Sayer AA, Scheet P, Seedorf U, Sharp SJ, Shields B, Sijbrands EJ, Silveira A, Simpson L,
Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Tönjes A, Uitterlinden AG, van Dijk
KW, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Ward KL, Watkins H,
Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki
IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Silander K, Salomaa V, Smith GD, Bornstein
SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Ríos M, Lind L, Palmer LJ,
Franks PW, Ebrahim S, Marmot M, Kao WH, Pramstaller PP, Wright AF, Stumvoll M, Hamsten A, Buchanan TA,
Valle TT, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Ferrucci L, Cao A, Scuteri
A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V,
Sladek R.
A genome-wide association search for type 2 diabetes genes in African Americans
PLoS One 2012; 7: e29202
Raimondi M T, Balconi G, Boschetti F, Di Metri A, Mohammed SAA, Quaglini V, Araneo L, Galvez BG, Lupi M, Latini
R, Remuzzi A
An opto-structural methods to estimate the stress-strain field induced by cell contraction on substrates of controlled
stiffness in vitro
J Appl Biomater Function Mater 2012; Epub
Ristagno G, Fumagalli F, Porretta-Serapiglia C, Orrù A, Cassina C, Pesaresi M, Masson S, Villanova L, Merendino
A, Villanova A, Cervo L, Lauria G, Latini R, Bianchi R
Hydroxytyrosol attenuates peripheral neuropathy in streptozotocin-induced diabetes in rats
J Agric Food Chem 2012; 60: 5859−5865
Ristagno G, Tantillo S, Li Y
Should we be afraid of mild hypothermia? Not at all! Just do not underestimate risk factors and optimize
postresuscitation care
Crit Care Med 2012; 40: 1029-1031
Ristagno G, Yu T, Quan W, Freeman G, Li Y
Comparison of defibrillation efficacy between two pads placements in a pediatric porcine model of cardiac arrest
Resuscitation 2012; 83: 755-759
Ristagno G, Yu T, Quan W, Freeman G, Li Y
Current is better than energy as predictor of success for biphasic defibrillatory shocks in a porcine model of
ventricular fibrillation
Resuscitation 2012; Epub
Rothwell PM, Price JF, Fowkes FGR , Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JFF, Wilson M,
Mehta Z, Meade TW
Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course
of risks and benefits in 51 randomised controlled trials
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Lancet 2012; 379: 1602-1612
Traina G, Bigini P, Federighi G, Sitia L, Paroni G, Fiordaliso F, Salio M, Bendotti C, Brunelli M
Lipofuscin accumulation and gene expression in different tissues of mnd mice
Mol Neurobiol 2012; 45: 247-257
LAY PRESS SELECTION (2012)
Monesi L, Baviera M, Cortesi L, Marzona I, Avanzini F, Monesi G, Nobili A, Tettamanti M, Riva E, Fortino I,
Bortolotti A, Fontana G, Merlino L, Roncaglioni MC
Dalla lettura dei database amministrativi: l’epidemiologia e il trattamento del diabete in Regione Lombardia dal 2000
al 2007.
G It Diabetol Metab 2012; 32; 70-78
Ristagno G, Li Volti G
Ricerca di base e medicina critica. Cap. 22
In: Gullo A, Murabito P, Governo clinico e medicina perioperatoria.
Springer-Verlag Italia, Milano, 2012; 297-313
Tognoni G
Promuovere lo sviluppo urgente del Paese mediante un più alto livello di tutela della salute
Informazioni sui Farmaci 2012; 36: 41-43
RESEARCH ACTIVITIES
Laboratory of Cardiovascular Clinical Pharmacology
Pulmonary injury by hydrochloric acid in the mouse: a model of
aspiration pneumonitis to test protective interventions
Aspiration pneumonitis (AP) occurs when the acid content of the stomach makes its way
through the larynx in the lower respiratory tract. Patients with consciousness disturbance are at
risk for this event. Specifically, it has been shown that pulmonary aspiration can complicate
between 0.47-1.41% general anesthesia procedures.
The course of AP can be extremely variable, ranging from the “silent aspiration” characterized
by a modest desaturation to the dramatic sequelae of Acute Lung Injury (ALI) and Acute
Respiratory Distress Syndrome (ARDS), requiring prolonged mechanical ventilation and
potentially leading to death. In a murine model of monolateral acid instillation established in our
laboratory, we have shown the protective effect of exogenous pulmonary surfactant instillation.
We are currently working on a model of ventilation-induced lung injury (VILI) in the rat to
assess the effect of angiotensin 1-7 and its synthetic analogues.
Pilot study on microangiopathy in diabetic foot ulcer
Microangiopathy is considered one of the major complications in the diabetic foot, although the
role of microvascular alterations in the etiopathogenesis and severity of the ulcer in diabetic foot
are still unknown. The purpose of this study will be the assessment of microangiopathy
determined by the increase of capillary basement membrane thickness and decrease of capillary
lumen area by transmission electron microscopy in the foot ulcer of neuropathic and
neuroischemic type 2 diabetic patients compared to healthy subjects. Furthermore, we will
investigate the correlation between the presence of capillary and thrombosis with ischemic
parameters (TcPO2, ankle-brachial index) and between presence of inflammatory infiltrate with
blood inflammatory parameters. After verified the possibility to identify the histopathological
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characteristic of microcirculation by histological and ultrastructural techniques, the study has
started and nowadays half of patients indicated in the study protocol have been enrolled.
Preclinical and clinical studies in cardiac arrest and cardiopulmonary
resuscitation
Cardiovascular disease remains the leading cause of death in the Western world with 350,000
Americans and 700,000 Europeans sustaining cardiac arrest each year. Instead of the initial
success of cardiopulmonary resuscitation, the majority victims die within 72 hours because of
severe heart contractile failure due to post-resuscitation myocardial dysfunction.
Furthermore, cardiac arrest and cardiopulmonary resuscitation represent a condition of systemic
ischemia-reperfusion injury causing multi-organ damage.
For this purpose we are currently studying a preclinical model of cardiac arrest and
cardiopulmonary resuscitation (CPR) in intact rats or in rats with metabolic syndrome (i.e.
obesity, diabetes) and in pigs (in collaboration with University of Milan) aiming to: (a) evaluate
inflammatory response and organ dysfunction after return of spontaneous circulation; (b)
evaluate success of cardiopulmonary resuscitation manoeuvres and survival after new
pharmacological approaches (i.e., pentraxin 3, toll like receptor 4 antagonists, and ventilation
with Argon).
Moreover, the severity of post-resuscitation myocardial dysfunction has been recognized to be
related, partially, to the magnitude of the total electrical energy delivered with defibrillation.
Consequently, the development of a non-invasive and real-time monitoring that allow prediction
of outcome of the defibrillation attempt is therefore of great importance in decreasing the
defibrillation energy.
At present, we are evaluating a clinically applicable method based on electrocardiographic
analysis of ventricular fibrillation waveform aiming to asses a non-invasive approach in order to
guide the priority of interventions, namely chest compression or defibrillation (collaborating
institutions: Emergency Department, San Gerardo Hospital, Monza and Azienda Regionale
Emergenza Urgenza - Lombardia).
Toll-like receptor 4 inhibition in murine cardiac ischemia and reperfusion
biohumoral substudy and urinary markers of renal injury
Myocardial ischemia and reperfusion injury is a typical “double-edged sword” that results in
disease specific changes within cardiomyocytes and circulating cells. The injury involves a
robust inflammatory response and increasing experimental evidence suggests an important role
for the innate immune system in initiating the inflammatory cascade leading to
detrimental/deleterious consequences. The most important innate immune receptors the Toll
like receptors (TLRs) play a central role in initiating and shaping innate and adaptive immune
responses after ischemia/reperfusion. TLRs are not only expressed in immune cells, but also in
cardiovascular cells; they are able to recognize endogenous ligands and may play a role in
myocyte death and survival. Results of experimental studies regarding the effects of the
pharmacological inhibition of TLRs by specific antagonists are contradictory. Our laboratory
is assessing in mice and in pigs with myocardial ischemia/reperfusion, the early and late effects
on myocardial infarction size and cardiac function of a new LPS-like molecule, derived from a
cyanobacterium (Oscillatoria planktothrix sp.), a compound which acts as TLR4-MD2
antagonist.
Ranolazine in pulmonary arterial hypertension
Pulmonary arterial hypertension is characterized by progressive obstruction and obliteration of
the pulmonary arteries causing right ventricular failure and premature death.
Despite the development of different therapeutics strategies pulmonary arterial hypertension is
an orphan disease. Intracellular sodium overload play a key role in both electrical and
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mechanical dysfunction in pathological settings linked to imbalances in oxygen supply and
demand, like pulmonary arterial hypertension. The inhibition of the late sodium current (INaL) by
ranolazine was proposed in order to decrease the intracellular sodium overload, and thereby to
improve right ventricular function and the expression of proteins involved in the regulation of
hypertrophy. Studies in our laboratory followed in collaboration with the Department of
Biotechnology and Biosciences, University of Milano Bicocca, (M. Ronchetti and A. Zaza),
have shown in an experimental rat pulmonary arterial hypertension model induced by
monocrotaline that, right ventricular remodeling and pulmonary arteriolar wall thickness
diminished in animals treated chronically with ranolazine.
GISSI-HF: biohumoral substudy, urinary markers of renal injury and
circulating levels of fatty acids
The GISSI-HF trial was designed to assess whether two treatments (a statin and n-3
polyunsaturated fatty acids or PUFA) can improve the prognosis of patients with heart failure of
any etiology, with preserved or compromised left ventricular ejection fraction. Main results
have been published (Lancet 2008; 372: 1223-1230 and Lancet 2008; 372: 1231-1239). Urine
samples were collected in more than 2000 patients to assess markers of glomerular injury
(microalbuminuria, Circ Heart Fail 2010; 3: 65-72) and early markers of renal tubular injury
(KIM-1, N-GAL e NAG), that predict a bad clinical outcome, even with preserved glomerular
function (Eur Heart J 2011; 32: 2705-2712). We submitted for publication a manuscript on the
value of these markers to predict worsening renal function.
Albumin Italian Outcome Sepsis Study. The ALBIOS Study (AIFA)
ALBIOS is a multicenter, controlled, randomized clinical trial that compares the efficacy of
human albumin and a crystalloid solution for volume replacement in patients with severe sepsis
or septic shock. The primary endpoint is survival at 28 and 90 days after enrolment. Secondary
endpoints include the number of organ dysfunctions, severity of organ dysfunction (SOFA
scale), and lengths of stay in intensive care unit (ICU) and in hospital. More than 150 ICU in
Italy have enrolled patients in this large study, coordinated by the Ospedale Maggiore
Policlinico in Milan and the Consorzio Mario Negri Sud. A group of 48 ICUs participates to a
biomarkers substudy, coordinated by the laboratory of Clinical Cardiovascular Pharmacology,
and have collected serial blood samples from 1000 patients to measure biomarkers related to
inflammation, infection, cardiac function and coagulation. Preliminary results on a new marker
of bacterial infection and sepsis (paper in preparation) and innate immunity (sST2 and PTX3)
are now available.
Prevalence of asymptomatic cardiac dysfunction and heart failure in a
population of elderly subjects from Lazio. The PREDICTOR Study
This observational study aims at evaluating the prevalence of asymptomatic cardiac dysfunction
and heart failure in a random sample of elderly subjects from the Lazio area. The secondary
objective is to identify clinical, biohumoral (natriuretic peptides) and non-invasive instrumental
(echocardiography and ECG) markers of asymptomatic cardiac dysfunction and heart failure.
The population under observation is a randomly selected sample of elderly subjects (age ranging
from 65 to 84 years) resident in the area of 10 hospital cardiology centers.. Blood samples have
been collected from 2000 individuals and are stored in the biobank of the Laboratory of Clinical
Cardiovascular Pharmacology. In a first paper (J Intern Med 2013; 273: 306-317), the
association between left ventricular mass and two cardiac markers (troponin and natriuretic
peptide) has been described. We have measured markers of inflammation (C-reactive protein),
renal function (Cystatin C), phosphate metabolism (FGF-23 and vitamin D, manuscript in
preparation) and collagen metabolism (PINP).
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OPERA: Omega-3 Fatty Acids for Prevention of Post-Operative Atrial
Fibrillation
Peri-operative administration of n-3 polyunsaturated fatty acids (PUFA) may significantly
reduce the incidence of post-operative atrial fibrillation (AF) in patients undergoing cardiac
surgery (CAS). The aim is to determine, using a randomized, double-blind, placebo-controlled,
clinical trial, whether peri-operative administration of n-3 PUFA (8 g total pre-op and then 2 g/d
for 14 days or until hospital discharge) reduces the incidence of AF in 1,516 patients
undergoing CAS. It is a multinational, multicenter, double-blind, parallel design clinical trial
enrolling patients undergoing CAS in 40-50 major medical centers in the U.S., Argentina and
Italy. A core laboratory for Italy and Argentina is at Mario Negri, that coordinates the assay of
cardiac (troponin and natriuretic peptide) and inflammatory markers (C-reactive protein). The
main results of the clinical trial have been recently published (Mozaffarian et al., JAMA 2012).
Coronary Atherosclerosis in Outlier Subjects: Protective and Individual
Risk Factor Evaluation. The GISSI-Outliers CAPIRE study
The risk of developing clinical signs of ischemic cardiopathy is currently estimated with
multivariable prediction models based on non-modifiable factors like age, sex and family
history for early ischemic cardiopathy, and on conventional modifiable risk factors like
hypertension, hypercholesterolemia, smoking and diabetes mellitus. However, there is a
component of individual variability underlying the fact that a relevant number of individuals
with multiple risk factors do not progress to coronary atherosclerosis or have clinical events,
while others have such events or coronary disease in the absence of risk factors (= outliers). The
purpose of the CAPIRE study is to identify possible novel protective or risk factors for coronary
disease in outlier subjects and generate new etiological hypotheses and therapeutic targets for
this disease. This is an observational, multicenter clinical study performed in 8 centers.
Enrolment of the patients will last 2 years and each patient will be followed for 5 years with
yearly clinical visit and phone contact every 6 months. The Laboratory of Clinical
Cardiovascular Pharmacology is acting as a core laboratory for the evaluation of circulating
biomarkers related to lipid profile, inflammation, metabolism and coagulation. By the end of
2012, 476 patients (out of the 600 expected) have been enrolled. Preliminary analyses in the
first 150 patients enrolled have shown that very low levels of troponin were associated with
atherosclerosis.
Cyclosporin A in reperfused acute myocardial infarction – The CYCLE
study
The final extent of myocardial infarction is the main determinant of prognosis in these patients.
A preliminary study has shown that a single bolus of cyclosporin A (CsA), administered
immediately before primary angioplasty, can reduce the final area of necrosis after a STsegment elevation myocardial infarction (STEMI). The primary objective of this trial is to
assess whether CsA can improve the outcome of a successfully reperfused STEMI, by favoring
myocardial reperfusion. Male and female patients, older than 18 years, with a large STEMI
(defined as angina pectoris o equivalent symptoms for more than 20 minutes) will be enrolled
within the first 6 hours from symptoms onset and with indication for primary angioplasty (PCI).
The secondary objectives are a reduction of high sensitivity cardiac troponin T release 4 days
after PCI, total heart failure mortality, cardiogenic shock or hospital admission for
cardiovascular reasons within 6 months after randomization. By the end of December 2012, 113
patients have been enrolled in 25 centers; enrollment should be concluded by the end of 2013.
Prevention of anthracyclin-induced cardiac toxicity: a multicenter
randomized clinical study comparing two strategies – The ICOS-ONE
study
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Chemotherapy with anthracycline often induces a progressive and dose-dependent cardiac
injury, reducing left ventricular output. The development of cardiac dysfunction, even if
asymptomatic, may have a negative impact on the prognosis of a cancer patient. Measuring
circulating cardiac troponin levels during chemotherapy with anthracycline allow to identify
early cardiac injury, before the development of overt left ventricular dysfunction. Treatment
with ACE inhibitors (ACEi) and beta-blockers (BB) before the elevation of circulating cardiac
troponin levels during or after chemotherapy with anthracycline can protect the heart, as shown
in a single-center study. Early prophylaxis with enalapril (ACEi) and possibly bisoprolol (BB)
may further decrease the incidence of cardiovascular injury and thereby raising the probability
of completing the chemotherapy. The primary objective of the ICOS-ONE study is to assess
whether a treatment with enalapril given since the beginning of anthracyclin therapy is more
efficient in preventing cardiac toxicity compared to the same treatment initiated at the first
occurrence of raised troponin levels. Patients with an indication for treatment with anthracyclin
for breast cancer, acute myeloid leukemia in older subjects, aggressive lymphoma or sarcoma
will be enrolled. This randomized clinical trial involves 16 Italian clinical centers. In the first
arm, enalapril will be given at the beginning of chemotherapy (primary prevention) while it will
be given only after the troponin elevation in the second arm (secondary prevention). The
patients will be followed for 1 year from the end of chemotherapy with periodical clinical visits.
14 centers have been activated by the end of 2012. This trial is promoted by the IEO (Istituto
Europeo di Oncologia) and coordinated in collaboration with the Laboratory of Clinical Drug
Evaluation.
Laboratory of Clinical Drug Evaluation
PROCARDIS: A genome-wide strategy to identify susceptibility loci in
precocious coronary artery disease
The PROCARDIS research programme, a genome-wide strategy to identify susceptibility loci
in precocious coronary artery disease (CAD) supported by the 6th Framework Programme of the
EC, was initiated as a collaboration between the Universities of Oxford and Munster, the
Karolinska Institute, and the Mario Negri Institute with the support of the GISSI group. The
objectives of the first stage of this programme were to collect a minimum of 2000 affected
sibling pairs (ASPs) and families with precocious CAD and to apply genome-wide linkage
mapping techniques, to identify chromosomal regions linked to the susceptibility to early-onset
CAD. The PROCARDIS collected 2036 CAD families from four European countries, in order
to maximise the power of detecting genes that confer modest risks. A genome-wide linkage scan
identified three promising regions for intensive study. Extensive clinical and biochemical
intermediate phenotype data have also been collected and assessed. The second stage of
PROCARDIS conducted a large GWAS (genome wide association study), where the patients
with myocardial infarction enrolled in the first stage have been compared with control subjects
to identify novel candidate genes. The results have been replicated in different populations. The
PROCARDIS study identified risk loci for coronary disease by using a novel gene chip
consisting of nearby 50,000 SNPs in 2100 candidate genes that were selected for their
potential relevance to coronary artery disease. With this gene chip, PROCARDIS confirmed
the previous identification of three chromosomal regions that were correlated with the risk of
coronary disease: 6q26–27, 9p21, and 1p13. In the chromosome 9p21 region PROCARDIS
has identified two SNPs, that are independently associated with CAD and with type 2 diabetes
(T2D) respectively. The study has identified two single nucleotide polymorphisms (SNPs) in
the 6q26-27 region at the LPA locus, strongly associated to coronary disease. Both variants
were associated also with an increased level of lipoprotein(a), a reduced copy number in LPA,
and a small lipoprotein(a) size. These common variants explain over a third of the variance in
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lipoprotein(a) levels in individuals of European descent. After adjustment for the plasma
lipoprotein(a) level, the association between these genotypes and coronary disease was
abolished, indicating a causal role of lipoprotein(a) in coronary disease.
The PROCARDIS together with the Coronary Artery Disease Genetics Consortium (C4D),
reported a meta-analysis of genome-wide association studies for coronary artery disease (CAD)
in discovery and replication cohorts including both European and South Asian studies. Five loci
newly associated with CAD have been identified. These results show that the effect sizes of
previously unidentified CAD-associated genes discovered by GWAS (gemome wide association
studies) have become progressively smaller, suggesting that there may not be large-effect
common variants remaining to be discovered, but rather that a large number of common variants
of small effect may contribute to CAD risk.
GISSI-HF Genetic Substudy
The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca) is a
collaborative group endorsed by ANMCO (Associazione Nazionale Medici Cardiologi
Ospedalieri) and by the Istituto Mario Negri, active from 25 years in the cardiovascular research
field. The GISSI-HF was the fifth large scale clinical trial conducted by the Group and was a
prospective, multicenter, randomized, double blind, placebo controlled study, with randomized
allocation of patients with a clinical diagnosis of heart failure to
n-3 PUFA and/or to rosuvastatin to assess the effects of long-term administration of n-3 PUFA
and/or rosuvastatin on all-cause mortality and cardiovascular hospitalizations.
The study randomized more than 7000 patients with the participation of 357 departments of
cardiology; results have been published (GISSI Investigators, Lancet 2008).
Several substudies focus on possible mechanistic effects of the study treatments. Among them a
genetic
substudy conducted by nearly 100 Centres that have included 2500 patients, gives the
opportunity to improve knowledge on the role of genetic factors involved in heart failure,
through a collection of blood samples of a large population of patients, involving cases of heart
failure of different etiologies, i.e. non-ischaemic and ischaemic heart disease.
The role of genetic factors in causes, evolution, prognosis and treatment of heart failure is
largely unexplored, with the exception of heart failure originated by specific cardiomyopathies
(such as dilated, hypertrophic, arrhythmogenic right ventricular cardiomyopathies), for which
the role of heritable gene mutations is increasingly well understood. Heart failure (HF) is a
syndrome with different etiologies, and more than one half is caused by coronary heart disease
(CHD). The objective of the genetic substudy is 1) to assess the relationships between the
polymorphysms of various candidate genes and the clinical outcome in patients enrolled in
GISSI-HF study; 2) to assess whether these relationships are modified by the experimental
treatments.
In collaboration with the Laboratory of Cardiovascular Clinical Pharmacology the influence of
some genetic variants on the circulating adiponectin and on the prognosis of diabetic patients
with heart failure has been assessed.
GISSI-Prevenzione-Genetic Study
Myocardial infarction is a multifactorial disease. While the role of known risk factors on
coronary heart disease susceptibility is well defined, the impact of the genetic components and
its interaction with environmental factors need investigation. The GISSI-Prevenzione trial
investigated the effects of pharmacological treatments with n-3 PUFA and pravastatin on
morbidity and mortality after myocardial infarction. During the study more than 8000 samples
of a large population of patients affected by this disease have been collected and stored with the
collaboration of SIBioC (Societê Italiana di Biochimica Clinica e Biologia Molecolare). The
GISSI-Prevenzione-Genetic Study investigates the role of genetic factors in ischaemic heart
disease. The objectives of the project are 1) to assess the relationships between the
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polymorphysms of various candidate genes and the clinical outcome in patients enrolled in the
large clinical trial GISSI-Prevenzione study; 2) to assess whether these relationships are
modified by the pharmacological treatments. According to these objectives, we investigated the
relationship between APOE, mortality and the response to treatment in 3300 myocardial
infarction survivors randomized to pravastatin or no treatment.
Association studies in the same population on the adiponectin gene variants, the CRP (C-reactive protein)
gene variants, some genetic variants on Chromosome 9p21 have been conducted. Results on the role of
genetic variants of PTX3 protein, a novel long pentraxin whose expression is induced by cytokines in
endothelial and mononuclear cells, and involved in the atherogenesis process, has been recently published
in collaboration with the Istituto Clinico Humanitas and the IRCCS San Giovanni Rotondo.
BeTACTIC Study: Best Therapy After Cardiac Transplantation, the Italian
Challenge
BeTACTIC is a multicenter, randomized, no-profit trial funded by the National Health Service.
The study compares the efficacy and safety of Everolimus (Ev) and Mycophenolate (MMF) in
association with Cyclosporine (CyA) in patients with acute multiple/late rejection, cardiac
allograft vasculopathy (CAV), renal dysfunction after cardiac transplantation (HTx). Survival
after HTx has improved in the last years, while the attrition rate beyond the 1st year after HTx
did not change substantially. CAV and cancer are the leading causes of death late after HTx.
Many factors as acute rejections and citomegalovirus infections are involved in CAV
pathogenesis. Cancer shows higher incidence in immunosuppressed patients. Significant
morbidity/mortality derive from renal insufficiency and vascular complications.
Ev and MMF were adopted due to better efficacy vs Azathioprine in de novo HTx.
However, Ev and MMF have not been tested in a head to head comparison late after HTx.
The planned length of the BeTACTIC study is 5 years. Patients will be enrolled at least 1year
after HTx. A total of 400 patients will be randomized in 11 Transplant Centers in Italy.
BeTACTIC is promoted by the Cardiology Department, Trapianti e Insufficienza Cardiaca,
Ospedale Niguarda Ca' Granda, Milano and coordinated by the Laboratory of Clinical Drug
Evaluation of the Istituto Mario Negri.
REGIA - Rischio Emorragico GInocchio e Anca
Assessment of the hemorrhagic risk of treatment with low molecular
weight heparins, oral anticoagulants, antiplatelet drugs in patients
undergoing total hip or knee replacement surgery.
Major orthopedic surgery is as a high-risk event for venous thromboembolism (VTE). The
anticoagulant prophylaxis reduces the risk of postoperative VTE by 50 to 70%. Major bleeding
is a possible complication of thromboprophylaxis with an estimated frequency of 1% to 3% in
randomized clinical trials (RCT). However, in clinical practice, the estimates may be argued
since: 1) bleeding rates are probably underestimated in RCT, due to frequent exclusion of the
high risk patients; 2) definition of bleeding is non-standardized and can vary from study to
study; 3) the type of intervention, of anesthesia, of prophylactic agent and the timing of
administration in relation to surgery may influence bleeding rate. There is scarce information on
the frequency of bleeding after hip or knee replacement in routine practice in Italy. The
objectives of the study are the incidence of major and minor bleedings in the first three months
after surgery.
The REGIA study is funded by the National Health Service and will collect data on bleedings in
nearby 3000 patients admitted for hip or knee replacement in the four participating hospitals
(Istituto Ortopedico Galeazzi, Milano; Istituto Rizzoli, Bologna; CTO Maria Adelaide, Torino,
Policlinico Tor Vergata, Roma) for hip or knee replacement, during surgery, hospitalization,
and their consequences at three month follow-up.
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RE-LY AF Registry: Risk Factors, Treatments and Outcomes for
Emergency Department Patients with Atrial Fibrillation in Multiple Regions
of the World
The Population Health Research Institute (PHRI), McMaster University, Hamilton, Ontario, is
the coordinating center of a multinational network of cardiology clinics that collaborate to
multicenter large scale clinical trials (nearly 40 Countries and more than 600 cardiology clinics).
The Laboratory of Clinical Drug Evaluation has been responsible for the scientific coordination
in Italy of some of these trials (INTER-HEART, CURE, ACTIVE, RE-LY, CURRENT,
OASIS-8 FUTURA, AVERROES, RIVAL). The RE-LY Registry is a prospective,
observational study promoted by PHRI with the following objectives: 1. To determine
variations in the predisposing conditions for atrial fibrillation and atrial flutter (AF/flutter)
between different regions of the world and practice settings. 2. To document regional variations
in the management of AF/flutter and associated cardiovascular disease, including the frequency
of anti-thrombotic and anti-hypertensive therapy and the degree of INR control. 3. To document
differences in the adverse cardiovascular outcomes of AF/flutter.
The study has recruited 15000 patients with documented atrial fibrillation or atrial flutter at the
time of an emergency department visit for any reason, in 164 participating clinical centres in 47
countries. Patients have been be followed-up at one year after the enrolment in the study.
Results, recently presented, showed that due to variations in medical practice and access to care,
there are geographical variation in presentation and management of patients with atrial
fibrillation. They have different predisposing conditions, presenting symptoms, rates of adverse
outcomes and are managed differently.
Laboratory of General Practice Research
Risk and Prevention Study (R&P)
R&P is a study on the optimization of cardiovascular prevention of subjects at high risk
performed at national level by General Practitioners.
Study objective and design
- Controlled clinical trial, double-blind and randomised, of the efficacy of a n-3 PUFA treatment
in reducing the incidence of cardiovascular events, both fatal and non-fatal, in a population
defined as at high risk by participating GPs.
- Practicability and overall yield of the preventive interventions adopted (outcome study) The
epidemiological and care history of this population shall form the object of a specific evaluation
according to a plan of formal predefined analyses.
Study population
Inclusion criteria
Among the subjects deemed by GPs to be at high cardiovascular risk, patients are selected if
presenting:
- multiple risk factors (e.g. hypertension, hypercholesterolemia, diabetes, smoking, family
history of myocardial infarction, obesity, sex and old age)
- previous cardio-cerebrovascular events or clinical manifestations of atherosclerotic disease
(stroke, TIA, peripheral arteriopathy, previous arterial revascularisation procedures, angina
pectoris).
Exclusion criteria
- serious co morbidity with an unfavourable prognosis over the short term (e.g. cancer)
- expected non-compliance over a long period of time; contraindications (known allergies to n3PUFA)
- indications (previous MI) for treatment with n-3 PUFA.
Efficacy measures
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The primary objective is to evaluate if a long-term administration of n-3 PUFA is more effective
than the corresponding placebo in reducing cardiovascular mortality and hospitalization for
cardiovascular causes (primary end-point).
Randomisation is central, stratified by GP.
The experimental treatment consists of one capsule containing 1g of n-3 PUFA, or the
corresponding placebo, to be taken daily.
The duration of follow-up is 5 years.
In order to document with sufficient statistical reliability that the experimental treatment with n3 PUFA reduces of 15% the incidence of the events considered in the primary end-point, a total
of 12,000 patients is required.
Up-date of the study: From February 2004 to March 2007 12,521 patients have been enrolled
by a network of 860 GPs. The Local Health Authorities involved are 57 and in each one
investigator’s meeting has been organized. The characteristics of the population so far enrolled
are the following: mean age 65 years, males 62%, hypertension 79%, hypercholesterolaemia
62%, diabetes 56%, smokers 16%, obesity 35%, family history of premature myocardial
infarction 20%. Twenty five% of patients have a clinical manifestation of atherosclerotic
diseases, 50% have diabetes in association with another risk factor and 23% have multiple risk
factors.
The Risk & Prevention study ended the 31st of October 2011. During a median follow up of 5
years 1,468 cardiovascular events occurred (the minimum expected number reported in the
protocol was 1,383 events). Only 62 GPs, out of a nationwide network of 860, withdrew from
the study and 86 patients were lost to follow up. Results on both the epidemioplogical study and
the clinical trial on n-3 PUFA efficacy are going to be published soon.
More information are available on the website www.rischioeprevenzione.it.
Epidemiological and clinical profile of diabetic patients in Lombardy
Region using administrative databases.
The study is part of an on-going pharmaco-epidemiological project in collaboration with the
Health Department of the Lombardy Region. Its main objective is the definition of a model to
assess and control the use of health resources of diabetic patients by means of integrated
administrative database.
Specific aims of the study are:
 To describe prevalence, incidence, hospitalization and mortality of the diabetic population
each year, from 2000 to 2009.
 To assess the prescriptions of both anti-diabetic and cardiovascular drugs
 To assess the prescriptions of laboratory test and specialist medical examinations as
indicators of process of care
The population analysed has been selected among the resident population of the Lombardy
Region throughout 8 years of observation (between 2000 and 2007). Diabetic patients have been
identified each year if they met one of the three following criteria: - a) presence of at least 30%
DDD (Defined Daily Dosage) of an A10 drug: insulin and/or oral glucose lowering agent; b) the
occurrence of at least one hospitalization with Disease Related Group (DRG)=294 (diabetes in a
subject > 35 years old) or DRG=295 (diabetes in a subject < 35 years old); c) presence of the
exemption code number 013.250 indicating diabetes. On the basis of these criteria 10 different
data sets have been created one for each year of observation. Data from prescription database,
hospital admission and outpatient clinic visits and examinations were also included in the
analysis via linkage to the personal identification number (national identifiers).
The aims of the ongoing analyses are: a) to investigate the sex difference in cardiovascular
outcome, pharmacological treatment and process of care in newly diabetic patients, b) to assess
the prescriptions rate of anti-diabetic drugs and concomitants therapies in elderly diabetic
patients (age ≥ 65 years) comparing two years (2000 versus 2010).
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“GLICINE-SPIDER” Study
“Glicine-Spider” is an observational study carried out in the Coronary Care Units (CCU) of
Lombardy. The protocol is a collaboration between the ANMCO (Italian Association of
Hospital Cardiologists) Lombardia , AMD (Association of Medical Diabetologists) Lombardia
and the Mario Negri Institute. The study is coordinated by the General Practice Research
Laboratory and the Clinical Drug Evaluation Laboratory.
Hyperglycemia at the onset of an acute coronary syndrome (ACS) constitutes a negative
prognostic factor in diabetic and non-diabetic patients and a poor control of blood glucose in the
early hours after hospital admission for ACS is an additional unfavourable prognostic factor.
Recent guidelines, although recognizing the importance of controlling blood glucose in ACS, do
not clearly define therapeutic strategies to apply and glicemic target values of the patients with
and without diabetes hospitalized in CCU for a confirmed ACS.
The aim of the study is to describe in a large sample of patients hospitalized in CCU for a ACS:
 the prevalence of diabetes and hyperglycemia
 the type of treatment and blood glucose control during the acute phase
 the incidence of mortality and cardiovascular complications occurred during the
hospitalization according to diagnosis and blood glucose level
From May 2009 to April 2010, 1,282 patients have been included from 31 CCUs. The data
analysis is in progress.
FOCUS
Study (Fixed Dose Combination Drug for Secondary
Cardiovascular Prevention. Improving Equitable Access and Adherence
to Secondary Prevention Therapy with a Fixed-Dose Combination Drug)
Several randomized controlled trials and metanalyses have demonstrated that the long term
administration of aspirin, statins, beta-blockers, and angiontensin converting enzyme inhibitors
(ACE inhibitor) improve prognosis in high risk patients, particularly those recovering from an
acute coronary event. However, wide variability in the pattern of prescription among physicians,
limited access to expensive drugs in emerging countries, and poor adherence to medications
limit the use of these drugs and the efficacy of cardiovascular prevention.
A Fixed Dose Combination (FDC) pill for cardiovascular prevention was first proposed by
Wald and Law in 2000 and supported by the WHO. During the last few years this concept,
particularly in the field of primary prevention has been questioned by some experts while the
potential role of a polypill for secondary cardiovascular prevention is receiving increasing
attention. However, a direct proof of the polypill effect on patients’ adherence is still lacking.
The global objective of the FOCUS consortium is to make FDC drugs for secondary
cardiovascular prevention available throughout the world at a low price, in order to improve
access to treatment in developing countries improving adherence to medication. The Centro
Nacional de Investigationes Cardiovasculares (CNIC) in Madrid is the coordinator of the
FOCUS study and the leader of the consortium composed also by Istituto Mario Negri,
DAMNIC Institute, Fundaciò Clinic per a la Recerca Biomèdica (FCRB), ARTTIC, the World
heart Federetion (WHF), the Instituto de Salud Carlos III (ISCIII), FERRER and the Federaciòn
Argentina de Cardiologia (FAC).
The Study is international, multicenter in two phases:
Phase 1 is a descriptive, non-interventional study. Its aim is to provide a comprehensive analysis
of factors precluding adequate secondary prevention, including health system characteristics,
drugs affordability and availability, as well as patients’ characteristics.
Phase 2 is an interventional, randomized, two-arm study. Patients are randomized to receive a
FDC of ramipril, simvastatin and acetilsalycilic acid or the three medications separately. The
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primary objectives is to compare the adherence to treatment in post myocardial infarction
patients receiving a FDC vs those with conventional treatment (3 drugs separately).
Secondary objectives are to evaluate the effect of a FDC on blood pressure control and lipid
profile and the safety and tolerability of FDC treatment.
Two countries in Europe (Spain and Italy) and three in South America (Argentina, Brazil e
Paraguay) are involved in the Study. A total number of 4,000 subjects will be included in phase
1 and 1,340 in the phase 2.
Twenty six Italian Cardiologic Hospital Departments are involved in this project. The study
started on March 2012 and currently 20 centers are recruiting patients.
“Il Sale è meglio averlo in Zucca” project
The idea for this project originated from the awareness that Italian diet is excessively rich in salt
and this can cause major cardiovascular diseases. Data available from previous studies showed
that a partial reduction in dietary salt intake leads to a decreased incidence and a better control
of hypertension. Reduction in dietary salt can, however, compromise food’s taste and therefore
this could represent an unacceptable option for the population. It is possible to reduce salt
supplement during food preparation without jeopardize its taste by substituting some foods with
other adding up spices and aromatic plants or utilizing salt substitutes. This project, conduct in
collaboration with the Laboratory of Nutrition Toxicology and Elior (an industrial catering
company), has the aim to gather data on tricks useful to reduce salt in the diet without modify
the food’s taste. The objective is to elaborate low sodium courses; currently the courses are
proposed to a company cafeteria that collects the consumers’ appreciation by an ad hoc
questionnaire.
The stratification of global cardiovascular risk in hypertensive patients of
the district of Borbon – Ecuador
The Laboratory is involved in a collaborative project with the Cecomet (Centro de
Epidemiologia comunitaria y Medicina tropical) in Esmeralda, Ecuador, on the prevalence and
treatment of hypertension in the district of Borbon, a rural zone of Ecuador in the northern part
of the country.
In this area, 36% of the adult population is affected by hypertension and more than half of
hypertensive patients present blood pressure levels > 160/110 mmHg.
From 2001, in the District is ongoing an intensive follow-up of the hypertensive population
with the following aims: to evaluate the global cardiovascular risk of the population, to better
control blood pressure levels increasing the number of subjects treated with hypertensive
therapy (in particular those at high cardiovascular risk) and monitoring of the clinical
complications. Preliminary data show that:
 Patients treated with hypertensive therapy are increased from 39% to 59%
 Antihypertensive drugs are mainly prescribed to subjects with high blood pressure levels
(80% of those with systolic blood pressure >180mmHg are actually under treatment) or at
high cardiovascular risk (82%)
 Blood pressure control is improved (patients with systolic blood pressure levels
> 180mmHg decreased from 33% to 24% and those with levels <160-179 increased from
26% to 34%)
 The fraction of patients at high or very high cardiovascular risk is decreased from 40% to
33%
However, the compliance to antihypertensive treatment is still unsatisfactory since only half of
the subjects are compliant with the prescribed therapy.
Laboratory of Medical Statistics
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The Laboratory of Medical Statistics develops applied research in three main fields: controlled
clinical trials, observational studies and genetic epidemiology.
Controlled clinical trials
The laboratory deals with planning, management and statistical analysis of controlled clinical
trials, carried out in the different laboratories of the Department of Cardiovascular Research, by
means of the GISSI trials experience.
At present, GISSI trials focus on GISSI-HF and GISSI-AF clinical studies, concerning heart
failure and atrial fibrillation and their subprojects aiming to assess the role of biomarkers, of
echocardiographic and electrocardiographic parameters on the patients’ prognosis. Recently,
two superiority trials have been activated: the BeTACTIC study that will randomize about 400
patients undergone heart transplantation and the CYCLE study that will recruit 444 patients in
reperfused acute myocardial infarction. Results regarding the large trial concerning
cardiovascular prevention, Risk & Prevention study (Rischio & Prevenzione) which included
more than 12000 patients have been presented. Statistical methodology applied to clinical
studies has a leading and developing role as far as methods are concerned (e.g.: missing data
management; development of prognostic risk scores, methods for the assessment of competing
risks, development of forecasting models for biomarkers based on Reclassification techniques
and on Discriminations Indices etc.).
Moreover, clinical trial management implies the setup of data planning and screening methods,
the ad interim analysis and the choice of the best study design (superiority, non-inferiority and
equivalence studies).
Observational studies
The activation of observational studies allows to characterize the epidemiological profile of
categories of patients followed in their natural clinical course. The prospective observational
study GLICINE-SPIDER has evaluated the risk profile of 1300 patients with hyperglycemia at
the onset of an acute coronary syndrome (ACS) in the hospitals of the Lombardia region. The
aim of the cohort study REGIA, presently ongoing, is the evaluation of the incidence of major
and minor hemorrhages and the characterization of the risk profile of about 3000 patients
undergoing hip and knee replacement surgery.
From a strictly epidemiologic point of view, the epidemiologic and health-care history of
diabetes mellitus in Regione Lombardia has been investigated by means of administrative
databases.
Genetic Epidemiology
The laboratory has recently developed specific skills on genetic epidemiology analysis. These
studies are carried out together with the laboratory of Clinical Drugs Evaluation. Statistical
analysis techniques concerning cardiovascular genetics have been developed in the last five
years.
The study of the genetic component of multifactorial diseases, such as the cardiovascular
disease, has been dealt with in the PROCARDIS study, by means of the genome-wide
screening. This technique aims at identifying genes that can cause coronary disease.
PROCARDIS database gave the opportunity of studying some quantitative traits such as the
level of lipids or body mass index.
During the second step of the PROCARDIS project, supported by the 6th Framework Program
of EEC, a screening on the whole genome has been carried out by means of the “genome-wide
association” technique. For this project about 1 million of polymorphisms (SNPs) have been
analyzed in order to identify a possible relationship with coronary disease.
Recently, the C4D genetic Consortium, of which the PROCARDIS Consortium takes part, has
demonstrated the existence of new susceptibility genes to coronary artery disease (CAD).
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Indeed CAD is caused by the occurrence of many genes as emerged from recent meta-analyses
on GWAS.
Concerning the GISSI-Genetic Prevention study, the laboratory has developed statistics
genetics techniques to analyze case control studies in order to assess the association of genetic
variants linked to adiponectin, HsCRP, PTX3 with coronary disease. Besides, the association
between some polymorphisms of chromosome 9p21 area and coronary disease has been
evaluated in diabetic patients. With regard to the GISSI-HF genetic substudy that has included
about 2500 patients to evaluate the role of genetic variants involved in heart failure, the
association of four polimorphisms of the adiponectin gene has been investigated by a casecontrol design.
Laboratory of Clinical Pharmacology
Quality of Life, Depression and Cognitive problems in heart failure
patients (QDF-GISSI-HF)
The QDF project is a sub-project of the GISSI-HF study. The aims of the study are 1) to
describe the evolution of depression, cognitive problems and the quality of life in a sample of
1500 heart failure patients; 2) to assess the use of common instruments that measure QDF
variables; 3) to compare the assessment of the instrument (Geriatric Depression scale, Mini
Mental State Examination, Kansas City Cardiomiopathy Questionnaire) with the clinical
perception of the nurses; 4) to describe if assessed or perceived patients' problems (low quality
of life, high depression or compromised cognitive function) lead to any caring intervention.
The baseline clinical characteristics of the 1564 patients included in the QDF study are closely
comparable with those of the GISSI-HF population. The study instruments could be validly
administered to the greatest majority of patients (KCQQ 97.2%, GDS 94.9%, MMSE 80.6% of
patients >70 years).
The nurses network nested in a major clinical trial has produced one of the largest prospective
cohort of HF patients who are comprehensively assessed and prospectively monitored, to allow
an integrated evaluation of the relevance and implications of QDF measurements also on the
clinical outcomes of this population. Manuscripts on the study results are in preparation.
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DEPARTMENT OF MOLECULAR
BIOCHEMISTRY AND
PHARMACOLOGY
STAFF
Head
Mario SALMONA, Food Technology D, Ph.D.
Laboratory of Biochemistry and Protein Chemistry
Head
Ph.D.
Mario SALMONA, Food Technology D,
Human Pathology in Model Organisms Unit
Head
Luisa DIOMEDE, Chem.Biol.Anal.D.
Laboratory of Molecular Biology
Head
Enrico GARATTINI, M.D.
Pharmacogenomics Unit
Head
Maddalena FRATELLI, Biol.Sci.D.
Gene Structure and Regulation Unit
Head
Mineko TERAO, Bioch.D., Ph.D.
Laboratory of Pharmacodynamics and Pharmacokinetics
Head
Marco GOBBI, Pharm.D.
Laboratory of Molecular Pathology
Head
Lavinia CANTONI, Biol.Sci.D.
Laboratory of Translational Proteomics
Head
Valentina BONETTO, Chem.Pharm.D.
Laboratory of Systems Biology
Head
Gianfranco BAZZONI, M.D.
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CURRICULA VITAE
Mario Salmona obtained his doctorate degree in Biochemistry and Food Technology at the University of
Milan in 1971. His background is in biochemistry, biophysics and pharmacology. His scientific interests
relate to problems of human and animal diseases originating from the aberrant folding of proteins. In this
context, a major portion of his studies was devoted to the etiopathogenesis and therapy of prion diseases.
He has published over 300 papers and 25 book chapters, the total number of citations of his papers is
9997 and his h factor is 50.
1971-1975 Research Fellow at the Laboratory of Biochemical Pharmacology, Mario Negri Institute
1976-1977 Post-doc at the Weizmann Institute for Science, Department of Biological Chemistry,
Rehovot, Israel
1977-1997 Head, Laboratory of Enzymology, Mario Negri Institute
1986- 1987 Visiting Scientist at the Weizmann Institute for Science, Department of Organic Chemistry,
Rehovot, Israel
1995-2011 Dean of the Advanced School of Pharmacology and Responsible of Educational Activities,
Mario Negri Institute
1995-present Member of the Board of Trustees of the Consortium “Mario Negri Sud”, Chieti, Italy
1997-present Head, Department Molecular Biochemistry and Pharmacology, Mario Negri Institute
1997-present Head, Laboratory of Biochemistry and Protein Chemistry, Mario Negri Institute
He has served in several national and international scientific committees, presently he is a component of
the EU panel developing the project “The European Advanced Translational Research Infrastructure in
Medicine” (EATRIS).
Selected publications

Airoldi C, Colombo L, Manzoni C, Sironi E, Natalello A, Doglia S M, Forloni G, Tagliavini F, Del Favero E, Cantu' L,
Nicotra F, Salmona M Tetracycline prevents Aβ oligomer toxicity through an atypical supramolecular interaction. Org
Biomol Chem, 2011 9: 463-72

Urru S A M, Veglianese P, De Luigi A, Fumagalli E, Erba E, Gonella Diaza R, Carrà A, Davoli E, Borsello T, Forloni G,
Pengo N, Monzani E, Cascio P, Cenci S, Sitia R, Salmona M. A new fluorogenic peptide determines proteasome activity
in single cells. J Med Chem 2010 53 : 7452-7460

Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T,
Chiesa R, Gobbi M, Salmona M, Forloni G. Synthetic amyloid-beta oligomers impair long-term memory
independently of cellular prion protein. Proc Natl Acad Sci U S A. 2010 107 : 2295-2300

Di Fede G, Catania M, Morbin M, Rossi G, Suardi S, Mazzoleni G, Merlin M, Giovagnoli A R, Prioni S, Erbetta A,
Falcone C, Gobbi M, Colombo L, Bastone A, Beeg M, Manzoni Claudia, Francescucci B, Spagnoli A, Cantu' L, Del
Favero A, Levy E, Salmona M, Tagliavini F. A recessive mutation in the APP gene with dominant-negative effect on
amyloidogenesis. Science 2009 323 : 1473-1477

Saracino GA, Villa A, Moro G, Cosentino U, Salmona M. Spontaneous beta-helical fold in prion protein: The case of
PrP(82-146). Proteins. 2009 Jun;75(4):964-76

De Luigi A, Colombo L, Diomede L, Capobianco R, Mangieri M, Miccolo C, Limido L, Forloni G, Tagliavini F,
Salmona M. The efficacy of tetracyclines in peripheral and intracerebral prion infection. PLoS ONE. 2008;3(3):e1888
Gianfranco Bazzoni got his Medicine and Surgery degree in 1988 (at the University of Milan) and the
specialisation in Pharmacological Research in 1992 (at the Mario Negri Institute, Milan). His area of
expertise is cell biology, with focus on the processes of cell adhesion and migration.
1988-2000 Research Fellow, Mario Negri Institute
1993-1997 Post-doctoral Fellow, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA
2000-2002 Research Scientist, Mario Negri Institute
2003 Head, Unit of Cell Adhesion, Mario Negri Institute
2004 to date Head, Laboratory of Systems Biology, Mario Negri Institute
2004 Regular Member of The American Physiological Society, Bethesda, MD
Referee for international scientific journals
Selected publications

Paris L, Bazzoni G. The protein interaction network of the epithelial junctional complex: a system-level analysis Mol
Biol Cell 19: 5409-5421, 2008

Paris L, Tonutti L, Vannini C, Bazzoni G. Structural organization of the tight junction. Biochim Biophys Acta 1778:
646-659, 2008

Huang H, Cruz F, Bazzoni G. Junctional adhesion molecule-A regulates cell migration and resistance to shear stress. J.
Cell Physiol 209; 122-130, 2006
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Martinez-Estrada OM, Manzi L, Tonetti P, Dejana E, Bazzoni G. Opposite effects of Tumor Necrosis Factor and soluble
fibronectin on Junctional Adhesion Molecule-A in endothelial cell. Am J Physiol (Lung Cell Mol Physiol) 288: L1081L1088, 2005
Bazzoni G, Tonetti P, Manzi L, Cera MR, Balconi G, Dejana E. Expression of Junction Adhesion Molecule-A prevents
spontaneous and random motility. J Cell Sci 118: 623-632, 2005
Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol
Rev 84: 869-901, 2004
Valentina Bonetto has got the degree in Pharmaceutical Chemistry and Technology at the University of
Padua, Italy in 1993. She has got the Ph.D in Medical Biochemistry and Biophysics at Karolinska
Institutet, Stockholm, Sweden.
Her principal lines of research are: 1) Study of the pathogenetic mechanisms at the basis of amyotrophic
lateral sclerosis (ALS); 2) Identification of biomarkers of ALS; 3) Role of the oxidative modification in
neurological disorders. These issues are investigated by different experimental approaches, including
proteomics and mass spectrometry.
2000-2009 Research Scientist, Laboratory of Biochemistry and Protein Chemistry, Mario Negri Institute
2002-2009 also Assistant Telethon Scientist at Dulbecco Telethon Institute
2007-2009 Head, Unit of Medical Biochemistry, Laboratory of Biochemistry and Protein Chemistry,
Mario Negri Institute
From 2009 to date, Head Laboratory of Translational Proteomics and Associate Telethon Scientist.
She is author of 35 publications from 1994 to 2011, in peer-reviewed journals. She is reviewer for
scientific journals in the field of Proteomics and Neuroscience.
Selected publications
•
Nardo G, Pozzi S, Pignataro M, Lauranzano E, Spano G, Garbelli S, Mantovani S, Marinou K, Papetti L, Monteforte M,
Torri V, Paris L, Bazzoni G, Lunetta C, Corbo M, Mora G, Bendotti C, Bonetto V. (2011) Amyotrophic lateral sclerosis
multiprotein biomarkers in peripheral blood mononuclear cells. PLoS ONE, 6:e25545.
•
Massignan T., Biasini E., Lauranzano E., Veglianese P., Pignataro M., Fioriti L., Harris D.A., Salmona M., Chiesa R.,
Bonetto V. (2010) Mutant prion protein expression is associated with an alteration of the Rab GDP dissociation inhibitor
alpha (GDI)/Rab11 pathway. Mol Cell Proteomics, 9: 611-622
•
Basso M., Samengo G., Nardo G., Massignan T., D’Alessandro G., Tartari S., Cantoni L., Marino M., Cheroni C., De
Biasi S., Giordana M. T., Strong M.J., Estevez A.G., Salmona M., Bendotti C., Bonetto V. (2009) Characterization of
detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS
ONE, 4:e8130.
•
Nardo, G., Pozzi, S., Mantovani, S., Garbelli, S., Marinou, K., Basso, M., Mora, G., Bendotti, C., Bonetto, V. (2009)
Nitroproteomics of peripheral blood mononuclear cells from patients and a rat model of ALS. Antioxid. Redox Signal.,
11: 1559-1567.
•
Basso M., Massignan T., Samengo G., Cheroni C., De Biasi S., Salmona M., Bendotti C., Bonetto V. (2006) Insoluble
mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J. Biol. Chem., 281:33325-33335.
•
Casoni, F., Basso, M., Massignan, T., Gianazza, E., Cheroni, C., Salmona, M., Bendotti, C., Bonetto, V. (2005) Protein
nitration in a mouse model of familial amyotrophic lateral sclerosis: Possible multifunctional role in the pathogenesis. J.
Biol. Chem., 280: 16295-16304.
Lavinia Cantoni obtained her degree in Biological Sciences in 1973 at the University of Milan. Then
she specialized in Pharmacological Research in 1977 at the Mario Negri Institute. Area of expertise: 1)
biochemical-molecular mechanisms activated by oxidative stress 2) drug metabolism 3) porphyrias.
1974-1977 Research Fellow, Mario Negri Institute
1977-1978 Post-doctoral Fellow, Medical Research Council, Toxicology Unit, Carshalton, UK (Winner
of a Welcome Trust Research Fellowship)
1979-1982 Research Scientist, Mario Negri Institute
1980-1990 Visiting Scientist, Toxicology Unit, Carshalton, UK, and Cornell Medical Center, New York,
NY (short periods)
1983-1997 Head, Unit of Heme and Hemoprotein Metabolism, Mario Negri Institute
1998 to date, Head, Laboratory of Molecular Pathology, Mario Negri Institute
1975 to date Member of the National Roll of Biologists
1983 to date Member of the Italian Toxicology Society
She is reviewer for international scientific journals in the field of oxidative stress and neuroscience.
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Selected publications

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D'Alessandro G, Calcagno E, Tartari S, Rizzardini M, Invernizzi RW, Cantoni L. Glutamate and glutathione interplay in
a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism. Neurobiol Dis. 2011,
43:346-55.
Tartari S, D’Alessandro G, Babetto E, Rizzardini M, Conforti L, Cantoni L. Adaptation to G93Asuperoxide dismutase 1
in a motor neuron cell line model of amyotrophic lateral sclerosis. The role of glutathione. FEBS J. 2009; 276: 28612874.
Raimondi A, Mangolini A, Rizzardini M, Tartari S, Massari S, Bendotti C, Francolini M, Borghese N, Cantoni L,
Pietrini G. Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALSlinked G93ASOD1. Eur. J. Neurosci. 2006; 24: 387-399.
Babetto E, Mangolini A, Rizzardini M, Lupi M, Conforti L, Poletti A, Rusmini P, Cantoni L. Tetracycline-regulated gene
expression in the NSC-34-tTA cell line for investigation of motor neuron diseases. Mol. Brain Res. 2005; 140: 63-72.
Cantoni L,Valaperta R, Ponsoda X, Castell JV, Barelli D, Rizzardini M, Mangolini A, Hauri L, Villa P. Induction of
hepatic heme oxygenase-1 by diclofenac in rodents: role of oxidative stress and cytochrome P-450 activity. J.
Hepatology 2003; 38: 776-783.
Rizzardini M, Zappone M, Villa P, Gnocchi P, Sironi M, Diomede L, Meazza C, Monshouwer M, Cantoni L. Kupffer
cell depletion partially prevents hepatic heme oxygenase 1 messenger RNA accumulation in systemic inflammation in
mice: role of interleukin 1 beta. Hepatology 1998; 27: 703-710.
Luisa Diomede is a Chemico-Biological Analysis Doctor (University “Carlo Bo”, Urbino, Ital) from
2007.
Her main areas of interest are: i) the use of Caenorhabditis elegans as model organism to investigate the
biochemical and molecular mechanisms underlying protein misfolding diseases; ii) the design and the
validation of innovative therapeutic strategies for these pathologies.
1985-now Researcher at “Mario Negri” Institute for Pharmacological Research, Milan, Italy.
1985-1991 Research Assistant, Laboratory of Enzymology, at “Mario Negri” Institute for
Pharmacological Research,
Milan.
1991-1992 Scientist for Angelini SpA, Pomezia (Roma).
1992-now Permanent position at “Mario Negri” Institute for Pharmacological Research, Milan.
1992-2010 Senior Scientist, Laboratory of Biochemistry and Protein Chemistry.
2005- now Member of Quality Assurance Committee of Mario Negri” Institute for Pharmacological
Research, Milan .
2011-now Head of “Human Pathologies in Model Organisms” Unit.
Co−author in more than 70 scientific publications on international journals. Reviewer “ad hoc” for
International journals.
Principali pubblicazioni

Diomede L, Cassata G, F. Fiordaliso, M. Salio, D. Ami, A. Natalello, S. M. Dogliad, A. De Luigi, M.Salmona.
Tetracycline and its analogues protect Caenorhabditis elegans from beta amyloid-induced toxicity by targeting
oligomers (2010) Neurobiol of Disease 40: 424-431.

Bigini P. Steffensen K.R, Ferrario A, Diomede L, Ferrara G, Barbera S, Salzano S, Fumagalli E, Ghezzi P, Mennini T,
Gustafsson J-A. Neuropathologic and biochemical changes during disease progression in liver X receptor beta-/- mice, a
model of adult neuron disease. (2010) Journal of Neuropathology and Experimental Neurology 69:593-605.
Bate C, Tayebi M, Diomede L, Salmona M, Williams A. Glimepiride Reduces the Expression of PrPC, Prevents PrPSc
Formation and Protects Against Prion Mediated Neurotoxicity. (2009) PLoS ONE, 4:e8221.
Bate C. Salmona M, Diomede L, William A. Squalestatin cures prion-infected neurones and protects against prion
neurotoxicity. J. Biol. Chem., (2004) 279: 14983-14990 .

Salmona M, Morbin M, Massignan T, Colombo L, Mazzoleni G, Capobianco R, Diomede L, Thaler F, Mollica L, Musco
G, Kourie JJ., Bugiani O, Sharma D, Inouye H, Kirschner DA, Forloni G, Tagliavini F. Structural properties of
Gerstmann-Sträussler-Scheinker disease amyloid protein. J Biol Chem, (2003) 278: 48146-48153

Diomede L, Albani D., Sottocorno M., Donati MB, Fruscella P., Bianchi M., Bruno A., Romano M., Salmona M. The in
vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products. Ather Thromb Vasc Biol, (2001)
21: 1327-1332.
Maddalena Fratelli got her degree in Biological Sciences at the University of Pisa and at the Scuola
Normale Superiore di Pisa in 1983. Then the specialization in Pharmacological Research at the Mario
Negri Institute in 1986.
Her main fields of interest are: 1. High throughput genomic systems for the study of drug action and
pharmacoresistance. 2. Redox regulation of protein function and gene expression: glutathionylation and
gene expression profiling of glutathione dependent responses to oxidant challenge.
1988-1989 Postdoctoral Research Fellow in the Medical Research Council, Neurobiology Unit,
Cambridge, UK.
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Since 1995, Head, Unit of Mediators of inflammation, Laboratory of Neuroimmunology, Mario Negri
Institute
Since 2005, Head, Unit of Pharmacogenomics, Laboratory of Molecular Biology, Mario Negri Institute
Selected publications

Fratelli M, Fisher J N, Paroni G, Di Francesco A M, Pierri F, Pisano C, Godl K, Marx S, Tebbe A, Valli C, Gianni M,
Stravalaci M, Gobbi M, Terao M, Garattini E. New insights into the molecular mechanisms underlying
sensitivity/resistance to the atypical retinoid ST1926 in acute myeloid leukaemia cells: The role of histone H2A.Z,
cAMP-dependent protein kinase A and the proteasome, Eur J Cancer 2012 E-pub

Garattini E, Fratelli M, Terao M. The mammalian aldehyde oxidase gene family. Hum Genomics. 2009 4: 119-30

Fratelli M, Goodwin LO, Orom UA, Lombardi S, Tonelli R, Mengozzi M, Ghezzi P. Gene expression profiling reveals
a signaling role of glutathione in redox regulation. Proc Natl Acad Sci U S A. 2005;102:13998-4003

Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E,
Diaz D, Gomez D, Hand C, Coleman T, Cerami A. Erythropoietin mediates tissue protection through an erythropoietin
and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004; 101:14907-12

Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P,
Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S,
Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M. Derivatives of
erythropoietin that are tissue protective but not erythropoietic. Science. 2004; 305:239-42

Fratelli M, Demol H, Puype M, Casagrande S, Eberini I, Salmona M, Bonetto V, Mengozzi M, Duffieux F, Miclet E,
Bachi A, Vandekerckhove J, Gianazza E, Ghezzi P. Identification by redox proteomics of glutathionylated proteins in
oxidatively stressed human T lymphocytes. Proc Natl Acad Sci U S A. 2002; 99:3505-10
Enrico Garattini obtained his degree in Medicine and Surgery with full marks (110/110) in 1982 at the
University of Milan. His scientific interests relate to problems of Cellular Biology and Molecular
Biology.
1982-1990 Research Fellow of the National Research Council, Mario Negri Institute
1983-1987 Postdoctoral Researcher at the Roche Institute of Molecular Biology, Department of
Neurosciences Nutley, New Jersey, US
1991-1997 Senior Researcher Regione Lombardia and Head of the Molecular Biology Unit, Mario Negri
Institute
1997 to date Head, Laboratory of Molecular Biology, Mario Negri Institute
From 2005 Dean, Advanced School of Pharmacology (Philosophy Doctor), Mario Negri Institute
From 2011 Dean, Educational Activities, Mario Negri Institute
Selected publications

Paroni G, Fratelli M, Gardini G, Bassano C, Flora M, Zanetti A, Guarnaccia V, Ubezio P, Centritto F, Terao M, and
Garattini E. Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA. Oncogene 2012; 31: 3431-3443

Gianni’ M, Peviani M, Bruck N, Rambaldi A, Borleri G, Terao M, Kurosaki M, Paroni G, Rochette-Egly C, and
Garattini E. The MAPK p38α interacts with Ser-369 and inhibits RARα: suppression of the kinase enhances the
therapeutic activity of retinoids in acute myeloid leukemia cells. Leukemia 2012; 26:1850-1861

Gianni M, Boldetti A, Guarnaccia V, Rambaldi A, Parrella E, Raska I Jr, Rochette-Egly C, Del Sal G, Rustighi A, Terao
M, Garattini E
Inhibition of the peptidyl-propyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid
via stabilization of RARα and PML-RARα. Cancer Res 2009 69 : 1016-1026

Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giudice C, Scanziani E, Mancuso A, Tiveron C,
Garattini E. Role of the molybdo-flavoenzyme, aldehyde oxidase homolog 2, in the biosynthesis of retinoic acid:


generation and characterization of a knock-out mouse, Mol Cell Biol 2009 29: 357-77
Gianni M, Parrella E, Raska I Jr, Gaillard E, Nigro EA, Gaudon C, Garattini E, Rochette-Egly C. P38MAPK-dependent
phosphorylation and degradation of SRC-3/AIB1 and RARalpha-mediated transcription. EMBO J. 2006; 25:739-51
Garattini E, Parrella E, Diomede L, Gianni M, Kalac Y, Merlini L, Simoni D, Zanier R, Ferrara F F, Chiarucci I,
Carminati P, Terao M, Pisano C. ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in
myeloid leukemia cells: Modulation of intracellular calcium homeostasis. Blood 2004; 103: 194-207
Marco Gobbi got his degree in Pharmacy at the University of Milan, Italy, in 1989.
His main fields of interest are: i) neurodegenerative diseases associated to misfolding and aggregation of
peptides/proteins, such as beta-amyloid and prions; ii) alterations of synaptic transmission in the CNS,
either due to diseases or to the effects of drugs on receptors and transporters; iii) nanoparticles for
diagnostic and therapeutic purposes. These research fields are investigated by a close integration of
pharmacodynamics (e.g. biomolecular interactions, mainly using surface plasmon resonance) and
pharmacokinetics studies.
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1981-1995 Researcher, Laboratory of Neuropharmacology and, from 1988, in the Laboratory of Receptor
Pharmacology, Mario Negri Institute
1995-2010 Head, Unit of Synaptic Transmission, Mario Negri Institute
From 2010, Head, Laboratory of Pharmacodynamics and Pharmacokinetics
Co-author in more than 100 scientific publications on peer-reviewed international journals. First or last
author in more than 50 of them.
Reviewer for international scientific journals operating in the
Neuroscience/Neuropharmacology/Biochemistry fields.
Selected publications

Stravalaci M, Bastone A, Beeg M, Cagnotto A, Colombo L, Di Fede G, Tagliavini F, Cantu L, Del Favero E, Mazzanti
M, Chiesa R, Salmona M, Diomede L and Gobbi M Specific recognition of biologically active amyloid-beta oligomers
by a new surface plasmon resonance-based immunoassay and an in vivo assay in Caenorhabditis elegans. J Biol Chem
287:27796-27805 (2012).

Orsini F, Villa P, Parrella S, Zangari R, Zanier ER, Gesuete R, Stravalaci M, Fumagalli S, Ottria R, Reina JJ, Paladini A,
Micotti E, Ribeiro-Viana R, Rojo J, Pavlov VI, Stahl GL, Bernardi A, Gobbi M and De Simoni MG Targeting mannosebinding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia.
Circulation 126:1484-1494 (2012).

Gobbi M, Re F, Canovi M, Beeg M, Gregori M, Sesana S, Sonnino S, Brogioli D, Musicanti C, Gasco P, Salmona M and
Masserini ME. Lipid-based nanoparticles with high binding affinity for amyloid-beta1-42 peptide. Biomaterials 31:65196529 (2010).

Caccia S and Gobbi M St. John's Wort components and the brain: Uptake, concentrations reached and the mechanisms
underlying pharmacological effects. Curr Drug Metab 10(9):1055-1065 (2009).

Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantù L, Kirschner DA, Manzoni
C, Beeg M, Ceci P, Ubezio P, Forloni G, Tagliavini F and Salmona M. Gerstmann-Sträussler-Scheinker disease amyloid
protein polymerizes according to the "dock-and-lock" model. J Biol Chem 281:843-849 (2006).

Crespi D, Mennini T, Gobbi M. Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)amphetamine, 3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine. Br J Pharmacol
121:1735-1743 (1997).
Mineko Terao obtained her doctorate degree in Pharmaceutical Science from the Kobe Women’s
College of Pharmacy, Japan in 1978. Her scientific interests relate to problems of Cellular Biology and
Molecular Biology.
1983 Ph.D in Molecular Biology, Kyoto University, Japan
1982-1983 Research Fellow, Department of Medical Chemistry, Kyoto University Faculty of Medicine,
Japan
1983-1987 Postdoctoral Associate of the Institute for Cancer Research, Philadelphia, US
From 1987 Visiting Scientist of Mario Negri Institute
From 1998 Head of the Unit of Gene Structure and Regulation, Mario Negri Institute
Selected publications

Locatelli D, Terao M, Fratelli M, Zanetti A, Kurosaki M, Lupi M, Barzago M M, Uggetti A, Capra S, D'Errico P,
Battaglia G S, Garattini E. Human axonal survival of motor neuron (a-SMN) protein stimulates axon growth, cell
motility, C-C motif ligand 2 (CCL2), and insulin-like growth factor-1 (IGF1) production. J Biol Chem 2012 287 : 2578225794

Terao M, Fratelli M, Kurosaki M, Zanetti A, Guarnaccia V, Paroni G, Tsykin A, Lupi M, Gianni M, Goodall G J,
Garattini E. Induction of miR-21 by retinoic acid in estrogen receptor-positive breast carcinoma cells: biological
correlates and molecular targets. J Biol Chem 2011 286 : 4027-4042

Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giudice C, Scanziani E, Mancuso A,
Tiveron C, Garattini E
Role of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoic acid: generation and
characterization of a knockout mouse. Mol Cell Biol 2009 29 : 357-377

Terao M, Kurosaki M, Barzago MM, Varasano E, Boldetti A, Bastone A, Fratelli M, Garattini E. Avian and canine
aldehyde oxidases. Novel insights into the biology and evolution of molybdo-flavoenzymes. J Biol Chem. 2006 Jul
14;281(28):19748-61

Garattini E, Parrella E, Diomede L, Gianni M, Kalac Y, Merlini L, Simoni D, Zanier R, Ferrara F F, Chiarucci I,
Carminati P,Terao M, Pisano C. ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in
myeloid leukemia cells: Modulation of intracellular calcium homeostasis. Blood 2004; 103: 194-207

Vila R, Kurosaki M, Barzago M M, Kolek M, Bastone A, Colombo L, Salmona M, Terao M, Garattini E. Regulation and
biochemistry of mouse molybdo-flavoenzymes. The DBA/2 mouse is selectively deficient in the expression of aldehyde
oxidase homologues 1 and 2 and represents a unique source for the purification and characterization of aldehyde oxidase.
J Biol Chem 2004; 279: 8668-8683
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ACTIVITIES
The Department comprises six laboratories. Research is heterogeneous in terms of
scientific interests and aims, but it is unified by the structural and functional study of
specific, pharmacologically important gene products, using a common body of
techniques. Classical biochemistry and molecular biology methods are used to define
proteins that might be targets for the pharmacological activity of drugs. Potential direct
interactions between drugs and proteins are studied at the molecular level by a variety of
approaches ranging from animal studies to computer simulation.
MAIN FINDINGS
Identification of the molecular mechanisms responsible of oligomer formation of
amyloidogenic proteins.
Development of a new protocol (depsipeptide technique) for the preparation of
homogeneous and reliable solutions of β-amyloid, a prerequisite for any analysis of the
properties of these highly aggregating peptides.Use of SPR to study the elongation
kinetics and the binding properties of the highly amyloidogenic Aβ 1–42 peptide.
Development and characterization of a new SPR-based immunoassay for the specific
detection of toxic Aβ oligomers.
A2V mutation favours the formation of toxic Aβ1-40 oligomers.
Epigallocatechine-gallate, a green tea bioactive polyphenol, prevents the formation of
toxic Aβ oligomers
Characterization of the binding properties of a new peptide inhibitor of β-amyloid
aggregation. Confirmation and characterization of the binding of β-amyloid oligomers
to prion protein.Development of new protocols to evaluate, by surface plasmon
resonance (SPR), the interaction between nanoparticles and their putative targets:
application to nanoparticles functionalized to bind β-amyloid.
Identification of tetracyclines as potential therapeutic agents for prion diseases.
Synthesis, biological and chemico-physical characterization of peptides deduced from
prion protein sequence.
Identification of a correlation between cholesterol synthesis and prion protein
production.
Protein identifications by mass spectrometry and data base searching using a
combination of techniques.
In collaboration with the “Istituto Neurologico Besta” we have identified two new
mutations in the MAPT gene causing frontotemporal lobar degeneration (FTLD). The
gene products tau were biochemically and structurally characterized to evaluate the
pathological features of the new mutations.
System-level analysis of protein interactions in the epithelial junctional complex.
Identification of a panel of protein biomarkers in peripheral blood mononuclear cells of
ALS patients and a rat model of ALS.
Development of constitutive and conditional motor neuronal cell models to unravel the
toxicity of mutant G93A superoxide dismutase 1 responsible for some forms of familial
amyotrophic lateral sclerosis.
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Drugs or exogenous compounds impairing the electron transport chain are a risk factor
to motor neurons of individuals carrying mutant forms of superoxide dismutase 1.
Mitochondrial damage due to mutant G93A superoxide dismutase 1 occurs selectively
in motor neurons.
Synthesis of glutathione, the main cellular antioxidant, and mitochondrial
glutamine/glutamate metabolism are altered in a motor neuronal model of familial
amyotrophic lateral sclerosis.
Identification and characterization of a novel class of retinoids endowed with strong and
selective apoptogenic activity on the neoplastic cell. Pre-clinical development of these
agents for the treatment of acute leukemia.
Identification and characterization of novel retinoid-based pharmacological
combinations for the treatment of acute myelogenous leukemia.
Molecular cloning and characterization of the cDNAs and genes of four novel members
of the mammalian molybdo-flavoprotein family. Definition of a novel gene cluster on
human chromosome 2 and mouse chromosome 1.
Development of knok-out animals for molybdo-flavoproteins: AOX1, AOH1, AOH2,
AOH3.
Creation of integrated instruments for the rationalization of Microarray analysis
processes.
The treatment with a non haematopoietic derivate of Erythropoietin (CEPO) reduces
motor neuron loss and clinical progression in a mouse model of ALS related to
alterations in vesicle trafficking, the wobbler mouse.
Treatment with a soluble TNF receptor in the wobbler mouse, reduces motor neuron
degeneration and the phosphorylation of the two main stress kinases (p38 e JNK)
activated by TNF receptors.
Riluzole treatment reduces motor neuron loss and clinical progression of wobbler
mouse by increasing the endogenous BDNF expression .
Oxidative stress, glial activation and inflammation occur in the retinopathy as well as
in cerebral and spinal cord dysfunction in the mnd mouse, a model of progressive
epilepsy with mental retardation related to mutation in the CLN8 gene. These findings
provide further evidence for the implication of TNF death receptor signalling in the
pathology of Neuronal Ceroid Lipofuscinosis.
Recombinant C1-inhibitor binds with high affinity with Mannose Binding Lectins, an
interaction possibly underlying its superior anti-ischemic properties in animal models.
Identification of a new synthetic MBL ligand, which proved to be neuroprotective in
animal models of ischemia.
Evidence for the binding between C3 and P-selectin, in a collaborative study regarding
the role of complement system in triggering microvascular thrombosis.
Confirmation and characterization of the binding of pentraxin-3 to P-selectin, a new
mechanism involved in the leukocyte recruitment at sites of inflammation.
Determination of the binding properties of new FGF-2 ligands with antiangiogenic
activities.
The expression of a mutant PrP (PG14) impairs glutamatergic transmission in mice
cerebellum, an effect down-hill to a defect of voltage-gated calcium channels.
Endogenous levels of reduced CoQ10 and CoQ9 were 10-25% higher in the CNS tissues of
SOD1G93A mice (a model of Amiotrophic Lateral Sclerosis), even at a presymptomatic stage.
Chronic treatment with Ubiquinone or Ubiquinol has no effect on the disease progression and
survival in SOD1G93A mice.
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Development of new protocols to evaluate, by surface plasmon resonance (SPR), the
formation of protein corona on the nanoparticles surface.
NATIONAL COLLABORATIONS
Advanced Biology Center, Genoa
Centro Clinico Nemo, Ospedale Niguarda, Milan
Fondazione S. Maugeri, Milan
Fondo Edo Tempia, Biella
IFOM Fondazione Istituto FIRC di Oncologia Molecolare, Milan
IRCCS Fondazione "Istituto C. Mondino", Laboratorio di Neurobiologia Sperimentale,
Pavia
IRCCS Istituto Nazionale Neurologico "C. Besta", Milan
Istituto Clinico Humanitas, Milan
Istituto di Neuroscienze C.N.R., Pisa
Istituto Nazionale dei Tumori, Milan
Istituto Nazionale dei Tumori, Naples
Istituto Oncologico Europeo, Milan
Istituto Regina Elena, Rome
Istituto Toscano Tumori, Florence
Istituto di Biologia Molecolare Buzzati Traverso, Naples
Istituto di Biomedicina e Immunologia Molecolare CNR, Palermo
Istituto di Chimica del Riconoscimento Molecolare CNR, Milan
Istituto di Clinica Neurologica, Ospedale Maggiore Policlinico, Milan
Nanovector srl, Turin
Newron Pharmaceuticals, Milan
Ospedale Maggiore Policlinico, Milan
Ospedale Pediatrico Bambino Gesu', Rome
Ospedale Pediatrico "Gaslini", Genoa
Ospedale S. Gerardo, Monza, Milan
Ospedale San Matteo, Pavia
Sigma-Tau, Pomezia, Rome
Università Bicocca, Dip. Medicina Sperimentale, Monza
Università degli Studi, Dip. Biotecnologie, Milan
Università degli Studi, Dip. Chimica Biochimica e Biotecnologie per la Medicina,
Milan
Università degli Studi, Dip. Chimica Farmaceutica e Tossicologica, Milan
Università degli Studi, Dip. Chimica Organica e Industriale, Milan
Università degli Studi, Dip. Farmaco-Chimico, Messina
Università degli Studi, Dip. Farmacologia Medica, Milan
Università degli Studi, Dip. Scienze Biomolecolari e Biotecnologie, Milan
Università degli Studi, Dip. Scienze Farmacologiche, Milan
Università degli Studi, Facoltà di Biologia, Milan
Università degli Studi, Facoltà di Chimica, Milan
Università degli Studi, Istituto di Endocrinologia, Centro di Eccellenza per le Malattie
Neurodegenerative, Milan
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University of Catania, Dip. Scienze Farmaceutiche, Catania
University of Ferrara, Facoltà di Chimica, Ferrara
University of Florence, Dip. Scienze Biochimiche, Florence
University of Genoa, Dip. Scienze Farmaceutiche, Genoa
University of Milan, Center of Excellence on Neurodegenerative Diseases, Segrate,
Milan University of Milan, Dip. Scienze Molecolari, Milan
University of Milan, Dip. Studi pre-clinici, Milan
University of Pavia, Dip. Biochimica, Pavia
University of Pavia, Dip. Scienze Fisiologiche e Farmacologiche, Pavia
University of Perugia, Dip. Medicina Sperimentale e Scienze Biochimiche, Perugia
University of Siena, Dip. Farmaco-Chimico-Tecnologico, Siena
University of Turin, Dip. Anatomia, Farmacologia, Medicina Legale, Turin
Zambon, Milan
INTERNATIONAL COLLABORATIONS
The Babraham Institute, Cambridge, UK
Boston College, Boston, MA, USA
Burke Medical Research Institute, White Plains, new York, USA
Case Western Research University, Cleveland, OH, USA
Dept. de Quimica-Fisica de Macromoleculas Biologicas, CSIC, Madrid, Spain
Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster
University, Lancaster LA1 4YQ, UK
Faculdad de Ciencias Medicas, Universidad de Santiago de Chile, Chile
ETH, Zurig, Switzerland
FMP, Berlin, Germany
Giessen Polyclinic University, Giessen, Germany
Houston University, TX, USA
Keio University, Tokyo, Japan
IBSN CNRS, Marseille, France
Indiana University, Indianapolis, IN, USA
Institut de Genetique et Biologie Moleculaire et Cellulaire, Strasbourg, France
Institut Pasteur, Paris, France
John Innes Centre, Norwich, UK
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, , Univ Paris-Sud 11,
Chatenay-Malabry, France
Lundbeck, USA
Max Planck Research Unit for Enzymology of Protein Folding, Halle, Germany
Mayo Clinic College of Medicine, Jacksonville, FL, USA
National Institute of Health, Bethesda, MD, USA
Nippon University, Tokyo, Japan
Pepscan System BV, Lelystad, The Netherlands
Polichem S.A., Lugano, Switzerland
Politecnico di Zurigo (ETH), Switzerland
Technical University Braunschweig, Germany
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The Alexander Silberman Institute of Life Sciences, The Hebrew University of
Jerusalem, Jerusalem, Israel
Trinity College, Dublin, Ireland
Universidad de La Laguna, Tenerife, Spain
Universidad Nova, Lisbon, Portugal
Universitat des Saarlandes, Hamburg, Germany
Universitat Freiburg, Germany
Université Paris, France
Université Victor Segalen Bordeaux 2, Bordeaux, France
University of Aberdeen, UK
University of Amsterdam, The Netherlands
University of Birmingham, UK
University of Cardiff, UK
University of Glasgow, UK
University of Gottingen, Germany
University of Muenster, Germany
University of Patrasso, Grece
University of Southampton, UK
University of Sussex, UK
University of Vienna, Austria
Waring-Webb Institute, University of Colorado, Denver CO, USA
Weizmann Institut, Rehovot, Israel
Westfaelische Wilhelms-Universitaet Muenster, Germany
EDITORIAL BOARD MEMBERSHIP
Current Opinion in Pharmacology ( M. Gobbi)
Neurobiology of Lipids (L. Diomede)
European Journal of Cancer (E. Garattini)
BioMolecular Concepts (V. Bonetto)
PEER REVIEW ACTIVITIES
Advanced Drug Delivery Reviews, American Journal Physiology, Antioxidants and Redox
Signaling, BBA-Proteomics, Biochemical Journal, Biochemical Pharmacology, Biochimica
Biophysica Acta, BioMolecular Concepts, Biosensors and Bioelectronics, BMC-Biochemistry,
Brain Research, Cancer Research, Cell Death and Differentiation, Cell Research, Cellular and
Molecular Life Sciences, Circulation, Drug Investigation, European Journal of Cancer,
European Journal of Immunology, European Journal of Neuroscience, International Journal of
Cancer, International Journal of Molecular Sciences, Journal of Alzheimer’s Disease, Journal of
Biomedical Nanotechnology, Journal of Cell Biology, Journal of Cellular Biochemistry, Journal
of Hepatology, Journal of Immunology, Journal of Investigative Dermatology, Journal of Lipid
Mediators, Journal of Neurochemistry, Journal of Neuroimmunology, Journal of Translational
Medicine, Life Sciences, Nanomedicine, Neuroscience, Neuroscience Letters, Neurobiology of
Disease, Neurochemistry International, Pharmacological Research, Physiological Genomics,
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PLoS ONE, Prion, Proceedings of the National Academy of Sciences, Proteomics, Proteome
Science, Sensors.
CONFERENCE AND WORKSHOP CONTRIBUTIONS
Meeting: “43rd Meeting, American Society for Neurochemistry”, “The complement system in
cerebral ischemic injury: specific role of the lectin pathway”, 3-7 March, Baltimora, MA, USA
Symposium: “International Symposium on Biology and Translational Aspects of
Neurodegeneration”, “Mutant prion protein suppresses glutamatergic neurotransmission in
cerebellar granule neurons by impairing membrane delivery of voltage-gated calcium channel
α2δ-1 subunit”, 12-14 March, Venezia, Italy
Congress: XIV Congresso Società di Neuroscienze,"Nanoparticles for the brain delivery of antiinflammatory agents, 20 April, Catania, Italy
Symposium: “ESRR’12 - 16th European Symposium on Radiopharmacy and
Radiopharmaceuticals”, "Synthesis of a [18F]-curcumin derivative, a potential tracer for Abeta
imaging in Alzheimer’s disease", 26-29 April, Nantes, France
Symposium: “7th International Symposium on Neuroprotection and neurorepair”, “Role of
Mannose Binding Lectin in ischemic injury”, 2-5 May, Potsdam, Germany
Congress: “Miniworkshop e Convegno CIMN: Misfolding Proteico e Amiloidosi”,
"Riconoscimento ed analisi di oligomeri di beta-amiloide mediante Risonanza Plasmonica di
Superficie (SPR)","Sviluppo di un test comportamentale in C. elegans per valutare il potenziale
cardiotossico delle catene leggere delle immunoglobuline, 4-5 May, Genova, Italy
Symposium: “XIII International Symposium on Amyloidosis - From misfolded proteins to welldesigned treatment”, "Investigation on the functional consequence of amyloidogenic light
chains on Caenorhabditis elegans", “C. elegans expressing human β2-m recapitulates the
molecular mechanisms underlying dialysis-related amyloidosis”, 6-10 May, Groningen, Holland
Conference: “AAIC>12 - Alzheimer’s Associations International Conference”, "Neuronal
expression of Aβ1-40 containing the A2V mutation in C. elegans produces synaptic
disfunctions mediated by oligomerization", "Phenotypic heterogeneity of Alzheimer’s disease:
towards the identification of molecular determinants underlying distinct clinico-pathological
subgroups", 14-19 June, Vancouver, Canada
Conference: “EMBO Conference Series: C. elegans Neurobiology”, "Neuronal expression of
human Abeta1-40 containing the A2V mutation in C. elegans produces synaptic dysfunctions
mediated by oligomerization", "Light chains causing heart amyloidosis specifically hurt the
pharyngeal function in C. elegans", "Pharyngeal behaviour of C. elegans reveals the heartspecific toxicity of amyloidogenic light chains", 14-17 June, Heidelberg, Germany
Conference: “8th FENS Forum of Neuroscience”, “The A2V mutation in Aβ drives the
formation of toxic oligomers, as assessed in vitro and in vivo”, 14-18 July, Barcellona, Spain
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Symposium: “EFMC-ISMC 2012 - XXIInd International Symposium on Medicinal Chemistry”,
"Multigram-scale synthesis and in vivo efficacy studies of the multitarget anti-Alzheimer
compound AVCRI104P4", 2-6 September, Berlino, Germany
Congress: “NUCE International”, “Amyloidomics and Caenorhabditis elegans: innovative
approaches for new treatments", 25-27 September, Milano, Italy
Meeting: “NAD - Nanoparticles for therapy and diagnosis of Alzheimer disease - 4th Annual
Meeting”, “Dually decorated liposomes with monoclonical antibody Ox26 and APO3 derivative
peptide", 25-27 September, Bilbao, Spain
Conference: “Omics – Approaches in Nutraceutical Science”, “Amyoidomics and C. elegans:
innovative approaches for nutraceuticals development”, 26 September, Milano, Italy
Congress: “Neuroscience 2012”, “Specific recognition of toxic Aβ oligomers by a new surface
plasmon resonance-based immunoassay and in vivo assay in C. elegans”, 13-17 October, New
Orleans, USA
Congress: 23rd International Symposium on ALS/MND, 5-7 December, Chicago, USA
GRANTS AND CONTRACTS
Agenzia Italiana del Farmaco, Rome, Italy
Associazione Italiana Ricerca sul Cancro (AIRC), Milan, Italy
Biotecnologie BT - Perugia, Italy
Comunità Europea (EU), Bruxelles, Belgium
Consiglio Nazionale delle Ricerche (CNR), Palermo, Italy
Fondazione Don Gnocchi, Milan, Italy
Fondazione Cariplo, Milan, Italy
Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), Milan,
Italy
Fondazione Mariani, Milan, Italy
Fondazione Monzino, Milan, Italy
Fondazione Weizmann-Pasteur-Negri, Paris, France
Indena, Milan, Italy
Istituto Auxologico Italiano, Milan, Italy
Istituto Nazionale Neurologico "C. Besta", Milan, Italy
Lundbeck A/S, Copenhagen, Denmark
Ministero della Salute, Roma, Italy
Ministero dell'Istruzione, Università e Ricerca Scientifica (MIUR), Rome, Italy
North Shore University Hospital, NY, USA
Perfetti-Van Melle, Lainate, Milan, Italy
Sigma Tau, Pomezia, Rome, Italy
Telethon, Milan, Italy
Università di Firenze, Italy
Università di Milano-Bicocca, Italy
Università di Siena, Italy
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Zambon Group, Bresso (Mi), Italy
SCIENTIFIC PUBLICATIONS (2012)
Arosio P, Owczarz M, Muller-Spath T, Rognoni P, Beeg M, Wu H, Salmona M, Morbidelli M
In vitro aggregation behavior of a non-amyloidogenic λ light chain dimer deriving from U266 multiple myeloma cells
PLoS One 2012 7 : e33372
Biasini E, Turnbaugh J A, Massignan T, Veglianese P, Forloni G, Bonetto V, Chiesa R, Harris D A
The toxicity of a mutant prion protein is cell-autonomous, and can be suppressed by wild-type prion protein on adjacent
cells
PLoS One 2012 7 : e33472
Bigini P, Diana V, Barbera S, Fumagalli E, Micotti E, Sitia L, Paladini A, Bisighini C, De Grada L, Coloca L, Colombo
L, Manca P, Bossolasco P, Malvestiti F, Fiordaliso F, Forloni G, Morbidelli M, Salmona M, Giardino D, Mennini T,
Moscatelli D, Silani V, Cova L
Longitudinal tracking of human fetal cells labeled with super paramagnetic iron oxide nanoparticles in the brain of mice
with motor neuron disease
PLoS One 2012 7 : e32326
Bigini P, Milanese M, Gardoni F, Longhi A, Bonifacino T, Barbera S, Fumagalli E, Di Luca M, Mennini T, Bonanno G
Increased [3H]D-aspartate release and changes in glutamate receptor expression in the hippocampus of the mnd mouse
J Neurosci Res 2012 90 : 1148-1158
Brambilla D, Verpillot R, Le Droumaguet B, Nicolas J, Taverna M, Kona J, Lettiero B, Hashemi S H, De Kimpe L,
Canovi M, Gobbi M, Nicolas V, Scheper W, Moghimi M, Tvaroska I, Couvreur P, Andrieux K
PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation: toward engineering of functional
nanomedicines for Alzheimer's disease
ACS Nano 2012 6 : 5897-5908
Canovi M, Lucchetti J, Stravalaci M, Re F, Moscatelli D, Bigini P, Salmona M, Gobbi M
Applications of Surface Plasmon Resonance (SPR) for the characterization of nanoparticles developed for biomedical
purpose
Sensors 2012 12 : 16420-16432
Canzi L, Castellaneta V, Navone S, Nava S, Dossena M, Zucca I, Mennini T, Bigini P, Parati E
Human skeletal muscle stem cells antiinflammatory activity ameliorates clinical outcome in amyotrophic lateral sclerosis
models
Mol Med 2012 18 : 401-411
Coelho C, Mahro M, Trincao J, Carvalho A.T.P., Joao Ramos M, Terao M, Garattini E, Leimkuhler S, Joao Romao M
The First Mammalian Aldehyde Oxidase Crystal Structure: Insights Into Substrate specificity
J Biol Chem. 2012 287 :40690-702
Dellanoce C, Canovi M, Matera C, Mennini T, De Amici M, Gobbi M, De Micheli C
A novel spirocyclic tropanyl-∆2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin
transporters as well as serotonin uptake
Bioorg Med Chem 2012 20 : 6344-6355
De Paola M, Mariani Alessandro, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P, Castellaneta V,
Boldrin V, Rossetti C, Chiabrando C, Forloni G, Mennini T, Fanelli R
Neuroprotective effects of Toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron
degeneration
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Mol Med 2012 18 : 971-981
DiFebo F, Curti D, Botti F, Biella G, Bigini P, Mennini T, Toselli M
Neural precursors (NPCs) from adult L967Q mice display early commitment to "in vitro" neuronal differentiation and
hyperexcitability
Exp Neurol 2012 236 : 307-318
Di Fede G, Catania M, Morbin M, Giaccone G, Moro M L, Ghidoni R, Colombo L, Messa M, Cagnotto A, Romeo M,
Stravalaci M, Diomede L, Gobbi M, Salmona M, Tagliavini F
Good gene, bad gene: New APP variant may be both
Prog Neurobiol 2012 99 : 281-292
Diomede L, Soria C, Romeo M, Giorgetti S, Marchese L, Mangione P, Porcari R, Zorzoli I, Salmona M, Bellotti V,
Stoppini M
C. elegans expressing human β2-microglobulin: a novel model for studying the relationship between the molecular
assembly and the toxic phenotype
PLoS One 2012 7 : e52314
Di Santo R, Costi R, Cuzzucoli Crucitti G, Pescatori L, Rosi F, Scipione L, Celona D, Vertechy M, Ghirardi O, Piovesan
P, Marzi M, Caccia S, Guiso G, Giorgi F, Minetti P
Design, synthesis and structure-activity relationship of N-Arylnaphthylamine derivatives as amyloid aggregation
inhibitors
J Med Chem 2012 55 : 8538-8548
Errede M, Girolamo F, Ferrara G, Strippoli M, Morando S, Boldrin V, Rizzi Marco, Uccelli A, Perris R, Bendotti C,
Salmona M, Roncali L, Virgintino D
Blood-brain barrier alterations in the cerebral cortex in experimental autoimmune encephalomyelitis
J Neuropathol Exp Neurol 2012 71 : 840-854
Fluharty B R, Biasini E, Stravalaci M, Sclip A, Diomede L, Balducci C, La Vitola P, Messa M, Colombo
L, Forloni G, Borsello T, Gobbi M, Harris D A
An N-terminal fragment of the prion protein binds to amyloid-β oligomers and inhibits their neurotoxicity
in vivo
J Biol Chem 2012, in press
Fratelli M, Fisher J N, Paroni G, Di Francesco A M, Pierri F, Pisano C, Godl K, Marx S, Tebbe A, Valli
C, Gianni M, Stravalaci M, Gobbi M, Terao M, Garattini E
New insights into the molecular mechanisms underlying sensitivity/resistance to the atypical retinoid
ST1926 in acute myeloid leukaemia cells: The role of histone H2A.Z, cAMP-dependent protein kinase A
and the proteasome
Eur J Cancer 2012 E-pub :
Fumagalli L, Pallavicini M, Budriesi R, Gobbi M, Straniero V, Zagami M, Chiodini G, Bolchi C, Chiarini
A, Micucci M, Valoti E
Affinity and activity profiling of unichiral 8-substituted 1,4-benzodioxane analogues of WB4101 reveals
a potent and selective α1B-adrenoceptor antagonist
Eur J Med Chem 2012 58 : 184-191
Galdeano C, Viayna E, Sola I, Formosa X, Camps P, Badia A, Clos M V, Relat J, Ratia M, Bartolini M,
Mancini F, Andrisano V, Salmona M, Minguillon C, Gonzalez-Munoz G C, Rodriguez Franco M I,
Bidon-Chanal A, Luque J F, Munoz-Torrero D
Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's
and prion diseases
J Med Chem 2012 55 : 661-669
Garattini E, Paroni G, Terao M
Retinoids and breast cancer: new clues to increase their activity and selectivity.
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Breast Cancer Res 2012 14:111
Garattini E, Terao M
The role of aldehyde oxidase in drug metabolism
Expert Opin Drug Metab Toxicol 2012 8 : 487-503
Gemma S, Camodeca C, Sanna Coccone S, Joshi B P , Bernetti M, Moretti V, Brogi S, Bonache de
Marcos M C, Savini L, Taramelli D, Basilico N, Parapini S, Rottmann M, Brun R, Lamponi S, Caccia S,
Guiso G, Summers R L, Martin R, Saponara S, Gorelli B, Novellino E, Campiani G, Butini S
Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: further structure-activity
relationships, in vivo studies, and preliminary toxicity profiling
J Med Chem 2012 55 : 6948-6967
Giannì M, Peviani M, Bruck N, Rambaldi A, Borleri G, Terao M, Kurosaki M, Paroni G, Rochette-Egly
C, Garattini E
The MAPK p38α interacts with Ser-369 and inhibits RARα: suppression of the kinase enhances the
therapeutic activity of retinoids in acute myeloid leukemia cells
Leukemia 2012 26:1850-1861
Hartmann T, Terao M, Garattini E, Teutloff C, Alfaro J F, Jones J P, Leimkuhler S
The impact of single nucleotide polymorphisms on human aldehyde oxidase
Drug Metab Dispos 2012 40 : 856-864
Kurosaki M, Bolis M, Fratelli M, Barzago MM, Pattini L, Perretta G, Terao M and Garattini E
Structure and evolution of vertebrate aldehyde oxidases: from gene duplication to gene suppression
Cell Mol Life Sci, 2012 [Epub ahead of print]
Lazzari S, Moscatelli D, Codari F, Salmona M, Morbidelli M, Diomede L
Colloidal stability of polymeric nanoparticles in biological fluids
J Nanopart Res 2012 14 : 920
Le Droumaguet B, Nicolas J, Brambilla D, Mura S, Maksimenko A, De Kimpe L, Salvati E, Zona C,
Airoldi C, Canovi M, Gobbi M, Noiray M, La Ferla B, Nicotra F, Scheper W, Flores O, Masserini M,
Andrieux K, Couvreur P
Versatile and efficient targeting using a single nanoparticulate platform: application to cancer and
Alzheimer's disease
ACS Nano 2012 7 : 5866-5879
Locatelli D, D'Errico P, Capra S, Finardi A, Colciaghi F, Setola V, Terao M, Garattini E, Battaglia G
Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of
motor neuron
J Neurochem 2012 121 : 465-474
Locatelli D, Terao M, Fratelli M, Zanetti A, Kurosaki M, Lupi M, Barzago M M, Uggetti A, Capra S,
D'Errico P, Battaglia G S, Garattini E
Human axonal survival of motor neuron (a-SMN) protein stimulates axon growth, cell motility, C-C
motif ligand 2 (CCL2), and insulin-like growth factor-1 (IGF1) production
J Biol Chem 2012 287 : 25782-25794
Luciani D, Bazzoni G
From networks of protein interactions to networks of functional dependencies
BMC Syst Biol 2012 6 : 44
Obici L, Cortese A, Lozza A, Lucchetti J, Gobbi M, Palladini G, Perlini S, Saraiva M J, Merlini G
Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study
Amyloid 2012 19 Suppl 1 : 34-36
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Orsini F, Villa P, Parrella S, Zangari R, Zanier E R, Gesuete R, Stravalaci M, Fumagalli S, Ottria R,
Reina J J, Paladini A, Micotti E, Ribeiro-Viana R, Rojo J, Pavlov V I, Stahl G L, Bernardi A, Gobbi M,
De Simoni M G
Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic
window in cerebral ischemia
Circulation 2012 126 : 1484-1494
Paroni G, Fratelli M, Gardini G, Bassano C, Flora M, Zanetti A, Guarnaccia V, Ubezio P, Centritto F,
Terao M, Garattini E
Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with
coamplification of ERBB2 and RARA
Oncogene 2012 31 : 3431-3443
Peviani M, Kurosaki M, Terao M, Lidonnici D, Gensano F, Battaglia E, Tortarolo M, Piva R, Bendotti C
Lentiviral vectors carrying enhancer elements of Hb9 promoter drive selective transgene expression in
mouse spinal cord motor neurons
J Neurosci Methods 2012 205 : 139-147
Piccini A, Borghi R, Guglielmotto M, Tamagno E, Cirmena G, Garuti A, Pollero V, Cammarata S,
Fornaro M, Messa M, Colombo L, Salmona M, Perry G, Tabaton M
β-amyloid 1-42 induces physiological transcriptional regulation of BACE1
J Neurochem 2012 122 : 1023-1031
Rossi G, Bastone A, Piccoli E, Mazzoleni G, Morbin M, Uggetti A, Giaccone G, Sperber S, Beeg M,
Salmona M, Tagliavini F
New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural
characterization
Neurobiol Aging 2012 33 : 834.e1-834.e6
Russo L, Marsella C, Nardo G, Massignan T, Alessio M, Piermarini E, La Rosa S, Finzi G, Bonetto V,
Bertuzzi F, Maechler P, and Massa O. Transglutaminase 2 transamidates cytoplasmic actin and
tropomyosin in glucose-stimulated INS1-E. Implications for insulin secretion. Acta Diabetol 2012 Epub
Senatore A, Colleoni S, Verderio C, Restelli E, Morini E, Condliffe S B, Bertani I, Mantovani S, Canovi
M, Micotti E, Forloni G, Dolphin A C, Matteoli M, Gobbi M, Chiesa R
Mutant PrP suppresses glutamatergic neurotransmission in cerebellar granule neurons by impairing
membrane delivery of VGCC α2δ-1 subunit
Neuron 2012 74 : 300-313
Stravalaci M, Bastone A, Beeg M, Cagnotto A, Colombo L, Di Fede G, Tagliavini F, Cantu' L, Del
Favero E, Mazzanti M, Chiesa R, Salmona M, Diomede L, Gobbi M
Specific recognition of biologically active amyloid-β oligomers by a new surface plasmon resonancebased immunoassay and an in vivo assay in Caenorhabditis elegans
J Biol Chem 2012 287 : 27796-27805
Traina G, Bigini P, Federighi G, Sitia L, Paroni G, Fiordaliso F, Salio M, Bendotti C, Brunelli M
Lipofuscin accumulation and gene expression in different tissues of mnd mice
Mol Neurobiol 2012 45 : 247-257
Zoja C, Garcia P B, Rota C, Conti S, Gagliardini E, Corna D, Zanchi C, Bigini P, Benigni A, Remuzzi G,
Morigi M
Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell
dysfunction in adriamycin-induced nephropathy
Am J Physiol - Renal Physiology 2012 303 : F1370-F1381
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RESEARCH ACTIVITIES
Laboratory of Biochemistry and Protein Chemistry
Development of new therapeutic strategies for the treatment of central
and peripheral amyloidosis
The development of an effective strategy for the prevention and cure of Alzheimer
disease and systemic amyloidosis is of great importance due to the absence of an
effective therapy. Their severity affects seriously the life of patients and their relatives.
The formation of amyloid fibrils and their deposition in specific tissues were for longtime considered the cause of the disease, however recent studies showed that soluble
oligomeric species are the actual culprits of the toxicity. The kinetics of protein
aggregation due to conformational modifications and the comprehension of genetic,
biochemical and structural determinants at the basis of this transformation are very
important for unveiling the pathogenic process and the development of therapeutic
strategies. Aiming at developing simple models that enable monitoring the
conformational changes that preceds fibril deposition, we have designed and developed
a variety of synthetic peptides as deduced from the primary sequence of human
amyloidogenic proteins in their wild-type or mutated forms.
In collaboration with the Istituto Neurologico “Carlo Besta” of Milan we have identified
a mutated form of beta-amyloid (A673V) that displays amazing biological features
since it binds to wild-type beta-amyloid and inhibits amyloid formation and the onset of
the disease. This observation opens new therapeutic perspectives both for genetic and
sporadic forms of Alzheimer disease based upon the use of protein fragments
containing this mutation or peptide-mimetic compounds. Moreover, we have
synthesized several Abeta peptides containing the same mutation and we have evaluated
its importance in the aggregation and amyloidogenic properties. Similar studies have
been carried out with prion protein and some amyloidogenic proteins responsible of
peripheral amyloidosis. The first approach for the development of candidate drugs
contemplates the development of molecules capable to interfere with oligomeric species
following direct interaction with protein molecules disrupting its beta-sheet
conformation or the fibrillary aggregates. This activity requires in vitro studies with cell
free models to determine the conformational features of amyloidogenic peptides, their
secondary structure, the hydrogen-deuterium exchange, the resistance to digestion by
proteases, the aggregation propensity and amyloidogenic characteristcs.
To understand the molecular and biochemical mechanisms of action underlying the
cause of the cytotoxic action, peptides are used for in vitro studies in variety of cellular
models trying to correlate their physical features and the biological effect. Moreover,
the subcellular distribution of peptides and their molecular targets are also investigated.
We have reported that tetracyclines are new candidates as anti-amyloidogenesis drugs,
in particular they disrupt amyloid tangles and increase the sensitivity of PrP to
proteinase K digestion. Tetracycline are able to inhibit neuronal cell death and astroglial
prolipheration induce by PrP peptides and, in animal model of disease, they prolong the
survival of animals inoculated with PrP.
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The nematode Caenorhabditis elegans as experimental model
to
investigate in vivo the molecular mechanisms underlying the aggregation
of amyloidogenic proteins
The description of the molecular events underlying the in vivo amyloidogenesis is
crucial for the design of effective therapeutic strategies. To this end, in our laboratory
we use Caenorhabditis elegans as experimental model since it offers the unique
opportunity to analyze the genetic and molecular functions of human disease-related
genes in vivo. This nematode offers also the major advantages of the easy generation of
transgenic strains expressing human genes, the production of distinct phenotypes offers
insight into the biology of the disease and help to elucidate fundamental cellular
processes related to it. In particular, it is possible to correlate the phenotype of the
transgene with the disease insurgence, the degeneration, the protein expression and its
aggregation into the oligomeric or fibrillar forms.
Different transgenic strains expressing various fragments of human β amyloid in
neurons or in muscles are available in our laboratory. We also developed new
transgenic strains expressing A-V or A-T mutated peptides in position 2 under a
neuronal promoter, to evaluate their in vivo effects.
The expression of these peptides results in the cytoplasmic amyloid β inclusion and in
the appearance of progressive phenotypes related to the disease. In these C. elegans
strains, amyloid aggregates were observed and they are similar to those observed in the
brain of patients with AD or in muscles of patients with sporadic forms of Inclusion
Body Myositis, the most common myopathy. These models were already used to study
the relationship between Aβ sequence, amyloid formation and toxicity. A transgenic C.
elegans strain producing only the oligomeric form of the β amyloid protein was also
available representing a good predictive model for the investigation of drugs
specifically interfering with oligomers. C. elegans is also applied to investigate the
molecular mechanisms underlying some systemic amyloidosis, like those caused by
tissue deposition of immunoglobulin light chain or 2 microglobuline. Using this
multidisciplinary genomic and molecular integrated approach, we will obtain important
informations for the development and validation of innovative therapeutic strategies and
for the comprehension of the in vivo molecular functions of genes related to human
amyloidosis.
Nanoparticles in pharmacology: new diagnosis and therapy systems
The clinical development of molecules with promising therapeutic activity for the
treatment of diseases with unfavorable prognosis, is sometimes limited by the
molecules’ scarse bioavailability, by a rapid clearance, or the difficulty to cross certain
biological barriers, and last but not least, by the onset of severe side effects. To
overcome those hurdles the usage of biocompatible and biodegradable nanoparticles
(NPs) has been suggested. These NPs “protect” the active compounds loaded in the NPs
and act as controlled release devices.
Various types of NPs, both lipidic and polymeric, have been used in our laboratories to
enhance the release kinetics of the loaded molecules. Modifying the NPs’ surfaces with
particular peptides, antibodies and ligands, it has been possible to change their
biodistribution with respect to healthy and tumoral tissues
Our laboratory has evaluated, within the European project “Nanoparticles for therapy
and diagnosis of Alzheimer Disease” (NAD), the ability of different NPs of lipidic and
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polymeric nature to cross the blood-brain-barrier in vivo, to deliver anti-amiloidogenic
drugs to the brain. Furthermore, in collaboration with Politecnico di Milano and the
Swiss Federal Institute of Technology (ETH), new polymeric NPs have been
synthesized and their stability has been evaluated in biological fluids. Utilizing non
degradable NPs loaded with fluorescent dyes and/or paramagnetic molecules,
biodistribution studies have been performed in vivo employing Optical Imaging
techniques, Magnetic Resonance Imaging, optical and fluorescence microscopy. These
results will represent the basis for the design of NPs for early diagnosis of specific
diseases and for monitoring the therapy’s efficacy.
A deeper analysis of the parameters influencing the in vitro and in vivo drug release
from NPs are currently in progress. All obtained data will be used for the development
of mathematical models able to describe the pharmacokinetics of the NPs and of the
released compounds.
Preclinical imaging to improve the translation of results from mice to
patients
One of the main goal of the modern pharmacological research is to translate the results
obtained form preclinical models (cells and animals) to the clinical practice. The use of
non invasive instruments of screening has been more and more taking place either for
the diagnosis or to follow the efficacy of therapy in different clinical fields. The recent
development of in vivo imaging instruments dedicated to small rodents may therefore
allow to perform the same strategy of investigation already at preclinical level.
The Department of Biochemistry and Molecular Pharmacology has been developing a
series of experimental procedures aimed at coupling the results obtained by different in
vivo analyses (Magnetic Resonance Imaging, micro Computerized Tomography,
Fluorescent Molecular Tomography, Ocular Coherence Tomography) to the data
obtained by ex vivo studies (histology and/or immunohistochemistry). The integration
of these two areas can be identified as “preclinical imaging”.
This approach has been recently exploited to better investigate the clinical progression
of an interesting of model of neuronal ceroid lipofuscinosis, the mnd mouse. Analyses
carried out by fluoro-angiography and ocular coherence tomography allowed us to
characterize the progressive ocular inflammation and retinal degeneration affecting mnd
mice by simply following the same group animals during the time. Histological
characterization, performed by sacrificing animals at different time points, confirmed
these data and highlighted that lipofuscin accumulation, apoptosis of retinal cells and
reactive gliosis, are the cellular bases for the alteration revealed by in vitro imaging
analyses. A series of experiments will be carried out, by three different degree of
resolution, to better characterize this peculiar accumulation of autofluorescent ceroid
and lipofuscin-like material in brain and in eyes of mnd mice. In collaboration with the
Department of Oncology, we investigated about the anatomical localization of
autofluorescent material by a non invasive approach (fluorescent molecular
tomography). Such strategy allowed us to follow the progressive deposition of
autofluorescent material in the same group of mice at different ages. A marked
fluorescence was first observed in the posterior area of forebrain and in the cerebellar
region. In older animals the fluorescent signal spread in the whole brain parenchyma
and in other peripheral organs.
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Histological analysis (by the observation of the autofluorescence in 20 µm thick
sections) confirmed the reliability of in vivo imaging and evidenced a selective
deposition of autofluorescent material in neurons. Finally, electron microscopy studies
(in collaboration with the Department of Cardiovascular Diseases) showed that
lipofuscin-like bodies were mainly segregated in swollen lysosomes and distributed in
the whole cytoplasm of neurons.
Contrast Enhanced (MnCl2) MRI experiments have demonstrated that in the
hippocampus of mnd micea marked process of hyperexcitability occurs before motor
symptom onset. Hippocampal hyperexcitabilty was further confirmed by EEG analysis
(in collaboration with the Laboratory of Experimental Neurology) and by c-fos
immunohistochemistry. The body of knowledge emerging from all these experiments
allow us to propose the mnd mouse as a reliable model of Epilepsy with mental
retardation, one of the most common form of neuronal ceroid lipofuscinosis and
associated with mutation(s) of the same gene (cln8) responsible for the phenotypic
changes found in mnd mice.
In collaboration with the Unit of Cancer Clinical Pharmacology we evaluated, by
Gadolinium enhanced MRI, the growth of an orthotopically implanted human
glioblastoma in the brain parenchyma of nude mice.
In addition, the internalization of paramagnetic and fluorescent probes in human foetal
stem cells has allowed to track the fate of these cells once transplanted in cerebral
ventricles of healthy and diseased mice (more specifically in a model of amyotrophic
lateral sclerosis: the wobbler mouse). Other studies with dual “paramagneticfluorescent” are now in progress to follow the route of human fetal stem cells by MRI
and fluorescent molecular tomography in the same group of animals at different times
after transplantation.
Laboratory of Molecular Biology
The family of molybdo-enzymes
Molybdo-enzymes are proteins requiring a molybdo-pterin cofactor (molybdenumcofactor, MoCo) for their catalytic activity. Until a few years ago, it was believed that
the family of molybdo-enzymes consisted only of three members: sulfite oxidase,
aldehyde oxidase and xanthine oxidoreductase. In the last few years of research, our
laboratory has determined the structure of the genes coding for different
molybdoenzymes in rodents and humans. In particular, we demonstrated that rodents
are endowed with four different aldehyde oxidase (AOX1, AOX3, AOX4 and
AOX3L1) characterized by remarkable structural and functional similarity. The
physiological substrate(s) and the physiological function(s) of this group of protein have
not yet been identified, although it is known that aldehyde oxidases can oxidize
aliphatic and aromatic aldehydes into the corresponding carboxylic acids and to
hydroxylate different types of n-heterocyclic aromatic rings. The four different
aldehyde oxidases of rats and mice are the product of an equivalent number of genes
located at the short distance one from the other on the same chromosome. These genes
originated through a number of a synchronous gene duplication events. Our studies
aimed at the determination of the evolutionary processes underlying the development of
the genes coding for aldehyde oxidases allowed us to establish that the natural history of
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this gene family is made of duplication and suppression events. These evolutionary
processes resulted in the presence of variable number of aldehyde oxidases in different
genomes. Man is characterized by the presence of a single active gene (AOX1) and two
inactive pseudo genes clustered on chromosome 2. In the last years we have focused on
the functional definition of the different mouse aldehyde oxidases and our long term
aim is to establish the reasons underlying the disparity in the number of these enzymes
between humans and rodents. To this purpose, we generated two knockout animals for
the AOX4 and AOX3L1 genes. The AOX4 knockout mouse was characterized
phenotypically demonstrating minimal alterations of the epidermis. Indeed, the AOX4
knockout animal shows epidermal hypertrophy, which is associated with a peculiar
fragility of the corneal layer. At the biochemical level, we observed a deficiency in the
synthesis of retinoic acid in the two organs where AOX4 is present in significant
amounts (skin and Harderian glands). This observation is in line with the idea that
AOX4 may have a role in the metabolism of retinaldehyde to retinoic acid, the active
metabolite of vitamine A. Recently we gathered novel data indicating a role for AOX4
in the control of the adipose tissue homeostasis. The observation is of particular
importance also in man as human AOX1 seems to exert a similar effect in the synthesis
and deposition of lipids. Currently we are performing similar studies in a knockout
mouse for AOX3L1.
Retinoids in the treatment and chemoprevention of myeloid leukemia and
mammary carcinoma
Our laboratory has a long standing interest in defining the therapeutic potential of
natural and synthetic derivatives of retinoic acid, the active metabolite of vitamin A.
These compounds, commonly defined as retinoids, are characterized by cytodifferentiating, anti-proliferative and apoptotic effects which are at the bases of their
therapeutic activity in the context of myeloid leukemia and mammary carcinoma.
Retinoids are very active therapeutic agents, although they are endowed with dose
limiting side effects, particularly chronic administration. A rational clinical use of
retinoids calls for a better knowledge of the mechanisms of action underlying the antineoplastic action exerted by these compounds. In-depth knowledge is of fundamental
value for the design of novel retinoid-based treatment strategies characterized by
increased therapeutic index. We have a long-standing interest in the definition of the
molecular mechanisms regulating the activity of retinoic acid nuclear receptors, as they
may lead to the identification of pharmacological targets to be modulated in a specific
manner. Indeed, we believe that knowledge in this field may lead to the development of
rational combinations between retinoids and other pharmacologically active agents to be
used in the treatment of different tumor types. Such an approach has led us to the recent
identification of the prolyl-isomerase, PIN1 as a negative regulator of the retinoic acid
receptor, RARα. Pharmacological inhibitors PIN1 proved to be particularly effective in
sensitizing the leukemic cell to the anti-neoplastic activity of retinoids. These results
open up the possibility to develop combinations based on PIN1 inhibitors and retinoids
for the treatment of acute myeloid leukemia. Following the same type of logic, we have
recently demonstrated that the inhibition of the microRNA, miR21 in mammary
carcinomas positive for estrogen receptor is of the utmost importance in potentiating the
anti-proliferative activity of retinoids in this particular type of tumor. Finally, we
observed that the peculiar subgroup of mammary cancer positive for HER2 may benefit
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from retinoid-based treatment or associations between retinoids and inhibitors of HER2
receptor tyrosine kinase activity.
Currently, we are conducting a series of studies aimed at defining the cellular and
molecular determinants of the sensitivity/resistance to retinoids operating in breast
carcinoma, using an approach which integrates the high-throughput genomic
methodologies and the molecular pharmacology of retinoids. To this aim, we are in the
process of defining the gene-expression profiles of retinoid responses in a panel
consisting of more than 40 breast carcinoma cell lines characterized for basal profile of
gene-expression, gene copy number variations (CNV) and the presence of genetic
polymorphisms. In addition, we have set up an in vitro methodology for the short-term
incubation of tissue slices obtained from surgical samples deriving from patients
suffering from different types of breast cancer.
Laboratory of Pharmacodynamics and Pharmacokinetics
Misfolding proteins and related diseases
One of the laboratory’s main research fields regards the diseases associated with protein
“misfolding”, i.e. the formation of aberrant tertiary conformations of proteins or
peptides, as a consequence of mutations, stress or aging. Besides the loss of the
protein’s physiological properties, the misfolding often results in new biochemical
properties, particularly the propensity to aggregate and form amyloid-like deposits. We
are particularly interested in Alzheimer’s disease (AD), in which there is aggregation of
amyloid-β (Aβ) peptides (Aβ1-40 and Aβ1-42, detectable in the amyloid plaques typical of
AD brain), and in spongiform encephalopathies, due to misfolding and aggregation of
the prion protein (PrP). Recent studies suggest that misfolding and the consequent
propensity to form toxic aggregates is common to different proteins and results in
different diseases (e.g. alpha-synuclein for Parkinson disease, poly-Q expansions for
Huntington disease, superoxide dismutase in amiotrophic lateral sclerosis, transthyretin
in systemic amyloidosis). Better knowledge of the molecular and cellular mechanisms
involved in these events is needed for the development of useful therapeutic strategies.
Our activities are mainly dedicated to the analysis of the aggregation features of
different proteins, in different experimental conditions, with the final aim to
identify/develop compounds interfering with the formation of toxic assemblies. For that,
we use different approaches including in silico computational simulations, in vitro
chemical-physical and biochemical techniques and some in vivo studies in collaboration
with other groups (in particular studies in C. elegans with Dr. L. Diomede of the
“Biochemistry and Protein Chemistry” lab). As regards in vitro studies, in particular, we
obtained interesting results by using Surface Plasmon resonance (SPR), a well known
and a powerful method to study molecular interactions. Thus, we have developed SPR
protocols to analyze the polymerization kinetics of PrP or Aβ1-42 amyloid fibrils, or for a
specific recognition of toxic Aβ oligomers. These protocols have been conveniently
applied to evaluate the effects of mutations, for screening molecules with potential antiamyloidogenic activities, or for investigating potential binding targets of aggregated
species, enabling, for example, to describe the interaction between Aβ1-42 oligomers and
PrP. SPR has also been applied, within the European FP7 project “NAD” (Nanoparticles
for Alzheimer’s Disease) to test functionalized nanoparticles for their binding to Aβ
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assemblies. Nanoparticles may conveniently carry drugs and/or imaging agents at the
site of interest (e.g. Aβ aggregates), thus representing new potential diagnostic and
therapeutic opportunities.
A number of observations suggest that the neuronal degeneration observed in some
misfolding diseases is preceded by subtle cellular dysfunctions of synaptic transmission
(synaptopathies), in many cases caused by the toxic oligomeric aggregates. In
collaboration with the “Neurobiology of Prions” lab (Dr. R. Chiesa), and using
biochemical methods to study neurotransmitter’s release and uptake, we have recently
found that the expression of a mutant PrP (PG14) impairs voltage-gated calcium
channels and, in turn, glutamatergic transmission in mice cerebellum.
We are also involved in other projects related to misfolding diseases, in charge of the
analytical determination of drugs levels in biological samples (e.g. plasma or brain
tissues), after in vivo treatments. Within the NAD project (see above), we evaluate in
mice the pharmacokinetic profile of the molecules carried by nanoparticles, looking in
particular at the passage of the blood-brain-barrier. The laboratory is also a partner in
an integrated project (PHARMACOG, IMI) aiming to develop and validate new
strategies for the identification of effective therapies for AD. Our task, in particular, is
to analyse the pharmacokinetics of old and new potential anti-AD drugs, to be
integrated with the pharmacodynamic properties and the drug’s activities in new
preclinical and clinical models. Finally, we are also in charge of the pharmacokinetics
studies included in clinical trials, coordinated at the Istituto Neurologico Besta (Milan)
and Ospedale San Matteo (Pavia), aiming at evaluating the effects of doxycicline for the
treatment of Creuzfeldt-Jacob diseases (PrP disease) or peripheral amyloidosys (dialysisrelated or transthyretin-related amyloidosis).
Q10 coenzyme in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease involving
brainstem and spinal cord motoneurons, leading to complete paralysis of skeletal
muscles and early death, usually from respiratory failure. Mutations in the copper-zinc
superoxide dismutase (SOD1) gene are responsible of some forms of familial ALS, and
on this basis transgenic rodents have been generated, contributing significantly to our
understanding of the pathogenic mechanisms of the disease. For example, transgenic
mice carrying the mutant SOD1, and showing motoneuron degeneration, have increased
oxidative stress associated with mitochondrial damage. The Q10 coenzyme (CoQ10, or
ubiquinone) is a major component of the mitochondrial respiratory chain, and its
reduced form ubiquinol has antioxidant proprieties. We have therefore investigated
whether there is a correlation between plasmatic/CNS CoQ10 levels and the disease
progression in mutant SOD1 transgenic mice, and the effects of a chronic treatment
with ubiquinol in the same mice. These studies have been carried out in collaboration
with the Laboratory of Molecular Neurobiology (Dr. C. Bendotti).
Glutamatergic and serotoninergic neuropharmacology
Our laboratory has long experience in neuropharmacological studies, particularly on the
glutamatergic and serotoninergic neurotransmission systems, and the instrumentation to
analyze the main mechanisms of synaptic transmission (neurotransmitter release,
binding to receptors and reuptake by specific transporters). On this ground we have
different collaboration with academic Chemico-Pharmaceutical departments for the
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characterization of new synthetic molecules acting on these mechanisms. Moreover, we
have collaborated with the laboratory of Experimental neurology (Dr. A. Vezzani),
studying the expression and localization of glutamatergic NDMA receptors during
epileptogenesis.
Nanotechnologies Nanotechnologies represent one of the main research endeavors of the 21st century,
with potential applications in many fields. With regard to biomedical applications, great
interest is currently being devoted to the development of nanoparticles (NPs) as suitable
carriers for imaging probes and therapeutic agents. We are applying our analytical
expertise to evaluate the in vitro kinetics of the release of compounds from
nanoparticles, and to evaluate the pharmacokinetic and biodistribution profile of the
carried molecule after in vivo treatment, in particular for the passage of the blood-brainbarrier.
We have also developed new approaches, based on Surface Plasmon
Resonance (SPR), for rapid and quantitative analyses of the interaction between NPs—
functionalized with specific ligands—and their putative biological targets. Moreover,
we showed that SPR can provide important details on the formation and the role of the
protein “corona”, i.e., the protein layer which coats NPs once they come into contact
with biological fluids. These novel applications of SPR sensors may be very useful to
characterize, screen and develop nanodevices for biomedical purposes.
Molecular interactions SPR, an advanced technique specifically developed for the study of molecular
interactions, enables us to contribute to different projects in collaboration with other
laboratories. In particular, one of these projects, carried out in collaboration with the Inflammation
and Nervous System Disease Laboratory (Dr. M.G. De Simoni) and the Department of
Organic and Industrial Chemistry, University of Milan (Dr. A. Bernardi) is investigating
the hypothesis that MBL play a role in ischemia-induced damage, and that MBL
inhibitors might have significant anti-ischemic effects. Studies include the synthesis of
new potential MBL ligands, the evaluation of their ability to interact with MBL in vitro
(through SPR studies in our laboratory) and their anti-ischemic effects in vivo.
We are also collaborating with laboratories of the “Mario Negri ” Institute in Bergamo
(Dr. M. Morigi and Dr. M. Noris), for studies regarding new molecular mechanisms
involved in the haemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic
purpura (TTP). We are using SPR to investigate whether new protein-protein
interactions may contribute to the link between thrombosis and complement cascade
activation.
The laboratory is a partner in a multicentre project entitled “Miniaturized System for
Molecular Diagnostic and Proteomic of Sepsis Based on Integration of Surface Plasmon
Resonance”, aiming at identifying new biomarkers of sepsis and exploiting new SPR
systems as low cost and rapid diagnostic tools. Our laboratory is in charge of the
identification and validation of suitable biomarkers, measuring them in plasma with our
conventional SPR system.
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Laboratory of Molecular Pathology
In vitro models for investigating motor neuron pathologies
Mutant forms of specific proteins play a key role in many neurodegenerative diseases.
Experimental models in vivo and in vitro are sorely needed to study the effects of these
toxic proteins. The motor neuronal cell line NSC-34, a widely used model to study
motor neuron degeneration, is available in the laboratory. We have applied the pTet-Off
system to control gene expression through the level of tetracyclines to the NSC-34 cell
line establishing a new cell line (NSC-34 tTA40) that stably expresses the
transactivating protein tTA. This cell line is suitable to study the pathogenic
mechanisms of motor neuron diseases after transient/stable transfection with genes of
interest for these pathologies.
The NSC-34 and the NSC-34 tTA40 cell lines were used to obtain in vitro models to
study the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). Mutant forms
of superoxide dismutase 1 are responsible for some of the familial forms of ALS. We
developed NSC-34-based cell lines expressing constitutively or conditionally human
G93A mutant superoxide dismutase 1 (G93ASOD1).
Novel intracellular targets in the selective degeneration of motor neurons
in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disease
characterized by loss of motor neurons. The management of this disease remains
essentially supportive and symptomatic. Understanding the mechanisms underlying the
disease is a way to favor more efficient therapeutic strategies. We utilized our cell
models to investigate the biochemical-molecular mechanisms underlying the alterations
of mitochondrial morphology observed in the early stages of the disease in the motor
nerve terminals of ALS patients and in the murine models of the disease. We showed
that motor neurons are selectively susceptible to mitochondrial damage induced by a
mutant form of human superoxide dismutase 1 (G93ASOD1) and that this damage was
modulated by the extent of expression of the mutant protein.
Furthermore the expression of G93ASOD1 protein increased the susceptibility of motor
neurons to inhibitors of the electron transport chain (ETC) and to oxidants. Exposure to
drugs or exogenous compounds impairing the ETC could thus be a risk factor to motor
neurons of individuals carrying mutant superoxide dismutase 1.
We have shown that in motor neuronal cells the activity of glutamate cysteine ligase,
the rate limiting enzyme for the synthesis of glutathione, the main cellular antioxidant,
was modulated by the level of G93ASOD1. A higher expression level of mutant SOD1
produces a decrease of glutathione level. This effect is associated to a lower level of
glutamate, an amino acid which is a precursor of glutathione and a neurotransmitter.
Furthermore the glutamine/glutamate mitochondrial metabolism is impaired and this
evidentiates a new aspect of mitochondrial damage due to mutant SOD1.
A variation in the level of glutathione may influence the formation of nitrated proteins,
a pathogenic mechanism in ALS, which was investigated in collaboration with the
laboratory of Translational Proteomics.
Cytochrome P-450 superfamily
Cytochrome(s) P-450 have evolved into a large superfamily which plays a major role in
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the metabolism of drugs and other chemicals. The majority of existing drugs depends on
the P-450 system for terminating their biological effects or for side effects or adverse
reaction. The laboratory has a long-standing interest in the induction/degradation
mechanisms of specific cytochrome P-450 families due to drug administration or to
disease states.
Activation of enzymes of the heme metabolic pathway (heme oxygenase
system, biliverdin reductase) as a protective response to stress
The enzymatic system of heme oxygenase (HO) is devoted to cellular degradation of
heme containing molecules, like cytochromes and hemoglobin, and to recycling of iron.
Products formed by the catalytic activity of HO - carbon monoxide and bile pigments are important regulating factors in the cell. An increase of HO activity (which is usually
sustained by activation of the inducible form HO-1) is now considered a protective
mechanism against untoward stimuli particularly when oxidative stress is involved. In
the past, the laboratory of Molecular Pathology identified cytokines as inducers of HO
activity and as transcriptional activators of the HO-1 gene. We are currently
investigating the functional significance of HO-1 activation in neurodegeneration.
Laboratory of Translational Proteomics
Identification of protein biomarkers of ALS in peripheral blood
mononuclear cells (PBMC) of patients and a rat model.
A biomarker is a molecule that underlines the physiological or pathological state of an
organism. A disease biomarker is potentially an important tool in clinical studies
because it can support prompt diagnosis, monitor disease progression and help to
evaluate the efficacy of any new therapy. Proteins, the most desirable biomarkers, can
help in identifying the molecular mechanisms at the basis of the disease and therefore
support research in developing new and more effective therapeutic approaches.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor
neurons, the cells that control movement. Generally there is a progressive loss of the
ability to control voluntary movement up to respiratory muscle paralysis and death. To
date for ALS there is no effective therapy. Moreover, there is no test or procedure to
ultimately establish the diagnosis of ALS. It is through a clinical examination and series
of diagnostic tests, often ruling out other diseases that mimic ALS, that a diagnosis can
be established. Therefore it would be important to identify validated biomarkers, i.e.
biomarkers verified in a large population of patients and controls. The search of
biomarkers for neurodegenerative diseases such as ALS it has been focusing principally
in the cerebrospinal fluid (CSF). CSF, the fluid that surrounds the central nervous
system and reflect its metabolic changes, is considered the source of excellence for
biomarker discovery in neurological diseases. Unfortunately, although the
advancements in the analysis of proteins (proteomics), the analysis of CSF is still
complex. Moreover, the withdrawal of CSF is highly invasive and not easily feasible in
large-scale validation or longitudinal studies.
In collaboration with the Laboratory of Molecular Neurobiology and the Laboratory of
Methodology for the Biomedical Research at the Mario Negri Institute, “Fondazione
Salvatore Maugeri”, IRCCS, Milano, and NEuroMuscular Omnicentre (NEMO),
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Niguarda Ca’ Granda Hospital, Milano we are conducting a series of studies with the
aim to identify biomarkers of ALS.
We look for biomarkers in peripheral blood mononuclear cells (PBMC), i.e.
lymphocytes and monocytes, easily isolated from peripheral blood and easily analyzed
by proteomics if compared with CSF. The rationale for this analysis is that ALS is now
recognized as extending beyond motor neurons, so it can be regarded as a multicellular/multi-systemic disease. In particular, PBMC display traits of the disease such as
down-regulation of Bcl-2, increased nitrative stress, intracellular calcium dysregulation
and glutamatergic dysfunction, suggesting that they can be a useful source of disease
biomarkers. By a two-dimensional difference in gel electrophoresis approach we
identified a panel of protein biomarkers in PBMC that are closely associated with ALS,
such as chloride intracellular channel protein 1 (CLIC1), heterogeneous nuclear
ribonucleoprotein A2/B1 (ROA2), and tyrosine nitrated actin that can distinguish with a
high discriminatory power ALS patients from healthy controls, interleukin-1 receptorassociated kinase 4 (IRAK4) and cyclophilin A (CypA) that can distinguish with a high
discriminatory power ALS patients from other neurological disorders. We demonstrated
also that CypA, protein disulfide isomerase A3 e TDP-43 associate with disease
progression in a longitudinal study. Translational biomarkers, that link responses
between human and animal model, are of particular interest because their role in the
pathogenesis can be investigated in detail in the animal model where they can also offer
important preliminary information for clinical trials. We found that CypA, CLIC1,
tyrosine nitrated actin, glutathione S-transferase omega-1 and far upstream elementbinding protein 1 are translational biomarkers since they are similarly regulated in ALS
patients and in a rat model of ALS already at a presymptomatic stage of the disease,
suggesting a possible involvement in pathways that trigger the disease. Further
mechanistic studies in the animal models with these proteins are now warranted. We are
planning to validate such PBMC candidate biomarkers in a large population of patients
and controls by immunochemical methods.
Laboratory for the Study of Biological Systems
System-level analysis of protein interactions in the epithelial junctional
complex
Inter-cellular junctions form the apical junctional complex and mediate adhesion
between adjacent cells, thus representing the cellular basis for tissue cohesion (for
instance, the epithelial lining of the intestine). In order to acquire system-level
understanding of the apical junctional complex, we have studied (using a
methodological approach of ‘network analysis’) all the protein interactions that have
been described at the junctions in epithelial cells of human origin. We also found that
proper ‘hubs’ (i.e., very rare proteins with an exceedingly high number of interactions
with other proteins) were absent from the junctional network. Nevertheless, we
observed that the most connected (albeit non-hub) proteins were also essential proteins.
In addition, we have detected modules within the junctional networks (i.e., densely
inter-connected groups of proteins). Analysis of the modules has highlighted general
organizing principles of the junctional complex, thus confirming the usefulness of
network analysis for studying the components and the interactions of the cell.
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DEPARTMENT OF EPIDEMIOLOGY
STAFF
Head
Carlo LA VECCHIA, M.D.
Laboratory of General Epidemiology
Head
Carlo LA VECCHIA, M.D.
Cancer Epidemiology Unit
Head
Cristina BOSETTI, Mat.Sci.D.
Lifestyle Habits and Prevention Unit
Head
Liliane CHATENOUD, Biol.Sci.D.
Epidemiology for Clinical Research Unit
Head
Silvano GALLUS, Comp.Sci.D.
Analytic Epidemiology Unit
Head
Claudio PELUCCHI, Stat.Sci.D.
Laboratory of Epidemiological Methods
Head
Eva NEGRI, Mat.Sci.D.
Laboratory of Epidemiology of Chronic Diseases
Head
Alessandra TAVANI, Biol.Sci.D.
Laboratory of Medical Informatics
Head
Eugenio SANTORO, Comp.Sci.D.
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CURRICULA VITAE
Carlo La Vecchia received his medical degree from the University of Milan and a Master of Science
degree in Clinical Epidemiology from Oxford University. He is recognized worldwide as a leading
authority in cancer etiology and epidemiology.
Work experiences: Presently, he is Chief of Epidemiology at the Mario Negri Institute in Milan, Italy and
Professor of Epidemiology at the School of Medicine at the University of Milan. Dr. La Vecchia serves as
an editor for numerous clinical and epidemiologic journals. He is among the most renowned and
productive epidemiologists in the field with over 1,690 peer-reviewed papers in the literature and he is
among the most highly cited medical researchers in the world, according to ISIHighlyCited.comsm, the
developer and publisher of the Science Citation Index (H-index 105). Dr. La Vecchia is an Adjunct
Professor of Medicine at Vanderbilt Medical Center and the Vanderbilt-Ingram Cancer Center and of
Epidemiology at the University of Lausanne, CH.
Dr. La Vecchia is a temporary advisor at the International Agency for Research on Cancer IARC/WHO
and at the World Health Organization in Geneva, and a registered journalist in Milan. He was Adjunct
Associate Professor of Epidemiology at Harvard School of Public Health between 1996 and 2001.
Areas of interest: Dr. La Vecchia’s main fields of interest include cancer epidemiology and the risk
related to diet, tobacco, oral contraceptive use and occupational or environmental exposure to toxic
substances; and analysis of temporal trends and geographical distribution of mortality from cancer,
cardiovascular diseases, perinatal and other selected conditions.
Eva Negri got a degree in Mathematics in 1985 at the University of Milan, School of Mathematics.
Work experiences: Since 2007: Laboratory Chief, Unit of Epidemiologic Methods, Department of
Epidemiology; 1992-2006: Unit Chief, Unit of Epidemiologic Methods, Laboratory Epidemiology; since
1990-1992: Researcher at the Laboratory of Epidemiology; 1984-1990: Collaborator of the Laboratory of
Epidemiology.
Areas of interest: Design, conduction and analysis of epidemiologic studies on chronic diseases (e.g.
cancer and myocardial infarction) and injuries, analysis of mortality of cohorts of workers, analysis of
temporal trends and geographic distribution of mortality from cancer, cardiovascular disease, injuries and
other selected conditions, analysis of national health surveys, application of linear modeling techniques to
the analysis of epidemiological data, collaborative re-analyses and meta-analyses of epidemiological
studies.
Awards: EEC scholarship for postgraduate training in Epidemiology (1988).
Selected publications

Bagnardi V, Rota M, Botteri E, Scotti L, Jenab M, Bellocco R, Tramacere I, Pelucchi C, Negri E, La Vecchia C, Corrao
G, Boffetta P. Alcohol consumption and lung cancer risk in never smokers: a meta-analysis. Ann Oncol. 2011;22:2631-9.

Negri E, La Vecchia C, Pelucchi C, Tavani A The risk of acute myocardial infarction after stopping drinking Prev Med
2005; 40: 725-728

Negri E, Pelucchi C, Talamini R, Montella M, Gallus S, Bosetti C, Franceschi S, La Vecchia C Family history of cancer
and the risk of prostate cancer and benign prostatic hyperplasia Int J Cancer 2005; 114: 648-652

Negri E, Little D, Boiocchi M, La Vecchia C, Franceschi S. B-cell non-Hodgkin’s lymphoma and hepatitis C virus
infection: A systematic review Int J Cancer 2004; 111: 1-8

Negri E, Ron E, Franceschi S, La Vecchia C, Preston-Martin S, Kolonel L, et al. Risk factors for medullary thyroid
carcinoma: A pooled analysis Cancer Causes Control 2002; 13: 365-372

Levi F, La Vecchia C, Boyle P, Lucchini F, Negri E Western and eastern European trends in testicular cancer mortality
Lancet 2001; 357: 1853-1854
Alessandra Tavani - degree in Biological Sciences, University of Milan, Italy (July 1977);
Pharmacological Research Specialist, “Mario Negri”Institute for Pharmacological Research, Milan, Italy
(July 1979).
Work experiences: 1979-81: Researcher at the laboratory of Drug Metabolism, “Mario Negri”Institute
for Pharmacological Research. 1981: Researcher at the Unit for Research on Addictive Drugs (director
prof. H.W. Kosterlitz), University of Aberdeen, Scotland, U.K. 1982-1990: Head of the Unit of Opioid
Neuropharmacology, “Mario Negri”Institute for Pharmacological Research. 1990: Researcher at the
Unit of Clinical Perinatal Pharmacology, “Mario Negri”Institute for Pharmacological Research. From
1991-2006: Head of the Unit of Epidemiology of Chronic Diseases of the Laboratory of Epidemiology,
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“Mario Negri”Institute for Pharmacological Research. 2007-: Head of the Laboratory of Epidemiology
of Chronic Diseases of the Department of Epidemiology, “Mario Negri”Institute for Pharmacological
Research.
Areas of interest: Epidemiology of cancer and coronary heart disease. Organization of case-control
studies and cohort studies on cancer and coronary heart disease, including biological sample collection.
Analyses of risk factors related to genetic factors and lifestyles, particularly coffee, diet, physical activity.
Awards: “Rafaelsen Scholar Award”from the Collegium Internationale Neuro-Psychopharmacologicum
(CINP), 16th Meeting, Munich (F.R.G.), 1988.
Selected publications
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Tavani A, Malerba S, Pelucchi C, Dal Maso L, Zucchetto A, Serraino D, Levi F, Montella M, Franceschi S, Zambon A,
La Vecchia C. Dietary folates and cancer risk in a network of case-control studies. Ann Oncol 2012; 23: 2737-2742
Tavani A, Rosato V, Di Palma F , Bosetti C, Talamini R, Dal Maso L, Zucchetto A, Levi F, Montella M, Negri E,
Franceschi S, La Vecchia C. History of cholelithiasis and cancer risk in a network of case-control studies. Ann
Oncol 2012; 23: 2173–2178
Galeone C, Tavani A, Pelucchi C, Turati F, Winn D M, Levi F, Yu G - P, Morgenstern H, Kelsey K, Dal Maso L, Purdue
M, McClean M, Talamini R, Hayes R B, Franceschi S, Schantz S, Zhang Z F, Ferro G, Chuang S - C, Boffetta P, La
Vecchia C, Hashibe M. Coffee and tea intake and risk of head and neck cancer: pooled analysis in the international head
and neck cancer epidemiology consortium. Cancer Epidemiol Biomarkers Prev 2010; 19: 1723-1736
Turati F, Galeone F, Edefonti V, Ferraroni M, Lagiou P, La Vecchia C, Tavani A. A meta-analysis of coffee
consumption and pancreatic cancer. Ann Oncol 2012; 23: 311–318
Turati F, Galeone C, La Vecchia C, Garavello W, Tavani A. Coffee and cancers of the upper digestive and respiratory
tracts: meta-analyses of observational studies. Ann Oncol 2011; 22: 536-544
Dal Maso L, Tavani A, Zucchetto A, Montella M, Ferraroni M, Negri E, Polesel J, Decarli A, Talamini R, La Vecchia C,
Franceschi S. Anthropometric measures at different ages and endometrial cancer risk. Br J Cancer 2011; 104: 1207-1213
Eugenio Santoro got his degree in Computer Science in 1990 at the Milan University. He started to
work at the “Mario Negri”Institute in 1985 as a research fellow. He was Head of the Applied Statistics
and Informatics Unit and of the Applied Statistics and Informatics laboratory, which was part of the
Department of Cardiovascular Research. Since 2001 he is Head of the Laboratory of Medical
Informatics that is currently part of the Department of Epidemiology. His main areas of interest have
been biostatistics and clinical informatics with the development of software for data management and
data analyses of large scale clinical trials in cardiology, such as the GISSI studies (Gruppo Italiano per
lo Studio della Sopravvivenza nell’Infarto miocardico). His main current area of interest is the Internet,
and more recently the web 2.0, the social media, and their application in the medical field, in clinical
research, and in medical education through the development of health related websites. He is author or
co-author of more than 200 scientific papers published in peer reviewed journals, and of more than 70
scientific abstracts submitted to the main international meetings in the cardiology and in the computer
science fields. He is also author of three books (available in Italian) about the use of the Internet in
medicine (“Web 2.0 and medicine”, “Guida alla medicina in rete”and “Internet in medicina. Guida
all’uso e applicazioni pratiche”, published by the Pensiero Scientifico Editore, Rome) and of one section
about Internet and medicine, included in one of the most important italian medical encyclopedia
(“Enciclopedia Medica Italiana”, UTET 2007). He also collaborates to the publication of the Italian
National Bioethics Committee’s guidelines about ethics, health, and the new information technologies.
Selected publications

Santoro E. "Web 2.0 e social media in medicina: come social network, wiki e blog trasformano la comunicazione,
l’assistenza e la formazione in sanità. 2° edizione. Il Pensiero Scientifco Editore, Roma 2011

Santoro E. “Facebook, Twitter e la medicina”,. Il Pensiero Scientifco Editore, Roma 2011

Santoro E., Tinazzi A.“Clinical Trials Data Management”. In “Clinical Trials Handbook” (Wiley 2009, Edited by Gad
S.C.).

Santoro E, Rossi Valentina, Pandolfini C, Bonati M. DEC-NET: The development of the European register of clinical
trials on medicines for children. Clin Trials 2006; 3: 366-375

Clivio L, Tinazzi A, Mangano S, Santoro E. The contribution of information technology: Towards a better clinical data
management. Drug Dev Res 2006; 67: 245-250

Santoro E. Internet and information on breast cancer: an overview. Breast 2003; 12: 424-431

Santoro E, Nicolis E, Franzosi M G, Tognoni G. Internet for clinical trials: Past, present, and future. Control Clin
Trials 1999; 20: 194-201
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Franzosi M G, Santoro E, Zuanetti G, Latini R, Maggioni A P, Tognoni G, GISSI. Indications for ACE inhibitors in
the early treatment of acute myocardial infarction. Systematic overview of individual data from 100.000 patients in
randomized trial. Circulation 1998; 97: 2202-2212
Cristina Bosetti got her degree in Mathematics in 1994 at the University of Milan, School of
Mathematics, and the Post-Graduate Diploma in Pharmacological Research in 1999 at the “Mario
Negri”Institute for Pharmacological Research in Milan.
Work experiences: She is Head of the Unit of Cancer Epidemiology, Department of Epidemiology,
Istituto di Ricerche Farmacologiche “Mario Negri”, Milan since 2005. Previous work experiences
include: Visiting scientist at “Life style and cancer group”of the International Agency for Research on
Cancer (IARC), Lyon, France (Oct 2009); Collaboration with the “International Epidemiology Institute”,
Rockville, MD, USA (2002-2009); Visiting scientist at the Unit of “Field and intervention studies”,
IARC, Lyon, France (Sept. 2000/June 2001); Visiting scientist at the Department of Epidemiology,
Harvard School of Public Health, Boston, MA (Sept-Nov 1998); Researcher at the Laboratory of
Epidemiology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan (1998-2005); Researcher at the
Laboratory of Mother and Child Health, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan
(1996-1997).
Areas of interest: Epidemiology of cancer, cardiovascular diseases and other chronic conditions. In
particular case-control studies on cancers of the upper respiratory and digestive sites, thyroid, breast,
hormone-related cancers, and on ischemic heart disease; analysis of risk related to diet, alcohol, tobacco,
reproductive and hormonal factors, occupational and environmental exposure to toxic substances, through
the application of generalized linear models; meta-analysis and systematic reviews of the epidemiologic
evidence on cancer risk in relation to various (environmental) exposures.
She authored/coauthored about 250 publications on peer-reviewed scientific Journals cited in
PubMed/MEDLINE. Mean Impact Factor: 4.3. H-index: 38 (Web of Knowledge).
Selected publications:

Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C. Aspirin and cancer risk: a quantitative review to 2011. Ann
Oncol. 2012 Jun;23(6):1403-15.

Bosetti C, Scelo G, Chuang SC, Tonita JM, Tamaro S, Jonasson JG, Kliewer EV, Hemminki K, Weiderpass E, Pukkala
E, Tracey E, Olsen JH, Pompe-Kirn V, Brewster DH, Martos C, Chia KS, Brennan P, Hashibe M, Levi F, La Vecchia C,
Boffetta P. High constant incidence rates of second primary cancers of the head and neck: a pooled analysis of 13 cancer
registries. Int J Cancer. 2011 Jul 1;129(1):173-9.

Bosetti C, Bertuccio P, Chatenoud L, Negri E, Levi F, La Vecchia C. Childhood cancer mortality in Europe, 1970-2007.
Eur J Cancer. 2010;46:384-94.

Bosetti C, Gallus S, Peto R, Negri E, Talamini R, Tavani A, Franceschi S, La Vecchia C. Tobacco Smoking, Smoking
Cessation, and Cumulative Risk of Upper Aerodigestive Tract Cancers.Am J Epidemiol. 2007; 167:468-73.

Bosetti C, Malvezzi M, Chatenoud L, Negri E, Levi F, La Vecchia C. Trends in cancer mortality in the Americas, 19702000. Ann Oncol 2005; 16: 489-511.

Bosetti C, Spertini L, Parpinel M T, Gnagnarella P, Lagiou P, Negri E, et al. Flavonoids and breast cancer risk in Italy.
Cancer Epidemiol Biomarkers Prev 2005; 14: 805-808.

Smith J S, Herrero R, Bosetti C, Munoz N, Bosch F X, Eluf-Neto J, et al. IARC Multicentric Cervical Cancer Study
Group Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl
Cancer Inst 2002; 94: 1604-1613.
Liliane Chatenoud Doctor in Science Biology, University of Milan (1987); Postgraduate Doctor in
Health Statistics University of Milan (1995). Ph.D. in Natural and Environmental Sciences, University of
Milan (2012).
Work experiences: Since Sept. 2005: Unit Head, “Lifestyle and Prevention”, 1991-2005: Researcher at
the Laboratory of Epidemiology; 1991-1993 contract-Researcher at the “Medicina del Lavoro Institute”
University of Milan, Italy, 1988-1990: Staff Statistician Bracco S.p.A., Milan.
Areas of interest: Epidemiological studies on obstetric diseases. Dermato-epidemiology. Cancer
epidemiology (case-control studies on cancers of the breast, female genital tract). Analysis of temporal
trends and geographical distribution of perinatal, infant mortality, cancer and other selected conditions
(over 150 publications on these topics, 1993-2005).
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Areas of interest: Dermatoepidemiologia, cancer epidemiology (case-control studies). Analysis
of temporal trends and geographical distribution of perinatal mortality, cancer and other
conditions.
Author / co-author of over 140 publications in peer-reviewed scientific journals listed in PubMed /
MEDLINE. I.F. average: 2.9, excluding letters to the editor in journals with IF> 16: average IF = 2.4. Hindex: 30 (Google Scholar or SCOPUS).
From 2007 to 2009, member of the Ethics Committee of the "Azienda ospedaliera Valtellina and
Valchiavenna"
Selected publications





Chatenoud L, Bertuccio P, Bosetti C, Rodriguez T, Levi F, Negri E, La Vecchia C Hodgkin lymphoma mortality in the
Americas, 1997-2008: Achievements and persistent inadequacies Int J Cancer 2013.
Pelucchi C, Chatenoud L, Turati F, Galeone C, Moja L, Bach J - F, La Vecchia C Probiotics supplementation during
pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology 2012; 23: 402-414.
Chatenoud L, Bertuccio P, Bosetti C, Levi F, Negri E, La Vecchia C. Childhood cancer mortality in America, Asia, and
Oceania, 1970 through 2007. Cancer. 2010;116:5063-74.
Chatenoud L, Malvezzi M, Pitrelli A, La Vecchia C, Bamfi F. Asthma mortality and long-acting beta2-agonists in five
major European countries, 1994-2004. J Asthma 2009 46: 546-551
Chatenoud L, Mosconi P, Malvezzi M, Colombo P, La Vecchia C, Apolone G. Impact of a major thermoelectric plant on
self-perceived health status. Prev Med. 2005;41:328-33.
Silvano Gallus was born in Milan on the 20th of November 1970, and got his degree in Computer
Science in 1999 at the University of Milan.
Work experiences: Chief of the Unit of Epidemiology for Clinical Research of the Department of
Epidemiology (since 2006); computer analyst, graphic designer, and statistical and epidemiological
consultant, Milan and Bergamo (since 2002); researcher at the Laboratory of Epidemiology (since 1997);
creator, designer and webmaster of the website of one of a major Italian public hospital, Milan (19992002).
Areas of interest: Monitoring of prevalence and trends of smoking habit and obesity in Italy and Europe.
Design, data managing, and statistical analyses of case-control studies on the associations between several
risk factors (including in particular tobacco smoking, alcohol drinking and Mediterranean diet) and risk of
cancer, coronary heart disease and several other conditions. Analyses of occupational cohort studies.
Since 2008, Dr Gallus is Associate Editor (Deputy Section Editor in 2010-2012) of the journal BMC
Public Health, and is member of the editorial board of the following journals: The Open Obesity Journal
(since 2008), The Open Demography Journal (since 2009), World Journal of Gastrointestinal Oncology
(since 2009), World Journal of Dermatology (since 2010).
He is referee for several journals, including BMJ, JAMA, JNCI and Tobacco Control.
In 2012 he received the European Research Advisory Board (ERAB) Publications Award.
He authored/coauthored more than 185 publications on peer-reviewed scientific Journals cited in
PubMed/MEDLINE. H-index: 30 (Web of Knowledge).
Selected publications

Joossens L, Lugo A, La Vecchia C, Gilmore AB, Clancy L, Gallus S. Illicit cigarettes and hand-rolled tobacco in 18
European countries: a cross-sectional survey. Tob Control. 2012 Dec 10. [Epub ahead of print].

La Vecchia C, Gallus S, Garattini S. Effects of physical inactivity on non-communicable diseases. Lancet.
2012;380:1553.

Gallus S, Muttarak R, Martínez-Sánchez JM, Zuccaro P, Colombo P, La Vecchia C. Smoking prevalence and smoking
attributable mortality in Italy, 2010. Prev Med. 2011;52:434-8.

Gallus S, Tramacere I, Boffetta P, Fernandez E, Rossi S, Zuccaro P, Colombo P, La Vecchia C. Temporal changes of
under-reporting of cigarette consumption in population-based studies. Tob Control. 2011 Jan;20(1):34-9.

Gallus S, Naldi L, Carli P, La Vecchia C; Italian Group for Epidemiologic Research in Dermatology (GISED). Nevus
count on specific anatomic sites as a predictor of total body count: a survey of 3,406 children from Italy. Am J
Epidemiol. 2007;166:472-8.

Clifford GM, Gallus S, Herrero R, Muñoz N, Snijders PJ, Vaccarella S, Anh PT, Ferreccio C, Hieu NT, Matos E,
Molano M, Rajkumar R, Ronco G, de Sanjosé S, Shin HR, Sukvirach S, Thomas JO, Tunsakul S, Meijer CJ, Franceschi
S; IARC HPV Prevalence Surveys Study Group. Worldwide distribution of human papillomavirus types in cytologically
normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet.
2005;366:991-8.
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Claudio Pelucchi got his degree in Statistical Science at the University of Milan-Bicocca, Italy, in 2003.
Work experiences: Head of Unit of Analytic Epidemiology, Department of Epidemiology, “Mario
Negri”Institute for Pharmacological Research (since 2011); Researcher at the Department of
Epidemiology (2007-2010); Collaborator of the Laboratory of Epidemiology (1999-2006). Other work
experiences: collaborations with the Institute of Pediatrics of the University of Milan, Italy (since 2006);
with the Department of Traumatology, Orthopaedics and Industrial Medicine of the University of Turin,
Italy (since 2003); with the International Prevention Research Institute, Lyon, France (2010-2011); with
the European Society of Clinical Microbiology and Infectious Diseases (2009-2010).
Areas of interest: Case-control and occupational cohort studies on risk factors for cancer and other
chronic diseases. Meta-analysis of observational studies and of clinical trials. Analysis of the clinical and
socio-economic impact of influenza and other infections in the pediatric age. Author/co-author of over
130 publications in international scientific journals. H-index: 24 (SCOPUS); 29 (Google Scholar).
Selected publications

Pelucchi C, Chatenoud L, Turati F, Galeone C, Moja L, Bach JF, La Vecchia C. Probiotics supplementation during
pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology 2012;23:402-14.

Pelucchi C, La Vecchia C, Bosetti C, Boyle P, Boffetta P. Exposure to acrylamide and human cancer-a review and metaanalysis of epidemiologic studies. Ann Oncol 2011; 22:1487-1499.

Pelucchi C, Negri E, Talamini R, Levi F, Giacosa A, Crispo A, Bidoli E, Montella M, Franceschi S, La Vecchia C.
Metabolic syndrome is associated with colorectal cancer in men. Eur J Cancer 2010; 46:1866-1872.

Esposito S, Bosis S, Pelucchi C, Begliatti E, Rognoni A, Bellasio M, Tel F, Consolo S, Principi N. Pediatrician
knowledge and attitudes regarding human papillomavirus disease and its prevention. Vaccine. 2007; 25:6437-6446.

Pira E, Pelucchi C, Buffoni L, Palmas A, Turbiglio M, Negri E, Piolatto P G, La Vecchia C. Cancer mortality in a cohort
of asbestos textile workers. Br J Cancer 2005; 92:580-586.

Tavani A, Pelucchi C, Negri E, Bertuzzi M, La Vecchia C. n-3 polyunsaturated fatty acids, fish, and nonfatal acute
myocardial infarction. Circulation 2001; 104:2269-2272.
ACTIVITIES
The Department of Epidemiology is involved in the epidemiology of several common cancers
(including cancers of the breast, female genital tract, respiratory and digestive sites, prostate and
urinary organs, lymphoid malignancies, etc.) and of cardiovascular diseases, both through a
descriptive and an analytical approach. Among the activities of descriptive epidemiology are the
analysis of temporal trends and geographical distribution of mortality from cancer,
cardiovascular diseases, and other selected conditions, in Italy and Europe; the analysis of
trends in tobacco consumption in the Italian and European populations, and the corresponding
effects on incidence and mortality from lung and other tobacco-related neoplasms; the analysis
of trend of obesity prevalence in Italy. The analytic epidemiology activities include the
conduction and analysis of case-control studies, aimed at identifying and better quantifying the
association between genetic factors (family history), selected lifestyle habits (diet, tobacco,
alcohol, coffee, etc.), use of exogenous hormones and exposure to various substances and the
development of various forms of cancers and cardiovascular diseases. In particular, the
Department works on the analysis of dietary correlates of cancer and cardiovascular disease
risk; quantification of health effects of tobacco smoking, alcohol consumption, coffee drinking
and implications for prevention; epidemiological studies on the risk related to oral contraceptive
and hormone replacement therapy use; evaluation of the impact of screening in the early
diagnosis and prevention of cancer. Other activities include: the conduction of quantitative
reviews and meta-analysis of published data; the re-analysis of original data from
epidemiological studies of cancers of the oral cavity and pharynx, pancreas, thyroid, breast,
ovary, cervix and bladder; the analysis of historical cohort studies of occupational exposures to
aromatic amines, asbestos, herbicides and other known or potential carcinogens; the study of the
role of infections in the etiology of atopic diseases (“Hygiene hypothesis”); and the evaluation
and monitoring of human papillomavirus (HPV) in women at high risk of cervical cancer.
Moreover, the Department of Epidemiology collaborates in epidemiological and clinical studies
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in pediatrics and oncology with other Italian and European groups. Another Department’s
activity is related to the development of medical websites, the study of the quality of medical
information available on the Internet, and the training and research on issues related to medical
informatics and those concerning the use in the medical field of the Internet, the social media,
and the web 2.0 applications.
MAIN FINDINGS
The identification of dietary correlates of cancer risk in Mediterranean populations, with
emphasis on the role of carbohydrates and glycaemic load.
The indication that Mediterranean diet has favorable implications on body mass index, and that
prevalence of overweight has not been rising in Italy. Overweight and obesity are correlates of
diabetes and metabolic syndrome, which have been linked to the risk of several cancers,
including colorectal and liver cancer.
The robust quantification of the separate and combined effects of alcohol and tobacco in upper
aerodigestive tract carcinogenesis, and their interaction with diet or family history. The
Department has also had a leader role in tobacco control in Italy and has contributed to the
rationale for total tobacco ban in Italy in all public and private indoor spaces since January
2005.
We have further quantified the risk of cancer in relation with diabetes. Besides
confirming the association of diabetes with colorectum, endometrium, liver, pancreatic,
and post-menopausal breast cancer, our data suggest that cancers of the oral cavity,
pharynx and esophagus are also associated to type-2 diabetes. We also revised the
scientific evidence on cancer risk in relation to metformin sulfonylurea in diabetics, and
showed that metformin, but not sulfonylurea, appears to reduce subsequent cancer risk.
The characterization of several aspects of pharmacoepidemiology, including systematic reanalyses on the role of aspirin in the risk of selected cancer sites, and the role of oral
contraceptives in the etiology of cancers of the breast, female genital tract and liver. This
provided important information on the long-term impact of oral contraceptives on breast
carcinogenesis, quantified the risk on cervical and liver cancer, and the long-term protection on
ovarian, endometrial and (possibly) colorectal cancer.
The conduction of several meta-analyses aimed at quantifying the role of alcohol consumption
on cancer risk. In particular, we investigated consumption of low doses of alcohol in relation to
cancer, and we published a series of in-depth meta-analysis on the effect of alcohol on cancers
of the oral cavity and pharynx, esophagus (adenocarcinoma) and gastric cardia, stomach, lung,
ovary, kidney, bladder, brain, and lymphomas, considering the results for various anatomical
subsites and/or histological subtypes and examining potential sources of heterogeneity of
results.
Insightful explorations of cancer patterns in Europe and the world, including cancer mortality
predictions for the current year in the EU, and the documentation of a substantial fall in cancer
rates over the last two decades in Europe. This can be translated to avoidance of approximately
150,000 premature deaths annually, and of the gap in cancer management, in several areas of
central and eastern Europe.
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The characterization of aspects of occupational carcinogenesis, with specific reference to the
model of bladder carcinogenesis following exposure to aromatic amines, and the crucial role of
latency on asbestos carcinogenesis, and its implications on predicting the number of
mesothelioma deaths in Europe.
The meta-analysis on probiotics supplementation during pregnancy or infancy for the
prevention of atopic dermatitis provided evidence in support of a moderate role of probiotics in
the prevention of atopic dermatitis (about 20% of protection). The favorable effect was similar
regardless of the time of probiotic use (pregnancy or early life) or the subject(s) receiving
probiotics (mother, child, or both).
NATIONAL COLLABORATIONS
Associazione Italiana di Oncologia Medica (AIOM)
Associazione Medici Diabetologi – Regione Lombardia
Accademia Nazionale di Medicina, Genova
Agenzia giornalismo scientifico Zadig, Milano
Arcispedale S. Maria Nuova, Reggio Emilia
Associazione Nazionale dei Medici Cardiologi Ospedalieri (ANMCO)
Azienda Ospedaliera Niguarda Ca’ Granda, Milano
Azienda Ospedaliera San Gerardo, Monza
Azienda Ospedaliero-Universitaria San Giovanni Battista Le Molinette, Torino
Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Udine
Azienda Unità Sanitaria Locale di Ravenna
Centro Cardiologico Monzino, Milano
Centro Studi Comunicazione sul Farmaco, Milano
Centro di Riferimento Oncologico, Servizio di Epidemiologia e Biostatistica, Aviano (PN)
Comune di Milano, Direzione centrale salute, Settore politiche per la Salute
Federazione Italiana delle Associazioni di Volontariato in Oncologia (FAVO)
Federazione Italiana Medici di Medicina Generale – Provincia Milano
Festival Internazionale del Giornalismo, Perugia
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano
Fondazione LuVI
Fondazione Politecnico di Milano
Fondazione SmithKline, Milano
Gruppo Italiano per lo Studio della Sopravivenza nell’Infarto miocardico (GISSI)
Gruppo Italiano Studi Epidemiologici in Dermatologia GISED, Bergamo
Gruppo Italiano Documentalisti dell’Industria Farmaceutica e degli Istituti di Ricerca
Biomedica
Gruppo Studi Tumori Urologici (GSTU)
International Centre for Pesticides and Health Risk Prevention, Milano
Istituto Auxologico Italiano, Divisione Malattie Metaboliche III, IRCCS, Piancavallo (VB)
Istituto Auxologico Italiano, Laboratorio Sperimentale di Ricerche Endocrinologiche (LSRE),
IRCCS, Milano
Istituto DOXA, Milano
Istituto Europeo di Oncologia, Divisione di Epidemiologia e Biostatistica, Milano
Istituto Europeo di Oncologia, Divisione di Chirurgia Cervico Facciale, Milano
Istituto Europeo di Oncologia, Divisione Melanomi e Sarcomi Muscolo Cutanei
Istituto di Fisiologia Clinica CNR, Sezione di Milano, Milano
Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione (INRAN), Roma
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Istituto Nazionale Neurologico “Carlo Besta”, Milano
Istituto Nazionale per lo Studio e la Cura dei Tumori, Dipartimento di Chirurgia Toracica,
Oncologia
Istituto Nazionale per lo Studio e la Cura dei Tumori, Struttura Complessa di Chirurgia
Generale Indirizzo Oncologico 4 (Melanomi e Sarcomi) Sperimentale, Unità di Eredità
Poligenica, Milano
Istituto Oncologico Romagnolo
Istituto Ortopedico Gaetano Pini, Centro di Chirurgia Ortopedica Oncologica, Milano
Istituto Superiore di Sanità, Osservatorio Fumo Alcol Droga, Roma
Istituto Tumori “Fondazione Pascale”, Servizio di Epidemiologia, Napoli
Novartis Vaccines SpA, Siena
Ordine dei Medici della Provincia di Bari
Ospedale Casa Sollievo della Sofferenza San Giovanni Rotondo
Ospedali Riuniti di Bergamo
Ospedale Alessandro Manzoni, Unità di Gastroenterologia, Lecco (LC)
Ospedale “Luigi Sacco” Azienda Ospedaliera – Polo Universitario
Policlinico di Monza, Unità Operativa di Endoscopia I, Monza (MB)
Prima Clinica Ostetrico Ginecologica, Mangiagalli, Milano
Regione Lombardia, U.O. Governo dei servizi sanitari territoriali e politiche di appropriatezza e
controllo Scuola Internazionale Superiore di Studi Avanzati (SISSA)
Società Italiana Attività Regolatorie
Società Italiana di Cure Palliative (SICP)
Struttura Sistemi di remunerazione e Osservatorio Epidemiologico Direzione Generale Sanità
Unione Nazionale dei Giornalisti Scientifici Italiani
Università Bocconi di Milano, Dipartimento di Analisi Istituzionale e Management Pubblico,
Milano
Università Cattolica del Sacro Cuore, Unità di Epidemiologia genetica e Biologia Molecolare,
Istituto di Igiene, Roma
Università di Milano - Bicocca, Dipartimento di Statistica, Milano
Università di Milano-Bicocca, I Clinica Otorinolaringoiatria, DNTB, Monza
Università degli Studi di Milano, Dipartimento di Scienze Materne e Pediatriche, Milano
Università degli Studi di Milano, Dipartimento di Scienze Cliniche e di Comunità, Sezione di
Statistica Medica e Biometria, Milano
Università degli Studi di Milano, Prima Clinica Ostetrico Ginecologica, Milano
Università di Pavia, Azienda di Servizi alla Persona, Pavia
Università di Torino, Istituto di Medicina del Lavoro, CTO, Torino
Università di Verona, Clinica Ostetrico Ginecologica, Verona
INTERNATIONAL COLLABORATIONS
Aichi Cancer Center Research Institute, Division of Epidemiology and Prevention and Nagoya
University Graduate School of Medicine, Nagoya, Japan
Catalan Institute of Oncology, Institut d’Investigaciò Biomédica de Bellvitge (IDIBELL),
Cancer Prevention and Control Unit, L’Hospitalet de Llobregat, Spain
Center of Oncology, Dept. of Epidemiology and Cancer Prevention, Varsavia, Poland
Centre for Research in Environmental Epidemiology (CREAL) and Municipal Institute of
Medical Research (IMIM), Barcellona, Spain
European Public Health Association (EUPHA)
Evidence and Risk Assessment Division, Centre for Chronic Disease Prevention and Control,
Public Health Agency of Canada, Ottawa, Ontario, Canada
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Harvard School of Public Health, Department of Epidemiology, Boston, USA
Harvard School of Public Health, Department of Nutrition, Boston, USA
Hellenic Health Foundation
Hôpital Necker - Enfants Malades, Centre of the Association Claude Bernard on Auto-immunes
diseases, Parigi, France
Institute de Academie des Sciences, Paris, France
International Agency for Research on Cancer, Lione, France
International Epidemiology Institute (IEI), Rockville, USA
International Life Science Institute (ILSI), Bruxelles, Belgium
International Prevention Research Institute (IPRI), Lyon, France
Karolinska Institute, Department of Medical Epidemiology and Biostatistics, Stockholm,
Sweden
National Cancer Institute, Environmental Studies Section, Bethesda, USA
National School of Public Health, WHO, Atene, Greece
NUTRIM School for Nutrition, Toxicology and Metabolism, Department of Complex Genetics,
Cluster of Genetics and Cell Biology, Maastricht University Medical Centre, Maastricht, The
Netherlands.
Registre Vaudois des Tumeurs, Institut Universitaire de Médecine Sociale et Préventive,
Losanna, Svizzera
Senologic International Society
Society for Internet in Medicine
The Tisch Cancer Institute and Institute for Translational Epidemiology, Mount Sinai School of
Medicine, New York, NY, USA
Tobacco Free Research Institute, Dublino, Ireland
UNDP/UNFPA/WHO/WORLD Bank special programme of research development and research
training in human reproduction, Ginevra, Switzerland
Universitat Pompeu Fabra, Department of Experimental and Health Sciences, Barcellona, Spain
University of Athens Medical School, Department of Hygiene and Epidemiology, Atene,
Greece
University of Cordoba, Faculty of Medical Diseases, Cordoba, Argentina
University of Las Palmas de Gran Canaria, Department of Clinical Sciences, Las Palmas de
Gran Canaria, Spain
University of Porto, Faculty of Medicine, Department of Clinical Epidemiology, Preventive
Medicine and Public Health. Porto, Portugal
Vanderbilt University, Department of Medicine, School of Medicine, Nashville, TN, USA
EDITORIAL BOARD MEMBERSHIP
Advances in Therapy (Eva Negri)
Alimentazione e Prevenzione (Carlo La Vecchia)
Annals of Oncology (Carlo La Vecchia, Associate Editor)
Archives of Medical Science (Carlo La Vecchia)
BMC Public Health (Silvano Gallus, Associate Editor)
Cancer Epidemiol Biomark & Prev (Carlo La Vecchia)
Cancer Letter (Carlo La Vecchia, Associate Editor)
Current Cancer Therapy Reviews (Carlo La Vecchia)
Dermatology Research and Practice (Carlo La Vecchia)
Digestive and Liver Disease (Carlo La Vecchia)
Economia Politica del Farmaco (Carlo La Vecchia)
Epidemiology, Biostatistics and Public Health (Carlo La Vecchia, Editor)
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European Journal of Cancer Prevention (Carlo La Vecchia, Associate Editor)
European Journal of Clinical Nutrition (Carlo La Vecchia)
European Journal of Nutrition (Carlo La Vecchia)
Evidence Based Dermatology (Carlo La Vecchia, Liliane Chatenoud)
Family Planning (Carlo La Vecchia)
In Scope Oncology & Haematology (Carlo La Vecchia)
Journal of Family Planning and Reproductive Health Care (Carlo La Vecchia)
ISRN Cardiology (Eugenio Santoro)
Maturitas (Carlo La Vecchia)
Nutrition and Cancer (Carlo La Vecchia)
Open Cancer Journal (Carlo La Vecchia)
Oral Oncology (Carlo La Vecchia)
Portale Partecipasalute.it – http://www.partecipasalute.it (Eugenio Santoro)
Revisiones en Ginecologìa y Obstetricia (Carlo La Vecchia)
Revista Española de Nutriciò Comunitaria (Carlo La Vecchia)
Revue d’Epidémiologie et de Santé Publique (Carlo La Vecchia)
Società Italiana Attività Regolatorie News, SIARNews (Eugenio Santoro)
The Open Demography Journal (Silvano Gallus)
The Open Obesity Journal (Silvano Gallus)
The Scientific World Journal (Cristina Bosetti)
Tumori (Carlo La Vecchia)
World Journal of Dermatology (Silvano Gallus)
World Journal of Gastrointestinal Oncology (Silvano Gallus)
PEER REVIEW ACTIVITIES
Acta Dermato-Venereologica; Acta Psychiatrica Scandinavica; Acta Oto-Rhino-Laryngologica
Italica; Alcologia; American Journal of Clinical Nutrition; American Journal of Epidemiology;
Annals of Epidemiology; Annals of Oncology; Appetite; Archives of Internal Medicine; BMC
Public Health; British Journal of Cancer; British Journal of Nutrition; British Medical Journal;
BMJ Open; Bulletin of the World Health Organization; Canadian Journal of Physiology and
Pharmacology; Cancer; Cancer Causes and Control; Cancer Detection and Prevention; Cancer
Epidemiology Biomarkers and Prevention; Computer Methods and Programs in Biomedicine;
Diabetes/Metabolism Research and Reviews; Digestive and Liver Disease; Epidemiologia &
Prevenzione; Epidemiology; Epidemiology & Biostatistic; European Heart Journal; European
Journal of Cancer; European Journal of Cancer Prevention; European Journal of Clinical
Nutrition; European Journal of Epidemiology; European Journal of Public Health; EvidenceBased Healthcare and Public Health; Food and Chemical Toxicology; Gynecological
Endocrinology; Gut; Hearth; Hepatology; Human Reproduction; International Journal of
Cancer; International Journal of Environmental Research and Public Health; International
Journal of Epidemiology; International Journal of Food Sciences and Nutrition; International
Journal of Hygiene and Environmental Health; International Journal of Obesity; ISRN Public
Health; JAMA; Journal of American College of Nutrition; Journal of Clinical Endocrinology
and Metabolism; Journal of Clinical Epidemiology; Journal of Epidemiology and Community
Health; Journal of Investigative Dermatology; Journal of Medical Economics; Journal of
Medical Internet Research; Journal of the National Cancer Institute; Journal of Women's Health;
Lancet Oncology; Lung Cancer; Maturitas; Melanoma Research; Nature Reviews Urology;
Nicotine & Tobacco Research; Nutrition and Cancer; Nutrition Journal; Obstetrics and
Gynecology; Oncology; PLoS Medicine; PLoS ONE; Preventive Medicine; Public Health;
Public Health Nutrition; QJM; Radiation Research; Recent Patents on Anti-Cancer Drug
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Discovery; Appetite; Revue d’Epidèmiologie et de Santé Publique; The Breast; The Cancer
Journal; The Lancet; The Open Obesity Journal; The Scientific World Journal; Tobacco
Control; Tumori; World Journal of Gastroenterology.
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
Advisory Committee of the Oxford Collaborative group on Aetiological Factors in Cancers of
the Female Genital Tract
Comitato Scientifico del Gruppo Italiano Studi Epidemiologici in Dermatologia
Comitato Scientifico della Società Italiana di Colposcopia e Patologia Cervico Vaginale
Comitato Scientifico del portale www.familyhealth.it
Data and Safety Monitoring Board of the “Phase II therapeutic trial with a humanized
nonmitogenic CD3 (ChAgly CD3) monoclonal antibody in recently diagnosed type I diabetic
patients”
Executive Committee, International Head and Neck Cancer Epidemiology (INHANCE)
consortium
Ministero della Salute, Sottocomitato fumo
Giuria del Premio Nazionale Comunicazione, Marketing e Informazione per la Salute – Festival
Internazionale del Giornalismo
Scientific Review Committee del UND/WHO/World Bank Human Reproduction Programme
EVENT ORGANIZATION
Corso Internet, web 2.0 e social media al servizio della formazione e dell’aggiornamento del
medico e dell’operatore sanitario, organizzato in collaborazione con gli Ospedali Riuniti di
Bergamo, Bergamo 10, 15 e 29 may 2012
Corso ECM Corso introduttivo sull’impiego di PubMed , Istituto di Ricerche Farmacologiche
Mario Negri, Milano, 23 may 2012
Corso ECM Corso avanzato sull'impiego di PubMed e metodi di valutazione della ricerca
biomedica , Istituto di Ricerche Farmacologiche Mario Negri, Milano, 24 may 2012
Corso ECM Il web 2.0 per l’aggiornamento del medico e dell’operatore sanitario , Istituto di
Ricerche Farmacologiche Mario Negri, Milano, 5 june 2012
Corso ECM Facebook, Twitter, YouTube e i nuovi social media per l’aggiornamento medico ,
Istituto di Ricerche Farmacologiche Mario Negri, Milano, 6 june 2012
Corso Internet, web 2.0 e social media al servizio della formazione e dell’aggiornamento del
medico e dell’operatore sanitario: corso avanzato, organizzato in collaborazione con l’ASL di
Bergamo
Dipartimento Cure Primarie e Continuità Assistenziale, Bergamo 6 e18 september 2012, 3 e 18
october 2012
Corso ECM Corso introduttivo sull’impiego di PubMed , Istituto di Ricerche Farmacologiche
Mario Negri, Milano, 22 october 2012
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Corso ECM Corso avanzato sull'impiego di PubMed e metodi di valutazione della ricerca
biomedica , Istituto di Ricerche Farmacologiche Mario Negri, Milano, 23 october 2012
Corso ECM Internet per l’aggiornamento del medico e dell’operatore sanitario , Istituto di
Ricerche Farmacologiche Mario Negri, Milano, 24 october 2012
Corso ECM Il web 2.0 per l’aggiornamento del medico e dell’operatore sanitario , Istituto di
Ricerche Farmacologiche Mario Negri, Milano, 25 october 2012
Corso Internet, web 2.0 e social media al servizio della formazione e dell’aggiornamento del
medico e dell’operatore sanitario: corso avanzato promosso dalla Scuola Umbra di
Amministrazione Pubblica, Perugia 13-14 settembre, 4-5 october, 13-14 november 2012
CONFERENCE AND WORKSHOP CONTRIBUTIONS
Convegno Dolcificanti intensi non calorici: focus sulla sicurezza d’impiego. “Evidenze
epidemiologiche nel caso di dolcificanti intensi non calorici e tumori”. Roma, Italy. 11/1/2012
ECRIN – Integrating Activity Kick-off meeting. “Progetto ECRIN-IA WP7 transnational
access”. Bruxelles, Belgium. 19/1/2012
Ca’ Granda Lectures and Seminars in Molecular Medicine. Il Policlinico incontra il Mario
Negri. “Alcool e rischio di cancro”. Milano, Italy. 30/1/2012
Mediterranean School of Oncology (MSO). Second Primary Cancer and Cancer Syndromes.
Second primary cancer in head and neck cancer patients. Rome, January 27, 2012.
OPEN project: kick-off meeting. Freiburg, Germany. 2-3 February 2012
Workshop Centro Studi Ilva. “Terza conversazione su salute e inquinamento”. Taranto, Italy.
15/2/2012
Meeting. Diabetes experts summit. Parigi, France. 24/2/2012
15th World Conference on Tobacco or Health (WCTOH). “WP2: European survey on the
economic aspects of tobacco”. Singapore. 20-24 March 2012
PPACTE project: final PPACTE Project Board and ESAB meetings, Singapore, 22/3/2012
Congresso. Prevenire la malattia tumorale: il ruolo della diagnostica, del laboratorio biomedico
e della alimentazione. “Rischio di cancro ed alimentazione”. Napoli, Italy 27-28/4/2012
9th Annual INHANCE Meeting. “Allium vegetables”, “Esophageal SCC”. Milano, Italy.
2/5/2012
III Forum. Pianeta nutrizione. “Alimentazione, obesità e tumori”. Parma, Italy. 8/5/2012
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Master di II livello in epidemiologia e biostatistica 2012. “Bias e confounding. Validità –
esempio, dieta e cancro. Epidemiologia occupazionale – asbestos e mesotelioma. Dimezzare i
morti da fumo. Materiale e metodi in epidemiologia”. Roma, Italy. 10/5/2012
XIV Convegno nazionale tabagismo e servizio sanitario nazionale. “L’influenza dell’industria
del tabacco nell’attuazione della Convezione Quadro dell’OMS”. Roma, Italy 31/5/2012
ERS Summit on bridging the health divide in Europe. Exchanging experience to reduce
avoidable health inequalities and preventable respiratory diseases. “Health inequalities in
Europe- Cancer”. Tallin, Estonia, 8-9/6/2012
Convegno regionale per gli operatori del network del contrasto al tabagismo della regione
Toscana Le politiche sul prezzo in Europa: conclusioni dell’Handbook IARC sul prezzo;
Florence, Italy 14/6/2012
Congresso. Medicina di laboratorio: sostanze di abuso e doping. “Attitudine e prevalenza del
doping negli atleti italiani”. Roma 18/6/2012
Congresso internazionale. La responsabilità civile e penale da uso e produzione di amianto. “La
modellistica epidemiologica del mesotelioma e delle altre patologie neoplastiche da amianto”.
Milano, 27/6/2012
“X-Files in Nutrizione Clinica ed Artificiale. Oncologia e Nutrizione, dalla Prevenzione alla
Terapia”. Corso di aggiornamento. Centro Internazionale di Studi Fondazione Germana Gaslini
(CISEF). Dieta mediterranea e cancro. Genova, Badia Benedettina della Castagna, 7-8 giugno
2012
5th International Congress of Nutrition and Cancer. “Overweight, selected aspects of
Mediterranean diet and cancer”, Dietary glycemic index, glycemic load and cancer”. Elazig,
Turchia, 9-11/9/2012
Evaluation thesis Mette Kalagar. “The Norwegian breast cancer screening program effects on
incidence, prognosis and mortality of breast cancer”. Oslo, Norway. 25-26/9/2012
The Second Annual Interventional Oncology Society Meeting. The beautiful breast? Brussels,
Beglium. 29/9/2012
Meeting. Un nastro rosa contro il tumore al seno. Milano, Italy. 3/10/2012
Meeting IEO Educational. Alimentazione e tumori: dalla prevenziobne al support nutrizionale.
“Indice glicemico, carico glicemico e cancro”. Milano, Italy. 5/10/2012
5th International Consortium of Bladder Cancer Meeting. “Non-genetic determinants of Bladder
Cancer”. Madrid, Spain. 8-9/10/2012
European Master in Sustainable Regional Health Systems: Erasmus Mundus, in collaboration
with the University of Verona. Course: A cross-sectional survey in 18 European countries on
the economic aspects of smoking, Milan, Italy, 23/10/2012.
Colloques 2012. CHUV. University of Lausanne. “A meta-analysis of alcohol and cancer risk”.
Lausanne, Switzerland. 30/10/2012
ANNUAL REPORT
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NCRI cancer conference. “Aspirin and cancer risk: a meta-analysis to 2011”. Liverpool, UK. 47/11/2012
The international congress. The apple in the world. “The apple and its components in the
prevention of cancer”. Bolzano, Italy. 15-17/11/2012
II conferenza governativa sull’amianto e le patologie correlate: stato dell’arte e prospettive.
Fondazione Giorgio Cini, Isola di San Giorgio Maggiore. Venezia, Italy. 22–24/11/2012
European Cancer Concord meeting. Empowering equity and innovation in cancer care and
research for Europe’s Citizens. Amsterdam, The Netherlands. 24-25/11/2012
HRRH Workshop. “Epidemiology of phenobarbital- is the published evidence sufficient to
demonstrate the non-human relevance of PB in liver tumor formation?”. Bad Durkheim,
Germany. 28-30/11/2012
Women&Technologies: e-nutrition. Conferenza Internazionale. Camera di Commercio di
Milano. Round Table on Nutrition and Health. Milano, 6 novembre 2012
Seminario Internet, web 2.0 e social media al servizio del clinico, promosso da AUSL di
Rimini, Rimini 14 febbraio 2012
Master in giornalismo scientifico digitale, Scuola Internazionale Superiore di Studi Avanzati
(SISSA) di Trieste, anno accademico 2011-2012. Ruolo di docenze nel modulo Medicina,
Trieste 19 marzo, 2 aprile, 7 maggio, 21 maggio, 5 giugno 2012
Corso avanzato di formazione su metodologia, strategie e tecniche della ricerca clinica,
promosso dalla Associazione Nazionale Medici Cardiologi Ospedalieri, Firenze 21 marzo 2012
Convegno: La formazione continua in AOUD: dai primi 10 anni di esperienza verso le sfide del
futuro, Azienda Ospedaliera e Universitaria Santa Maria della Misericordia di Udine. Titolo
intervento: Oltre la formazione tradizionale: le metodologie didattiche e-learning. Udine 22
marzo 2012.
Corso: Il web 2.0 ed i social media al servizio della formazione e dell’aggiornamento dei
professionisti sanitari, Azienda Ospedaliera Universitaria Santa Maria della Misericordia,
Udine. 3-4 aprile 2012
Festival Internazionale del Giornalismo, convegno Comunicazione, marketing e informazione
per la salute, Perugia, 27 aprile 2012.
XXII Congresso Nazionale Associazione Chirurghi Ospedalieri Italiani (ACOI) Videochirugia,
Castelvoltruno 7-9 giugno 2012. Partecipazione alla tavola rotonda SMARTPHONE IN SALA
OPERATORIA: INNOVAZIONE TECNOLOGICA?
Corso: Internet, web 2.0 e social media al servizio della formazione e dell’aggiornamento del
medico e dell’operatore sanitario, presso Roche S.p.A. Monza 2-13 july 2012
Convegno: e.Government & e-Health, 9th International meeting, Desio 8-10 july 2012
ANNUAL REPORT
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Seminario: Il web 2.0 e i social media nell’aggiornamento del medico e dell’operatore sanitario,
Ospedale Maggiore di Bologna, Bologna, 3 september 2012
Corso: Il web 2.0 ed i social media al servizio della formazione e dell’aggiornamento dei
professionisti sanitari, seconda edizione, Azienda Ospedaliera Universitaria Santa Maria della
Misericordia, Udine 11 e 12 september 2012
Seminario: 20° edizione Incontri pediatrici di Villa Olmo 12. Titolo relazione: Twitter,
Facebook, Youtube come strumenti di aggiornamento, formazione e ricerca. Como. 20
september 2012.
Congresso: 1° Congresso Nazionale Unità e valore della chirurgia italiana. Roma 23-27
settembre 2012. Partecipazione a tavola rotonda dal titolo La privacy e la gestione dei dati
sensibili in chirurgia. La sfida del web, Roma 26 september 2012
Convegno Nazionale della Federazione Nazionale degli Ordini dei Medici Chirurghi e
Odontoiatri (FNOMCeO). Cybermedicine: l’integrazione delle tecnologie dell’informazione e
della comunicazione nei processi decisionali del sistema sanitario e nelle cure dei pazienti.
Titolo della relazione: Il ruolo e l’influenza della information and communication technology
sull’efficacia e sull’appropriatezza della cura. Padova 28-29 september 2012
Tavola rotonda nell’ambito della conferenza Trieste Next – Salone Europeo dell’Innovazione e
della Ricerca Scientifica, Trieste 28-30 settembre. Titolo della tavola rotonda: Aperta, gratuita e
collaborativa: la scienza tra innovazione digitale e intelligenza collettiva, Trieste 30 september
2012
XIX Congresso Nazionale Società Italiana di Cure Palliative (SICP), Torino 9-12 ottobre 2012.
Titolo relazioni: La ricerca bibliografica: strumenti e metodi nell’ambito della sessione Cercare,
leggere e valutare gli articoli scientifici e Pazienti, famigliari ed Internet nell’ambito della
sessione Il web nelle cure palliative, 10 october 2012
Corso: Il web 2.0 ed i social media al servizio della formazione e dell’aggiornamento del
medico e dell’operatore sanitario, Azienda USL di Imola, Imola 17 october 2012
Corso: Aggiornamento e formazione professionale tramite il web, Azienda Ospedaliera San
Gerardo di Monza, Monza 7 november 2012
Master Universitario di II° livello in Statistica Medica e Metodi Statistici per l’Epidemiologia,
Università degli Studi di Milano, Facoltà di Medicina e Chirurgia, anno accademico 2011-2012.
Ruolo di docenze nel modulo Internet e le nuove tecnologie per la ricerca clinica, Milano 19-22
november 2012
Master Universitario di I° livello in Ricerca Clinica, Università degli Studi di Milano, anno
accademico 2011-2012. Ruolo di docenze nel modulo Internet e le nuove tecnologie per
l’aggiornamento medico-scientifico, Milano 28 november 2012
Tavola rotonda organizzata dal Corriere della Sera dal titolo: Mamme (e papà) che navigano a
vista. Una nuova bussola con corriere.it/pediatria, Milano 26 november 2012
Convegno AIDS e malattie a trasmissione sessuale: da rischio virtuale a rischio reale, da
problema personale a problema globale, promosso in occasione della giornata mondiale contro
ANNUAL REPORT
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l’IADS dalla Commissione Interaziendale AIDS AUSL-Azienda Ospedaliero-Universitaria di
Ferrara, Ferrara 1 december 2012
Convegno AIOP Evolution 2.0. Il futuro della sanità e il ruolo dei social network, organizzato
dalla Associazione Italiana Ospedalità Privata (AIOP). Titolo della relazione: I social network
in campo medico, Roma 3 december 2012
Seminario Web 2.0 e medicina promosso da Unione Nazionale Medico Scientifica di
Informazione (UNAMSI), Assodigitale e Comunicatori Digitali Associati, Milano, Circolo della
stampa, 19 december 2012
53° Congresso della Società Italiana di Nefrologia. Titolo relazione: Web 2.0 e nefrologia: la
comunicazione nell'era dei social network, Milano 3-6 october 2012
GRANTS AND CONTRACTS
AIFA
Arcispedale Santa Maria Nuova, Azienda Ospedaliera di Reggio Emilia
Associazione Italiana Oncologia Medica
Associazione Italiana per la Ricerca sul Cancro (AIRC)
Azienda Ospedaliera San Gerardo di Monza
Centro Cardiologico Monzino
Lega Italiana Lotta contro i Tumori (LILT)
European Commission (FP7)
European Research Council (ERC)
Federazione Italiana Medici di Medicina Generale – Provincia Milano
Federazione Medico Sportiva Italiana – Regione Puglia
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Fondazione Politecnico di Milano
Fondazione Umberto Veronesi
GISED
Istituto Oncologico Romagnolo
Ministero della Salute
Ospedale “Luigi Sacco” Azienda Ospedaliera – Polo Universitario
Regione Lombardia
Weber Shandwich
Consorzio Assomela
ISA
Perfetti Van Melle
Provincia Autonoma di Bolzano
Roche S.p.A.
Regione Lombardia
Scuola Umbra di Amministrazione Pubblica
Unione Nazionale dei Giornalisti Scientifici Italiani
ANNUAL REPORT
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SCIENTIFIC PUBLICATIONS (2012)
Lucenteforte E, La Vecchia C, Silverman D, Petersen G, Bracci PM, Ji B-T, Bosetti C, Li D,
Gallinger S, Miller AB, Bueno-de-Mesquita HB, Talamini R, Polesel J, Ghadirian P, Baghurst
PA, Zatonski W, Fontham E, Bamlet WR, Holly EA, Gao Y-T, Negri E, Hassan M, Cotterchio
M, Su J, Maisonneuve P, Boffetta P, Duell EJ
Alcohol consumption and pancreatic cancer: a pooled analysis in the international pancreatic
cancer case-control consortium (PANC4)
Ann Oncol, 23: 374–382 (2012)
Tavani A, Colombo P, Scarpino V, Zuccaro P, Pacifici R, La Vecchia C.
Beliefs on and Attitude toward Doping Use Among Athletes: an Italian Survey
IJPH, 9: e8669-1-7 (2012)
Bravi F, Edefonti V, Randi G, Garavello W, La Vecchia C, Ferraroni M, Talamini R,
Franceschi S, Decarli A
Dietary patterns and the risk of esophageal cancer
Ann Oncol, 23: 765–770 (2012)
Gallus S, Rosato V, Zuccaro P G, Colombo P, Manzari M, La Vecchia
Attitudes towards the indoor smoking ban and its extension to selected outdoor areas in Italy
Tob Control, 21:59-62 (2012)
Turati F, Edefonti V, Bravi F, Ferraroni M, Talamini R, Giacosa A, Montella M, Parpinel M, La
Vecchia C, Decarli A
Adherence to the european food safety authority’s dietary recommendations and colorectal
cancer risk.
Eur J Clin Nutr, 66: 517–522 (2012)
Martinez-Sanchez J M, Gallus S, Zuccaro P G, Colombo P, Fernandez E, Manzari M, La
Vecchia C
Exposure to secondhand smoke in Italian non-smokers 5 years after the Italian smoking ban
Eur J Publ Health, 22: 707-711 (2012)
Tramacere I, Negri E, Bagnardi V, Rota M, Scotti L, Islami F, Corrao G, La Vecchia C,
Boffetta P
A meta-analysis on alcohol drinking and gastric cancer risk
Ann Oncol, 23: 28–36 (2012)
Garavello W, Turati F, Bosetti C, Talamini R, Levi F, Lucenteforte E, Chiesa F, Franceschini S,
La Vecchia C, Negri E
Family history of cancer and the risk of laryngeal cancer: a case-control study from Italy and
Switzerland
Int J Cancer, 130:665-70 (2012)
Matsuo K, Rossi M, Negri E, Oze I, Hosono S, Ito H, Watanabe M, Yatabe Y, Hasegawa Y,
Tanaka H, Tajima K, La Vecchia C
Folate, alcohol, and aldehydedehydrogenase 2 polyrmorphism and risk of oral and pharyngeal
cancer in Japanese.
Eur J Cancer Prev, 21: 193-198 (2012)
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Tramacere I, Pelucchi C, Bagnardi V, Rota M, Scotti L, Islami F, Corrao G, Boffetta P, La
Vecchia C, Negri E
A meta-analysis on alcohol drinking and esophageal and gastric cardia adenocarcinoma risk
Ann Oncol, 23: 287–297 (2012)
Bosetti C, Bertuccio P, Negri E, La Vecchia C, Boffetta P
Pancreatic cancer: overview of descriptive epidemiology
Molecular Carcinogenesis, 51: 3–13 (2012)
Bidoli E, Pelucchi C, Zucchetto A, Negri E, Dal Maso L, Polesel J, Boz G, Montella M,
Franceschi S, Serraino D, La Vecchia C, Talamini R
Fiber intake and pancreatic cancer risk
Ann Oncol, 23: 264–268 (2012)
Sverzellati N, Cademartiri F, Bravi F, Martini C, Gira A F, Maffei E, Marchianò A, La Vecchia
C, De Filippo M, Kuhnigk J M, Rossi C, Pastorino U
Relationship and Prognostic value of a modified Coronary
Artery Calcium Scoring, Forced Expiratory Volume in one
second and Emphysema in a lung cancer screening
population: the MILD trial
Radiology, 262: 460-467 (2012)
Frullanti E, La Vecchia C, Boffetta P, Zocchetti C
Vinyl chloride exposure and cirrhosis: a systematic review and meta-analysis
Dig Liver Dis, 44: 775– 779 (2012)
Giacosa A, Adam-Blondon A F, Baer-Sinnott S, Barale R, Bavaresco L, Di Gaspero G, Dugo L,
Curtis Ellison R, Fernandez J R, Gerbi V, Gifford D, Janssens J, La Vecchia C, Negri E,
Pezzotti M, Santi L, Santi Luca, Rondanelli M
Alcohol and wine in relation to cancer and other diseases.
Eur J Cancer Prev, 21:103–108 (2012)
Bosetti C, Rosato V, Polesel J, Levi F, Talamini R, Montella M, Negri E, Tavani A, Zucchetto
A, Franceschi S, Corrao G, La Vecchia C
Diabetes mellitus and cancer risk in a network of case-control studies
Nutr Cancer, 2012;64:643-51 (2012)
Hu J, La Vecchia C, De Groh M, Negri E, Morrison H, Mery L, Canadian Cancer Registries
Epidemiology Research Group
Dietary cholesterol intake and cancer
Ann Oncol, 23: 491–500 (2012)
Bonifazi M, Rossi M, Moja L, Scigliano V D, Franchi M, La Vecchia C, Zocchetti C, Negri E
Bevacizumab in clinical practice: prescibing appropriateness relative to national indications and
safety
Oncologist, 17:117–124 (2012)
Rossi M, Lugo A, Lagiou P, Zucchetto A, Polesel J, Serraino D, Negri E, Trichopoulos D, La
Vecchia C
Proanthocyanidins and other flavonoids in relation to pancreatic cancer: a case-control study in
Italy
Ann Oncol, 23: 1488–1493 (2012)
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Bosetti C, Lucenteforte E, Silverman D T, Petersen G, Bracci P M, Ji B - T, Negri E, Li D,
Risch H A, Olson S H, Gallinger S, Miller A B, Bueno-De-Mesquita H B, Talamini R, Polesel
J, Ghadirian P, Baghurst P A, Zatonski W, Fontham E, Bamlet W R, Holly E A, Bertuccio P,
Gao Y - T, Hassan M, Yu H, Kurtz R C, Cotterchio M, Su J, Maisonneuve P, Duell E J,
Boffetta P, La Vecchia C
Cigarette smoking and pancreatic cancer: an analysis from the international pancreatic cancer
case-control consortium (PanC4)
Ann Oncol, 23: 1880–1888 (2012)
Orsi C, Bertuccio P, Morandi A, Levi F, Bosetti C, La Vecchia C
Trends in motor vehicle crash mortality in Europe, 1980–2007
Safety Science, 50: 1009–1018 (2012)
Peleteiro B, Barros R, Carrilho C, Artiaga J, Cunha L, Modcoicar P, Ferreira R, Almeida R, La
Vecchia C, David L, Barros H, Lunet N
Determinants of gastric CDX2 expression: a study in Mozambique
Eur J Cancer Prev, 21:532–540 (2012)
Peleteiro B, La Vecchia C, Lunet N
The role of Helicobacter pylori infection in the web of gastric cancer causation
Eur J Cancer Prev, 21: 118-125 (2012)
Bosetti C, Bertuccio P, Levi F, Chatenoud L, Negri E, La Vecchia C
The decline in breast cancer mortality in Europe: an update (to 2009)
The Breast, 21: 77-82 (2012)
Polesel J, Gheit T, Talamini R, Shahzad N, Lenardon O, Sylla B, La Vecchia C, Serraino D,
Tommasino M, Franceschi S
Urinary human polyomavirus and papillomavirus infection and bladder cancer risk
Br J Cancer, 106: 222 – 226 (2012)
Campolo J, De Maria R, Frontali M, Taroni F, Inzitari D, Federico A, Romano E, Puca E,
Mariotti C, Tomasello C, Pantoni L, Pescini F, Dotti M T, Stromillo M L, De Stefano N, Tavani
A, Parodi O
Impaired vasoreactivity in mildly disabled CADASIL patients
J Neurol Neurosurg Psychiatry, 83:268-74 (2012)
Tagliaferri L, Prunotto G, Hakizimana J, Peves Rios W, Pelucchi C, Principi N, Esposito S
Knowledge of malaria among women of Burundi and its impact on the incidence of the disease
J Trop Ped, 58:258-62 (2012)
Turati F, Edefonti V, Talamini R, Ferraroni M, Malvezzi M, Bravi F, Franceschi S, Montella M,
Polesel J, Zucchetto A, La Vecchia C, Negri E, Decarli A
Family history of liver cancer and hepatocellular carcinoma
Hepatology 55:1416-1425 (2012)
Bosetti C, Filomeno M, Riso P, Polesel J, Levi F, Talamini R, Montella M, Negri E, Franceschi
S, La Vecchia C
Cruciferous vegetables and cancer risk in a network of case-control studies
Ann Oncol, 23: 2198–2203 (2012)
ANNUAL REPORT
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Chuang SC, Jenab M, Heck JE, Bosetti C, Talamini R, Matsuo K, Castellsague X, Franceschi S,
Herrero R, Winn DM, La Vecchia C, Morgenstern H, Zhang ZF, Levi F, Maso LD, Kelsey K,
McClean MD, Vaughan T, Lazarus P, Muscat J, Ramroth H, Chen C, Schwartz SM, Eluf-Neto
J, Hayes RB, Purdue M, Boccia S, Cadoni G, Zaridze D, Koifman S, Curado MP, Ahrens W,
Benhamou S, Matos E, Lagiou P, Szeszenia-Dabrowska N, Olshan AF, Fernandez L, Menezes
A, Agudo A, Daudt AW, Merletti F, Macfarlane GJ, Kjaerheim K, Mates D, Holcatova I,
Schantz S, Yu GP, Simonato L, Brenner H, Mueller H, Conway DI, Thomson P, Fabianova E,
Znaor A, Rudnai P, Healy CM, Ferro G, Brennan P, Boffetta P, Hashibe M.
Diet and the Risk of Head and Neck Cancer: A Pooled Analysis in the INHANCE Consortium
Cancer Causes Control. 23:69-88 (2012)
Pelucchi C, Galeone C, Tramacere I, Bagnardi V, Negri E, Islami F, Scotti L, Bellocco R,
Corrao G, Boffetta P, La Vecchia C.
Alcohol drinking and bladder cancer risk: a meta-analysis
Ann Oncol, 23: 1586–1593 (2012)
Carreras G, Gorini G, Gallus S, Iannucci L, Levy DT.
Predicting the future prevalence of cigarette smoking in Italy over the next three decades.
Eur J Public Health, 22: 699-704 (2012)
Edefonti V, Hashibe M, Ambrogi F, Parpinel M, Bravi F, Talamini R, Levi F, Yu G,
Morgenstern H, Kelsey K, McClean M, Schantz S, Zhang Z, Chuang S, Boffetta P, La Vecchia
C, Decarli A
Nutrient-based dietary patterns and the risk of head and neck cancer: a pooled analysis in the
International Head and Neck Cancer Epidemiology consortium
Ann Oncol, 23:1869-80 (2012)
Ph Janssens J, La Vecchia C.
Cancer control and prevention in Europe: the contribution of the European Journal of Cancer
Prevention.
Eur J Cancer Prev, 21:317–322 (2012)
Tavani A, Rosato V, Di Palma F, Bosetti C, Talamini R, Dal Maso L, Zucchetto A, Levi F,
Montella M, Negri E, Franceschi S, La Vecchia C
History of cholelithiasis and cancer risk in a network of case-control studies
Ann Oncol, 23: 2173–2178 (2012)
Pira E, Pelucchi C, Romano C, Manzari M, Negri E, La Vecchia C
Mortality from cancer and other causes in an Italian cohort of male rubber tyre workers
J Occup Environ Med, 54:345-9 (2012)
Galeone C, Augustin L, Filomeno M, Zucchetto A, Pelucchi C, Montella M, Talamini R,
Franceschi S, La Vecchia C
Dietary glycemic index, glycemic load and endometrial cancer risk: a case-control study and
meta-analysis
Eur J Cancer Prev, 22: 38-45 (2012)
Gallus S, Muttarak R, Franchi M, Zuccaro P G, Colombo P, Boffetta P, Leon M E, La Vecchia
C
Why do smokers quit?
EJCP, 22: 96-101 (2012)
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Niclis C, Del Pilar Diaz M, Eynard A R, Roman M D, La Vecchia C
Dietary Habits and Prostate Cancer Prevention: A
Review of Observational Studies by Focusing on South
America
Nutrition and Cancer, 64: 23-33 (2012)
Levy D, Gallus S, Blackman K, Carreras G, La Vecchia C, Gorini G
Italy SimSmoke: the effect of tobacco control policies on smoking prevalence and smoking
attributable deaths in Italy
BMC Public Health, 12:709 (2012)
Seitz H K, Pelucchi C, Bagnardi V, La Vecchia C
Epidemiology and pathophysiology of alcohol and breast cancer: update 2012
Alcohol Alcohol., 47:204-12 (2012)
Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E
European Cancer mortality predictions for the year 2012
Ann Oncol, 23: 1044–1052 (2012)
Turati F, Galeone F, Edefonti V, Ferraroni M, Lagiou P, La Vecchia C, Tavani A
A meta-analysis of coffee consumption and pancreatic cancer
Ann Oncol, 23: 311–318 (2012)
Tramacere I, Pelucchi C, Bonifazi M, Bagnardi V, Rota M, Bellocco R, Scotti L, Islami F,
Corrao G, Boffetta P, La Vecchia C, Negri E
A meta-analysis on alcohol drinking and risk of Hodgkin lymphoma
Eur J Cancer Prev, 21:268–273 (2012)
Bosetti C, Rosato V, Gallus S, La Vecchia C
Aspirin and urologic cancer risk: an update
Nat Rev Urol, 9: 102-110 (2012)
Pastorino U, Rossi M, Rosato V, Marchianò A, Sverzellati N, Morosi C, Fabbri A, Galeone C,
Negri E, Sozzi G, Pelosi G
Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the
MILD trial
EJCP, 21: 308-315 (2012)
Becker N, Falster M, Vajdic C M, de Sanjosé S, Martinez-Maza O, Bracci P M, Melbye M,
Smedby K E, Engels E A, Turner J, Vineis P, Costantini A S, Holly E A, Spinelli J J, La
Vecchia C, Zheng T, Chiu B C H, Montella M, Cocco P, Maynadie M, Foretova L, Staines A,
Brennan P, Davis S, Severson R, Cerhan J R, Breen E C, Birmann B, Cozen W, Grulich A E,
Newton R
Self-reported history of infections, surgery and pet ownership in childhood and the risk of nonHodgkin lymphoma: an InterLymph pooled analysis.
Int J Cancer, 131:2342-8 (2012)
Stott-Miller M, Chen C, Chang S - C, Amy Lee Y - C, Boccia S, Brenner H, Cadoni G, Dal
Maso L, La Vecchia C, Lazarus P, Levi F, Matsuo K, Morgenstern H, Muller H, Muscat J,
Olshan A F, Purdue M P, Serraino D, Vaughan T, Zhang Z F, Boffetta P, Hashibe M, Schwartz
SM
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History of diabetes and risk of head and neck cancer a pooled analysis form the international
head and neck cancer epidemiology consortium
CEBP, 21: 294-304 (2012)
La Vecchia C, Boffetta P
Role of stopping exposure and recent exposure to asbestos on the risk of mesothelioma.
Eur J Cancer Prev, 21:227–230 (2012)
R. Bellocco, E. Pasquali, M. Rota, V. Bagnardi, I. Tramacere, L. Scotti, C. Pelucchi, P. Boffetta,
G. Corrao, C. La Vecchia.
Alcohol Drinking and risk of Renal Cell Carcinoma: results of a meta-analysis.
Ann Oncol, 23:2235-44 (2012)
Tramacere I, Pelucchi C, Bonifazi M, Bagnardi V, Rota M, Bellocco R, Scotti L, Islami F,
Corrao G, Boffetta P, La Vecchia C, Negri E
Alcohol drinking and non-Hodgkin lymphoma risk: a systematic
review and a meta-analysis
Ann Oncol, 23:2791-8 (2012)
Collaborative Group on Epidemiological Studies of Ovarian Cancer (Negri E, La Vecchia C)
Ovarian cancer and body size. Individual participant meta-analysis including 25,157 women
with ovarian cancer from 47 epidemiological studies
PLoS Medicine 9: e1001200 (2012)
ESHRE Capri Workshop Group (La Vecchia C)
Health and fertility in World Health Organization group 2 anovulatory women
Hum Rep Up, 18:586-99 (2012)
Turati F, La Vecchia C
Risk factors for breast cancer in China: similarities and differences with western populations
Archives Medical Sciences, 8:179-82 (2012)
Tavani A, Malerba S, Pelucchi C, Dal Maso L, Zucchetto A, Serraino D, Levi F, Montella M,
Franceschi S, Zambon A, La Vecchia C
Dietary folates and cancer risk in a network of case-control studies
Ann Oncol, 23: 2737-2742 (2012)
Claudio Pelucchi, Liliane Chatenoud, Federica Turati, Carlotta Galeone, Lorenzo Moja, JeanFrançois Bach, Carlo La Vecchia
Probiotics supplementation during pregnancy and/or infancy
For the prevention of atopic dermatitis: a meta-analysis
Epidemiology, 23: 402-414 (2012)
Rota M, Pasquali E, Scotti L, Pelucchi C, Tramacere I, Islami F, Negri E, Boffetta P, Bellocco
R, Corrao G, La Vecchia C, Bagnardi V
Alcohol drinking and epithelial ovarian cancer risk. A systematic review and meta-analysis
Gynecol Oncol, 125:758-63 (2012)
Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C
Aspirin and cancer risk: a quantitative review to 2011
Ann Oncol, 23: 1403–1415 (2012)
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Rota M, Scotti L, Turati F, Tramacere I, Islami F, Bellocco R, Negri E, Corrao G, Boffetta P, La
Vecchia C, Bagnardi V.
Alcohol consumption and prostate cancer risk: a meta-analysis of the dose-risk relation.
Eur J Cancer Prev. 21: 350-359 (2012)
Soranna D, Scotti L, Zambon A, Bosetti C, Grassi G, Catapano A, La Vecchia C, Mancia G,
Corrao G
Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a metaanalysis
The Oncologist, 17: 813-822 (2012)
Kane E V, Roman E, Becker N, Bernstein L, Boffetta P, Bracci P M, Cerhan J R, Chiu B,
Cocco P, Costas L, Foretova L, Holly E A, La Vecchia C, et al
Menstrual and reproductive factors, and hormonal contraception use: associations with nonHodgkin lymphoma in a pooled analysis of Interlymph case-control studies
Ann Oncol, 23: 2362-2374 (2012)
Rosso T, Malvezzi M, Bertuccio P, Negri E, La Vecchia C, Decarli A
Cancer mortality in Italy, 2008, and predictions to 2012
Tumori, 98(5):559-567 (2012)
Orlando G, Tanzi E, Chatenoud L, Gramegna M, Rizzardini G, et al.
Rationale and design of a multicenter prospective cohort study for the eVALuation and
monitoring of HPV infections and relATEd cervical diseases in high-risk women
(VALHIDATE study)
BMC Public Health, 12: 204 (2012)
Matsuo K, Gallus S, Negri E, Kawakita D, Oze I, Hosono S, Ito H, Hatooka S, Hasegawa Y,
Shinoda M, Tajima K, La Vecchia C, Tanaka H
Time to first cigarette and upper aerodigestive tract cancer risk in Japan
Cancer Epidemiol Biomarkers Prev, 21:1986-92 (2012)
Giacosa A, Barale R, Bavaresco L, Gatenby P, Gerbi V, Janssens J, Johnston B, Kas K, La
Vecchia C, Mainguet P, Morazzoni P, Negri E, Pelucchi C, Pezzotti M, Rondanelli M
Cancer prevention in Europe: the Mediterranean diet as a protective choice.
Eur J Cancer Prev, 22: 90-95 (2012)
Bosetti C, Malvezzi M, Rosso T, Bertuccio P, Gallus S, Chatenoud L, Levi F, Negri E, La
Vecchia C
Lung cancer mortality in European women: trends and predictions
Lung Cancer 78: 171– 178 (2012)
Galeone C, Pelucchi C, La Vecchia C
Added sugar, glycemic index and load in colon cancer risk
Curr Opinion Clin Nutr Met Care, 15:368-73 (2012)
ESCMID Sore Throat Guideline Group -, Pelucchi C, Galeone C
Guideline for management of acute sore throat
Clinical Microbiology and Infection18: 1–27 (2012)
Gandini S, Negri E, Boffetta P, La Vecchia C, Boyle P
Mouthwash and oral cancer risk-quantitative meta-analysis of epidemiologic studies
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Ann Agric Environ Med, 19: 173-180 (2012)
Collaborative Group Epidemiological Studies Ovarian Cancer, La Vecchia C, Negri E
Ovarian cancer and smoking: individual participant meta-analysis including 28,114 women with
ovarian cancer from 51 epidemiological studies
Lancet Oncology, 13: 946-956 (2012)
Gallus S, La Vecchia C
Tobacco control: Economic aspects of smoking
Prev Med, 55: 546-547 (2012)
La Vecchia C, Bosetti C.
Urological cancer: Aspirin and the risk of prostate cancer mortality.
Nat Rev Clin Oncol. 9:616-7 (2012)
Polesel J, Negri E, Serraino D, Parpinel M, Barzan L, Libra M, Bosetti C,
Garavello W, Montella M, La Vecchia C, Franceschi S, Talamini R.
Dietary intakes of carotenoids and other nutrients in the risk of nasopharyngeal carcinoma: a
case-control study in Italy.
Br J Cancer 107:1580-3 (2012)
La Vecchia C, Gallus S, Garattini S.
Effects of physical inactivity on non-communicable diseases.
Lancet. 380:1553; (2012) author reply 1553-4.
The ESHRE Capri Workshop Group (La Vecchia C, Negri E)
Family planning 2011: better use of existing
methods, new strategies and more informed choices for female contraception.
Hum Reprod Update 18:670-681 (2012)
Duell EJ, Lucenteforte E, Olson SH, Bracci PM, Li D, Risch HA, Silverman DT, Ji BT,
Gallinger S, Holly EA, Fontham EH, Maisonneuve P, Bueno-de-Mesquita HB, Ghadirian P,
Kurtz RC, Ludwig E, Yu H, Lowenfels AB, Seminara D, Petersen GM, La
Vecchia C, Boffetta P.
Pancreatitis and pancreatic cancer risk: a pooled analysis in the International Pancreatic Cancer
Case-Control Consortium (PanC4).
Ann Oncol. 23:2964-70 (2012)
Bravi F, Edefonti V, Randi G, Ferraroni M, La Vecchia C, Decarli A
Dietary patterns and upper aerodigestive tract cancers: an overview and review
Ann Oncol, 23:3024-3039 (2012)
Rizzo A M, Corsetto P A, Montorfano G, Opizzi A, Faliva M, Giacosa A, Ricevuti G, Pelucchi
C, Berra B, Rondanelli M
Comparison between the AA/EPA ratio in depressed and non depressed elderly females:
omega-3 fatty acid supplementation correlates with improved symptoms but does not change
immunological parameters.
Nutr J 11:82 (2012)
Esposito S, Daleno C, Tagliabue C, Scala A, Tenconi R, Borzani I, Fossali E, Pelucchi C,
Piralla A, Principi N
Impact of rhinoviruses on pediatric community-acquired pneumonia
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J Clin Microbiol Infect Dis, 31; 1637-1645 (2012)
Polesel J, Zucchetto A, Talamini R, Dal Maso L, Serraino D, La Vecchia C,
Franceschi S.
Re: Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professional
Follow-up Study.
J Natl Cancer Inst 104:1684-6 (2012)
Carreras G, Gallus S, Iannucci L, Gorini G
Estimating the probabilities of making a smoking quit attempt in Italy: stall in smoking
cessation levels, 1986-2009.
BMC Public Health, 12: 183 (2012)
Esposito S, Daleno C, Baggi E, Ciarmoli E, Lavizzari A, Pierro M, Semino M, Groppo M, Scala
A, Terranova L, Galeone C, Principi N
Circulation of different rhinovirus groups among children with lower respiratory tract infection
in Kiremba, Burundi
Eur J Clin Microbiol Infect Dis, 31: 3251-3256 (2012)
Michelotti A, Cioffi I, Landino D, Galeone C, Farella M.
Effects of experimental occlusal interferences in individuals reporting different levels of
wake-time parafunctions. J Orofac Pain. 26:168-75 (2012)
LAY PRESS SELECTION (2012)
Santoro E. Social media: un nuovo modo di informare i medici. Ricerca & Pratica 2012; n. 165:
133
Santoro E. Google+ e la sfida a Facebook. Ricerca & Pratica 2012; n.163: 37
Santoro E. Social media, strutture sanitarie e cittadino. Ricerca & Pratica 2012; n. 164: 80
Santoro E. Social media e associazioni dei malati. Ricerca & Pratica 2012; n. 166: 174-175
Santoro E. Anche i ricercatori hanno il loro Facebook. Ricerca & Pratica 2012; n. 167: 226
Santoro E. Blog per medici e per pazienti. Colloquia 2011;.4; 13-14.
Santoro E. eBook. Aggiornamenti sociali, Dicembre 2011; 771-774
Santoro E. Dati sanitari: i pazienti preferiscono condividerli. Care 2012; 1: 14-14
Santoro E. eHealth. Care 2012;2: 23-25
Santoro E. Quanto sono interessati i ricercatori a condividere i dati delle proprie ricerche? Care
2012, 4; 10
Santoro E. Wikidata, open source della ricerca. Il Sole 24 Ore Sanità 9-15 ottobre; pag. 16
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Santoro E. I social media nella strategia comunicativa delle associazioni no-profit: una
miniguida all’uso (parte 1). Partecipasalute 3 settembre 2012;
http://www.partecipasalute.it/cms_2/node/1912
Santoro E. I social media nella strategia comunicativa delle associazioni no-profit: una
miniguida all’uso (parte 2). Partecipasalute 27 settembre 2012;
http://www.partecipasalute.it/cms_2/node/1924
OTHER PUBLICATIONS (2012)
Parazzini F, Paolo Vercellini, Claudio Pelucchi
Endometriosis: epidemiology and aetiological factors
In: Endometriosis. Science and Practice. (LC Giudice, JLH Evers, DL Healy, eds.) WileyBlackwell: UK. pp.59-75 (2012)
Negri E
Meta-analysis
In: Statistical Methods in Healthcare (FW Faltin, RS Kenett, F Ruggeri, eds). Wiley, Chichester,
UK. pp. 230-249 (2012)
RESEARCH ACTIVITIES
Laboratory of General Epidemiology
CASE-CONTROL STUDIES OF LIFESTYLE, GENETIC FACTORS AND
CANCER RISK
The Laboratory of Epidemiology has developed an integrated series of case-control
studies of several cancer sites, which has been a uniquely productive resource for
epidemiological research and risk quantification in Italy, with over 1,000 publications
over the last 30 years. The study integrates newer studies (generally more sophisticated,
including also biological material) with earlier datasets (including over 22,000 cases
and a comparable number of controls) and allows to study key cancer risk factors
(tobacco, alcohol, overweight, selected dietary factors, hormones) on a uniquely large
dataset, as well as to understand their changing role over time. The Laboratory has also
developed and integrated various sources of cancer epidemiology research, including
questionnaire data, biobanks and record linkage systems, in order to quantify the
associations between exposure and risk of major selected cancers in Italy, to test newer
hypotheses and to prioritize primary and secondary prevention.
Among aspects investigated in the network of case-control studies are:
1. Nutrition and diet, including various measures of overweight and their implications
on metabolic aspects on cancer risk, the separate and integrated role (e.g, dietary
patterns) of food groups and nutrients, with focus on several specific diet
components (e.g., flavonoids).
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2. Alcohol and tobacco, with a focus on low doses for alcohol, time-risk relations after
stopping smoking and drinking, and meta- and pooled-analyses with other datasets
worldwide.
3. Familial and genetic factors, given the availability of history of any cancer in
relatives (and age at cancer diagnosis), with the possibility to obtain lifetime-risk of
familial cancer, as well as of biological samples to analyze genetic polymorphisms.
4. Hormonal factors, not only for recognized hormone-related cancers in collaborative
re-analyses, but also for cancers of the pancreas, liver, lymphomas and sarcomas,
where the role of hormones is open to discussion.
5. Other environmental factors, including, among others, disinfection-by-products
(DBPs) and colorectal cancer, infections, hair dyes and occupational exposures and
bladder cancer, hepatitis C and B and lymphomas, viruses and polychlorinated
biphenyls (PCBs) and sarcomas.
6. Cohort studies on factors associated with cancer risk, survival and mortality, by
linking our database with local and national (administrative) data.
7. Meta- and pooled-analyses. The project is part of a series of collaborative re-analysis
conducted in Europe and worldwide on cancers of the upper digestive and respiratory
tract, pancreas, breast and female genital tract, thyroid and lymphomas.
8. Food composition database, to include additional food components (e.g.,
proanthocyanidines, gluthatione, total antioxidant capacity) and update the existing
one.
META-ANALYSIS OF ALCOHOL CONSUMPTION AND CANCER RISK
Cancer sites causally related to alcohol consumption are those of the oral cavity and pharynx,
esophagus (squamous cell carcinoma), larynx, liver, colorectum, and breast. For many other
cancers the evidence is inconsistent and still open to discussion. Further, selected aspects of
alcohol consumption on cancer risk need clarification, particularly the dose-risk relation and the
heterogeneity of results across different populations. In this project, we investigated the relation
between alcohol drinking and risk of cancer using a meta-analytical approach. The study
scheme was based on an already available database of 235 epidemiological studies published
from 1966 to 2000 and investigating 18 different cancer sites, integrated with new papers
published until the end of 2011. Primary aims of this project were to estimate the parameters of
the dose-response functions relating alcohol consumption to the risk of several types of cancer,
using various meta-regression models and an ad hoc developed SAS macro software, and to
identify the sources of heterogeneity (e.g., drinking pattern, geographical area, etc.) in the
parameter estimates. For sites where the role of alcohol is still debated, the association with
exposure to alcohol was investigated, regardless of the dose. All cancer sites were considered
together in a single paper, in order to overview the strength of the evidence on the association
between alcohol and cancer. We considered not only common cancers, but also rarer neoplasms,
for which sparse information is available. Further, all cancer sites have been examined in
another investigation, aimed to quantify the role of low doses of alcohol consumption and to
elucidate whether there is any threshold in intake below which no effect on cancer is evident.
Besides meta-analyses of all neoplasms, we investigated in-depth the effect of alcohol on the
risk of several cancers, including oral cavity and pharynx, esophagus (adenocarcinoma) and
gastric cardia, stomach, lung, ovary, kidney, bladder, brain, and lymphomas, considering results
for different anatomic subsites and/or histological types and explored several potential sources
of heterogeneity of results. The project has relevant prevention and public health implications,
particularly the analysis focused on low doses.
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META-ANALYSES OF ASPIRIN AND CANCER RISK
Among other meta-analyses and review papers conducted by the Laboratory of Epidemiology is
a meta-analysis on cancer risk in relation to aspirin use. Aspirin has been associated to a
reduced risk of colorectal, and possibly of a few other common cancers. To provide an up-todate quantification of this association, we conducted a meta-analysis of all observational studies
on aspirin and 12 selected cancer sites published up to September 2011. From the literature
search through PubMed/Medline, we identified and screened 450 records, of which 195 were
considered of interest and their full-texts were retrieved. After considering 32 additional studies
identified through the references of the retrieved papers, and having excluded 88 papers non
satisfying inclusion criteria, a total of 139 studies were considered in the meta-analysis,
including the findings of case-control and cohort studies on aspirin and the risk of cancer at 12
sites. Regular aspirin was associated with a statistically significant reduced risk of colorectal
cancer (summary relative risk from random-effects models 0·73, 95% confidence interval 0·670·79), and of other digestive tract cancers (0·61, 0·50-0·76, for squamous cell esophageal cancer,
0·64, 0·52-0·78, for esophageal and gastric cardia adenocarcinoma, and 0·67, 0·54-0·83, for
gastric cancer), with somewhat stronger reductions in risk in case-control than in cohort studies.
Modest inverse associations were also observed for breast (0·90, 0·85-0·95) and prostate cancer
(0·90, 0·85-0·96), while lung cancer was significantly reduced in case-control studies (0·73,
0·55-0·98), but not in cohort ones (0·98, 0·92-1·05). No meaningful overall associations were
observed for cancers of the pancreas, endometrium, ovary, bladder, and kidney. The metaanalysis allowed to indicate that aspirin has beneficial role for colorectal and other digestive
tract cancers; modest risk reductions were also observed for breast and prostate cancer. Results
were, however, heterogeneous and dose- and duration-risk relationships still unclear.
INTERNATIONAL HEAD AND NECK CANCER EPIDEMIOLOGY (INHANCE)
STUDY
The International Head and Neck Cancer Epidemiology (INHANCE) Consortium was
established in 2004, based on the collaboration of research groups leading large molecular
epidemiology studies of head & neck cancer that are on-going or have been recently completed.
When taken collectively, questionnaire data on over 26,000 cases and 34,000 controls, and
biological samples from a majority of the study population would be available. The 33
epidemiological studies included in the consortium have been conducted in various regions of
the world. Worldwide, an estimated more than half a million head & neck cancer cases and
320,000 deaths due to head & neck cancer occurred in the year 2008. Head and neck cancers are
a related group of cancers that involve the oral cavity, pharynx and larynx. While it is wellestablished that tobacco and alcohol account for at least 75% of head & neck cancers, important
etiologic questions remain to be addressed: (i) the role of low penetrance genetic susceptibility
factors (e.g. SNPs) and their interactions with environmental factors, (ii) etiology in rare
subgroups including young age at onset, and nonsmokers and nondrinkers, (iii) the effect of
human papillomavirus (HPV), particularly with respect to cancer subsite. The INHANCE
consortium conducted pooled analyses of lifestyle risk factors such as alcohol beverage type and
concentration, and also pooled analyses in rare groups such as early onset head and neck cancer
cases, and nonsmokers/nondrinkers. Working groups have been formed for research topics such
as HPV, genetics/ DNA repair, nonsmokers/nondrinkers, early onset cases and occupational
factors. Future directions for the consortium will be to coordinate genotyping from a list of
priority SNPs and to assess the effect of HPV infection. We anticipate that the INHANCE
consortium will be a major step toward improving our understanding of the causes and
mechanisms of head & neck cancers and the beginning of a long-standing cooperation. To date,
26 articles on INHACE data consortium were published. Our Department is actively involved in
the scientific collaboration and analyzed data on several modifiable and non-modifiable risk
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factors for cancer including family history of cancer, coffee and tea intake and dietary patterns.
Under the supervision of our Department, several other dietetic aspects have been analyzed
during 2012.
INTERNATIONAL PANCREATIC CANCER CASE-CONTROL CONSORTIUM
(PANC4)
The Pancreatic Cancer Case Control Consortium (PanC4) has been created by a group of
scientists from diverse biomedical disciplines (Epidemiology, Genetics, Biostatistics,
Bioinformatics, Molecular Biology, Gastroenterology, Surgery) across the world who have
joined together to improve our understanding of the causes of pancreatic cancer through joint, or
pooled analyses of data. The PanC4 consortium includes 14 case-control studies of pancreatic
cancer conducted in North America, Europe, China, and Australia, besides the IARCcoordinated Surveillance of Environmental Aspects Related to Cancer in Humans (SEARCH)
study from Canada, Europe and Australia, and includes overall about 6500 cases of
adenocarcinoma of the exocrine pancreas and about 13,000 corresponding controls. The original
datasets were restructured either by the original study investigators or by the central
coordinators using a uniform format for data harmonization. Among the risk factors already
analyzed within PanC4 are cigarette smoking, smoking of other tobacco products, alcohol
intake, and selected medical conditions (allergy, pancreatitis, ulcer and gastrectomy). New
analyses are on-going for selected dietary items (including acrylamide, vitamin D, …), early
onset pancreatic cancers, and reproductive factors.
TOBACCO CONTROL IN ITALY
Tobacco smoking remains the leading global cause of preventable disease and death, and is
responsible for approximately 6 million deaths worldwide every year. In order to plan strategies
to control tobacco in one country, it is important to systematically collect data on smoking
prevalence and trends, using surveys conducted with standardized methods on representative
samples of a country’s population. This allows to implement the most efficient interventions to
control tobacco. Besides collecting and storing data on smoking, it is also crucial to promptly
interpret them to provide to policy makers updated recommendations on which tobacco control
strategy is more urgent, feasible and efficient. In order to monitor smoking prevalence in Italy,
since 2001, in collaboration with the National Institute of Health and DOXA, we annually
conduct a face-to-face survey on more than 3000 individuals representative of the general
Italian population aged 15 years and over. Each year we update the standardized questionnaire
in order to study specific issues on tobacco control in Italy. In 2012 we added a few questions
on the emerging phenomenon of hand-rolled tobacco, a type of tobacco whose consumption was
negligible a few years ago. We observed that the proportion of hand-rolled cigarettes on total
tobacco trades is dramatically increasing in Italy (~6% in 2012), particularly among young
smokers, largely following a switch to affordable cigarettes in a period of economic downturn.
TOBACCO CONTROL IN EUROPE (FP7-PPACTE PROJECT)
Despite the favourable trends of smoking prevalence over the last few decades in high-income
countries, tobacco remains the first cause of disease and death in North America and Europe. A
collaborative project entitled Pricing Policies And Control of Tobacco in Europe (PPACTE),
was conducted to provide a comprehensive analysis of tobacco pricing policy, which is
considered the most effective intervention to control tobacco. Within the PPACTE project, in
2010 we conducted a face-to-face representative survey on smoking in 18 European countries
(~18,000 adults). We showed that the proportion of tobacco tax evasion was 6.5% in Europe
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and was unrelated to the price of cigarettes. Moreover, increases in tobacco prices appear to be
supported by the European population. Findings from the PPACTE project confirm that price
and tax measures are effective, feasible and important means of reducing tobacco consumption.
OBESITY CONTROL IN ITALY
In order to monitor trends and determinants of underweight, overweight and obesity in Italian
adults, since 2004 we added to the face-to-face surveys on smoking, which are annually
conducted by DOXA on approximately 3000 individuals, representative of the general Italian
adult population, selected questions including information on weight and height. Considering
data between 2006 and 2010, we found favorable overweight and obesity prevalence and trends
compared to most of other high income countries. However, there are specific subgroups of the
population with elevated prevalence of overweight and obesity, mainly populations from
southern Italy and less educated subjects.
THE ROLE OF REGULATORY AGENCY TO CONTROL PUBLICATION BIAS
(FP7-OPEN PROJECT)
We are involved in the project Overcome the Failure to Publish Negative Findings (OPEN),
financed by the European Commission within the Seventh Framework Programme (FP7). Our
work package aims to evaluate the role of the main regulatory agencies, including in particular
the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), on
controlling failure to publish negative findings from clinical trials. We found that, although
FDA has the most advanced policies to control publication bias worldwide, it does not provide
sufficient regulations to fight against failure to publish negative findings from CTs. Currently,
EMA has even less adequate procedures to control publication bias, but it recently announced a
plan to improve transparency, through policies providing public access to CT results. Learning
from limitations, knowledge gaps and loopholes of FDA policies, EMA has the opportunity to
create a set of regulations more efficient to control publication bias.
THE HYGIENE HYPOTHESIS: REVISITING THE CONCEPT BY
INTEGRATING EPIDEMIOLOGY AND MECHANISTIC STUDIES (FP7 ERC
PROJECT)
The hygiene hypothesis postulating the paradoxical protective role of infections on immunemediated diseases including atopy (i.e. atopic dermatitis, rhinitis, asthma) and more recently
autoimmune diseases has been the matter of extensive investigation. Aim of the present project
is to validate this hypothesis integrating epidemiological and experimental studies, the latter
being performed by another research group in Paris. Our epidemiological section includes both
a systematic review approach, i.e., meta-analyses of studies of direct and indirect markers of
infections and atopic diseases, and an original case-control study, to analyze the association
between infections and atopy using atopic dermatitis as a prototypic model.
In particular 193 cases and 180 controls were recruited to date, and we expect to achieve the
quota of 500 cases and 500 controls during 2014. With reference to the systematic review
approach, we conducted a meta-analysis of probiotics supplementation during pregnancy and
childhood for the prevention of atopic dermatitis. Two other meta-analyses of observational
studies are currently in progress to assess whether exposure to infectious agents (including
indirect markers, such as the presence of pets) may influence the development of atopic
dermatitis in childhood.
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EVALUATION AND MONITORING OF HPV INFECTION AND RELATED
DISEASES IN WOMEN AT HIGH RISK OF CERVICAL CANCER VALHIDATE STUDY
Infection from human papillomavirus (HPV) is a necessary cause of cervical cancer, which
represents the second cause of death from total cancer in women worldwide. The Valhidate
Study is an ongoing multicenter, prospective cohort study funded by the Health General
Direction, Lombardy Region for the period November 2010 - November 2014. It aims to
evaluate, in a cross-sectional study, and to monitor, in a prospective cohort study, HPV
infection and cervical related diseases in high risk women, from HIV-infected women (DHIV),
recent migrant women (DDRI), girls aged 13-18 years recruited through pediatric visit
(D1318P) and young women aged 13–25 years (D1325), compared to one control group of
women attending a spontaneous screening program (DASS). Adult participants undergo
conventional cervical cytology, HPV DNA screening and genotyping. Pediatric participants
undergo HPV DNA testing and genotyping of urine samples. HPV DNA, cytological
abnormalities and HPV types will be analyzed according to demographic, epidemiological,
behavioral, and clinical data collected in an electronic case report form. The follow up timing
was defined by specific algorithms based on cytology and biomolecular results. The results
from this study will allow to define specific strategies of primary and secondary prevention of
the cervical cancer in the studied population. Between November 2010 and December 2012,
625 women were enrolled in the DHIV cohort, 367 in the DDRI, 1252 in the D1318P, 377 in
the D1325G, and 1233 in the DASS, for a total of 3,854. Of these, 313 had at least one followup.
GENETIC VARIANTS AND SUSCEPTIBILITY TO SEVERE AND/OR
RECURRENT LOWER RESPIRATORY TRACT INFECTIONS WITH
WHEEZING IN CHILDREN
Lower respiratory tract infections (LRTIs) with wheezing are common in young children, and
have a cumulative prevalence of up to 40% in the first six years of life. They are a major cause
of morbidity and reduce the affected children's health-related quality of life because they are
often severe and/or highly recurrent, and because up to 50% of children experiencing recurrent
virus-induced wheezing in infancy later develop chronic asthma. Almost all LRTIs are due to
viruses, the most frequent being respiratory syncytial virus (RSV), rhinovirus, parainfluenza
virus and human metapneumovirus. The main aim of this project – that started in 2012 and will
end in 2015, conducted by the Pediatric Clinic of the Fondazione IRCCS Ca' Granda Ospedale
Maggiore Policlinico, with the collaboration of our Laboratory – is to analyze possible
correlations between specific genetic defects in innate immunity (such as TLR mutations)
and/or cytokine production and the risk of developing severe and/or recurrent LRTIs with
wheezing in children. We also investigate the relative importance of the different viruses
capable of causing LRTIs with wheezing in determining severity and recurrences. Finally, as
inhaled steroids can significantly modify the outcome of wheezing episodes, in this project we
assess the importance of steroid prophylaxis in reducing the risk of recurrences in genetically
predisposed children.
SPIRAL COMPUTED TOMOGRHAPHY AND MIRNA ASSOCIATED TO A
PRIMARY PREVENTION PROGRAM FOR THE EARLY DETECTION OF
LUNG CANCER
The efficacy of lung cancer screening in heavy smokers by spiral-computed tomography (CT)
remains a controversial issue. The MILD study conducted by the Istituto Nazionale per lo
Studio e la Cura dei Tumori of Milan aims to assess whether a primary prevention program with
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or without the regular chest spiral CT and other diagnostic methods is able to reduce mortality
from lung cancer in high-risk subjects. The first analysis conducted on 4000 subjects
randomized to a control group, a group with the CT scan performed every year and a group with
the CT scan performed every two years, showed that there was no protective effect in terms of
mortality in subjects who carried out a CT scan every year or every two years compared to those
who did not carry CT after 6 years of follow-up. We are also following another prospective
study of 4000 heavy smokers that is starting at the Istituto Nazionale per lo Studio e la Cura dei
Tumori and aims to determine whether the examination of microRNAs in plasma is able to
improve the effectiveness of spiral CT in the early diagnosis of lung cancer in high-risk
individuals. The results of this prospective study will assess the effectiveness of the test with
plasma miRNAs as first-line examination, non-invasive, low-cost screening of lung cancer in
high-risk individuals and the choice of optimal treatment.
PUBLIC HEALTH PREVENTION AND INFORMATION
The major products of our activity have also been published in the lay press, in order to increase
the project impact on prevention and public health.
Laboratory of Epidemiological Methods
CANCER MORTALITY IN EUROPE
The Laboratory of Epidemiologic Methods has developed an integrated system for monitoring,
modeling and interpreting cancer mortality statistics in Europe. Since its beginning in 1992, the
project has had a considerable scientific production in spite of its low costs, and the Laboratory
has acquired new tools and expertise, and collaborations with Italian and international research
groups have been established. At the core of the project there is the European database on
cancer mortality that the Laboratory has built and periodically updated, which derives from the
WHO raw mortality data, integrated by other sources, whenever required. The database includes
numbers of cancer deaths by country, cause, period, sex and age in Europe and selected other
countries, together with estimates of the resident population. The aim of the project is to: i)
periodically update the project’s database with data for more recent years; ii) update the
systematic analysis of cancer mortality in Europe, and verify if the forecasts of a continuing fall
in cancer mortality in Europe are met; iii) apply age-period-cohort models to help in the
interpretation of rates, and assist in projection of trends; iv) monitor cancer mortality in Central
and Eastern Europe and in selected middle income countries of the world, where delays in the
adoption of effective strategies for cancer prevention, management and treatment have been
apparent; v) further monitor tobacco-related mortality in Europe, highlighting successes and
failures in smoking prevention efforts in various populations, with specific focus on women; vi)
evaluate to what extent mortality statistics can contribute to the current scientific debate on the
effectiveness of (organized) screening programs for cancers of the breast, prostate and
colorectum; vii) quantify the burden and investigate trends of cancer mortality in older people;
and viii) develop and test a system to obtain short-term projections of cancer mortality. The
project is not merely descriptive, since specific effort is devoted to the interpretation of the
observed data in the light of epidemiological knowledge, highlighting information that can
generate new hypotheses on cancer etiology. It offers a unique opportunity for the continuous
exploitation of vital statistics in Europe, with the primary aim of monitoring and improving
cancer prevention.
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NOVEL HIGH COST CHEMOTHERAPIES: CLINICAL USE, SAFETY AND
EFFECTIVENESS AFTER MARKETING APPROVAL IN ONCOLOGY
PRACTICE
The objective of this project is to provide a detailed description of clinical use of selected new
“targeted” high cost drugs in Lombardy oncology practice, including the time trends of
prescriptions, the physician compliance to Italian Medicine Agency (AIFA) approval
indications, and the evaluation of the frequencies of major side effects and of the survival after
treatment. An additional objective is to investigate the clinical effectiveness of the therapies of
interest on selected cancers, including colorectal, breast and lung cancers.
A first publication investigated the clinical use of bevacizumab in patients with metastatic
colorectal cancer (mCRC). There was a gap between bevacizumab approval indication and
clinical practice pattern. The frequency of serious adverse events and the survival rates of
mCRC patients were similar to the results reported in experimental clinical trials leading to drug
approval.
Laboratory of Epidemiology of Chronic Diseases
CASE-CONTROL STUDIES CONDUCTION
Organization for the collection of information on patients’ selected
characteristics and lifestyles, and of biological samples for case-control
studies
Data collection of epidemiological data is going on and it includes: 1) interviews and
interviewer management and training activity for new interviewers; 2) contacts with hospital
department and ethical committee for study approval and conduction; 3) check for consistency
and codification of patient questionnaires; 4) diagnosis and histological exam check; 5)
organization and management of biological sample collection; 6) data input management.
Ongoing case-control studies include: adenocarcinoma of the esophagus-cardias, cancer of the
bladder, and sarcomas.The overall updated dataset include about: 1250 cases of cancers of oral
cavity and pharynx, 700 of the esophagus, 1100 of the stomach, 6500 of the colorectum, 600 of
the liver, 120 of the biliary tract, 600 of the pancreas, 850 of the larynx, 500 cutaneous
malignant melanoma, 7000 of the breast, 1000 of the cervix, 1000 of the endometrium, 200 of
trophoblastic gestational disease, 200 of the vulva, 2000 of the ovary, 1300 of the prostate, 700
of the bladder, 800 of the kidney and renal pelvis, 600 of the thyroid, 200 of Hodgkin disease,
500 of non-Hodgkin disease, 450 of sarcomas, 300 of myelomas and about 18,000 controls.
Biological sample collection, aimed to study genetic polymorphisms, includes cancers of the
oral cavity, pharynx, larynx, bladder, colorectum and sarcoma.
SOFT TISSUE SARCOMAS: CASE-CONTROL STUDY OF RISK FACTORS
AND A DESCRIPTIVE STUDY OF PRE-DIAGNOSTIC CLINICAL HISTORY
Soft tissue sarcomas (STS) have low incidence resulting in a low statistical power in etiological
studies and a limited experience of general practitioners in the clinical practice, often leading to
diagnostic delays. Their dual classification by anatomical site and histology causes confusion in
assessing their etiology. This project includes two integrated studies. The first study (casecontrol, coordinated by the Mario Negri Institute) is based on a validated questionnaire (with
many covariates and based on a detailed food composition databases), the use of appropriate
statistical analyses and measurements of toxic agent levels in biological tissues. The second
(clinical study, coordinated with the collaboration of the University of Turin, Dipartimento di
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Medicina del Lavoro/CTO Maria Adelaide) is based on questionnaires reporting the history of
medical visits and procedures before hospital admission, and detailed socioeconomic
characteristics of cases. Cases are followed-up for 5 years. We collect blood samples and
adipose tissue (in chirurgic patients) from cases and controls and neoplastic tissues from cases.
The case-control study is aimed to identify and quantify risk factors and attributable risks in
Italy for STS whose etiology is largely unknown. The clinical study is aimed to assess the
clinical history of STS before hospital admission and its impact on the severity of the disease at
correct diagnosis, and whether they can be influenced by patient socioeconomic characteristics
and geographic area of residence. The major strengths of this project are: the large dataset due
to the participation of most Italian reference hospitals for STS treatment; the detailed
information on anatomical site and hystopathological type of STS; the interdisciplinary
approach; the quantification of STS risk factors; the creation of a research biorepository for
molecular genetic and for cytogenetic analyses; the preparation of guidelines contributing to
early management of STS by general practitioners.
BLADDER CANCER STUDY
This project includes two parts: 1) the conduction of a case-control study of risk factors and
genetic susceptibility of bladder cancer; 2) the collaboration in the International Consortium of
Bladder Cancer (ICBC). Besides tobacco and exposure to aromatic amines, the main known risk
factors for bladder cancer, several other factors have been considered, although their
quantification and causal relation have not be assessed. Our case-control study of risk factors
and genetic susceptibility of bladder cancer is designed to collect information and analyze the
association with bladder cancer in relation to: family history, known risk factor whose
quantification is still undetermined; coffee consumption, to establish whether, the moderate
direct association observed in a few studies is real or due to confounding; fluid intake, as a low
intake concentrate metabolites in urines and increases the contact of bladder epithelium with
potential cancerogens; intake of selected drugs; diet, in terms of macro- and micronutrients,
food groups and dietary patterns; professional and personal use of hair-dyes. The International
Consortium of Bladder Cancer was formed in 2005 as an open scientific forum for
epidemiologic research in bladder cancer. Investigators with bladder cancer studies, completed
or ongoing, consider proposals for projects that pool data across studies or undertake
coordinated research. The main aims of the bladder cancer consortium are: to have a forum for
discussion in studying the molecular epidemiology of bladder cancer, and to facilitate the
pooling of comparable data on environmental and genetic risk factors across studies in order to
overcome the limited power of individual studies. Possible areas of collaboration include the
evaluation of complex multigenic effects, interactions with cigarette smoking and other
exposures, evaluation of sex-specific effects, evaluation of heterogeneity of genetic effects by
cancer subgroups. We participate to three proposal evaluated by the Coordinating Committee:1)
to evaluate the association between hair dye use with bladder cancer, pooling data from casecontrol studies on bladder cancer with high quality information on hair-dye use. Moreover,
genotyping data on metabolic pathways are also considered, mainly to evaluate the interaction
of polymorphisms of genes involved in the metabolic pathways of hair-dyes (NAT1, NAT2,
CYP2A1, GSTs and possibly other) on the risk of bladder cancer, and possibly to evaluate
whether exposure to hair-dyes is associated with presence of p53 mutations; 2) to study the
effect of the family history on the risk of bladder cancer, by investigating the risk associated
with probands having first and second degree family members with bladder cancer and with
cancers at other anatomical sites; 3) to investigate the effect of diet on the risk of bladder cancer,
considering individual foods, macro- and micronutrients, groups of foods and dietary patterns.
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COFFEE INTAKE AND THE RELATION WITH VARIOUS DISEASES
Coffee is the second most common beverage in the world after tea. Thus, any health effect of
coffee is an important issue of public health. Besides caffeine, coffee contains many bioactive
compounds with potential effects on health, including minerals and antioxidants, mainly
phenolic compounds (such as chlorogenic, caffeic, ferulic and cumaric acids), melanoidins and
diterpenes (such as cafestol and kahweol), and coffee has been related with lower incidence of
several diseases. In the last ten years we have studied the relation of coffee and decaffeinated
coffee intake and cancer at several sites in our case-control studies, finding no relation with
cancer of the esophagus, stomach, pancreas, larynx, melanoma, breast, ovary, prostate, kidney
and non-Hodkgin disease, and finding an inverse relation of coffee with cancer of the oralcavity and pharynx, colorectum, liver (including liver cirrhosis) and endometrium. Moreover we
have conducted a series of meta-analysis on the relation of coffee and decaffeinated coffee with
cancers of the esophagus, pancreas, larynx and brain, confirming the absence of relation, and
with cancers of the oral-cavity and pharynx (including a pooled analysis), colorectum, liver and
endometrium confirming an inverse association.
Laboratory of Medical Informatics
Development of a medical collaborative platform
In collaboration with the Arcispedale S. Maria Nuova of Reggio Emilia a project with the
following three aims has been started: the training of the medical staff working at the
Arcispedale hospital in using web 2.0 tools and social media for professional education and
update; the designing of tools to allow physicians to share medical knowledge; the development
of a collaborative platform to allow physicians to share evidence-based medical practices,
practice management information and other relevant medical information, and to discuss clinical
cases. More than 80 physicians, health professionals and medical librarians have been trained on
these issues. In addition, in collaboration with the Medical Library of the Arcispedale S. Maria
Nuova of Reggio Emilia, we have developed a blog where physicians may access to and discuss
on selected evidence-based medical literature.
Maintenance of the CARDIO.CARE, ONCO.CARE, GASTRO.CARE,
NEURO.CARE, PNEUMO.CARE, BPCO.CARE, PAIN.CARE and
DERMA.CARE websites
These indexes have been developed by the Laboratory of Medical Informatics in order to
collect, classify, evaluate, and describe the most useful medical information on the web, and to
provide Internet users with an easy means to surf the net. Several medical areas are covered
including oncology (http://www.oncocare.it), neurology (http://www.neurocare.it),
gastroenterology (http://www.gastrocare.it), cardiology (http://www.cardiocare.it),
pulmonology (http://www.pneumocare.it, http://www.bpcocare.it), the pain care and
management (http://www.paincare.it), and dermatology (http://www.dermacare.it). The project
is in collaboration with intramural departments (Department of Oncology, Laboratory of
Neurological Disorders and Department of Cardiovascular Research, Laboratory of General
Practice Research, Laboratory of Translational and Outcome Research in Oncology) and
extramural research groups (Italian Group for Epidemiologic Research in Dermatology,
GISED). During 2010, information about the use of web 2.0 tools and technologies (such as
podcast, RSS feeds, blogs, webcasts, and webinars) by the indexed websites has been collected.
RSS feeds and podcasting services have been activated on the CARE websites in order to allow
the users to access to the corresponding applications available on the classified websites.
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Use of social media by health organizations in Italy
The Laboratory of Medical Informatics is involved in a survey which aim is to describe how the
1.200 health organizations In Italy are using the web 2.0 and the social media tools (with
particular interest on Facebook, Twitter and YouTube) as new media to communicate and share
information with patients and citizens. The results will be available in spring 2013.
Studies on the typology of the web 2.0 applications in medicine
The Laboratory of Medical Informatics is involved in studies and surveys which aim is to
describe the typology of the web 2.0 applications and tools (including social networks, podcasts,
feed RSS, blogs, and wikis) in medicine available on the net, and how these are perceived by
the medical community.
Training activities
In 2012, the Laboratory of Medical Informatics continued its training activity on issues related
to the use of the Internet in medicine, and extended it to the use of the recent social media and
web 2.0 technologies and tools in the medicine area. The members of the Laboratory staff
activated (or attended as invited teachers) a number of training courses, workshops, and master
courses. Onsite CME courses for the Italian physicians have also been organized using the
training/educational facilities and equipment available at the Mario Negri Institute.
.
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DEPARTMENT OF PUBLIC HEALTH
STAFF
Head of Department
Maurizio BONATI, MD.
"Angelo & Angela Valenti" Centre for Health Economics (CESAV)
Head of Laboratory
Livio GARATTINI, Econ.D.
Laboratory of Clinical Epidemiology
Head of Laboratory
Guido BERTOLINI, MD.
Clinical Knowledge Engineering Unit
Head of Unit
Davide LUCIANI, MD.
Laboratory for Mother and Child Health
Head of Laboratory
Maurizio BONATI, MD.
Pharmacoepidemiology Unit
Head of Unit
Antonio CLAVENNA, MD.
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CURRICULA VITAE
Maurizio Bonati has a Medical School degree at the University of Milan.
Areas of interest: Monitoring and epidemiological evaluation of drug utilisation and effects of drugs and
vaccines in motherhood and childhood. Research methodology in general hospital and paediatric
community practice. Transfer of information to the community. Epidemiology of paediatric and perinatal
care.
Past and present roles both at the Mario Negri Institute and in other institutions: 1973-77 Research Fellow
at the IRFMN, within the Neurochemistry Lab.; 1977-85 Research Assistant at the IRFMN, within the
Clinical Pharmacology Lab.; 1986-93 Chief of the Perinatal Clinical Pharmacology Unit at the IRFMN;
Advisor to WHO for the Drug Utilization Research Group (pregnancy, paediatrics and breastfeeding);
1987-92 coordinator of the International Cooperative Study of Drug Use in Pregnancy, under the auspices
of WHO and the support of EEC; 1992-93 co-editor of The Kangaroo; 2000-05 coordinator of the
European Cooperative Study: “Development of the European register of clinical trials on medicines for
children” (DEC-net), under the 5th Framework Programme’s Quality of life and Management of Living
Resources; since 1989 he has been director of the Centre for Drug Information; since 1993 head of the
Lab. for Mother and Child Health; since 1997 teacher for the Lombardy region’s professional training
courses; since 2000 teacher for the Lombardy region’s professional training courses; since 2002 Editor of
the Ricerca & Pratica scientific journal; since 2003 professor of the School of Specialisation in
Paediatrics - University of Milan Bicocca; teacher at the annual European course “Evaluation of
Medicinal Products in Children” (promoted by ESDPPP and Eudipharm); from May 2008 Head of
Department Public Health at the "Mario Negri" Institute for Pharmacology Research; since 2010
coordinator of the European Cooperative Study “COHEMI-Coordination resources to Assess and
Improve health status of migrants from Latin America”, under the 7th Framework Programme for
Research and Technological Development (Programme Cooperation- Health).
Selected publications

Clavenna A, Rossi E, De Rosa M, Bonati M. Use of Psychotropic Medications in Italian Children and adolescents. Eur J
Pediatr 2007;166:339-47.

Maschi S, Clavenna A, Schiavetti B, Campi R, Bernat M, Bonati M. Neonatal outcome following pregnancy exposure to
antidepressants: a prospective controlled cohort study. BJOG 2008;115:283-289.

Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfeeding: a review of the evidence. Pediatrics
2009;124:e547-e556.

Fortinguerra F, Maschi S, Clavenna A, Bonati M. Pain management in the paediatric population. The regulatory
situation in Europe. Arch Dis Child 2010;95:749-753.

Didoni A, Sequi M, Panei P, Bonati M, on behalf of the “Lombardy ADHD Registry Group”. One-Year Prospective
Follow-up of Pharmacological Treatment in Children with Attention-Deficit/Hyperactivity Disorder. Eur J Clin
Pharmacol 2011;67:1061-67.

Clavenna A, Cartabia M, Costantino A, Bortolotti A, Fortino I, Merlino L, Bonati M. Burden of mental disorders in
childhood estimate using administrative health data. Pharmacoepidemiol Drug Saf 2012;21 SUPPL.3:150.
Antonio Clavenna graduated from the University of Milan with a degree in Medicine in 1994 and he is
specialist in Clinical Pharmacology. He took his PhD at the Open University, London, in 2009.
Since 2000 he has been working at the "Mario Negri" Research Institute of Milan as a Research Fellow in
the Laboratory for Mother and Child Health, Department of Public Health.
Since January 2012 he is the head of Pharmacoepidemiology Unit of the Laboratory of Mother and Child
Health.
Selected publications

Usala T, Clavenna A, Zuddas A, Bonati M. Randomised controlled trials of selective serotonin reuptake inhibitors in
treating depression in children and adolescents: A systematic review and meta-analysis. Eur Neuropsychopharmacol
2008;18:62-73.

Clavenna A, Bonati M. Drug prescriptions to outpatient children: a review of the literature. Eur J Clin Pharmacol
2009;65:749-755.

Clavenna A, Berti A, Gualandi L, Rossi E, De Rosa M, Bonati M. Drug utilisation profile in the Italian paediatric
population. Eur J Pediatr 2009; 168:173-180.

Clavenna A, Bonati M. Adverse drug reactions in childhood: a review of prospective studies and safety alerts. Arch Dis
Child. 2009;94:724-8.

Bianchi M, Clavenna A, Sequi M, Bortolotti A, Fortino I, Merlino L, Bonati M. Anti-asthma medication prescribing to
children in the Lombardy Region of Italy: chronic versus new users. BMC Pulm Med 2011;11:48.

Piovani D, Clavenna A, Cartabia M, Bonati M; on behalf of the Antibiotic Collaborative Group. The regional profile of
antibiotic prescriptions in Italian outpatient children. Eur J Clin Pharmacol 2012;68:997-1005
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Livio Garattini: got his degree in Economics in March 1983 at the Bocconi University in Milan.
Educational activities: “King’s Fund College”, London: courses of health care management; “Centre for
Health Economics”, York: review of publications on the English NHS; “Ecole Nationale de la Santé
Publique”, Rennes: courses of health policy.
Areas of interest: Health Economics and Health Policy Analysis.
At present he is the Director of CESAV (Centre of Health Economics A. e A. Valenti - M. Negri
Institute); 1981-1983: researcher at M. Negri Institute; 1983-1984: clerk at Banca Commerciale Italiana
in Milan; 1984- 1985: junior consultant at “Sogess srl” in Milan; 1985-1990: researcher at Bocconi
University in Milan.
Selected publications:
 Garattini L, Cornago D, De Compadri P. Pricing and reimbursement of in-patent drugs in seven European countries: A
comparative analysis. Health Policy 2007;82:330-339.
 Garattini L, Motterlini N, Cornago D. Prices and distribution margins of in-patent drugs in pharmacy: A comparison in
seven European countries. Health Policy 2008;85(3):305-313.
 Garattini L, Casadei G. Health technology assessment: for whom the bell tolls? The European Journal of Health
Economics 2008;9(4):311-312.
 Garattini L, Casadei G, Freemantle N. Continuing medical education funding and management in Europe: room for
improvement? (Editorial) JME 2009;12(1):56-59.
 Garattini L, Gritti S, De Compadri P, Casadei G. Continuing Medical Education in six European countries: A
comparative analysis. Health Policy2010;94:246-254.

Garattini L, Koleva D, Casadei G. Modeling in pharmacoeconomic studies: Funding sources and outcomes.
International Journal of Technology Assessment in Health Care 2010;26(3):330-333.
Guido Bertolini got his Medical degree in 1989 at the University of Bologna, and the specialization in
Pharmacological Research in 1993 at the “Mario Negri” Institute and in Gastroenterology in 1994 at the
University of Pavia.
He founded and chaired from 1997 to 2000 the School of Clinical Methodology and Quality of Care
Improvement at the Ospedali Riuniti di Bergamo and the Istituto di Ricerche Farmacologiche Mario
Negri. From 1999 to 2003 he has been contract professor at the post-doctoral schools in Anaesthesia and
Intensive Care, University of Brescia and Milano; from 2002 to 2005 he has been contract professor of
Educational Science at the Faculty of Lettere e Filosofia, University of Bergamo.
Current research interests: Clinical Research Methodology, Continuous Quality of Care Assessment and
Improvement, Health services research and outcome, Medical decision making, Medical Education.
These interests are mainly developed within the fields of Intensive Care Medicine and Rare Diseases.
Since 1997 he chairs the GiViTI Coordinating Center for research in intensive care medicine. He has been
Head of the Unit of Epidemiology and Education for Clinical Practice at the “Mario Negri” Institute and
since 2001 he is the Head of the Laboratory of Clinical Epidemiology. From 2001 to 2005 he has been
Vice-chairman of the Research Group on Cost-effectiveness, Section on Health Services Research and
Outcomes – European Society of Intensive Care Medicine and, from 2001 to 2005, he has been President
of the Scientific Committee of the “Ospedale maggiore” in Crema.
Selected publications

Bertolini G, Rossi C, Anghileri A, Livigni S, Addis A, Poole D. Use of drotrecogin alfa (activated) in Italian intensive
care units: the results of a nationwide survey. Intensive Care Med 2007;33:426-434.

Malacarne P, Langer M, Nascimben E, Moro ML, Giudici D, Lampati L, Bertolini G, GiViTI. Building a continuous
multicenter infection surveillance system in the intensive care unit: findings from the initial data set of 9,493 patients
from 71 Italian intensive care units. Crit Care Med 2008;36:1105-1113.

Poole D, Bertolini G, Garattini S. Errors in the approval process and post-marketing evaluation of drotrecogin alfa
(activated) for the treatment of severe sepsis. Lancet Infect Dis 2009;9:67-72.

Bertolini G, Boffelli S, Malacarne P, Peta M, Marchesi M, Barbisan C, Tomelleri S, Spada S, Satolli R, Gridelli B,
Lizzola I, Mazzon D. End-of-Life Decision-Making and Quality of ICU Performance: An Observational Study in 84
Italian Units. Intensive Care Med 2010 Sep;36(9):1495-504.

Marchall JC, Reinhart K, Angus D, Argent A, Bernard G, Bertolini G, Bhagwanjee S, Cobb JP, Cook DJ, Fedson D,
Finfer S, Fowler R, Gomersall C, Jimenez E, Kissoon N, McAuley N, Opal S, Vincent JL, Webb S. InFACT: a global
vritical care clinical research reponse to severe pendemic H1N1. Lancet 2010;375(9708):11-3.

Finazzi S, Poole D, Luciani D, Cogo PE, Bertolini G, GIVITI. Calibration belt for quality of care assessment based on
dichotomous variables. PLoS ONE 2011;6:e16110.

Bertolini G, Rossi C, Crespi D, Finazzi S, Morandotti M, Rossi S, Peta M, Langer M, Poole D. Is influenza A(H1N1)
pneumonia more severe than other community-acquired pneumonias? Results of the GiViTI survey of 155 Italian ICUs.
Intensive Care Med 2011;37: 1746-55.
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
Poole D, Rossi C, Latronico N, Rossi G, Finazzi S, Bertolini G. Comparison between SAPS II and SAPS 3 in predicting
hospital mortality in a cohort of 103 Italian ICUs. Is new always better? Intensive Care Med 2012;38:1280-88.
Davide Luciani got his Medical Degree at the University of Bologna in 1995, and the post-doctoral
certificate in "Tropical Medicine and Hygiene" at the University of Liverpool in 1997. In 2001, he spent
one year at the Department of Statistical Science (University College London). Bayesian probabilistic
applications, decision theory and the graphical approach to pathophysiological modelling represent his
main interests. Within his research activity, these skills are meant as the main methodological
ingredients in the formalization of clinical reasoning, in order to improve its effectiveness and to exploit
its educational value.
Since 2005 he is responsible of the Unit of Clinical Knowledge Engineering.
Selected publications

Luciani D, Marchesi M, Bertolini G. The role of Bayesian Network in the diagnosis of pulmunary embolism. J Thromb
Haemost 2003;1:698-707.

Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of
thrombosis in the antiphospholipid syndrome. Blood 2003;102 (8):2717-23.

Luciani D, Cavuto S, Antiga L, Miniati M, Monti S, Pistolesi M, Bertolini G. Bayes pulmonary embolism assisted
diagnosis: a new expert system for clinical use. Em Med J 2007;24:157-164.

M.Cesana, R.Cerutti, E.Grossi, E.Fagiuoli, M.Stabilini, F.Stella, D Luciani. Bayesian Data Mining Techniques: The
Evidence Provided by Signals Detected in Single-Company Spontaneous Reports Databases. Drug Information Journal
2007;41:11-21.

Latronico N, Bertolini G, Guarneri B, Botteri M, Peli E, Andreoletti S, Bera P, Luciani D, Nardella A, Vittorielli E,
Simini B, Candiani A Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian
multi-centre CRIMYNE study. Crit Care 2007;11(1):R11.

Bertolini G, Luciani D, Biolo G Immunonutrition in septic patients: A philosophical view of the current situation. Clin
Nutr 2007;26:25-29.

Squizzato A, Luciani D, Rubboli A, Gennaro LD, Landolfi R, De Luca C, Porro F, Moia M, Testa S, Imberti D,
Bertolini G. Differential diagnosis of pulmonary embolism in outpatients with non-specific cardiopulmonary symptoms.
Intern Emerg Med. 2011 Nov 18. [Epub ahead of print]
ACTIVITIES
The main aim of the Public Health Department is to understand which factors affect the health
of individuals or entire populations and to define effective interventions for responding to their
health needs. Special emphasis is therefore placed on prevention, so that the risks of contracting
illness are lowered, and on the dissemination of independent, evidence-based information.
The department’s effort cannot disregard the National Health System, however, which must
guarantee access to, and quality of, care that is based on principles of equity and appropriateness
and must guarantee it especially to the more vulnerable patient groups. It is in this context that
the Public Health Department carries out its activities.
In addition to its formal research activity, the department participates in, and organises,
initiatives involving information dissemination, training, and debate aimed at healthcare
operators and social care workers, but also at the general population. These activities are also
supported by the publication of the department’s two journals: Ricerca&Pratica and Quaderni
di Farmaco Economia.
"A. and A. Valenti" Centre for Health Economics (CESAV)
The "Angelo e Angela Valenti" Centre for Health Economics (CESAV) was established in 1992
at the "M. Negri Institute" and based at Villa Camozzi- Ranica (Bergamo)-Italy. CESAV is
primarily a research centre, but also does educational work. The centre is involved in health
economics and health policy research. The main areas of research are: Economic Evaluation of
Health Care Programs (i.e. assessment of costs and benefits of alternative health care treatments
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and services) and Comparative Health Policy Analysis (i.e. study of domestic and foreign health
care systems, in particular aimed at identifying possible innovations for European countries).
Laboratory of Clinical Epidemiology
The general aim of the Laboratory of Clinical Epidemiology is to contribute to the improvement
of health care in different medical fields. The guiding principles are mainly two: to help
physicians in using the available knowledge and resources at their best, and to contribute to the
growth of applied knowledge for clinical practice. The Laboratory operates in the field of
Intensive Care Medicine. In the main area of activity the laboratory developed an electronic
health record for the ICU which serves the dual purpose of simplifying and improving clinical
documentation and provide accurate data to search for the improvement of quality of care.
Within the Laboratory, the Unit of Clinical Knowledge Engineering aims to bring the value of
clinical reasoning out, through the implementation of probabilistic models for its formalization,
thus favouring the evaluation and the continuous improvement of complex clinical activities.
Laboratory for Mother and Child Health
The main objective of the Laboratory for Mother and Child Health is to ensure a better mother
and child well-being by undertaking interdisciplinary and collaborative work in the field.
Four broad areas, or spheres, of research have been selected:
- monitoring and epidemiological evaluation of utilisation and effects of drugs and vaccines;
- research methodology in general hospital and paediatric community practice;
- public health determinants of children’s well-being;
- transfer of health information to the community.
Special attention is given to activities involving countries in the north and south of the world.
In addition to the formal research activities, the Laboratory promotes initiatives in the public
health field, in particular those involving mother and child health care.
The initiatives involve the participation in, and the organisation of, educational, training, and
information-dissemination activities.
The critical and active transfer of scientific knowledge is a continuous, daily stimulus to the
laboratory’s activity.
NATIONAL COLLABORATIONS
"A. and A. Valenti" Centre for Health Economics (CESAV)
Public and private institutions, other health care organizations (Ministry of Health, Regional and
Local Health Authorities, Hospital Trusts).
Laboratory of Clinical Epidemiology
 Ospedale A. Manzoni, U.O. Anestesia e Rianimazione 1, Lecco.
 Ospedale San Giovanni Bosco, Servizio Anestesia e Rianimazione, Torino
 Università degli Studi di Brescia, Dipartimento di Specialità Chirurgiche,
Scienze Radiologiche e Medico Forensi, Cattedra di Anestesia.
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 Università di Firenze, Facoltà di Medicina e Chirurgia,Cattedra di Fisica e
Informatica Medica.
 Università di Milano Bicocca, Dipartimento di Informatica Sistemistica e
Comunicazione.
 Università degli Studi di Verona.
 CNT, Centro Nazionale Trapianti.
Laboratory for Mother and Child Health
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Centro per la Salute del Bambino, (CSB)
Cultural Paediatric Association, (ACP)
Federfarma Lombardia
Hospital of Brescia “Spedali Civili”
Hospital of Bergamo “Ospedali Riuniti”, Poison Control Centre, Unit Clinical
Toxicology
Institute “Don Calabra” (CTD), Negrar
Italian Drug Agency, (AIFA)
Italian Global Health Watch (OISG)
Italian National Institute of Health (ISS)
Italian Society of Preparers Pharmacists (SIFAP)
Il Pensiero Scientifico Editore
Lombardy Region, Ministry of Health
Operating unity of Neuropsychiatry of the childhood and of the adolescence,
Foundation “Policlinico di Milano”, (UONPIA)
Società Italiana di Farmacisti Preparatori (SIFAP)
University of Florence, Departments Area Biomedical, Medical Surgical Critical Area
University of Milan-Bicocca, Faculty Medicine, Paediatric Clinic
INTERNATIONAL COLLABORATIONS
"A. and A. Valenti" Centre for Health Economics (CESAV)
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CES (Collège des Economistes de la Santé) of Paris
Corvinus University of Budapest
Global Fund of Geneva
WidO of Bonn
Servicio Canario de la Salud, S/C de Tenerife
University of Birmingham
University of Hannover
University of York
University Pompeu Fabra of Barcelona
University Erasmus of Rotterdam
Laboratory of Clinical Epidemiology
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Istituto Bloomsbury di Cure Intensive, Istituto di Ricerca Biomedica, University
College Londra, Regno Unito
Clinica di Anestesiologia e Terapia Intensiva, Jena, Germania
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Machine Intelligence Group, Università di Aalborg, Danimarca (chiedere a Davide)
Istituto di Anestesia e Cure Intensive, Università di Semmelweis, Budapest, Ungheria
Dipartimento di Anestesiologia e Cure Intensive, Università di Varsavia, Polonia
Dipartimento di Cure Intensive, Ospedale Generale di Novo Mesto, Slovenia
Dipartimento di Pneumologia e Cure Intensive, Ospedale Generale di Nicosia, Cipro
Medicina Intensiva, Ospedale Regionale Beata Vergine, Mendrisio - Ticino, Svizzera
Terapia Intensiva Pediatrica, Soroka University Medical Center, Beer-Sheva, Israele
Laboratory for Mother and Child Health
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Centre for Tropical Diseases (CECOMET), Ecuador
Clínica Infantil Colsubsidio, Bogotà, Colombia
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European Medicines Agency (EMA)
European Society for Developmental, Perinatal and Paediatric Pharmacology (ESDPPP)
European Union (EU)
Fundació Privada Clinic per la Ricerca Biomedica, Spain
Fundacion Salud Ambiente y Desarrollo, Ecuador
Hospital Robert Debré, Paris, France
International Society of Drug Bulletins (ISDB)
Taller de Educacion y Comunicacion Guarani Asociacion, Bolivia
World Health Organization (WHO)
Universidad Peruana Cayetano Heredia, Perù
University of Amsterdam, Universiteit Van Amsterdam, Netherlands
University College London Hospital NHS Fuondation Trust, United Kingdom
University of Nottingham, Derbyshire Children’s Hospital, Derby, United Kingdom
Universidad Peruana Cayetano Heredia, Perù
 Coletivo de Estudios Aplicado y Desarrollo Social Juan XXIII, Bolivia
EDITORIAL BOARD MEMBERSHIP
"A. and A. Valenti" Centre for Health Economics (CESAV)
INTERNATIONAL:
Acta Bio Medica; Applied Health Economics and Health Policy; Biomedical Statistics and
Clinical Epidemiology; BMC-Health Services Research; Health Policy; Journal of Medical
Economics; The European Journal of Health Economics.
NATIONAL:
FarmacoEconomia
News;
Farmeconomia
e
Percorsi
Terapeutici;
L'Internista;
PharmacoEconomics Italian Research Articles; Quaderni di FarmacoEconomia.
Laboratory of Clinical Epidemiology
INTERNATIONAL:
Intensive Care Medicine
NATIONAL:
Ricerca & Pratica;
Dedalo. Gestire i sistemi complessi in sanità.
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Laboratory for Mother and Child Health
INTERNATIONAL:
European Journal Clinical Pharmacology; Revista Paulista de Pediatria; Journal of Clinical
Pharmacology & Pharmacoepidemiology; Saludarte.
NATIONAL:
Dialogo sui Farmaci; Disturbi d’Attenzione e Iperattività; Quaderni di Farmacoeconomia;
Ricerca & Pratica.
PEER REVIEW ACTIVITIES
"A. and A. Valenti" Centre for Health Economics (CESAV)
Applied Health Economics and Health Policy; BMC-Health Services Research; Health Policy;
PharmacoEconomics; The European Journal of Health Economics; Epilepsia; British Medical
Journal.
Laboratory of Clinical Epidemiology
INTERNATIONAL:
Intensive Care Medicine; Critical Care Medicine; Clinical Sarcoma Research; Annals of
Internal Medicine.
NATIONAL:
Ricerca & Pratica
Laboratory for Mother and Child Health
INTERNATIONAL:
Acta Paediatrica; Annals of African Medicine; Archives of Disease in Childhood; Basic &
Clinical Pharmacology & Toxicology; BMC Clinical Pharmacology; BMJ Open; Breastfeeding
Medicine; British Journal of Clinical Pharmacology; European Child and Adolescent
Psychiatry; European Journal of Clinical Pharmacology; Expert Opinion On Drug Safety;
Health and Quality of Life Outcome; Infection; International Journal of Tropical Disease &
Health; Italian Journal of Pediatrics; Journal of Child Health Care; Springer Plus;
Pharmacoepidemiology and Drug Safety; Pediatric Pulmonology; Pediatrics; PLoS ONE; The
Journal of Pediatrics; The Pediatric Infectious Disease Journal.
NATIONAL:
Dialogo sui Farmaci; Medico e Bambino; Quaderni ACP.
NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
Laboratory of Clinical Epidemiology

Scientific Council of the Health and Illness Interdisciplinary Research Centre,
Bergamo University
 Scientific Commitee of the Lombardy Region on cancer research
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 National Health Plan Research Commission, Emilia Romagna Region
Laboratory for Mother and Child Health
 Ethical committee A.O. "Ospedale Maggiore" of Crema
 Therapeutic Formulary, Valle d'Aosta Autonomous Region
EVENT ORGANIZATION
"A. and A. Valenti" Centre for Health Economics (CESAV)
National Congress of Pharmacoeconomics: “Economia del farmaco: fra soluzioni tecniche e
decisioni politiche”, May 29-30, Ranica (BG).
Laboratory of Clinical Epidemiology
Workshop, PROSAFE Final Meeting, February 23-24, Ranica (BG).
Workshop, Meeting MargheritaTre, June 06, Ranica (BG).
Congress, Meeting annuale GiViTI, November 14-16, Pesaro.
Laboratory for Mother and Child Health
Congress “La Drug Utilization attraverso i database amministrativi” Laboratory for Mother
and Child Health, IRFMN, Milan.
CONFERENCE AND WORKSHOP CONTRIBUTIONS
"A. and A. Valenti" Centre for Health Economics (CESAV)
April
Congress: “Bosnian-Herzegovinian and second adriatic congress on pharmaco-economics and
outcomes research”, 25-26 April, Sarajevo
June
Congress: “Home Care, le cure domiciliari nella medicina della complessità” , 6-9 June, Milano
Congress: “L’oggi e il domani, costi e prospettive dei farmaci in onco-ematologia per un futuro
sostenibile” , 22 June, Udine
July
Congress: “Ematologia e Biosimilari” , 9 July, Milano
September
Congress: “Las Reformas Sanitarias en España e Italia: Descentralización, Cartera de Servicios,
e incorporación de la Innovación”, 13 September, Madrid
October
Congress: “I farmaci biosimilari, un impiego intelligente di risorse” , 9 October, Bergamo
November
Congress: “Il protocollo di gestione del paziente diabetico” 29 November, Lecco
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Laboratory of Clinical Epidemiology
February
Course: “Il nursing e la riabilitazione in area post-critica” – Galato di Pavullo (MO).
Workshop: “Final Meeting PROSAFE” – Ranica (BG).
March
Congress: Pneumotrieste” – Trieste.
April
Course: Manager in sanità, SDA Bocconi; Milano.
Congress: “Incontro GiViTI Zingonia” – Zingonia (BG).
Course: “Utilizzo del software Margherita Tre” – Grosseto.
May
Seminary: “Seminari su i temi chiave dei nuovi Ospedali per Intensità di cure” – Pistoia.
Course: Lezione specialità, medici d’urgenza – Ceresole D’Alba (CN).
Course: “Utilizzo del software Margherita Tre” – Genova.
June
Congress: “Tuscany-XV Annual Meeting” – Firenze.
September
Congress: “Weil Conference: “Cardiac arrest, shock and trauma. Save patients lives through
research in Critical Care and education” – Milano.
Congress: “WORLD SEPSIS DAY” – Firenze.
Congress: “WORLD SEPSIS DAY: Il quadro delle iniziative di lotta alla sepsi in Regione
Lombardia” – Milano.
Workshop: “PROSAFE project” – Budapest.
Congress: “Riunione Terapie Intensive aderenti al GiViTI dell’Emilia Romagna” – Forlì.
November
Congress: Meeting GiViTI 2011; Pesaro.
Congress: “Riunione Monotematica: I Network della Nutrizione Artificiale” – Bologna.
Course: “Utilizzo del software Margherita Tre” – Siena.
December
Course: “Utilizzo del software Margherita Tre” – Roma.
Laboratory for Mother and Child Health
January
Percorsi di cura dei disturbi neuropsichiatrici in età evolutiva. Seminary “Il Policlinico
incontra il Mario Negri”. Fondazione IRCCS Ca’ Granda; Milan.
March
ADHD in Italia: prossimo anno. IV ADHD. Workshop: “Dalle evidenze alla pratica
clinica”. Università degli Studi di Cagliari, Dipartimento di Scienze Biomediche; Azienda
Ospedaliero-Universitaria di Cagliari, Clinica di NeuroPsichiatria Infantile. Cagliari.
Lo screening della depressione post partum nel setting della pediatria di famiglia. Uno studio
osservazionale con i PLS della ASL Milano 1. Course: “I disturbi psicopatologici nel
periodo perinatale. Evidenze internazionali e nuove progettualità”. Azienda Ospedaliera
Guido Salvini Garbagnate Milanese e Regione Lombardia; Rho, (MI).
La prescrizione dei farmaci off-label. Course: “Agitazione psicomotoria: proposta di un
percorso diagnostico terapeutico”. Ospedale Niguarda Ca’ Granda; Milan.
Farmaci, salute, bambini ... Incontro Scuola Telethon. Istituto di Ricerche Farmacologiche
Mario Negri; Milan.
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April
Epidemiologia geografica delle prescrizioni di antibiotici. 13° conferenza italiana: “Utenti
ESRI”. Esri Italia Intelligenza del Territorio; Rome.
May
Different types of pediatric research. Course: “Ethics of Pediatric Research”. Università
degli studi di Padova; Padova.
The TINN2 safety and ethics monitoring board – presentation of the members and on-going
activities. Seminary: “TINN2 First 18 months General Meeting”. TINN2; Paris, France.
La prescrizione dei farmaci in età pediatrica. Farmaci in gravidanza e allattamento. Course.
Associazione Culturali Pediatri (ACP); Brindisi.
Farmaci essenziali: reperimento conservazione, distribuzione. Corso di formazione base.
Medici in Africa; Genoa.
L’informazione sull’uso dei farmaci in allattamento. Formazione sull’uso dei farmaci,
farmacovigilanza e gestione dell’allattamento (FARFALLA). Istituto Superiore di Sanità;
Rome.
June
La nascita e l’infanzia indicatori di diritto. Summer School Course “Salute e/è diritto.
Popolazioni invisibili, competenze, networking”. Certosa Gruppo Abele e LEC; Turin.
Vulnerabilità/disastro. Seminary “Architettura per lo sviluppo”. Architetti Senza Frontiere
Italia e Fondazione Ordine Architetti P.P.C. Provincia di Milano; Milan.
Coordinating resources to assess and improve the health status of migrants from Latin
America (COHEMI). 4th Conference on Migrant and Ethnic Minority Health in Europe:
“Facts Beiong Figures. Communi-Care for Migrants and Ethnic Minorities”. Università
Bocconi; Milan.
Reazioni avverse in gravidanza. Master “Corso di Perfezionamento in Farmacovigilanza”.
Servizio di Epidemiologia e Farmacologia Preventiva; Milan.
Il self help infettivo logo: perchè. Course “Self help infettivologico”. ASL Milano Regione
Lombardia; Milan.
Farmaci e bambini. Course “Scuola di specializzazione in Farmacia Ospedaliera”.
Università degli Studi di Milano; Milan.
July
L’uso dei farmaci per i bambini. Course “Summer Students”. Istituto di Ricerche
Farmacologiche Mario Negri; Milan.
September
“Terapia psicofarmacologica nell’età evolutiva: uso razionale dei farmaci” ADHD.
Seminary “Qualità delle cure in età pediatrica. Un Progetto da sostenere e difendere”.
Università degli Studi di Pavia, Scuola di Specializzazione in Neuropsichiatria Infantile,
Pavia.
Farmaci essenziali in pediatria: utilizzo razionale nelle patologie infettive, respiratorie e
gastroenteriche. 2° National Cogress SiMPeF “Qualità delle cure in età pediatrica. Un
Progetto da sostenere e difendere”. Sindacato Medici Pediatri di Famiglia (SiMPeF);
Baveno (VB).
La prescrizione di antibiotici in età pediatrica. Course. Associazione per la Formazione
permanente dei Pediatri altoatesini (AFPA); Bolzano.
“Terapia psicofarmacologica nell’età evolutiva: uso razionale dei farmaci” ADHD, GTS,
Autismo. Seminary “Qualità delle cure in età pediatrica. Un Progetto da sostenere e
difendere”. Università degli Studi di Pavia, Scuola di Specializzazione in Neuropsichiatria
Infantile, Pavia.
October
Maternal Health Concerns. 16th ISRHML Conference “Breastfeeding and the Use of
Human Milk. Science & Practice”. International Society for Research in Human Milk and
Lactation; Trieste.
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Registro Regionale Lombardia per l’ADHD. Convegno “ADHD dalla clinica, alla scuola,
alla famiglia. Una sfida da vincere insieme”. AIFA Onlus; Naples.
Linee Guida: come sceglierle. Seminary “Il medico e l’industria della salute: rischi e
benefici”. ASL Cagliari; Associazione Culturali Pediatri (ACP); Associazione Nazionale
cardiologi Extraospedalieri (ANCE). Cagliari.
“Efficienza ed efficacia della psicofarmacologia nell'età evolutiva”. Seminary “Qualità delle
cure in età pediatrica. Un Progetto da sostenere e difendere”. Università degli Studi di
Pavia, Scuola di Specializzazione in Neuropsichiatria Infantile, Pavia.
Research and activities in mother and child health. European Master “Sustainable Regional
Health System: Erasmus Mundus”. Istituto di Ricerche Farmacologiche “Mario Negri”
(IRFMN); Milan.
Farmacoterapia: farmaci utili, inutili e farmaci futili. Meeting “III Focus di Pediatria”.
Ospedale “Sacro Cuore di Gesù” Fatebenefratelli - U.O.C. di Pediatria Neonatologia - UTIN;
Benevento.
November
Il monitoraggio dei pazienti con ADHD: esperienze regionali italiane. Course “Sindrome da
Deficit Attentivo ed Iperattività”. Scuola Umbra di Amministrazione Pubblica; Perugia.
Le priorità per una persona con malattia cronica. XVIII Congress of the Italian Cystic
Fibrosis and VIII National Congress of the Italian Society for the Study of Cystic Fibrosis
“Ridefiniamo le priorità delle persone con FC”. Società Italiana di Fibrosi Cistica; Tirrenia
(PI).
Problematiche etiche dell’uso dei farmaci off-label. 3° project Congress MEAP “La
farmacovigilanza tra Scienza ed Etica”. Regione Lombardia e Ospedale Luigi Sacco; Milan.
I farmaci Anti VEGF nel neonato prematuro. Il punto di vista del farmacologo. 92° National
Congress SOI “… dove si incontrano i protagonisti dell’oftalmologia”. Società
Oftalmologica Italiana; Rome.
I farmaci EQUIVALENTI. Il profilo prescrittivo dei farmaci in pediatria. Corso di
Aggiornamento Pediatri “La prescrizione dei farmaci in pediatria”. ASL di Taranto; Martina
Franca (TA).
December
Molteciplità. Congress “La sanità tra ragione e pasione”. LIB talks; Bologna.
Farmaci e bambini. Course. Università degli Studi di Milano-Bicocca, Facoltà di Medicina e
Chirurgia, Scuola di Specializzazione in Pediatria; Monza (MB).
GRANTS AND CONTRACTS
"A. and A. Valenti" Centre for Health Economics (CESAV)
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Abbott
Astra Zeneca
AIFA
Boehringer-Ingelheim
Daiichi Sankyo
Eisai
Grunenthal-Prodotti Formenti
Hospira
Novartis
Sanofi Aventis
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 Sanofi Pasteur MSD
 Nycomed
 Vivisol
Laboratory of Clinical Epidemiology
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Bellco SpA
Regione Lombardia
Commissione Europea DG SANCO
Brahms
SINPE
CNT
A.O. Como
A.O. Lecco
ASL 1 Sassari
ASL 2 Olbia
ASL AL
ASL TO2
ASL TO4
IRCCS Policlinico S.Matteo di Pavia
A. O. Reggio Emilia
USL1 Massa Carrara
USL di Cesena
USSL9 Treviso
Ospedale Evangelico Internazionale di Genova
Azienda USL9 Grosseto
Azienda Sanitaria di Firenze
A.O. Sant'Andrea di Roma
USL 7 di Siena
ASL 3 Genovese
Laboratory for Mother and Child Health
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Brescia’s A.O. Spedali Civili
European Commission DG SANCO
ICEI, Istituto Cooperazione Economica Internazionale.
IRCCS Burlo Garofolo, Trieste
IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano
Italian Drug Agency, (AIFA)
Lombardy Region – Assessorato alla Sanità
Milan Province
Valle d'Aosta Region – Assessorato alla Sanità
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SCIENTIFIC PUBLICATIONS (2012)
"A. and A. Valenti" Centre for Health Economics (CESAV)
Garattini L, Van de Vooren K. Extending HPV vaccination to boys: an economic perspective. BMJ 13 Jan 2012
http://www.bmj.com/rapid-response/ 2012/01/13/re-should-hpv-vaccine-be-given-men. [e-pub]
Garattini L, Van de Vooren K. HPV vaccination for boys? Talking economic sense for the Journal of Sexual
Medicine. Journal of Sexual Medicine 2012;9(8):1-2.
Garattini L, Van de Vooren K. Could co-payments on drugs help to make EU health care systems less open to
political influence? Eur J Health Econ 2012 Sep 9 [e-pub ahead of print]
Garattini L, Van de Vooren K, Curto A. Pricing Human Papillomavirus Vaccines, Lessons from Italy.
PharmacoEconomics 2012;30:213-17.
Garattini L, Van de Vooren K, Curto A. Human papillomavirus vaccination is not exclusively a matter of price. The
author's reply. PharmacoEconomics 2012;30(5):444-45.
Garattini L, Van de Vooren K, Curto A. Will the reform of community pharmacies in Italy be of benefit to patients or
the Italian National Health Service? Drugs and Therapy Perspectives 2012;28(11):23-25.
Garattini L, de Vooren K, Curto A. Regional HTA in Italy: promising or confusing? Health Policy 2012;108(23):203-206.
Raho G, Koleva D, Garattini L, Naldi L. The Burden of Moderate to Severe Psoriasis: An Overview.
PharmacoEconomics 2012;30:1005-13.
Laboratory of Clinical Epidemiology
Bonaldi G, Bertolini G, Marrocu A, Cianfoni A. Posterior Vertebral Arch Cement Augmentation (Spinoplasty) to
Prevent Fracture of Spinous Processes after Interspinous Spacer Implant. AJNR Am J Neuroradiol 2012;33:522-8.
Gatti E, Luciani D, Stella F. A continuous time Bayesian network model for cardiogenic heart failure. Flexible
Services Manufacturing Journal 2012;24:496-515.
Luciani D, Bazzoni G. From networks of protein interactions to networks of functional dependencies. BMC Syst Biol
2012;6:44.
Luciani D, Stefanini FM. Automated interviews on clinical case reports to elicit directed acyclic graphs. Artif Intell
Med 2012;55:1-11.
Pereira JM, Moreno RP, Matos R, Rhodes A, Martin-Loeches I, Cecconi M, Lisboa T, Rello J, Bertolini G; ESICM
H1N1 Registry Steering Committee; ESICM H1N1 Registry Contributors. Severity assessment tools in ICU patients
with 2009 influenza A (H1N1) pneumonia. Clin Microbiol Infect 2012;18:1040-8.
Poole D, Bertolini G, Garattini S. Withdrawal of ‘Xigris’ from the market: old and new lessons. J Epidemiol
Community Health 2012;66:571-2.
Poole D, Rossi Carlotta, Latronico N, Rossi G, Finazzi S, Bertolini G, GIVITI. Comparison between SAPS II and
SAPS 3 in predicting hospital mortality in a cohort of 103 Italian ICUs. Is new always better? Intensive Care Med
2012;38:1280-8.
Squizzato A, Luciani D, Rubboli A, Gennaro LD, Landolfi R, De Luca C, Porro F, Moia M, Testa S, Imberti D,
Bertolini G. Erratum to: Differential diagnosis of pulmonary embolism in outpatients with non-specific
cardiopulmonary symptoms. Intern Emerg Med 2012 Nov 18. [Epub ahead of print].
ANNUAL REPORT
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Laboratory for Mother and Child Health
Arcieri R, Germinario EAP, Bonati M, Masi G, Zuddas A, Vella S, Chiarotti F, Panei P and Italian regional reference
centers. Cardiovascular Measures in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder Who
Are New Users of Methylphenidate and Atomoxetine. Journal of Child and Adolescent Psycopharmacology
2012;22:423-431.
Bianchi M, Clavenna A, Sequi M, Bortolotti A, Fortino I, Merlino L, Bonati M. Spirometry testing in a population of
italian children: age and gender differences. Respiratory Medicine 2012;106(10):1383-1388.
Bonati M, Clavenna A. Seasonal influenza immunization in early infancy? BMC Public Health 2012;12:873.
Cartabia M, Campi R, Clavenna A, Bortolotti A, Fortino I, Merlino L, Bonati M. Geographical of antibacterials in the
preschool age. Intern J Health Geographics 2012;11(1):52.
Clavenna A, Cartabia M, Sequi M, Costantino A, Bortolotti A, Fortino I, Merlino L, Bonati M. Burden of psychiatric
disorders in the pediatric population. Eur Neuropsychopharm 2012 (http://dx.doi.org/10.1016/
j.euroneuro.2012.04.008); May 4[e-pub].
Gallo M, Clavenna A, Bonati M, Siani P, Irpino A, Rossi F, Capuano A and ADR Regional Study Group. Active
surveillance of adverse drug reactions in children in five Italian paediatric wards. Open Journal of Pediatrics
2012;2:111-117.
Fortinguerra F, Clavenna A, Bonati M. Ocular medicines in children. BMC Pediatrics 2012;12:8 [e-pub].
Kaguelidou F, Pandolfini C, Manzoni P, Choonara I, Bonati M, Jacqz-Aigrain E. European survey on the use of
prophylactic fluconazole in Neonatal Intensive Care Units. Eur J Ped 2012;171:439-445.
Pandolfini C, Sequi M, Jacqz-Aigrain E, Choonara I, Turner M, Manzoni P, Bonati M. Wide intra- and inter-country
variability in drug use and dosage in very-low-birth-weight newborns with severe infections. Eur J Clin Pharmacol
2012; (doi:10.1007/s00228-012-1415-2) 5 Oct [e-pub].
Piovani D, Clavenna A, Cartabia M, Bonati M. The regional profile of antibiotic prescriptions in Italian outpatient
children. Eur J Clin Pharmacol 2012;68:997-1005.
Review
Sequi M, Campi R, Clavenna A, Bonati M. Methods in Pharmacoepidemiology: a review of statistical analyses
applied in pediatric drug utilization studies. Eur J Clin Pharmacol 2012 (doi:10.1007/s00228-012-1354-y: e-pub) Jul
26.
Letter
Bonati M, Confalonieri V. Global rights for global diseases. The shortage of benznidazole case. Eur J Public Health
2012; http://eurpub.oxfordjournals.org/ forum/topic/eurpub_el%3b316 [e-pub].
Comment
Bianchi M, Clavenna A, Bonati M. Age and number of prescriptions are relevant when estimating asthma prevalence.
PLoS
ONE
2012;
http://www.plosone.org/annotation/listThread.action;jsessionid=631AA80FB4BB8FB75F956D6EECFB41F1?root=5
0785: e-pub.
LAY PRESS SELECTION (2012)
"A. and A. Valenti" Centre for Health Economics (CESAV)
Casadei G, Garattini L. Liberalizzazioni in farmacia: Cosa cambia e cosa cambiare? Dialogo sui Farmaci 2012;1:1821.
Casadei G. Recessione economica e HTA: una sinergia da sviluppare. QdF 2012;18:5-7.
Casadei G, Garattini L. Liberalizzazioni e farmacie: eppur si muove. R&P 2012;165:99-102.
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Casadei G. Farmaci oncologici e tempi di accesso al mercato in Italia. R&P 2012;28 (6):241-251.
Curto A, Garattini L. Estensione della vaccinazione HPV ai maschi: una chiave di lettura economica. QdF 2012;17:58.
Curto A, Garattini L. Liberalizzazioni dei farmaci. Consumatori, Diritti e Mercato 2012;2:150-158.
Curto A, Garattini L. Liberalizzazioni in farmacia: un’analisi della riforma in prospettiva europea. QdF 2012;18:1726.
Curto A, Lo Muto R, Casadei G. Health Technology Assessment a livello regionale: fra mito e realtà. QdF
2012;17:22-32.
Curto A, Van de Vooren K, Garattini L. Compartecipazione alla spesa farmaceutica in una prospettiva europea. QdF
2012;19:20-28.
Garattini L. Decretone ‘Balduzzi’: basteranno i buoni propositi. QdF 2012;19:5-7.
Lo Muto R, Caiazzo M, Fabiano V, Giacomet V, Rampon O, Garattini L. Il costo delle infezioni HIV in età
pediatrica. Quaderni di Farmaco Economia 2012;18:8-16.
Lo Muto R, Curto A. Revisione delle valutazioni economiche sul Cetuximab applicato al CCR. QdF 2012;17:8-21.
Lo Muto R, Curto A, De Compadri P, Garattini L. Assistenza domiciliare: revisione critica delle valutazioni
economiche in Europa. QdF 2012;19:8-19.
Laboratory for Mother and Child Health
Bonati M. Vaccinare i neonati contro l’influenza stagionale? Medico e Bambino 2012;31:46-48.
Bonati M. Un anno di saudade! R&P 2012;167:239-40.
Bonati M. Sandro Liberati: ragione e passione giocose. R&P 2012;163:3-4.
Bonati M, Confalonieri V. The need of more equality for global health. The shortage of benznidazole case. R&P
2012;164:84-86.
Campi R. Guida pratica al monitoraggio della CRC. R&P 2012;163:39-41.
Clavenna A. La profilassi con vitamina K nel neonato. Medico e Bambino 2012;31:422-423.
Clavenna A, Fortinguerra F, Piovani D. Bambini, malattie (più o meno) trascurate e accesso ai farmaci: cattive nuove
e buone nuove. Quaderni acp 2012;19:39.
Clavenna A, Fortinguerra F, Piovani D. Antibiotici: a chi troppi e a chi… niente? Qualche autocitazione (forse di
troppo) per riflettere sulla prescrizione di antibiotici in età pediatrica. Quaderni acp 2012;19:133.
Clavenna A, Fortinguerra F, Piovani D. Cefalosporine per la faringotonsillite: una raccomandazione che lascia
perplessi. Quaderni acp 2012;19:180.
Clavenna A, Fortinguerra F, Piovani D. Farmaci e bambini: persiste il divario tra carico di malattia e sperimentazione
clinica. Quaderni acp 2012;19:284.
Clavenna A, Fortinguerra F, Piovani D. Psicofarmaci e bambini: il monitoraggio è essenziale. Quaderni acp
2012;19:84.
Confalonieri V. QI vs QE: quoziente intellettivo vs quoziente emotivo. R&P 2012;165:136-137.
Confalonieri V. Non smettere di interrogarsi sulle notizie in medicina. R&P 2012;167:225.
Confalonieri V. Farmaco per ridurre la trasmissione sessuale dell’HIV. R&P 2012;167:231-32.
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Fortinguerra F. Licenze d'uso ed etichette dei farmaci utilizzati in un reparto di oncologia pediatrica. Farmacia
Clinica Pediatrica. GIFC 2012;26:45.
Fortinguerra F. Le iniziative pediatriche nel mondo. A che punto siamo? Farmacia Clinica Pediatrica. GIFC
2012;26:515-516.
Guarnaccia S, Bianchi M, D’Agata E, Boldini G, Pluda A, Boldi A, Clavenna A, Cartabia M, Bonati M. Valutazione
dell’efficacia di un percorso terapeuticoeducazionale nel migliorare il controllo dell’asma in bambini e adolescenti.
Medico & Bambino 2012; pagine elettroniche 15(9) http://www.medicoebambino.com/?id=RIC1209_10.html.
Piovani D. I database amministrativi per la sorveglianza della sicurezza del farmaco. R&P 2012;167:223.
Piovani D. Segnalazioni in rete. R&P 2012;166:172-173.
Piovani D, Clavenna A, Sequi M, Cartabia M, Bortolotti A, Merlino L, Fortino I, Bonati M. Voce di spesa per
antibiotici ai bambini in Lombardia: si puo' risparmiare. R&P 2012;164:52-59.
Rezzonico R, Caccamo M L, Sanchez N, Parades S, Cartabia M, Froesch P, Cavalli F. Efficacia della ventilazione
non invasiva neonatale a basso costo in Nicaragua. R&P 2012;167:193-209.
Tranfert Information Press
Bonati M, Garattini S. Sindaco, il garante per l'infanzia? Corriere della Sera 2012;20 novembre:pag. 7.
OTHER PUBLICATIONS (2012)
Laboratory of Clinical Epidemiology
GiViTI. Progetto MargheritaPROSAFE – PROmoting patient SAFEty research and quality improvement in critical
care medicine. RAPPORTO 2011. Bergamo: Edizioni Sestante, 2012
Laboratory for Mother and Child Health
Clavenna A, Piovani D, Fortinguerra F. Farmaci in gravidanza: l'esperto risponde. Un team di specialisti a
disposizione
per
i
quesiti
dei
lettori
di
Corriere.it.
Corriere
della
Sera.it;
http://www.corriere.it/salute/esperto/farmaci_gravidanza/forum-farmaci-gravidanza-introduzione_7c1c63c8-339411e0-ae6d-00144f486ba6.shtml. [Popular Press]
“Child Health in the European Union”. Unione Europea. Editori: Cattaneo A, Cogoy L, Macaluso A, Tamburlini G.
[report]
RESEARCH ACTIVITIES
"A. and A. Valenti" Centre for Health Economics (CESAV)
Educational activities
Educational activities are developed only if related to research studies, in order to offer
original contributions which naturally reinforce the research aims.
Economic Evaluation of Health Care Programmes
The aim of this research area is to assess the costs of pathologies and the cost-effectiveness
ratios of the diagnostic/therapeutic existing alternatives. In general, analyses can be
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classified into two groups: partial economic evaluations (e.g. cost of illness analysis) and full
economic evaluations (e.g. cost-effectiveness analyses).
Comparative Health Policy Analysis
The aim of this research area is to study the organization of health care systems, in order to
draw lessons from international comparisons. This is particularly important in a "market" like
health care where economic competition lacks by definition and therefore public regulation
plays a crucial role.
Quaderni di FarmacoEconomia
QdF is a quarterly journal of pharmacoeconomics published by CESAV. It is designed as a
tool to favour a critical approach to the economic aspects of the pharmaceutical sector
among NHS professionals, with particular reference to economic evaluations and drug
policies at the national and international levels. It was first published in 2006 with the aim to
keep the "voice" of independent research alive and to improve the critical skills of Italy’s
health workers. The editors of QdF believe in the importance of offering the chance to
receive updates and critical inputs on pharmacoeconomy to health system operators without
a strong background on the subject. The ultimate goal is a context in which those working in
this field won’t have the illusion of finding a "magic solution" and won’t accept for gold
everything that is published. There is a critical risk, however, of disappointment in the long
run and a loss of credibility in the pharmacoeconomy field. This magazine represents an
opportunity to read the more debated economic and drug policy issues with a critical mind
and adequate tools.
Laboratory of Clinical Epidemiology
Quality of care in the Intensive Care Units
The main purpose of these research projects is the assessment and improvement of the
quality of care in Italian Intensive Care Units (ICUs). It is a multi-annual project promoted
on behalf of GiViTI, a collaborative network composed by more than half of the Italian ICUs
and coordinated by the Laboratory. The main focus is the Project Margherita. Its aim is the
continuous evaluation of the quality of care and it is based on a free software developed by
the Laboratory and distributed to all the ICUs adhering to the GiViTI group. The software
has been realized on a modular structure, which enables to easily integrate the basic data
collection (the “core” of Margherita) with the data collection of specific research projects
(the “petals” of Margherita).
Since January 2011, Margherita became an international project. Thanks to funding from the
European Union and other contracts of the laboratory have in fact been able to develop new
software and to distribute the project to eigth countries: Slovenia, Hungary, Poland, Cyprus,
Israel, Afghanistan, Sudan and Switzerland.
Appropriateness of the Intensive Care Units
ICU is a high technology environment, that requires a high number of high-level personnel.
Hence, the cost of these units is extremely important and a special attention not to waste
resources is mandatory. In this field, the Laboratory launched a study to assess the level of
appropriateness of the use of ICU beds, in an Italian regions: Lombardia. Such an evaluation
is based on the understanding that the level of care provided by an ICU should correspond to
the level of care it can theoretically provide, given the available resources. In this
framework, patients are classified as requiring high-, low-, or ordinary-care, and beds are
independently classified are high- or low-level. The appropriateness evaluation protocol
adopted verify the concordance between these two separate classifications.
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The reconstruction of clinical reasoning in the medical practice and
education
This area represents the main concern of the Unit of Clinical Knowledge Engineering, whose
objective is the valorization of clinical reasoning in solving complex clinical problems.
The diagnosis of pulmonary embolism still represents a relevant clinical challenge, due to
the complexity of the patient's clinical presentation and the variability of diagnostic
resources among Centres. In this regards, we are conducting an Italian multicenter study,
involving mainly Emergency Units, with the aim of prospectively validating the diagnostic
software BayPAD (Bayes Pulmonary embolism Assisted Diagnosis). Such a tool, relying on
a probabilistic model covering 72 clinical variables and doing without the need to input all
the contemplated observations, would overcome the main reasons which prevented ordinary
clinical guidelines to be largely accepted. Moreover, the results of the retrospective
validation of the system have been obtained.
The Unit started a project for the realization of a software assisting the physician in tracing
back the basis of his clinical decisions before the description provided by clinical reports,
among those that are typical of particular medical specialty. The software has the double
target to create specific applications based on probabilistic models representing complex
clinical decision problems, and to involve physicians in their construction. The last target is
achievable given the strong analogy between the causal structure of the exploited models
(bayesian networks) and the pathophysiological structure of medical knowledge. By this, it
will be given the chance to adopt this system within medical training projects, with a special
attention to e-learning programs.
An electronic health record to promote research in Intensive Care
Medicine
The main aim of this project is the continued development of an electronic health record
(EHR) the allows the assessment of indicators of the process of care in the ICU. A
multidisciplinary team of intensivists, ICU nurses, epidemiologists, statisticians, and IT
specialists, had the responsibility of planning the HER, that is now already shared by 30
Italian ICUs. This made it possible to launch the first analysis of the process that has as its
goal the improvement of the practice of weaning from the ventilator.
Home artificial nutrition in Italy
The SINPE (Italian Society of Artificial Nutrition and Metabolism) with the support of the
Laboratory of Clinical Epidemiology promotes the project "DOMUS, the new register of
home artificial nutrition".
DOMUS project created with the aim to describe three types of patients who are subjected to
artificial nutrition at home:
- cancer patients
- patients with benign severe chronic intestinal
- patients undergoing enteral nutrition at home
and to reveal the activity, efficacy and safety of programs of NAD (Artificial Nutrition at
Home), on base of SINPE indicators.
Laboratory for Mother and Child Health
Efficacy of Nebulised Beclometasone versus placebo in preventing viral
wheezing in pre-school children. (ENBe)
The Laboratory for Mother and Child Health coordinates the “Efficacy Of Nebulised
Beclometasone Versus Placebo In Preventing Viral Wheezing In Pre-School Children”
(ENBe) randomised controlled trial.
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The study is funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA)
with a grant for independent research on drugs and it is performed in collaboration with the
Associazione Culturale Pediatri and the "Angelo and Angela Valenti" Centre for Health
Economics (CESAV). The ENBe study involved 40 family paediatricians in 9 Italian local
health units (LHU) representative of geographical distribution and setting.
The aim of the study was to evaluate the safety and effectiveness of beclometasone in
preventing wheezing in viral upper respiratory tract infection (URTI).
The study started in October 2010 and ended in October 2012.
In all, 1371 children 1-5 years of age with upper respiratory tract infection and at least one
viral wheezing episode in the 12 months preceding the visit were visited. A total of 525
children were enrolled: 319 males and 206 females, with a mean age of 2 years.
The main reason for exclusion was the presence of wheezing at the entry visit (71% of the
excluded children). Parents did not provide the consent for 20% of the eligible children.
264 children were randomized to beclometasone (400 mcg) and 261 to placebo. Both drug
and placebo were administered twice daily through a nebuliser. The therapy lasted 10 days.
521 children were visited at the end of the treatment period and 507 completed the 6 month
observational follow up period.
The percentage of children with wheezing (diagnosed by the paediatrician) during the URTI
episode was the primary outcome measure.
The data analyses are ongoing.
ENBe Newsletter. As part of the ENBe study the Laboratory set up a newsletter aimed at
providing investigators and interested health operators with a periodic bibliographic update
of the recent scientific literature via email. A total of 9 issues have been sent to 104 health
professionals (mainly family paediatricians). The newsletter has identified a total of 127
scientific articles. ([email protected])
Pharmacoepidemiology in the Lombardy Region
The Laboratory for Mother and Child Health is involved in the analysis of the drug
prescription profile in children and adolescents in the EPIFARM (Epidemiologia del
farmaco) project funded by the Lombardy Region.
During 2012 the activities regarded, in particular, an evaluation of the:
1) paediatric prescription profile of antibiotic drugs; 2) generic drug prescribing; 3)
evaluation of diagnostic and therapeutic pathways of asthmatic children.
1) Paediatric prescription profile of antibiotic drugs
The evaluation of the antibiotic prescription profile focused on the analysis of territorial
differences.
Wide differences have been observed in antibiotic prescription prevalence rates. These
differences are greater when comparing the municipalities and smaller when comparing
Local Health Units (LHUs).
Clusters of municipalities characterised by different prevalence rates have been found. In
particular, the eastern part of the region is characterised by a higher prevalence rate, while in
the northern part the prevalence is lower. There was no significant correlation between
prevalence and hospitalisation rates, both at the district and the municipality levels. These
data shows that the differences observed among geographical areas do not seem to be related
to differences in epidemiology of diseases; on the contrary, these differences may be due to a
different prescribing attitude of the paediatricians.
2) Generic drug prescribing
The evaluation of generic drug prescriptions was focused on antibiotics. Overall, 79% of
antibiotic prescriptions involved off-patent drugs, but only 29% were generic drugs. Generic
medicines covered about 15% of the total expenditure for antibiotics.
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The percentage of generic prescriptions varied among the different active substances from
6% (clarithromycin) to 72% (amoxicillin). Differences have been observed between Local
Health Units, ranging from 12 to 48%.
The average percentage of generic prescriptions per paediatrician was 38.5 (median 37.7).
The percentage of generic drugs used was slightly lower for paediatricians classified as high
prescribers with respect to their colleagues classified as low prescribers (median: 32.0 versus
40.6; p=0.02).
The exclusive prescription of generic drugs for the four most prescribed antibiotics
(amoxicillin, amoxicillin clavulanate, clarithromycin, and cefaclor) would have allowed the
parents to save about 670.000 Euros.
3) Evaluation of diagnostic and therapeutic pathways in asthmatic children
The Laboratory evaluated the diagnostic-therapeutic pathways of asthmatic children and
adolescents (6-17 year olds) of the Lombardy Region prior to, and after, hospitalization for
asthma (indicator of asthma attacks not manageable at home). 183 subjects undergoing an
incident hospitalization for asthma (without hospitalization during the previous 24 months)
were identified. 45% of children and adolescents hospitalized did not receive anti-asthma
therapy during the 12 months prior to hospitalization, and 23% did not receive any therapy
also during the 12 months after hospitalization.
83% of children and adolescents with anti-asthma therapy before hospitalization received
short acting ß2 agonists, 74% of whom in association with a controller therapy (mainly
inhaled corticosteroids and long acting ß2 agonists).
Prevalence of post-partum depression in mothers and fathers
The Laboratory for Mother and Child Health participates in the study “Valutazione
dell’incidenza della depressione post-partum nelle madri e nei padri”. (Evaluation of postpartum depression in mothers and fathers). The project is funded by the Local Health Unit
“Milan 1”, and involves family paediatricians and mental health services.
The aim of the study was to estimate the prevalence of post-partum depression in mothers
and fathers, through a screening with the Edinburgh Postnatal Depression Scale performed in
the paediatric primary care setting.
The screening was proposed by paediatricians to parents of children born between 1
February and 31 July 2012. Parents with depressive symptoms were advised to contact a
mental health service.
In all, 4,128 EPDS were collected, 2705 completed by mothers and 1423 by fathers (for a
total of 2727 newborns). The data analyses are ongoing.
FP7 Projects
1) TINN – Treat Infections in NeoNates
The TINN project, Treat Infections in Neonates, is part of the European Union’s Seventh
Framework Project and is aimed at gathering the experience in the neonatal research field of
numerous centres across Europe in order to produce detailed evidence on the safety and
efficacy of ciprofloxacin and fluconazole use in neonatal sepsis. The final goal of the project
is to obtain a Paediatric Use Marketing Authorization (PUMA) for the two drugs.
A survey on the use of ciprofloxacin and fluconazole by neonatal intensive care units
(NICU) in Europe was conducted in the first phase of the project (2009/2010) and 200
NICUs participated, representing 32 countries, mainly Italy, the UK, and France. The survey
found great variability in therapeutic schemes and indications for use of the two drugs, both
between and within countries. Significant doubts on the part of clinicians concerning safety
and efficacy issues were also revealed, highlighting a need for additional evaluation and
information on the optimal use of the drugs. The survey, however, also found a notable
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interest on the part of NICUs across Europe in participating in studies on the two drugs in
order to obtain the necessary, lacking information. http://tinn-project.org/
2) TINN 2
The TINN2 (Treat Infections in Neonates 2) project began in January 2011 and is a
complementary part of the first TINN project. It is also part of the European Union’s 7th
Framework Programme (GA-260908). TINN2’s aim is to study azithromycin, an antibiotic
effective against Ureaplasma causing broncopulmonary dysplasia (BPD) in neonates. BPD
is one of the European Medicines Agency’s selected therapeutic areas that need specific
pharmacological assessments specific to neonates. The final goal of the TINN2 project is the
PUMA (Pediatric Use Marketing Authorization).
As for the first TINN, the initial stage of the project included a European survey intended to
define the use of this antibiotic in the neonatal intensive care units (NICU), and to collect the
opinion of senior neonatologists about its use in the treatment of Ureaplasma infections.
Over 800 TIN, located in 28 different countries, have been selected and contacted and about
200 TIN have completed the entire questionnaire. The results show that there is still much
uncertainty about the actual involvement of Ureaplasma in the development of BPD,
azithromycin is a drug of first choice for the treatment of BPD, but there are still doubts
about its safety and efficacy in neonates. http://tinn2-project.org/
3) COHEMI
Coordinating resources to assess and improve health status of migrants from Latin
AmericaCOHEMI Project- HEALTH.2010.3.4-5
European health systems are committed to meeting the challenge of understanding the
needs of migrant populations and adapting their services to meet these needs. The
difficulties inextricably linked to this challenge are caused by the complexity of migration
patterns and the differences between migrant population across EU countries.
Currently, the limited available data show that attempts to incorporate migrants’ health
needs, in particular those of migrants from non-EU countries, into EU health systems have
remained scattered and uncoordinated.
In January 2011 a project called COHEMI-Coordination resources to Assess and Improve
health status of migrants from Latin America, began. It is a three-year project, funded
under the 7th Framework Programme for Research and Technological Development
(Programme Cooperation- Health, GA-261495), that sees the Mario Negri Institute as
coordinator of a major consortium of 10 partners located in Europe (Italy, Spain, The
Netherlands and UK) and Latin America (Bolivia, Ecuador and Peru).
COHEMI’s general objective is to coordinate referral centres dealing with endemic Latin
American (LA) diseases in order to:
 provide an analysis of health systems and legislation on migrants and assess the
determinants of health;
 evaluate the care strategy of 3 diseases typical of LA countries (Chagas,
Cisticercosis/Epilepsy, Strongyloidiasis);
 produce, as a product of the first two steps, new procedures and suggestions shared at
the migration policies level, that take into account the specific cultural needs of
migrants.
Many bibliographic reviews have been carried out in the different specific sections of the
project (health care organization and legislation, Chagas disease, Cisticercosis/Epilepsy,
Strongyloidiasis, tuberculosis, hypertension and cardiovascular diseases, anthropological
and socio-cultural aspects) and the study design for evaluating specific diseases has been
defined. The work done has been shared among all the partners and presented at public
scientific meetings in Italy and abroad.
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COHEMI Newsletter. Publication of the of the COHEMI project’s newsletter began in
2011. The newsletter, which is one of the project’s official products, represents an
information and updating tool for two types of users: health staff and members of the general
public interested in migrant health, and COHEMI partners working on the project alongside
the Mario Negri Institute.
The version addressed to the general public includes a bibliographic update from the recent
scientific literature on migrant health and diseases covered by the COHEMI project: Chagas
disease, Strongyloidiasis, Cisticercosis, Tuberculosis, and Cardiovascular diseases. Those
who wish to receive the newsletter may insert their email address on the related section of
the project webpage http://www.cohemi-project.eu/Pages/Newsletter/Newsletter.aspx
In addition to a bibliographical update, the version designed for the project’s partners
includes news and updates on the work performed and information on scheduled meetings
and events.
Two newsletters were published in 2011 and three in 2012. The COHEMI newsletter (2012
issues) is available on the Mario Negri’s website in the section: “L’Istituto Mario Negri per il
Medico”: http://www.marionegri.it/mn/it/index.html
The Lombardy Region’s ADHD Register
The project called “Sharing diagnostic-therapeutic approaches for ADHD in Lombardy” was
launched in January 2012 with funding from the Lombardy Region. The project involves 18
referral centres and the coordinator is the UONPIA A.O. Spedali Civili of Brescia. The
project includes training initiatives for health care workers who provide assistance to ADHD
patients and their families, initiatives to increase information on ADHD, and a regional
register of ADHD cases. The register was designed as a disease registry and therefore
collects information not only on patients diagnosed with ADHD under pharmacological
treatment (as foreseen by the national register), but also on all potential ADHD patients who
visit the referral centres. The register will then permit the:
 monitoring of diagnostic paths;
 outlining of the prevalence of the disorder;
 monitoring of non-drug treatment programs as well;
 continuation of pharmacovigilance by extending the monitoring on the use of the drugs,
including drugs other than atomoxetine and methylphenidate;
 quantifying the workload for the referral centres
The Register has been accessible to the 18 referral centers since June 30th, 2011. 1001
patients have been included, 520 of whom with a confirmed diagnosis, 219 without ADHD,
and 262 still under evaluation. In most cases those who referred the patients to the centers
have been the school (33%) and the parents (28%). Of the 520 patients with ascertained
ADHD diagnosis, 54% received a prescription that involved non pharmacological therapy,
6% only pharmacological, 20% both, and the remaining patients is awaiting therapy. The
most frequent comorbidities were learning disabilities (32%) and oppositional/defiant
disorder (10%).
ADHD Newsletter. The publication of ADHDNEWS continues. It is a laboratory initiative
aimed mainly at providing a monthly bibliographic update of the recent scientific literature
to those interested. By December 2012, 62 issues of the newsletter had been published and
sent to the 420 people registered (137 psychiatrists and neuro-psychiatrists, 75 psychologists,
72 medical doctors, 35 paediatricians, 25 members of school staff, and 76 “others”) and 3549
scientific studies had been reported. The newsletter is available on the Mario Negri’s
website
in
the
section
“L’Istituto
Mario
Negri
per
il
Medico”:
http://www.marionegri.it/mn/it/index.html
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The activities of the Italian NGO Group for the CRC
The laboratory is part of the Working Group for the "Convention on the Rights of the Child"
(CRC) in Italy. The Laboratory has actively contributed to the writing and distribution of the
5th update Report on the implementation of the UN Convention on the Rights of the Child
(CRC) in Italy and its Optional Protocols, presented on 5 June 2012. During over ten years
of collaborative work, participation in the CRC group was expanded to new associations,
extending the monitoring of children’s rights to cover new issues. CRC reports have a wide
distribution throughout the country and represent a point of reference for updated content
and references to specific standards and practices - not only for the organizations but also for
institutions and professionals. The report is available at: http://www.gruppocrc.net.
Foster care families in Mantova
Familynet Mantova is a project that aims to strengthen networks of available foster care
families and to raise awareness among families in the community in order to support
children living in difficult situations and foster families. The project will also activate a
collaboration network between social services, associations, and cooperatives. In order to
identify problems and needs and forms of support available to foster families, a study was
undertaken that involved six districts of the province of Mantova. The information was
gathered through interviews with the operators of social services and family care. The
reported cases concern 53 children, 42 foster families, and 40 families of origin, constituted
by both parents or by a single parent (40 mothers, 33 fathers). The types of fosters are:
consensual (21%), judiciary (77%), and non-formalized (2%). 45% of fosters were set up
before being formalized by a court order. The most frequent reasons that have contributed to
foster care were severe neglect and abandonment, abuse, and death of a parent. Foster care
was considered, by the operators, to be a succesful intervention with respect to the reestablishment of the parental role in 30% of cases, the welfare of the child in 89% of cases,
and the ability of caregivers to best fulfill their role in 70% of cases. Due to the
heterogeneity of situations and needs documented it was not possible, however, to identify a
specific type of support that could be considered useful in all cases. The project also
highlighted the absence of systematic and detailed information on the conditions of the child
as well as a lack of integration and working methods between the various parties involved in
foster care (social services / child protection, associations, other services).
Summer School
The laboratory has participated in the organization and promotion of the Summer School
held in Avigliana (TO) from 31 May to 2 June 2012. The Summer School was designed not
as training in the classical sense, but as a laboratory for research and innovation, aimed at
health, social, and justice professionals. The school made available a method for creating
local search paths that give visibility to the most fragile and vulnerable populations that risk
having their right to health denied. Four workshops animated by four working groups formed
by the promoters were organized on the following topics:
1) Programming the territory: measure the health and well-being;
2) Child-migrant-health;
3) Home care of people with serious health conditions;
4) Deprivation, segregation, health, and personal autonomy.
The task of the laboratory was to facilitate the exchange of skills available for the
construction of one or more ideas to be translated into a research protocol and presented to
all participants of the summer school during the final afternoon. Materials are available at:
http :/ / lec.negrisud.it
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Co-operation with countries with limited resources
As an expression, test, and original method of manifesting the choice to make the
laboratory’s research transferable and accessible to all populations, the laboratory promoted
and provided assistance to projects in, and for, the South of the world, in collaboration with
Non-Governmental Organizations (NGOs) and the World Health Organization. The
technical and organisational support for carrying out socio-sanitary projects in countries with
limited resources continues.
Le Survey
Survey on prescriptions in paediatric outpatients. A plethora of drugs are prescribed to
paediatric outpatients, and only a limited amount of active substances is shared by the
majority of paediatricians. The laboratory led a survey including 67 paediatricians working
in the area of Monza and Brianza, which have been involved in cultural and educational
initiatives concerning appropriateness of care for several years. The aim of the study was to
identify the most common drugs among those prescribed in daily clinical practice, including
those prescribed following a specialist’s indication. A total of 35,381 packages were
prescribed during two consecutive months: 86% were class A drugs, 7% were SOP/OTC,
and 7% were class C. About 4% of prescriptions were filled following indication by a
specialist. The drugs shared by at least half of the paediatricians were 8.4%, while those
shared by over 75% of the paediatricians were 4.6% of the total. Five active substances were
shared among all paediatricians: amoxicillin, salbutamol, betamethasone, cetirizine, and
amoxicillin clavulanate.
The study represents the first phase of a project whose aim is to identify a common
therapeutic list.
Survey on Migrants and Health. As part of the activities performed by the Laboratory for
the COHEMI project, a series of interviews to policy makers working in the field of
migration was carried out in Italy on priority issues for the implementation and development
of policies on the health of migrants.
Evaluation of the assistance provided in the transition to adult ADHD services for
patients in the National Register. The literature review highlights the fact that 40% of
adolescents with ADHD may need to maintain therapy into adulthood, especially those who
have one or more psychiatric comorbidities. Up to now, the prevalence of patients who have
continued to access the territorial child neuropsychiatric services once they turned 18 years
old, as well as the transition passages to adult psychiatric services, have not been formally
assessed.
For these reasons the project foresees the involvement of both the ADHD referral centres
and the Lombardy Region’s territorial child neuropsychiatric services.
The main objective is to evaluate the current provision of assistance and the transition
passage to adult ADHD services in order to:
-
perform a quantitative and qualitative analysis of ADHD subjects who have
reached the adult age and of those who are almost adults (16-17 years);
analyse the procedures currently employed in the transition from child and
adolescent neuropsychiatric services to adult psychiatry services and the
difficulties in this passage;
set out shared procedures that can guarantee continued assistance while
taking into consideration the needs of ADHD patients and their families.
Hey mom, did you know?
Lo sai Mamma
The laboratory, along with the Associazione Culturale Pediatri (Paediatricians’ Cultural
Association) and the Federfarma Lombarda participates in the initiative “Lo sai mamma?”
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(“Mom, did you know?”). The initiative is aimed at providing mothers with information on
their children’s health through the creation of informational pamphlets distributed in
pharmacies throughout the Lombardy Region.
Ricerca & Pratica
Ricerca & Pratica was born in January, 1985, as a manifestation of the “Mario Negri”
Institute for Pharmacological Research. Today, the journal is part of the International Society
of Drug Bulletins (ISDB), which represents independent journals.
For more than twenty years, the journal has represented an arena for all those professionals
who collect data and carry out studies in general practice with the aim to increase their
knowledge and to improve their practice. Ricerca & Pratica is also appreciated for its ability
to go beyond the merely clinical aspect of medicine, without, however, forgetting that it is to
this aspect that the readers dedicate most of their time and effort.
Through its activity, Ricerca & Pratica can therefore represent an exclusive, independent
observation point. It is also an area that promotes contemplation, evaluation, and information
by applying, tools, such as data trustworthiness and importance, the balance between benefits
and risks and between benefits and costs, independence from conflicts of interest, and the
realistic objective to contribute to a progressive, equally distributed improvement in the
population’s health.
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LABORATORY OF REGULATORY
POLICIES
STAFF
Head
Vittorio BERTELE’, M.D.
Senior scientist
Rita BANZI, ChemPharm. D, PhD
Senior scientist
Brian GODMAN, PhD
Visiting scientist
Roberta JOPPI, ChemPharm. D
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CURRICULUM VITAE
Vittorio Bertele’ is a clinical pharmacologist. He got his MD degree in 1977 and the specialization in
Internal Medicine in 1982, both at the Milan University Medical School. He was research fellow at the
Harvard Medical School and then worked at the Milan University and the “Mario Negri” Institute.
His main areas of interest have been clinical pharmacology of drugs active on the haemostatic and
vascular system, epidemiology of interventions in the cardiovascular area, and clinical trials and drug
utilization studies in the cardiovascular area. He was CPMP expert at the EMEA, member of the
Committee for Drug Price Negotiation at the Italian Ministry of Health, and member of the TechnicalScientific Committee at the Italian Drug Agency. At present he is head of the Regulatory Policies
Laboratory at the "Mario Negri" Institute, secretariat of the ECRIN Scientific Board, and member of the
Italian Horizon Scanning Center.
Selected recent publications
1. Garattini S, Bertele’ V, Li Bassi L. Light and shade in the proposed revision of the EU drugs
regulatory legislation. Lancet 2003; 361: 635-636
2. Garattini S, Bertele’ V, Li Bassi L. European Council waters down European Parliament’s drug
regulatory legislation. Lancet 2003; 362:1688-9
3. Garattini S, Bertele’ V, Li Bassi L. How can research ethics committees protect patients better?
BMJ 2003; 326:1199–201
4. Joppi R, Bertele' V, Garattini S. Disappointing biotech. BMJ 2005; 331: 895-897
5. Garattini S, Bertele' V. Non-inferiority trials are unethical because they disregard patients'
interests. Lancet 2007; 370 : 1875-1877
6. Garattini S, Bertele' V. How can we regulate medicines better? BMJ 2007; 335 : 803-805
7. Garattini S, Bertele' V. Homoeopathy: not a matter for drug-regulatory authorities. Lancet 2009;
374 : 1578-1580
8. Garattini S, Bertele' V. Europe's opportunity to open up drug regulation. BMJ 2010; 340:c1578
9. Garattini S, Bertele' V. Bevacizumab and ranibizumab. A matter of public interest. BMJ 2010;
341 : c3721
10. Garattini S, Bertele' V. Dutasteride and prostate cancer. N Engl J Med 2010 363 : 794
11. Banzi R, Torri V, Bertele' V, Garattini S. Antibiotics versus surgery for appendicitis. Lancet 2011:
378 : 1067-1068
12. Garattini S, Bertele' V. The scientific community should lobby to be able to apply for drug
licences. BMJ 2012 344 : e3553
13. Garattini S, Bertele' V, Banzi R. Informed consent: meet patients' needs. Nature 2012 483 : 36
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ACTIVITIES
Critical appraisal of clinical methodology.
Critical evaluation of the benefit-risk profile of drugs.
Assessment of emerging technologies.
Optimisation of drug use and healthcare fund stewardship including potential reforms and
initiatives to achieve this for both new and existing drugs.
Critical appraisal and recommendations for European Pricing and Reimbursement systems
including generics, interchangeable products within a class and new innovative medicines.
Cooperation to the design and conduct of pharmacovigilance and pharmacoepidemiology
studies in Europe.
Evaluation of the appropriateness of drug legislation, institutions, and regulatory procedures
with respect to public health needs.
Cooperation to the development and functioning of the pan-European Infrastructure for clinical
trials (ECRIN, European Clinical Research Infrastructure Network) provided as Secretariat of
the ECRIN Scientific Board and European Correspondent for Italy.
Support to the activities of the ECRIN-IA (European Clinical Research Infrastructure NetworkIntegrating Activities) Scientific Board which is in charge of assessing projects requiring the
services of ECRIN. Coordination of the evaluation process conducted by the Board and external
peer-reviewers.
Support to the organization and management of the ECRIN-IA WP7 competitive Call aimed to
facilitate the conduction of multinational studies by providing free services for their
multinational implementation. Support to the ECRIN-IA WP7 Call Scientific Board evaluation
of the candidate proposals.
Support to the conduction of multinational clinical trials in Italy (local project management).
Coordination of the Task 9.3 “Identification of key steps on monitoring activities” within the
WP9 of the ECRIN, European Clinical Research Infrastructure Network
MAIN FINDINGS
Critical appraisal of clinical research methodological aspects as the adoption of placebo as a
control or non-inferiority design in clinical trials.
Critical evaluation of seven transnational clinical research projects to be conducted with the
methodological and operating support of ECRIN.
Local management of an European clinical trial on the use of nilvadipine for the treatment of
Alzheimer disease (Nilvad trial).
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Support to the development of an Italian clinical research network (Ita-CRIN).
Coordination of the Italian activities of ECRIN.
Development of Pan-European strategies for the rational use of new and existing drugs
including policies to enhance the managed entry of new drugs as well as reduce prescribing of
more expensive interchangeable single sourced products in a class once generics are available:
establishment of the Piperska Group.
Development of new models and strategies to optimise the managed entry of new drugs
including suggestions for risk sharing arrangements given current concerns. This co-ordinated
via the Piperska group leading to changes such as the recent changes in the German Health
Insurance system for pricing new drugs.
Recommendations for Pan-European pricing policies for generics as well as interchangeable
brands in a class once generics are available; with countries increasingly learning from each
other. Alongside this, potential additional demand side measures that countries can introduce to
further enhance their prescribing efficiency, with countries continuing to learn from each other.
Assessment of emerging technologies in the frame of the Italian Horizon Scanning Project
which provides decision makers with timely information on the potential clinical impact and
cost-effectiveness of new health technologies.
Critical review of the criteria to assess pharmaceutical innovation and include new drugs in the
national reimbursement schemes.
Participation in the ENCePP (European Network of Centres of Pharmacovigilance and
Pharmacoepidemiology) and the PROTECT consortium which under the coordination of the
European Medicines Agency (EMA) and the support of IMI aims at improving design and
conduct of pharmacovigilance activities and pharmacoepidemiological studies in Europe. The
PROTECT consortium is also developing and testing innovative methods to integrate and
present information on drug-related benefits and risks.
Raising awareness among interested parties about the deficiencies of the present EU
pharmaceutical legislation and about our proposals to improve it in the public health interest.
NATIONAL COLLABORATIONS
Italian Drug Agency (AIFA)
Istituto Superiore di Sanità
Department of Health Lombardy Region
Italian Horizon Scanning Project
Italian Cochrane Network
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University of Milan
INTERNATIONAL COLLABORATIONS
European Medicine Agency (EMA)
European Clinical Research Infrastructure Network (ECRIN)
European Network of Centres in Pharmacoepidemiology and Pharmacovigilance (ENCePP)
International Society for Pharmacoepidemiology (ISPE) – European chapter - EuroDURG
Piperska network involving health authority and health insurance personnel from across Europe
to enhance the rational use of new and existing drugs
Karolinska Institutet, Division of Clinical Pharmacology, Department of Laboratory Medicine,
and Centre for Pharmacoepidemiology; Department of Drug Management and Informatics, SE
University of Liverpool Management School, Prescribing Research Group, UK
Cochrane Collaboration
International Information Network on New and Emerging Health Technologies (EuroScan)
World Health Organisation (Department of Essential Drugs and Medicines Policy)
EDITORIAL BOARD MEMBERSHIP
Ricerca & Pratica
Dialogo sui Farmaci
Frontiers in Clinical Trials and Pharmacotherapy (associate editor)
Frontiers in Pharmacology: Pharmacoeconomics and Outcomes Research (associate editor)
Internal and Emergency Medicine (editorial board)
Generics and Biosimilar Initiatives (international editorial board)
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NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP
European Clinical Research Infrastructure Network (ECRIN) Scientific Board, Secretariat
EuroDURG - Treasurer
Scientific Committee of the Italian Horizon Scanning Project
Verona Local Ethics Committee
SCIENTIFIC PUBLICATIONS (2012)
1. Abuelkhair M, Abdu S, Godman B et al. Imperative to always consider multiple initiatives to maximise
prescribing efficiency from generic availability: case history from Abu Dhabi. Expert Review
Pharmacoeconomics and Outcomes Research 2012; 12: 115-124
2. Avanzini F, Bertele' V, Pistotti V, Mannucci P M, Garattini S. Solicited self-referencing undermines the
credibility of researchers and journals. J ThrombHaemost 2012 10 : 481-482
3. Baumgärtel C, Godman B, Malmström R, Andersen M et al. What lessons can be learned from the launch of
generic clopidogrel? GABI 2012;1 (2): 10-20
4. Bennie M, Godman B, Bishop I, Campbell S. Multiple initiatives continue to enhance the prescribing
efficiency for the proton pump inhibitors and statins in Scotland. Expert Review Pharmacoeconomics and
Outcomes Research 2012; 12: 125-130
5. Bertele' V, Banzi R, Gluud C, Garattini S. EMA's reflection on placebo does not reflect patients' interests.
Eur J Clin Pharmacol 2012 68 : 877-879
6. Brkičic L, Godman B, Vončina L, Sovic S, Relja M. Initiatives to improve prescribing efficiency for drugs
to treat Parkinson’s Disease in Croatia; influence and future directions. Expert Rev Pharmacoeconomics and
Outcomes Research 2012; 12:373-84
7. Bucsics A, Godman B, Burkhardt T et al. Potential to enhance the prescribing of generic drugs in patients
with mental health problems in Austria; implications for the future. Expert Review Pharmacoecon
Outcomes Res 2012; 12: 809-19
8. Garattini S, Bertele' V, Banzi R. Informed consent: meet patients' needs. Nature 2012 483 : 36
9. Garattini S, Bertele' V, Banzi R. Placebo? no thanks, it might be bad for me!. Eur J Clin Pharmacol 2012 Epub : DOI 10.1007/s00228-012-1383-6
10. Garattini S, Bertele' V. The European Commission should require better medicines, not just faster
reimbursements.Eur J Intern Med 2012 E-pub : http://dx.doi.org/10.1016/j.ejim.2012.10.007
11. Garattini S, Bertele' V. The scientific community should lobby to be able to apply for drug licences. BMJ
2012 344 : e3553
12. Godman B, Malmstrom RE, Bennie M, Sakshaug S, Burkhardt et al. Prescribing restrictions - a necessary
strategy among some European countries to enhance future prescribing efficiency? Reviews in Health Care
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2012; 3: 5-16
13. Godman B, Wettermark B, Bishop I, Burkhardt T, Fürst J et al. European payer initiatives to reduce
prescribing costs through use of generics. GABI 2012; 1:22-27
14. Godman B, Abuelkhair M, Vitry A, Abdu S et al. Payers endorse generics to enhance prescribing efficiency;
impact and future implications, a case history approach. GABI 2012; 1(2): 21-35
15. Godman B, Paterson K, Malmstrom R et al. Improving the managed entry of new medicines: sharing
experiences across Europe. Expert Review Pharmacoeconomics and Outcomes Res 2012; 12: 439–41
16. Godman B, Bennie M, Baumgärtel C, Sović Brkičić L et al. Essential to increase the use of generics in
Europe to maintain comprehensive healthcare? Farmeconomia: Health Economics and Therapeutic
Pathways 2012; 13 (Suppl 3): 5-20
17. Joppi R, Bertele V, Garattini S. Orphan drugs, orphan diseases. The first decade of orphan drug legislation
in the EU. Eur J Clin Pharmacol DOI 10.1007/s00228-012-1423-2
18. Kalaba M, Godman B, Vuksanovic A, Bennie M, Malmstrom RE. Possible ways to enhance reninangiotensin prescribing efficiency: Republic of Serbia as a case history? Journal of Comparative
Effectiveness Research 2012; 1:539-49
19. Markovic-Pekovic V, RankoŠkrbić R, Godman B, Gustafsson LL. Ongoing initiatives in the Republic of
Srpska to enhance prescribing efficiency: influence and future directions. Expert Review of Pharmacoecono
Outcomes Res 2012; 5: 661-71
20. Moja L, Fernandez del Rio MP, Banzi R, Cusi C, D'Amico R, Liberati A, Lodi G, Lucenteforte E, Minozzi
S, Pecoraro V, Virgili G, Parmelli E. Multiple systematic reviews: methods for assessing discordances of
results. Intern Emerg Med. 2012; 7:563-8
21. Snijders PJ, Verhoef VM, Arbyn M, Ogilvie G, Minozzi S, Banzi R, van Kemenade FJ, Heideman DA,
Meijer CJ. High-risk HPV testing on self-sampled versus clinician-collected specimens: A review on the
clinical accuracy and impact on population attendance in cervical cancer screening. Int J Cancer. 2012 doi:
10.1002/ijc.27790. [Epub ahead of print]
22. van Woerkom M, Piepenbrink JF, Godman B et al. Ongoing measures to enhance the efficiency of
prescribing of PPIs and statins in the Netherlands; influence and future implications. Journal of Comparative
Effectiveness Research 2012; 1: 527-38
23. Vart G, Banzi R, Minozzi S. Comparing participation rates between immunochemical and guaiac faecal
occult blood tests: a systematic review and meta-analysis. Prev Med. 2012; 55:87-92
RESEARCH ACTIVITIES
Critical appraisal of clinical methodology
Raising awareness about potential biases in clinical research
Critical evaluation of the EU pharmaceutical legislation
Raising awareness among interested parties about the deficiencies of the present EU
pharmaceutical legislation and about our proposals to improve it in the public health interest
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Development of a Pan-European Infrastructure for clinical trials
Participation in a distributed infrastructure linking national networks of clinical research centres
and clinical trials units (ECRIN, European Clinical Research Infrastructure Network) which
provides integrated ‘one-stop one-shop’ services to investigators and sponsors in multinational
studies.
Critical appraisal of ongoing reforms including pricing reforms in major
European countries
Evaluation of ongoing reforms across Europe to drive down generic prices and corresponding
originator brands, as well as potential prices of interchangeable brands once standards become
available as generics, and the potential for cross cultural learnings, to release valuable resources
to fund increased volumes and new innovative drugs without prohibitive increases in general
taxation or health insurances to continue to provide equitable and comprehensive healthcare in
Europe.
Development of Pan-European strategies to enhance the rational use of
existing drugs
Enhancing the rational use of drugs including increased prescribing of generics with an
approach that has become known as the ‘four Es’, namely: economics; enforcement; education
and engineering. The objective again being to help fund increased volumes and new valuable
innovative drugs within finite budgets. In addition, development of new models to optimize the
managed entry of new drugs including horizon scanning and critical drug evaluation pre-launch
(below) and post launch activities
Development of strategies to optimize the managed entry of new drugs
This includes the development of new models to optimize the managed entry of new drugs
incorporating horizon scanning, budget impact and critical drug evaluation activities pre- and
peri-launch, as well as post launch activities including evaluation of risk sharing arrangements
and patient registries.
Development of Pan-European strategies for pharmacovigilance
Developing and testing innovative methods to integrate and present information on benefits and
risks in order to provide all stakeholders (patients, prescribers, regulators and pharmaceutical
companies) with accurate and useful information on drug-related risks and benefits
Assessment of emerging technologies
Collecting information on emerging medicines with respect to their potential clinical impact and
their cost effectiveness and ranking the new products according to their possible marketing
authorization date, their potential innovation grade, therapeutic and economic impact, possible
price and NHS sustainability with the aim to provide decision makers with timely information
on the potential clinical impact and cost effectiveness of new health technologies
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CENTRE OF COMPUTER SCIENCE
ENGINEERING
STAFF
Research and Communication Informatics
Head of Division
ROSSI Lorenzo Marco
Division of I.C.T. Services and Management
Head of Division
BAZZI Davide
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CURRICULA VITAE
Lorenzo Marco Rossi graduated in Biomedical Engineering with specialization in
Hospital Clinical Instrumentation at Politecnico of Milan. He has been working with the
Institute Mario Negri since 1998.
Main areas of interest are:
1.Planning and realization of software for clinical research
2.Planning and realization of software system for in-plant automatization
3.Planning and realization of products for multimedia divulgation
Davide Bazzi graduated in Informatics with ABACUS specialization at Istituto Tecnico
Industriale Statale of Corsico. He has been working with the Institute of Mario Negri
since 1997.
Main areas of interest are:
1. Planning, realization and management of communication Network and Data Center
2. Definition and management of technological innovation for ICT systems
4. Planning and realization of technological innovation for ICT systems
3. Definition and application of organization’s methodologies and processes for the
Informatics Security Management
ACTIVITIES
In order to fulfill even more specialization needs in informatics development, the Centre
of Computer Science Engineering is organized, considering the acquired skills, in three
distinct division bound each other by a strong collaborative relationship.
The Centre of Computer Science Engineering gathering informatics multidisciplinary
aspects promotes and propose itself to coordinate and harmonize the development of the
tools for the management information, improving the integration between informative
procedures making more efficacious communication process and management of
scientific and administrative data, in order to support and fasten decisional,
management, clinical trials and scientific processes.
RESEARCH ACTIVITIES
Implementation of Clinical Trials’ gathering forms (E-CRF)
-
Lab. Translational and Outcome Research in Oncology (Dep. Oncology)
 Trial CERP
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Maintenance and management of data gathering forms for the following clinical
trials
-
Lab. Neurological Disorders (Dip. Neuroscience):
 Registro Europeo SLA
 Trial L-ACETYLCARNITINE
 Trial ANTIEPILETTICI
 Trial EPILESSIA E STROKE
 Trial EPO VS MP IN SPINAL SHOCK
 Trial VALPROATO
 Trial THEOREM
 Trial ANTIEPILETTICI
 Trial ADONE
 Trial EDU-COM
-
Lab. Clinical Trials (Dip. Oncology)
 Trial FOLFOX
 Trial TOP
 Trial COMETS
 Trial TAILOR
 Trial HEAD & NECK
 Trial GLAUCOMA PEDIATRICO
 Amendment to Trial TAILOR
 Trial ITACAS 2
-
Lab. New Drug Development Strategies (Dip. Oncology)
 Trial MAPS
 Trial STARPAN
 Trial TRIAC
-
Dip. Epidemiology
 Trial CADASIL
-
Lab. Quality Assessment of Geriatric Therapies and Services
 Trial GISAS
 Patients registry for Polipathologies and Politherapies – SIMI web
Web based applications connected to the projects
 Design clinical Trials Management System
 Design and Development of the Order Management System
 Design and Development of the Human Resources Management System
 Management of the Database hosting data about recovers, prescriptions and
examinations provided from Regione Lombardia for covenant data analysis.
 Support to data processing in recipes analysis for Regione Lombardia
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THE CATULLO AND DANIELA
BORGOMAINERIO CENTER
One of the buildings on the Mario Negri Institute campus is The Catullo and Daniela
Borgomainerio Center built in 1987 thanks to a donation from Mrs. Angela Marchegiano
Borgomainerio. This is a Center for the study of rare childhood diseases and even today some of
the laboratories housed in the building still conduct this research. For example, the study of new
therapies used to treat a very rare form of acute myeloid leukemia, know as acute promyelocytic
leukemia. A number of new studies are being done to identify new drugs having different
mechanisms able to synergize with trans retinoic acid.
Research on epidemiological childhood leukemia is also done at the Borgomainerio and a
similar line of research involves testicular cancer in adolescents and young adults.
We also do research aimed at finding evidence based therapies for children.
Paediatric research activities done at the Borgomainerio Center are also performed in
collaboration with groups located at other Institute locations including, The Aldo and Cele
Daccò Center for Clinical Research on Rare Diseases at Ranica in Bergamo, the Regional
Centre for Drug Information (CRIF) and the Laboratory for Mother and Child Health
(Department of Public Health) which are both located in Milan.
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THE LIBRARY
STAFF
Head Librarian
Vanna Pistotti
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The Library, specialized in pharmacology and clinical epidemiology, was founded in 1963
thanks to a generous donation from the Gustavus and Louise Pfeiffer Research Foundation, in
Denville, New Jersey, USA.
Numerous public and private organizations help keep it operative, through donations in money
or books, and subscriptions to periodicals.
STAFF
One Head and two Assistants plus a clerical worker
WHAT THE LIBRARY OFFERS
The library has a collection of about 5000 textbooks, monographs and congressional
proceedings, and 100 periodicals of which a major part are in an electronic format. The books
are classified according to the US National Library of Medicine Classification and the Medical
Subject headings of Medline (MeSH). Besides the internal collection, the Library has access to
other Library consortia (SBBL, GIDIF-RBM).
DATABESES AND ELECTRONIC JOURNALS
From every computer in the Institute it is now possible to have access to more than 8000
electronic journals and to three of the most important databases, PubMed, the Cochrane Library
and Embase.
SPECIAL PROJECTS
The Library cooperates to the realization of the Italian Information Specialists’
(GIDIF, RBM) journal catalog which is updated annually and to the catalog of the
Lombardy Biomedical Library Consortium, a network that serves, through Internet,
the scientific community in this District.
It collaborates to the Institute web site, particularly taking care of the Publications section, both
scientific and lay press.
TRAINING
Every year courses on the use of the database and electronic journals are organized. These
courses are designed for use by those working at the Institute but outsiders who are interested
may attend.
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CONTRACTS
Since 1994 the library has been part of the Lombard Biomedical Library System. 14 university
and research organisation libraries in Lombardy take part in this project, which allows easy, free
access to scientific information to over 140 centres and institutions the Lombardy Region.
EVENTS AND COURSES
Master on Clinical Research “The bibliografic databases”, Istituto di Ricerche Farmacologiche
Mario Negri University of Milan, 29 November 2012
Advanced course on systematic reviews, meta-analysis and practice guidelines “ Search
strategies, Istituto di Ricerche Farmacologiche Mario Negri and University of Milan , 20112012
ECM course, 9 edition “"Bibliographic search on medical databases. ", Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan, 23-24 May 2012
ECM course, 10 edition “"Bibliographic search on medical databases ", Istituto di Ricerche
Farmacologiche “Mario Negri”, Milan, 22-26 October 2012
PUBLICATIONS
1
Avanzini F, Bertele' V, Pistotti V, Mannucci P M, Garattini S
Solicited self-referencing undermines the credibility of researchers and journals
J Thromb Haemost 2012 10 : 481-482
Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, D'Amico R. Trastuzumab
containing regimens for early breast cancer. Cochrane Database of Systematic Reviews 2012, Issue 4.
Art. No.: CD006243. DOI: 10.1002/14651858.CD006243.pub2.
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Anna Maria Astori Center
Bergamo
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REPORT 2012
departments and laboratories
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DEPARTMENT OF MOLECULAR
MEDICINE
STAFF
Head
Ariela BENIGNI, Biol.Sci.D., Ph.D.
Laboratory of Cell Biology and Regenerative Medicine
Head
Marina MORIGI, Biol.Sci.D., Ph.D.
Unit of Platelet-Endothelial Cell Interaction
Head
Miriam GALBUSERA, Biol.Sci.D.
Unit of Developmental Biology
Head
Barbara IMBERTI, Biol.Sci.D., Ph. D.
Laboratory of Immunology and Genetics of Organ Transplantation and
Rare Diseases
Head
Marina NORIS, Chem.Farm.D., Ph.D.
Unit of Cellular Biology of Autoimmunity and Transplant Rejection
Head
Sistiana AIELLO, Biol.Sci.D
Unit of Cellular and Molecular Biology of Transplantation Tolerance
Head
Federica CASIRAGHI, Chemist
Unit of Genetics and Molecular Basis of Renal Diseases
Head
Roberta DONADELLI, Biol Sci D.
Laboratory of Pathophysiology of Experimental Renal Disease and
Interaction with other Organ systems
Head
Carla ZOJA, Biol.Sci.D., Ph.D.
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Unit of Pathology and Immunopathology
Head
Mauro ABBATE, M.D.
Unit of Experimental Models of Kidney Diseases
Head
Daniela CORNA, Chemist
Laboratory of Gene Therapy and Cellular Reprogramming
Head
Susanna TOMASONI, Biol.Sci.D., Ph.D.
Unit of Advanced Microscopy
Head
Elena GAGLIARDINI, Biol.Sci.D., Ph.D.
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CURRICULA VITAE
Ariela Benigni got the Biol.Sci. degree in 1979 at the University of Milano, Italy, and the Ph.D. at
Maastricht University, Netherlands, in 2001.
Educational training: in 1979 Post Doctoral Fellow, Istituto di Ricerche Farmacologiche Mario Negri
(IRFMN), Laboratory of Cancer Chemotherapy, Milan, Italy; in 1980-1981 Post Doctoral Fellow,
Associazione Bergamasca per lo Studio delle Malattie Renali, Laboratory of the Division of Nephrology
and Dialysis, Ospedali Riuniti di Bergamo, Italy; in 1982 Post Doctoral Fellow, Centre Regional de
Transfusion Sanguigne de Strasbourg, France; in 1989 intership at Brigham and Women’s Hospital,
Laboratory of Prof. Barry Brenner, Boston.
Areas of interest: vasoactive and inflammatory mediators of progressive renal injury with a particular
emphasis on endothelin-1; combined treatment of antipertensive and renoprotective drugs to halt
progressive chronic renal injury; use of stem cells for tissue regeneration in acute and chronic renal
failure; study of the renal regeneration mechanisms; in vivo e in vitro gene transfer; prevention of acute
and chronic graft rejection through gene therapy; induction of kidney transplant tolerance by gene
therapy; correction of genetic deficiency in rare diseases.
Employement: in 1983 Scientist, IRFMN, Laboratory of Kidney Disease, Bergamo, Italy; in 1990-1994
Head Laboratory of Prostaglandin and Leukotriene Metabolism, IRFMN, Bergamo, Italy; from January
1991 Scientific Secretary, IRFMN, Bergamo, Italy; in 1994-1999 Head Laboratory of Vasoactive and
Inflammatory Mediators of Tissue damage, IRFMN, Bergamo, Italy; from January 2000 Head,
Department of Molecular Medicine, IRFMN, Bergamo, Italy; 1996-1998: Associate Editor, Journal of
Nephrology; 2003-2005: Associate Editor, Kidney International. Associated Editor International Journal
of Artificial Organs. 2007-2012 Consultant World Health Organization (WHO) for the multicentre
observational study “Screening for Pre-eclampsia: evaluation of the predictive ability of angiogenic
factors for Pre-eclampsia”; during 2007 Senior Fellow at the University of Oxford, Nuffield Department
of Obstetrics & Gynaecology. She trained 4 Ph.D students from Open University, London.
Selected publications:

C. Zoja, D. Corna, V. Nava, M. Locatelli, M. Abbate, F. Gaspari, F. Carrara, F. Sangalli, G. Remuzzi, A. Benigni.
Analogues of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. Am J Physiol
Renal Physiol 2012 [Epub ahead of print]

C. Zoja, S. Cattaneo, F. Fiordaliso, V. Lionetti, V. Zambelli, M. Salio, D. Corna, C. Pagani, D. Rottoli, C. Bisignini, G.
Remuzzi, A. Benigni. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental
type 2 diabetes. Am J Physiol Renal Physiol 2011;301:F1114-F1123

B. Imberti, M. Morigi, A. Benigni. Potential of mesenchymal stem cells in the repair of tubular injury. Kidney Int Suppl
2011;1:90-93

D. Macconi, S. Tomasoni, P. Romagnani, P. Trionfini, F. Sangalli, B. Mazzinghi, P. Rizzo, E. Lazzeri, M. Abbate, G.
Remuzzi, A. Benigni. MicroRNA-324-3p promotes renal fibrosis and is a target of ACE inhibition. J Am Soc Nephrol
2012;23:1496-1505

S. Conti, P. Cassis, A. Benigni. Aging and the renin-angiotensin system. Hypertension 2012;60:878-883

A. Benigni, S. Orisio, M. Noris, P. Iatropoulos, D. Castaldi, K. Kamide, H. Rakugi, Y. Arai, M. Todeschini, G. Ogliari,
E. Imai, Y. Gondo, N. Hirose, D. Mari, G. Remuzzi. Variations of the angiotensin II type 1 receptor gene are associated
with extreme human longevità. Age (Dordr) 2012 [Epub ahead of print]
Marina Morigi got her Biol.Sci. degree in 1987 at the University of Milano, Milano, Italy and the Ph.D.
at Maastricht University, Netherlands, in 2005.
Educational training: in 1984-1987 Research training, IRFMN, Bergamo, Italy; in 1987-1995 Post
Doctoral Fellow, IRFMN, Bergamo, Italy; in 1991 Stage at Brigham and Women’s Hospital, Laboratory
of Dr. P. Marsden, Boston, USA.
Employement: since 1995 Scientist, IRFMN, Bergamo, Italy; in 1996-1999 Head, Unit of Renal and
Endothelial Cell Biology; since 2000 Head, Laboratory of Cell Biology and Xenotransplantation,
IRFMN, Bergamo, Italy.
Areas of interest: Stem cell therapy and tissue regeneration: the potential of adult stem cells of different
origin, and renal progenitor cells to differentiate and to regenerate renal tissue in acute and chronic
experimental models of renal disease. Stem cell therapy with embryonic stem cells to cure acute and
chronic renal diseases and to correct genetic defects in experimental mouse models. Kidney
Organogenesis. Role of Shigatoxin in the pathogenesis of endothelial dysfunction and microvascular
thrombosis in Hemolytic Uremic Syndrome. In vitro model of hyperacute xenograft rejection (porcine
endothelium exposed to human serum as a source of xenoreactive natural antibodies and complement).
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Renal toxicity of the proteins filtered through the capillary barrier: in vitro model to study intracellular
signals, gene expression and production of inflammatory mediators in cultured proximal tubular cells
and glomerular epithelial cells.
Selected publications

S. Tomasoni, L. Longaretti, C. Rota, M. Morigi, S. Conti, E. Gotti, C. Capelli, M. Introna, G. Remuzzi, A. Benigni.
Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells.
Stem Cells Dev 2012 [Epub ahead of print]
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C. Xinaris, V. Benedetti, P. Rizzo, M. Abbate, D. Corna, N. Azzollini, S. Conti, M. Unbekandt, J.A. Devies, M. Morigi,
A. Benigni, G. Remuzzi. In vivo maturation of functional renal organoids formed from embryionic cell suspensions. J
Am Soc Nephrol 2012;23:1857-1868

C. Zoja, P. Bautista Garcia, C. Rota, S. Conti, E. Gagliardini, D. Corna, C. Zanchi, P. Bigini, A. Benigni, G. Remuzzi,
M. Morigi. Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell
dysfunction in adriamycin-induced nephropathy. Am J Physiol Renal Physiol 2012;303:F1370-F1381

F. Casiraghi, N. Azzollini, M. Todeschini, R.A. Cavinato, P. Cassis, S. Solini, C. Rota, M. Morigi, M. Introna, R.
Maranta, N. Perico, G. Remuzzi, M. Noris. Localization of mesenchymal stromal cells dictates their immune or
proinflammatory effects in kidney transplantation. Am J Transplant 2012;12:2373-2383

M. Morigi, M. Galbusera, S. Gastoldi, M. Locatelli, S. Buelli, A. Pezzotta, C. Pagani, M. Noris, M. Gobbi, M. Stravalaci,
D. Rottoli, F. Tedesco, G. Remuzzi, C. Zoja. Alternative pathway activation of complement by Shiga toxin promotes
exuberant C3a formation that triggers microvascular thrombosis. J Immunol 2011;187:172-180

Benigni, M. Morigi, G. Remuzzi. Kidney regeneration. Lancet. 2010;375:1310-1317

Morigi M, Rota C, Montemurro T, Montelatici E, Lo Cicero V, Imberti B, Abbate M, Zoja C, Cassis P, Longaretti L,
Rebulla P, Introna M, Capelli C, Benigni A, Remuzzi G, Lazzari L. Life-sparing effect of human cord bloodmesenchymal stem cells in experimental acute kidney injury. Stem Cells. 2010 Mar 31;28(3):513-22

M. Morigi, M. Introna, B. Imberti, D. Corna, M. Abbate, C. Rota, D. Rottoli, A. Benigni, N. Perico, C. Zoja, A.
Rambaldi, A. Remuzzi, G. Remuzzi. Human bone marrow mesenchymal stem cells accelerate recovery of acute renal
injury and prolong survival in mice. Stem Cells 2008;26:2075-2082
Marina Noris got her degree in Pharmaceutical Chemistry and Technologies in 1986 at the University
of Rome “La Sapienza) and the Ph.D. at Maastricht University, Netherlands, in 2005.
Educational training: in 1984-1986 Fellow, Istituto di Chimica Farmaceutica e Tossicologica, University
of Rome, Italy; in 1986-1987 Post Doctoral Fellow, Istituto di Chimica Farmaceutica e Tossicologica,
University of Rome, Italy; in September 1987-March 1994 Post Doctoral Fellow, IRFMN, Unit of
Mediators of Inflammation and Tissue Damage, Laboratory of Kidney Disease, Bergamo, Italy.
Areas of interest: immunology of transplantation, tolerance induction; genetics of hemolytic uremic
syndrome, thrombotic thrombocytopenic purpura, focal segmental glomerulosclerosis, diabetic
nephropathy, role of nitric oxide and arginine dysfunctions in uremia and in pre-eclampsia.
Employment: in 1994-1996 Head, Unit of Endothelial Cell Pathophysiology, IRFMN, Bergamo, Italy;
1996-1999 Head, Laboratory of Cellular and Molecular Biology of the immune response and
autoimmunity, IRFMN, Italy; from January 2000: Head, Laboratory of Immunology and Genetics of Rare
Diseases and Organ Transplantation, Department of Molecular Medicine, IRFMN, Bergamo, Italy.
Selected publications

Iatropoulos P, Daina E, Mele C, Maranta R, Remuzzi G, Noris M. Discordant phenotype in monozygotic twins with
renal coloboma syndrome and a PAX2 mutation. Pediatr Nephrol. 2012 Oct;27(10):1989-93
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Lotta LA, Wu HM, Mackie IJ, Noris M, Veyradier A, Scully MA, Remuzzi G, Coppo P, Liesner R, Donadelli R, Loirat
C, Gibbs RA, Horne A, Yang S, Garagiola I, Musallam KM, Peyvandi F. Residual plasmatic activity of ADAMTS13 is
correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood. 2012 Jul 12;120(2):440-8
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Daina E, Noris M, Remuzzi G. Eculizumab in a patient with dense-deposit disease. N Engl J Med. 2012 Mar
22;366(12):1161-3
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Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R,
Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G. Relative role of genetic
complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc
Nephrol. 2010 Oct;5(10):1844-5
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Mele C, Iatropoulos P, Donadelli R, Calabria A, Maranta R, Cassis P, Buelli S, Tomasoni S, Piras R, Krendel M, Bettoni
S, Morigi M, Delledonne M, Pecoraro C, Abbate I, Capobianchi MR, Hildebrandt F, Otto E, Schaefer F, Macciardi F,
Ozaltin F, Emre S, Ibsirlioglu T, Benigni A, Remuzzi G, Noris M; PodoNet Consortium. MYO1E mutations and
childhood familial focal segmental glomerulosclerosis. N Engl J Med. 2011 Jul 28;365(4):295-306
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Cassis P, Azzollini N, Solini S, Mister M, Aiello S, Cugini D, Scudeletti P, Gagliardini E, Abbate M, Gallon L, Remuzzi
G, Noris M. Both darbepoetin alfa and carbamylated erythropoietin prevent kidney graft dysfunction due to
ischemia/reperfusion in rats. Transplantation. 2011 Aug 15;92(3):271-9
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Aiello S, Cassis P, Mister M, Solini S, Rocchetta F, Abbate M, Gagliardini E, Benigni A, Remuzzi G, Noris M. Rabbit
anti-rat thymocyte immunoglobulin preserves renal function during ischemia/reperfusion injury in rat kidney
transplantation. Transpl Int. 2011 Aug;24(8):829-38
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Noris M, Remuzzi G. Atypical Hemolytic Uremic Syndrome N Engl J Med. 2009 Oct 22;361(17):1676-87
Susanna Tomasoni got her Biological Science degree in 1991 at the University of Milan and the Ph.D in
Physiology at the University of Milan in 1995.
Educational training: in 1989-1991 Graduate student, University of Milan; in 1991-1994 PhD student,
University of Milan; in 1994 Research Fellow, Renal Division, Brigham & Women’s Hospital, Harvard
Medical School, Boston, USA; 1995-1998: Post Doctoral Fellow, IRFMN, Bergamo, Italy.
Areas of interest: construction of adenoviral vectors for gene therapy; in vitro and in vivo gene transfer
techniques; use of adenoviral and adeno-associated viral vectors to prevent acute and chronic allograft
rejection; induction of kidney transplant tolerance by cell and gene therapy; correction of genetic
deficiency in rare diseases by gene therapy; involvement of microRNAs in the progression of renal
disease; generation of induced-pluripotent stem cell from adult somatic cells; mesenchymal stem cellderived exosomes as mediators of cell-to-cell communication.
Employment: in 1998-2000 Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of Gene Therapy,
IRFMN, Bergamo, Italy; from 2010 Head, Laboratory of Gene Therapy and Cellular Reprogramming,
IRFMN, Bergamo, Italy.
Selected publications:

Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, Capelli C, Introna M, Remuzzi G, Benigni A. Transfer of
Growth Factor Receptor mRNA Via Exosomes Unravels the Regenerative Effect of Mesenchymal Stem Cells. Stem
Cells Dev. 2012 Dec 21. [Epub ahead of print]

Macconi D, Tomasoni S, Romagnani P, Trionfini P, Sangalli F, Mazzinghi B, Rizzo P, Lazzeri E, Abbate M, Remuzzi G,
Benigni A. MicroRNA-324-3p promotes renal fibrosis and is a target of ACE inhibition. J Am Soc Nephrol. 2012
Sep;23(9):1496-505

Mele C, Iatropoulos P, Donadelli R, Calabria A, Maranta R, Cassis P, Buelli S, Tomasoni S, et al. Myo1e mutations and
childhood familial focal segmental glomerulosclerosis. NEJM 2011; 365: 295-306

Trionfini P, Tomasoni S, Galbusera M, Motto D, Longaretti L, Corna D, Remuzzi G, Benigni A. Adenoviral-mediated
gene transfer restores plasma ADAMTS13 antigen and activity in ADAMTS13 knockout mice. Gene Therapy 2009; 16:
1379-1385

Tomasoni S, Remuzzi G, Benigni A. Allograft rejection: acute and chronic studies. Contrib Nephrol. 2008; 159:122-34.
Review.

Imberti B, Morigi M, Tomasoni S, Rota C, Corna D, Longaretti L, Rottoli D, Valsecchi F, Benigni A, Wang J, Abbate
M, Zoja C, Remuzzi G. Insulin-like growth factor-1 sustains stem cell mediated renal repair. J Am Soc Nephrol. 2007;
18: 2921-8

Benigni A, Tomasoni S, Turka LA, Longaretti L, Zentilin L, Mister M, Pezzotta A, Azzollini N, Noris M, Conti S,
Abbate M, Giacca M, Remuzzi G, Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched
renal allografts from chronic rejection. J Am Soc Nephrol, 2006, 17: 1665-72
Carlamaria Zoja got her Biol.Sci. degree at the University of Milano, Italy, in 1979 and the Ph.D. at
the University of Maastricht, The Netherlands in 2001.
Educational Training: in 1979-1981 Post Doctoral Fellow, ‘Associazione Bergamasca per lo studio delle
Malattie Renali’, Laboratory of the Division of Nephrology and Dialysis, Ospedali Riuniti di Bergamo,
Italy; in 1981-1983 Post Doctoral Fellow, Center for Thrombosis and Vascular Research, Department of
Research Katholieke Universiteit, Leuven, Belgium; in 1983-1985: Post Doctoral Fellow, IRFMN,
Laboratory of Kidney Disease, Bergamo, Italy; in 1988 stage at Case Western Reserve University,
Cleveland, Ohio, USA; in 1989 stage at Brigham and Women’s Hospital, Boston, USA.
Areas of interest: experimental models of kidney diseases of immunological and non immunological
origin; vasoactive and inflammatory mediators of renal disease progression; role of proteinuria in
progressive kidney damage; protection of renal disease progression by a multidrug approach; novel
immunosuppressive and anti-inflammatory strategies for the treatment of lupus nephritis; role of
Shigatoxin in the pathogenesis of endothelial dysfunction in Hemolytic Uremic Syndrome.
Employement: since 1985 Scientist, IRFMN, Bergamo, Italy; in 1990-1994: Head, Unit of Experimental
Modelling for Human Renal Diseases, Laboratory of Kidney Diseases, IRFMN, Bergamo, Italy; since
1995: Head, Laboratory of Experimental Models of Kidney Diseases, IRFMN, Bergamo, Italy. In
November 2010 Lab denomination changed to ‘Laboratory of Physiopathology of Experimental Renal
Disease and Interaction with other Organ Systems’.
In 2004-2007 member Editorial Board, Journal of the American Society of Nephrology. Since January
2010 Leader WP5.2, SysKid collaborative project (FP7).
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Selected publications:
Zoja C, Corna D, Nava V, Locatelli M, Abbate M, Gaspari F, Carrara F, Sangalli F, Remuzzi G, Benigni A. Analogs of
bardoxolone methyl worsen diabetic nephropathy in rats with additional effects. Am J Physiol Renal Physiol. 2012 Nov
7 (Epub ahead of print)
Zoja C, Garcia PB, Rota C, Conti S, Gagliardini E, Corna D, Zanchi C, Bigini P, Benigni A, Remuzzi G, Morigi M.
Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in
adriamycin-induced nephropathy. Am J Physiol Renal Physiol. 2012 Nov; 303:F1370-1381
Zoja C, Locatelli M, Pagani C, Corna D, Zanchi C, Isermann B, Remuzzi G, Conway EM, Noris M. Lack of the lectinlike domain of thrombomodulin worsens Shoga Toxin-associated Hemolytic Uremic Syndrome in mice. J immunol.
2012 Oct; 189:3661-3668
Zoja C, Cattaneo S, Fiordaliso F, Lionetti V, Zambelli V, Salio M, Corna D, Pagani C, Rottoli D, Bisighini C, Remuzzi
G, Benigni A. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2
diabetes. Am J Physiol Renal Physiol. 2011;301:F1114-23
Morigi M, Galbusera M, Gastoldi S, Locatelli M, Buelli S, Pezzotta A, Pagani C, Noris M, Gobbi M, Stravalaci M,
Rottoli D, Tedesco F, Remuzzi G, Zoja C. Alternative pathway activation of complement by Shiga toxin promotes
exuberant C3a formation that triggers microvascular thrombosis. J Immunol. 2011;187:172-80
Sangalli F, Carrara F, Gaspari F, Corna D, Zoja C, Botti L, Remuzzi G, Remuzzi A. Effect of ACE inhibition on
glomerular permselectivity and tubular albumin concentration in the renal ablation model. Am J Physiol Renal Physiol.
2011 Jun;300(6):F1291-300
Zoja C, Corna D, Gagliardini E, Conti S, Arnaboldi L, Benigni A, Remuzzi G. Adding a statin to a combination of ACE
inhibitor and ARB normalizes proteinuria in experimental diabetes which translates into full renoprotection. Am J
Physiol Renal Physiol. 2010 Nov;299(5):F1203-11
Zoja C, Buelli S, Morigi M. Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial
dysfunction. Pediatr Nephrol. 2010 Nov;25(11):2231-40
Mauro Abbate obtained his M.D. degree in 1988 at the University of Brescia, Italy.
Educational training: in 1984-1988 Graduate Student, IRFMN, Bergamo, Italy; in 1988-1992 Post
Doctoral Fellow, IRFMN, Bergamo, Italy; in 1992-1994 Research Fellow, The Renal Unit,
Massachusetts General Hospital, HMS, Boston, USA.
Areas of interest: renal disease progression: the role of proteinuria, complement, and mediators of injury
in progressive kidney damage; mechanisms of glomerular injury; anti-GBM glomerulonephritis;
mechanisms of tubular injury; kidney fibrosis; the renal biopsy; membranous nephropathy.
Employement: in 1996 - 2000: Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of Renal
Pathology and Immunopathology, IRFMN, Bergamo, Italy.
Selected publications

Zoja C, Corna D, Nava V, Locatelli M, Abbate M, Gaspari F, Carrara F, Sangalli F, Remuzzi G, Benigni A. Analogues
of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. Am J Physiol Renal Physiol.
2012 Nov 7. [Epub ahead of print]

Xinaris C, Benedetti V, Rizzo P, Abbate M, Corna D, Azzollini N, Conti S, Unbekandt M, Davies JA, Morigi M,
Benigni A, Remuzzi G. In vivo maturation of functional renal organoids formed from embryonic cell suspensions. J Am
Soc Nephrol. 2012 Nov;23(11):1857-68
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Benigni A, Morigi M, Rizzo P, Gagliardini E, Rota C, Abbate M, Ghezzi S, Remuzzi A, Remuzzi G. Inhibiting
angiotensin-converting enzyme promotes renal repair by limiting progenitor cell proliferation and restoring the
glomerular architecture. Am J Pathol. 2011 Aug;179(2):628-38
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Cravedi P, Abbate M, Gagliardini E, Galbusera M, Buelli S, Sabadini E, Marasà M, Beck LH Jr, Salant DJ, Benigni A,
D'Agati V, Remuzzi G. Membranous nephropathy associated with IgG4-related disease. Am J Kidney Dis. 2011
Aug;58(2); 272-5
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Buelli S, Abbate M, Morigi M, Moioli D, Zanchi C, Noris M, Zoja C, Pusey CD, Zipfel PF, Remuzzi G. Protein load
impairs factor H binding promoting complement-dependent dysfunction of proximal tubular cells. Kidney Int. 2009
May;75(10):1050-9
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Ruggenenti P, Cravedi P, Sghirlanzoni MC, Gagliardini E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G.
Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol. 2008
Nov;3(6):1652-9
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Abbate M, Zoja C, Corna D, Rottoli D, Zanchi C, Azzollini N, Tomasoni S, Berlingeri S, Noris M, Morigi M, Remuzzi
G. Complement-mediated dysfunction of glomerular filtration barrier accelerates progressive renal injury. J Am Soc
Nephrol. 2008 Jun;19(6):1158-67
Sistiana Aiello got the Biol.Sci. degree in 1993 at the University of Milano, Italy, and the Specialization
in Pharmacology Research in 1996, at IRFMN, Bergamo, Italy.
Educational training: in 1990-1993 research training, IRFMN, Bergamo; in 1993-2000 post doctoral
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fellow, IRFMN, Bergamo.
Areas of interest: transplant immunology with a particular interest on dendritic cell biology and
mechanisms by which Tegulatory cells arise and work; in vitro and in vivo studies on new compounds
with immunosuppressive capacity or capable to prevent ischemia/reperfusion tissue injury; vasoactive and
inflammatory mediators of progressive renal injury with a particular emphasis on platelet activating factor
(PAF) and nitric oxide (NO).
Employement: since 2000 Scientist within Laboratory of Immunology and Genetics of Rare disease and
Organ Transplantation; IRFMN, Bergamo; since 2006 Head, Unit of Cellular Biology of Autoimmunity
and Transplant Rejection, IRFMN, Transplant Research Center “Chiara Cucchi de Alessandri e Gilberto
Crespi”, Ranica.
Selected publications:
 Solini S, Aiello S, Cassis P, Scudeletti P, Azzollini N, Mister M, Rocchetta F, Abbate M, Pereira RL, Noris M.
Prolonged cold ischemia accelerates cellular and humoral chronic rejection in a rat model of kidney allotransplantation.
Transpl Int. 2012; 25(3):347-56
 Aiello S, Cassis P, Mister M, Solini S, Rocchetta F, Abbate M, Gagliardini E, Benigni A, Remuzzi G, Noris M. Rabbit
anti-rat thymocyte immunoglobulin preserves renal function during ischemia/reperfusion injury in rat kidney
transplantation. Transpl Int. 2011;24(8):829-38.
 Rocchetta F, Solini S, Mister M, Mele C, Cassis P, Noris M, Remuzzi G, Aiello S. Erythropoietin enhances
immunostimulatory properties of immature dendritic cells. Clin Exp Immunol. 2011;165(2):202-10
 Aiello S, Noris M. Klotho in acute kidney injury: biomarker, therapy, or a bit of both? Kidney Int. 2010
Dec;78(12):1208-10.
 Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, Todeschini
M, Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. The
Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts. J Immunol. 2009,
183(7): 4249-60
 Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E, Noris M, Buelli S, Zoja C, Corna D, Mele C,
Fanelli R, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic
peptides. J Am Soc Nephrol. 2009;20(1):123-30
Federica Casiraghi has obtained his degree in Industrial Chemistry in 1988, and the degree in Clinical
Monitoring and in Biochemical Research in 1993-1994 at IRFMN, Bergamo, Italy.
Educational Training: 1989-1994 research fellow, IRFMN, Bergamo.
Areas of interest: Transplant immunology with particular focus on pharmacological and cellular therapies
for induction and maintenance of transplantation tolerance. Characterization of regulatory T cells in renal
transplant patients and in experimental models of allograft tolerance. Impact of different
immunosuppressive drugs on T cell function in renal transplant patients. Vasoactive and inflammatory
mediators of progressive renal injury with a particular emphasis on arachidonic acid metabolites.
Employment: since 1994 Scientist within Laboratory of Immunology and Genetics of Rare Disease and
Organ Transplantation, IRFM, Bergamo; since 2006 Head, Unit of Cellular and Molecolar Biology of
Transplantation Tolerance, Transplant Research Center “Chiara Cucchi de Alessandri e Gilberto Crespi”,
Ranica.
Selected Publications:
 Casiraghi F, Azzollini N, Todeschini M, Cabinato RA, Cassis P, Solini S, Rota C, Morigi M, Introna M, Maranta R,
Perico N, Remuzzi G, Noris M. Localization of mesenchymal stromal cells dictates their immune or proinflammatory
effects in kidney transplantation. Am J Transplant. 2012 Sep;12(9):2373-83
 Casiraghi F, Perico N, Remuzzi G. Mesenchymal stromal cells to promote solid organ transplantation tolerance. Curr
Opin Organ Transplant 2013, 18:51–58
 Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P, Rizzo P,
Cortinovis M, Marasà M, Golay J, Noris M, Remuzzi G. Autologous Mesenchymal Stromal Cells and Kidney
Transplantation: A Pilot Study of Safety and Clinical Feasibility. Clin J Am Soc Nephrol. 2011Feb ;6(2):412-22
 Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, Todeschini
M, Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. The
Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts. J Immunol.
2009;183(7): 4249-60
 Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, Sonzogni A,
Perico N, Remuzzi G, Noris M. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a
semiallogeneic heart transplant through the generation of reg