the clinical departments

Transcript

S C I E N T I F I C
R E P O R T
2009
00intro
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COVER IMAGES
top left:
Unpublished image by Vania Broccoli
(see Stem cells and neurogenesis, page 39)
Rosettes-like structures organized by neural progenitors derived by direct in vitro cell differentiation of human iPS cells.
top middle:
Hierarchical clustering of gene expression profiles in healthy tissues (rows, genes; columns, tissues)
(Giorgio Casari, Head of Neurogenomics Unit, page 169)
top right:
Unpublished image by Gian Giacomo Consalez
(see Developmental neurogenetics Unit, page 36)
Progenitors tagged during early embryogenesis by a genetic inducible fate mapping approach develop into mature
Purkinje neurons in the adult cerebellar cortex.
bottom:
Unpublished image by Enrico Gherlone
(see Dento-facial histopathology Unit, page 162)
The graft material particles (GM) appeared well-included and showed continuity with the new bone (NB) tissue and
deposition of osteoid matrix.
Some of the images in this book has been published in scientific papers:
Fig. 1, p. 14: EMBO Reports
Fig. 4, p. 42: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders
Fig. 5, p. 43: Neurobiology of Disease
Fig. 10, p. 78: Radiology
Fig. 16, p. 154: Science
Fig. 17, p. 155: PLoS One
Fig. 18, p. 156: Journal of Neuroscience
Fig. 19, p. 157: Molecular and Cellular Proteomics
Fig. 20, p. 159: Molecular and Cellular Biology
Fig. 24, p. 172: Angewandte Chemie
Fig. 25, p. 186, toke part in "GE Healthcare IN Cell World Image Competition Award" 2009
Edited by the San Raffaele Library
Layout by Roberto Cremonesi
Printed by Grafiche Parole Nuove, Brugherio
INDEX - III
INDEX
INTRODUCTIONS
VII
Introduction by the President
Introduzione del Presidente
Introduction by the Scientific Director
Introduction by the Chief Operating Officer
VIII
IX
XIII
XXII
San Raffaele Scientific Retreat 2009
I ragazzi della via Olgettina
Introduction by the General Director
Clinical Area
2009 Seminars and lectures
XXV
XXIX
XXXII
XXXIV
DIVISION OF MOLECULAR
ONCOLOGY
Introduction by the Directors
Research Units
Lymphoid malignancies Unit
B-cell neoplasia
Biology of multiple myeloma
Cell activation and signalling
Dynamic fluorescence spectroscopy in biomedicine
Lymphoid organ development
Preclinical models of cancer
Tumour microenvironment
Immuno-biotherapy of melanoma and solid
tumors Unit
Cancer gene therapy
Functional genomics of cancer Unit
Model genetics of membrane trafficking Unit
Molecular histology and cell growth Unit
Tumor biology and vascular targeting Unit
Clinical Research Units
1
5
7
7
8
8
9
9
10
10
11
11
12
13
13
14
Digestive and pancreatico-biliary endoscopy Unit
Endosonography: diagnostic and therapeutic
endoscopic ultrasound
Gastrointestinal surgical oncology Unit
Head and neck oncology Unit
Multidisciplinary group for thoracic surgical oncology
Oncogenesis in liver neoplasms Unit
Onco-hematology Unit
Pancreatic cancer Unit: biology and new therapeutic
approaches
Pathology Unit
Clinical lymphoid malignancies
Gynecologic oncology
Medical oncology Unit - Clinical trials
Medical oncology Unit - Phase I and lung cancer
clinical trials
Urological Research Institute (URI)
Selected publications
15
15
16
17
17
18
18
19
19
20
20
21
21
22
23
DIVISION OF NEUROSCIENCE 27
Research Units
32
Neuropsychopharmacology Unit
Cell adhesion Unit
Cellular and molecular neurobiology Unit
Cellular neurophysiology Unit
Developmental neurogenetics Unit
Neurobiology of learning Unit
Proteomics of iron metabolism Unit
Molecular genetics of mental retardation Unit
Neural degeneration Unit
Stem cells and neurogenesis
34
34
35
35
36
37
37
38
38
39
IV - SAN RAFFAELE SCIENTIFIC INSTITUTE
Acute brain protection, Acute post-operative pain,
Drugs and central nervous system Unit
40
Eye repair Unit
40
Cognitive neuroscience Unit
41
Experimental neurosurgery Unit
41
Functional neuroradiology Unit
42
In vivo Human molecular and structural neuroimaging
Unit
43
Neuroothology Unit
43
Psychiatry and clinical psychobiology
44
Sleep medicine
44
Clinical psychology
45
Motor function rehabilitation
45
INSTITUTE OF EXPERIMENTAL
NEUROLOGY (INSPE)
46
Introduction by the Director
Research Units
Experimental neuropathology
Experimental neurophysiology
Molecular genetics of behaviour
Neuromuscular repair
Neuroimmunology Unit
Clinical neuroimmunology
CNS repair
Neuroimaging research Unit
Neuroimaging of CNS white matter
Human inherited neuropathies Unit
Axo-glia interactions Unit
47
47
48
48
49
50
50
51
51
52
52
Inflammatory CNS disorders Unit
Cerebrovascular disorders
Memory disorders
Movement disorders
Neuromuscular disorders
Paroxysmal events
DIVISION OF METABOLIC
AND CARDIOVASCULAR
SCIENCES
53
54
54
55
55
56
57
63
Introduction
Research Units
66
Amino acid and stable isotopes Unit
Complications of diabetes
Obesity and metabolic related diseases
67
67
68
Bone metabolism Unit
Coagulation service & thrombosis research Unit
Cardiodiabetes & core lab
Pediatric endocrinology research
68
69
69
70
Diabetes and endocrinology Unit
Cardio-metabolic and clinical trials
Clinical pediatric endocrinology
Diabetes and metabolic diseases in children and
adolescents
Neonatology
Foetal-maternal medicine
Infertility
Cardiovascular interventions Unit
Clinical cardiovascular biology Unit
Ischaemic heart disease, heart failure and
echocardiography Unit
Organ protection in critically ill patients, advanced
cardiac failure and mechanical supports Unit
Structural heart disease Unit
Study and treatment of aortic disease Unit
Center for arrhythmia research
Vision first Unit
71
71
72
72
73
73
74
75
75
76
77
77
78
79
79
81
DIVISION OF REGENERATIVE
MEDICINE, STEM CELLS, AND
GENE THERAPY
85
Research Units
89
Skeletal muscle development and therapy Unit
Functional genetics of muscle regeneration
Gene expression and muscular dystrophy Unit
Molecular and functional immunogenetics
Neural stem cell biology
Autoimmunity & vascular inflammation Unit
Innate immunity and tissue remodelling
Cellular pharmacology Unit
Experimental hematology Unit
Angiogenesis and tumor targeting
91
91
92
92
93
94
94
95
95
96
Hematology and hematopoietic stem cell
transplantation Unit
Immunohematology and transfusion medicine Unit
PSIEP - Strategic Program of Pediatric
Immunohematology
96
97
97
INDEX - V
THE SAN RAFFAELE TELETHON INSTITUTE
FOR GENE THERAPY (HSR-TIGET)
98
Research Units
Gene transfer technologies and new gene
therapy strategies Unit
Gene/neural stem cell therapy for lysosomal
storage diseases
Hematopoietic stem cell based gene therapy for
the treatment of lysosomal storage disorders
Safety of gene therapy and insertional
mutagenesis
Gene transfer into stem cells Unit
Immunological tolerance Unit
From FOXP3 mutation to IPEX syndrome
Tolerogenic dendritic cells
Pathogenesis and therapy of ADA-SCID Unit
Gene therapy FOR WASP/Omenn
Tumor immunology Unit
Viral evolution and transmission Unit
Viral pathogens & biosafety Unit
126
127
127
99
99
100
100
101
101
102
102
103
103
Pediatric Clinical Research Unit - Gene therapy for
Wiskott-Aldrich Syndrome
104
Pediatric Clinical Research Unit - ADA gene transfer
into hematopoietic stem cells for the treatment of
ADA-SCID
105
Pediatric Clinical Research Unit - Clinical trial of gene
therapy in metachromatic leukodystrophy
105
106
DIVISION OF IMMUNOLOGY,
TRANSPLANTATION, AND
INFECTIOUS DISEASES
111
Research Units
116
Leukocyte biology Unit
Cellular and molecular allergology
Human virology
Infection and cystic fibrosis
Protein engineering and therapeutics
γδ T cells in innate and adaptive immunity
Immunobiology of HIV
AIDS immunopathogenesis Unit
Biocrystallography Unit
Cellular immunology Unit
Emerging bacterial pathogens Unit
Experimental immunology Unit
Immunopathology Unit
Lymphocyte activation Unit
118
118
119
120
120
121
122
122
123
123
124
125
125
126
Management and antiretroviral treatment of HIV
infection
128
Neurovirology
128
Study and treatment of hepatotropic viruses related
diseases
129
Vaccine and immunotherapy
129
Clinical immunopathology and advanced medical
therapeutics Unit
130
Clinical transplant Unit
130
Gynecological cancers immunology
131
Immunology in liver neoplasms
131
Pancreatic tumors: immunotherapy and β cell function
substitution
132
Clinical hepato-gastroenterology
132
Transplant surgery
133
DIABETES RESEARCH INSTITUTE (DRI)
134
Research Units
Immune tolerance
Experimental diabetes
β cell biology
Cell imaging
135
135
136
137
Islet transplantation
Prevention in type 1 diabetes
Epidemiology & data management
Childhood diabetes
Islet processing activity
137
138
138
139
139
141
DIVISION OF GENETICS AND
CELL BIOLOGY
149
Research Units
152
Protein transport and secretion Unit
Age related diseases
Molecular immunology
Chromatin dynamics Unit
In vivo Chromatin and transcription
Biology of myelin Unit
Biomolecular mass spectrometry Unit
Gene expression Unit
Genetics of common disorders Unit
153
153
154
154
155
156
157
157
158
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VI - SAN RAFFAELE SCIENTIFIC INSTITUTE
Molecular basis of polycystic kidney disease Unit
Molecular genetics Unit
Molecular dynamics of the nucleus
NeuroGlia Unit
Regulation of iron metabolism Unit
Molecular genetics of renal disorders Unit
158
159
159
160
160
161
Dento-facial histopathology Unit
Genomics of renal diseases and hypertension Unit
Tissue engineering and biomaterials
CENTER FOR GENOMICS,
BIOINFORMATICS AND
BIOSTATISTICS
162
163
163
165
167
Research Units
168
Neurogenomics Unit
Theoretical biology
Organelle biogenesis and motility Unit
Genomic Unit for the diagnosis of human
pathologies
Proteome biochemistry Unit
Biomolecular NMR laboratory
169
170
170
170
171
172
173
CFCM, Core Facility for Conditional Mutagenesis 187
FRACTAL, Flow cytometry Resource, Analytical
Cytology Technical Applications Laboratory
CERMAC, Centre of Excellence of High Field Magnetic
Resonance
187
Mouse histopathology
THE CLINICAL
DEPARTMENTS
177
178
Clinical and experimental radiology Unit
High technology in radiation therapy Unit
Medical physics Unit
Molecular imaging Unit
Neuroradiology research group
179
179
180
181
181
182
FACILITIES
185
ALEMBIC, Advanced Light and Electron Microscopy
BioImaging Center
186
188
191
Department of arrhythmology
192
Cardio-thoracic-vascular Department
193
Department of general and specialistic surgery
196
Head and neck Department
199
Department of infectious diseases
202
Maternal and child health Department
204
Department of internal and specialistic medicine
206
Department of clinical neuroscience
208
Department of neurology
210
Department of oncology
211
Department of radiology
213
Department of urology
215
CLINICAL SERVICES
CENTER FOR IMAGING
187
216
Pathology
218
Laboratory medicine
218
Immunohematology and Transfusion medicine
service
218
Emergency medicine
219
General intensive care
220
Anaesthesia and neurointensive care Unit
220
AISPO - San Raffaele in the world
221
PUBLICATIONS
227
Best papers 2009
229
List of 2009 publications
230
INTRODUCTIONS - VII
INTRODUCTIONS
VIII - SAN RAFFAELE SCIENTIFIC INSTITUTE
Introduction by the President
I am particularly delighted to present this Annual Report of
the scientific research work carried on by the numerous researchers operating in our University and Research Centers.
I personally believe that it is impossible to choose a path of
research while not following at the same time different others: a
research is made out of different paths interweaved together.
Thus, I cannot help but notice my satisfaction in observing
such an important and great scientific platform as San Raffaele
is.
Such platform includes the basic research, the translational
research and the clinic and applied researches into a joined
unity.
Dear Raffaelians, Physicians, Researchers, and all Personnel
You all, who here in Italy and in our San Raffaele centres
abroad form a true Army to fight illness and death, which were
never sought after by God. (God, that is, who created man in a
condition of full strength, apt for a perfectly healthy life.)
You are in charge of searching for the adequate biological,
environmental, and ethical conditions to carry man back to his original state of perfection, as a king-owner of
the Generating Universe, with the duty of ruling it and mastering it [possidete eam].
Do not surrender to difficulties.
Your self-awareness - which is to say, your awareness of the human value which resides in each one of us leads us to responsibility, prudence, and, at the same time, to the requisite resilience and audaciousness.
You shall know that “Everything is possible to him who has faith”.
Even I, poor man and penniless, have shown this to You, raising Your “City of Man - S. Raffaele” out of a
swamp.
Seek out and you shall find: “you will receive whatever you ask for in prayer.”
I think about You and love You all.
Yours,
don Luigi Maria Verzè
(Founder, President, Provost)
INTRODUCTIONS - IX
Introduzione del Presidente
Sono particolarmente felice di presentare anche quest’anno il lavoro dei
nostri eccellenti ricercatori.
Sono convinto da sempre che non ci sia cura senza ricerca. È perciò che
mi sento soddisfatto di vedere una piattaforma scientifica del San Raffaele
di così vaste proporzioni.
Una piattaforma che comprende in una unità strettamente organizzata e
integrata la ricerca di base, la ricerca traslazionale, la ricerca clinica e applicata.
Carissimi Raffaeliani Medici, Ricercatori di base e Clinici, Personale tutto,
che costituite in Italia e nei nostri San Raffaele all’estero un vero esercito
per battere la malattia e la morte mai volute da Dio.
Lui, infatti, ha creato l’uomo in condizione eucrasica, atto a vivere in
longevità perfettamente sano.
Tocca a Voi ricercare le condizioni biologiche, ambientali, ed etico-equilibranti adeguate a far tornare l’uomo
al suo stato perfetto originale, quale re-padrone dell’Universo Creatore con l’ordine di dominarlo “possidete
eam”.
Non arrendeteVi alle difficoltà.
La consapevolezza del Vostro “io”, cioè del valore uomo che sta in ciascuno di noi, ci induce alla responsabilità, alla prudenza e, insieme, alla tenacia e all’audacia necessarie.
Sappiate che “Tutto è possibile a chi crede”.
Anch’io, pover-uomo e squattrinato, Ve ne ho dato l’esempio tirando fuori da una marcita la Vostra “Città
dell’uomo S. Raffaele”.
Cercate e troverete “pregate e vi sarà dato”.
Vi penso e Vi amo tutti.
Vostro
don Luigi Maria Verzè
(Fondatore, Presidente, Rettore)
X - SAN RAFFAELE SCIENTIFIC INSTITUTE
THE ETHICS COMMITTEE
CHAIRMAN: Gianna Zoppei, Health Care Supervisor, San Raffaele Scientific Institute
VICE CHAIRMAN: Guido Pozza, Physician, Professor Emeritus of Internal Medicine, Università
Vita-Salute San Raffaele
SECRETARY: Alfredo Anzani, Expert in Bioethics, San Raffaele Scientific Institute
MEMBERS:
Giliola Calori, Biostatistician, San Raffaele Scientific Institute
Ilaria Carretta, Psychologist and Psychoterapist, San Raffaele Scientific Institute
Francesco Caviezel, Physician, Professor Emeritus of Endocrinology, University of Milan
Maurizio Chiodi, Theologian, Professor at the Theological Faculty of Northern Italy, Milan
Francesco Clementi, Pharmacologist, Professor Emeritus of Pharmacology, University of Milan
Cesarina Curti, Expert in Medical Devices, San Raffaele Scientific Institute
Maria Grazia Fusi, Regional Area GPs, Milan
Andrea Gentilomo, Medical Examiner, Professor of Legal Medicine, University of Milan
Roberts Mazzuconi, Hospital Director, San Raffaele Scientific Institute
Massimo Reichlin, Expert in Bioethics, Professor of Phylosophy, Università Vita-Salute San Raffaele
Maria Grazia Roncarolo, Scientific Director, San Raffaele Scientific Institute
Claudio Rugarli, Physician, Professor Emeritus of Internal Medicine, Università Vita-Salute San Raffaele
Patrizia Tadini, Pharmacist, San Raffaele Scientific Institute
Cesare Triberti, Expert in Legal Procedures
Liliana Villa, Representative of the Fondazione Centro San Raffaele del Monte Tabor
Ewa Wysocka, Representative of Nursing Area
Maria Elisabetta Zanardelli, Volunteer association member, Associazione per l’Aiuto ai Giovani Diabetici
(Onlus)
CONSULTANT: Gianvincenzo Zuccotti, Head of Pediatrics Unit, Luigi Sacco Hospital, Milan
The Ethics Committee complies with the legislative requirements of May 1998 as well as with the EU, national, and local rules concerning pharmacological trials.
INTRODUCTIONS - XI
SAN RAFFAELE SCIENTIFIC INSTITUTE
BOARD OF DIRECTORS: Roberto Cusin, Ennio Doris, Carlo Salvatori, Laura Ziller, Gianna Zoppei
PRESIDENT: professor don Luigi Maria Verzè
VICE-PRESIDENT: Mario Cal
HEAD OF HUMAN RESOURCES CORPORATE DEPARTMENT: Antonio Limardi
HEAD OF ADMINISTRATION & FINANCE CORPORATE DEPARTMENT: Mario Valsecchi
HEAD OF LEGAL & GENERAL AFFAIRS CORPORATE DEPARTMENT: Alessandro Cremaschi
HEAD OF TECHNICAL DEPARTMENT: Andrea Roma
HEAD OF PUBLIC RELATIONS DEPARTMENT: Cristina Poma
HEAD OF COMMUNICATION: Paolo Klun
GENERAL DIRECTOR OF CLINICAL AREA: Renato Botti
SCIENTIFIC DIRECTOR: Maria Grazia Roncarolo
CHIEF OPERATING OFFICER OF RESEARCH AREA: Maurizio Savi
ORGANIZATION CHART
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RESEARH
DIVISIONSANDENdERS
The San Raffaele Scientific Institute is a teaching hospital affiliated to the Università Vita-Salute San Raffaele
(DGR .3 dicembre 1999, n. 6/46798)
XII - SAN RAFFAELE SCIENTIFIC INSTITUTE
Scientific Directorate
SCIENTIFIC DIRECTOR: Maria Grazia Roncarolo
CHIEF OPERATING OFFICER: Maurizio Savi
SECRETARY: Titti Meroni
PROGRAM MANAGER TO THE SCIENTIFIC DIRECTOR: Marina Castellano
STUDIES, DEVELOPMENT & QUALITY OFFICE MANAGER: Vanda Parezanovic
ASSISTANT TO THE SCIENTIFIC DIRECTOR: Laura Reiss
HEAD OF SCIENTIFIC OFFICE: Giulio Negri
Maria Grazia Roncarolo
GRANT OFFICE: Stefano Apollonio, Riccarda Daneri, Michele Granetto,
Paola Rebagliati
HEAD OF CLINICAL TRIAL OFFICE: Elisabetta Riva
CLINICAL TRIAL OFFICE: Raffaella Biagetti, Giovanna Bombelli, Anna Cantoni,
Giliola Calori, Margherita Ianniello, Maria Rosa Mandelli, Veronica Savia
HEAD OF BIOTECHNOLOGY TRANSFER OFFICE: Daniela Bellomo (as of January
2010 Lucia Faccio)
BIOTECHNOLOGY TRANSFER OFFICE: Fabrizio Bacchi, Lucia Faccio, Simona Locatelli,
Paola Pozzi, Roberto Santarella
Maurizio Savi
HEAD OF LIBRARY: Laura Tei
LIBRARY: Diego Maria Bertini, Francesco Curci, Elena Ponzi, Maria Samarati
HEAD OF ADMINISTRATIVE OFFICE: Maria Rosa Pedrazzi
ADMINISTRATIVE OFFICE: Roberto Barchi*, Giovanna Bernardi, Francesca Dodero, Barbara Lapio,
Massimiliano Meoni, Ornella Muraro, Marco Picariello, Patrizia Scotti, Miriam Togni
HEADS OF MARKETING & FUNDRASING OFFICE: Luca Isotti, Lisa Orombelli
MARKETING & FUNDRASING OFFICE: Federica Cattaneo, Patrizia Mogliani, Chiara Scolari, Cristiana Secchi
HEAD OF HUMAN RESOURCE OFFICE: Giuseppe Defidio
HUMAN RESOURCE OFFICE: Roberta Berno, Alberto Martoglio
LOGISTICS & IT SERVICES: Marco Crespi, Giuseppe Miracoli
* Università Vita-Salute San Raffaele
INTRODUCTIONS - XIII
Introduction by the Scientific Director
THE MISSION AND THE VISION
The mission of the San Raffaele Scientific Institute (SRSI) is to conduct innovative research to benefit the care
and cure of our patients and also to provide state-of-the-art education and training for new generations of doctors, physician scientists and research scientists with a high level of social responsibility. To achieve this objective, we want to perform cutting-edge science and to advance the knowledge of human diseases resulting in the
identification of novel therapies.
Our vision is that Research is the backbone of the SRSI, intersecting and connecting with both the clinical
and the teaching programs. Our objective is to further integrate research, teaching and clinical activities by
aligning preclinical and clinical research with our clinical strengths.
THE SCIENTIFIC INSTITUTE
The SRSI comprises the clinical activities of the research hospital with more than 1400 beds and the research
activities conducted in Di.Bi.T.1 and Di.Bi.T.2. The SRSI is part of the San Raffaele Biomedical Science Park,
which also includes the Vita-Salute San Raffaele University that was established in 1996. The University hosts
the faculties of medicine, psychology and philosophy and provides specialized post-graduate courses, resident
programs in various medical specialties and international PhD programs in Cellular/Molecular Biology and
Molecular Medicine. In addition, the San Raffaele Biomedical Science Park hosts several biotechnology companies, including MolMed, Telbios and Axxam, which interact with the SRSI.
Established in 1971, the SRSI was one of Italy’s first private hospitals. In 1972 it was granted the status of
“Research Hospital” (IRCCS: “Istituto di Ricovero e Cura a Carattere Scientifico”), focusing mainly on diabetes and metabolic diseases and consequently received dedicated funding from the Italian Ministry of Health.
In 1992, a research building (about 40,000 sq m or 431,000 sq ft) was opened to accommodate the Department
XIV - SAN RAFFAELE SCIENTIFIC INSTITUTE
of Biotechnology (Di.Bi.T.1). The initial areas of research covered by Di.Bi.T.1 were genetics, cell biology and
immunology, while in the late 90s gene therapy, stem cell biology and molecular mechanisms of diseases were
added. In recognizing the SRSI as a center of excellence in the area of molecular medicine research, the Italian
Ministry of Health granted it the status of Molecular Medicine Research Institute in 2001. This status was renewed in 2008, following an audit by the Ministery of Health.
In 2009 the construction (Di.Bi.T.2), consisting of three new buildings, was completed. This allowed the
much needed growth of the University and will create additional space for SRSI research groups, with dedicated space for new state-of-the-art technology platforms, and expansion of our translational research efforts in
key disease areas such as regenerative medicine, neuroscience, immunology, inflammation, cardiovascular and
oncology.
In the last two years a new research strategy and research organization has been implemented, building on
current strengths to invest in new strategic areas in order to further increase our competitiveness as a center of
excellence in biomedical research and to create the best environment for the translation of fundamental research into clinical applications. Together with the implementation of this new research organization, the administrative and supporting research structure has also been extensively reorganized (see introduction by Maurizio Savi, the Chief Operating Officer for research).
In this organizational model, preclinical and clinical research activities are consolidated in six Research Divisions and two Research Centers:
RESEARCH DIVISIONS
Molecular Oncology
Neuroscience
Metabolic and Cardiovascular Sciences
Regenerative Medicine, Stem Cells and Gene Therapy
Immunology, Transplantation and Infectious Diseases
Genetics and Cell Biology
RESEARCH CENTERS
Imaging
Genomics, Bioinformatics and Biostatistics
At present, approximately 1402 people are working in these Research Divisions and Research Centers: 729
people, including scientists, technicians, service managers, as well as postdoctoral fellows, PhD students and
undergraduate students, in Di.Bi.T 1 and Di.Bi.T 2 and 673 people, including physicians, research nurses, residents and clinical fellows, on clinical research projects in the hospital.
Activities within the Research Divisions include genetics, cell biology, stem cell biology, gene therapy and immunology focusing on disease areas such as cancer, transplant rejection, autoimmune/inflammatory diseases,
infections, neurodegenerative, cardiovascular and metabolic diseases. The research conducted in these areas
has the common goal to increase knowledge on the molecular basis of diseases and to identify innovative therapies and new diagnostic options.
The SRSI also hosts three Research Institutes, which are fully integrated within the Divisional organization,
but have a high degree of scientific and administrative independence based on specific agreements and funding
from external entities:
- The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), which is a joint venture with the
Telethon Foundation, is pioneering cell and gene therapy strategies in genetic diseases
- The Institute for Experimental Neurology (INSPE), supported by a research contract with Merck-Serono,
INTRODUCTIONS - XV
investigates the biological and molecular mechanisms underlying diseases of the nervous system and their
clinical translation, with a strong focus on multiple sclerosis
- The recently established Diabetes Research Institute (HSR-DRI), which is part of the international Diabetes
Research Institutes Federation. The main objectives of HSR-DRI are to identify and apply novel treatments
to prevent islet beta cell destruction and to restore sufficient insulin production in type-1 diabetes patients
Furthermore, the SRSI hosts several scientists belonging to the Dulbecco-Telethon Institute (DTI), which
sponsors research on the molecular and biological mechanisms of gene regulation and genetic diseases.
Research activities within Research Divisions and Centers are at the intersection of clinical activities, which
are organized in 12 Clinical Departments (see introduction by Renato Botti, General Director of the clinical
area). In this classical matrix model the Research Divisions intersect with many Clinical Departments in which
basic research units (BRU) and clinical research units (CRU) are fully integrated and aligned.
Figure1. Matrix of research activities in the research Divisions and Centers integrated with the Clinical
Departments.
SCIENTIFIC ACTIVITIES IN 2009
2009 was an important year to make the new research organization operational and to reinforce the research
activities in the six Research Divisions and the two Research Centers. The following five research divisions:
Molecular Oncology; Neuroscience; Regenerative Medicine Stem Cells and Gene Therapy; Immunology Transplantation and Infectious Diseases; Genetics and Cell Biology became fully operational, whereas operational establishment of the Research Division in Metabolic and Cardiovascular Science is progressing well and will be
completed by the end of 2010. The Research Center for Genomics, Bioinformatics and Biostatistics and the Research Center for Imaging were all started in 2009 with the aim to meet the increasing need for state-of-the-art
imaging and functional genomic technologies. A new director for the Center for imaging was appointed. These
two technology platforms will support all pathological and therapeutic areas and are expected to further favor
integration between basic and clinical research and to provide strong impulses for translational research from
bench to bed-side and back again.
XVI - SAN RAFFAELE SCIENTIFIC INSTITUTE
The Research Programs within the Research Divisions are also crucial for promoting integration between laboratory and clinical research. The Research Programs are aimed at creating synergies between groups with different expertise and defining common strategic investments, which will favor fast-track translational research.
During 2009, eight Research Programs across Research Divisions and Clinical Departments were implemented:
RESEARCH PROGRAMS
Stem Cells: from basic research to clinical experimentation
Brain Regeneration usIng medical Devices, Gene vectors and stEm cells (BRIDGE)
Program in Immunology and Bio-immunotherapy of Cancer (PIBIC)
Pancreatic Islet Transplantation
Human Brain Invivo Mapping with neuroimaging (BRAINMAP)
Bone Physiopathology Program (BoNetwork)
Correlates of HIV-Associated Immune Response Modulation (CHARM)
Microenvironment and Genes in Cancers of the Blood (MAGIC)
During 2009, one of the major tasks for the Directors of the Research Divisions and Research Centers was to
prepare a five-year research plan in which the vision and the mission, the goals with related implementation and
the investments plan are clearly defined for each Research Division and Research Center. Currently, the overall
five-year strategic plan has been completed and will be presented to our International Scientific Advisory
Board. The Board is composed of four renowned scientists:
• Professor Aaron Ciechanover (Director, Rappaport Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel), 2004 Nobel Prize in Chemistry;
• Professor Paul Herrling (Head of Corporate Research, Novartis International; Member of the Board of
Trustees of The Scripps Research institute; Vice-President of the Board of ETH - Swiss Federal Institutes of
Technology);
• Professor Jacques Banchereau (Director, Baylor Institute for Immunology Research, Dallas, USA), 2009
Award in Human Immunology Research - American Association of Immunologists - Dana Foundation;
• Professor Irving Weissman (Director, Institute of Stem Cell Biology and Regenerative Medicine, Stanford
University School of Medicine, USA; member of the American Academy of Science).
The Advisory Board was appointed by the Board of Directors of the San Raffaele Foundation and has the primary function to assist the Board in the evaluation of the quality of our research, our research strategies and implementation plans in keeping with the highest international research standards.
Despite the worldwide financial and economical crisis of 2009, which also had an impact on our research organization, a number of initiatives were successfully carried out:
- The first among the three new research buildings of Di.Bi.T 2 was equipped and is now fully occupied. It accommodates new research groups within the Institute of Experimental Neurology (INSPE) as well as a new
research group, established in collaboration with the Cystic Fibrosis Foundation, which carries out research
projects in the area of cystic fibrosis and host/pathogens relationship. In addition, the new space allowed the
expansion of our cytofluorimetry and FACS sorting facility.
- A new career path for physician scientists was implemented. We believe this is a key achievement in the integration of clinical, teaching and research activities as these professionals will be at the interface that allows
optimal communication and interaction between the three areas.
- We implemented a competitive international postdoctoral program, which will enable us to recruit from a
highly skilled pool of researchers to further increase the international dimension of our institution.
- We worked with the Human Resources Office to establish a new career path for scientists. The aim of this
project is to define the career path for young investigators, allowing them more independence and recognition with more responsibility and accountability and to establish transparent and well-defined criteria for
periodical evaluations of the performance of our scientists.
- We have implemented a new series of weekly seminars, named San Raffaele Research Seminars. The speakers at these seminars are Unit Heads, both from Basic Research Units and from Clinical Research Units. The
INTRODUCTIONS - XVII
intention of these seminars is to allow the SRSI scientific community to learn about ongoing research in the
Institute and to foster integration and cross-fertilization between clinical and basic scientists.
2009 was a very productive year for the SRSI in terms of scientific publications and clinical trials.
The total number of scientific publications was 773, with a total Impact Factor of 4153. More than 10% of all
SRSI publications are in top-level scientific journals (Impact Factor over 10). Based on these results, our Institution is the most highly ranked Italian IRCCS in terms of scientific level and scientific productivity (figures 2
and 3).
Figure 2.
Publications and total Impact Factor of SRSI
in the past 3 years
4.153,262
3870,073
3561,234
740
693
2007
(average IF: 5,139)
2008
(average IF: 5,230)
Total IF 2007-2009
773
2009
(average IF: 5,373)
Publications 2007-2009
Figure 3.
% of SRSI publications sorted according to Impact Factor ranges
100,0%
80,0%
62,8% 62,2% 63,4%
60,0%
40,0%
27,7%
30,0%
26,0%
20,0%
9,5% 7,8% 10,6%
0,0%
< 5,000
5,000-9,999
Impact Factor ranges
2007
2008
2009
10,000
XVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE
The scientific productivity of the SRSI is also demonstrated by its ability to design and conduct clinical trials,
which were in part enabled through support from pharmaceutical and biotechnology companies.
In 2009, the Ethics Committee examined 234 protocols, 119 (51 %) of which were sponsored by Pharmaceutical Companies. Submission of these 234 clinical trial protocols were supported and guided by the Clinical Research Office.
Figure 4. Clinical trials evaluated by the HSR Ethics Committee in 2009
Pharmaceutical companies sponsored trials
No-profit groups sponsored trials
HSR investigators initiated trials
30%
51%
19%
21%
27%
Pharmacological protocols
Observational protocols
Basic research protocols
Medical device protocols
2%
50%
INTRODUCTIONS - XIX
Figure 5. Clinical trials run by Clinical Departments and approved in 2009
Sponsored trials
Department of arrhythmology
Department of general and specialistic surgery
Other
1%
8%
1%
4%4% 3%
4%
8%
24%
4%
11%
13%
15%
No-profit trials
12%
3%
2%
7%
12%
5%
21%
9%
3%
26%
As of December 2009, the Office of Biotechnology Transfer, which is in charge of the management of intellectual property, patents and know–how, and of the creation of spin–off companies, managed 295 sponsored research and industrial collaboration contracts, illustrating that SRSI is a preferential partner for scientific and
clinical collaborators. The high level of innovative research in the SRSI is also reflected in the issue of 96
patents and 38 patent families, while 52 licenses were taken out by external parties.
The competitiveness of the SRSI is shown by its ability to attract funding, not only from the public sector
(Ministry of Health, Superior Institute of Health, Ministry of University and Research), but also from private
XX - SAN RAFFAELE SCIENTIFIC INSTITUTE
Italian sources (mainly Telethon, the Italian Association for Cancer Research and Bank Foundations) and from
international sources (e.g. European Community, European Research Council, American National Institute of
Health, World Health Organization, Association for International Cancer Research, Gates Foundation, Wellcome Trust, Juvenile Diabetes Research Foundation).
The impressive critical mass and quality of our scientific community was highlighted during our yearly scientific retreat, which in 2009 was again organized in Stresa with three full days of scientific presentations given by
basic and clinical scientists. During the San Raffaele Research retreat, the three top publications of 2008 were
awarded with the SRSI innovation prize.
Finally, in 2009 a number of important educational initiatives, scientific events and prestigious international
meetings were organized and hosted by our basic and clinical scientists. A special mention should go to the scientific symposium organized in honour of Professor Guido Pozza who was the scientific director of the SRSI
for 15 years and who continues to be a highly experienced mentor and advisor to our scientists.
THE FUTURE
We are very much looking forward to moving to the second and third new research buildings of Di.Bi.T 2.
The new space will be used to further optimize current key research activities, such as stem cell and gene therapy, and to accommodate research groups working in new strategic areas, such as molecular oncology, translational genomics and preclinical imaging.
The SRSI will continue to be a multidisciplinary Institute, but we will also pay particular attention to invest in
research on those diseases with a high unmet medical need and in therapeutic areas of increasing medical demand, such as oncology and cardiovascular research. The main efforts in 2010 will be devoted to a new project
aimed at integrating clinical, teaching and research activities in the area of oncology. This new initiative in cancer research and therapy will be built on all the know-how, expertise and resources already present at the SRSI.
In addition, we plan to establish a strong and fully operational Metabolic and Cardiovascular Diseases Research
Division. Investments in basic research in this latter increasingly important area, in which the SRSI has proven
clinical excellence, will significantly increase our visibility and competitiveness.
The SRSI will continue to support and strengthen its areas of excellence: genetics and cell biology, stem cell
and gene therapy (with HSR-TIGET), immunology inflammation and infectious diseases (with DRI), and neuroscience (with INSPE).
We will continue to strengthen our position as a leading center for translational medicine by giving rise to a
Clinical Research Center. In this context, close collaboration between basic researchers, clinical investigators
and physician scientists will be strongly supported with the ultimate goal to apply new therapeutic principles,
invented at the laboratory benches, as efficiently as possible to our patients. In particular, we are aiming towards expertise in the fields of wide genomic analyses of complex diseases, stratification of patients by genotyping and phenotyping, pharmacokinetics and pharmacogenomics, besides becoming an active Center for the
clinical proof of concept trials.
I am confident that this research strategy and structure will further enhance the SRSI’s position as an Institute
of excellence conducting innovative science in the field of Molecular Medicine, which in the end will benefit
our patients. I am also convinced that it will make us attractive for young Italian scientists who currently work
abroad, but are highly motivated to return home and contribute to the international competitiveness of Italian
medical science.
The worldwide financial and economical crisis is not yet over and 2010 will also be a year of constraints,
which will be a challenge for the speed of implementation of our strategic research plan. However, nothing will
stop us continuing with the integration of high quality basic and clinical research by devoting dedicated investments to new translational research units.
The vision of our President, which can be summarized in three key elements: “there is no cure without research”, “research is the backbone of our Institution” and “basic research is the foundation of our knowledge
and culture”, continues to inspire us and help us to overcome innumerable hurdles. We therefore wish to thank
our President and Vice-President, as well as the Board of Directors, for their trust in our vision and their con-
INTRODUCTIONS - XXI
tinuous support.
Many thanks also to our Research Directors and Associate Directors for their dedication and determination
in designing the new organizational and strategic research plan, which will further strengthen the SRSI’s leading
position in Italy and contribute to its position among the leading institutes in biomedical science internationally. I also would like to express my gratitude to the project and group leaders and all members of the scientific
community for their continuous support and sense of responsibility in this difficult year.
Finally, a special thank you goes to all scientists, physicians, staff, post-doctoral fellows and students who,
through their work, efforts, enthusiasm and passion, contributed to the research progress illustrated in this
2009 scientific report and who make the SRSI such a wonderful place to work at. I hope you will find our report interesting and informative
Scientific director
XXII - SAN RAFFAELE SCIENTIFIC INSTITUTE
Introduction by the Chief Operating Officer
The San Raffaele Scientific Institute is one of the most important biomedical research centers in Italy and is in
a leading position in the sector which has the highest potential impact on people’s health. This fact, together
with its potential to attract grants for further growth at an international level, is confirmation that we need not
only to finance and support our already excellent and high-quality research program, but also to aim to become
the largest melting pot of top-level doctors and researchers of future generations through strategic planning
over a medium/long-term period.
With this in mind, the organizational-management structure of the Research Area has developed and implemented a shared and integrated governance and management system, both of the structures and processes of
the core business (i.e. scientific production) and of the support areas, which are all part of the Research Management Staff, as shown in figure 1.
Figure 1: The Research Area processes network
Four fundamental areas have been identified, characterizing the operating-management processes which support the core business: economic-financial management, organizational development, human resources and infrastructures, and marketing and fundraising activities, meaning communication ‘with’ and ‘for’ our external
stakeholders. (See figure 2)
INTRODUCTIONS - XXIII
Figure 2: Areas characterizing the operating-management processes
We have therefore identified the following medium-long-term objectives for each of these areas:
ª To guarantee the Research sustainability, while meeting the requirements of efficacy, efficiency and economy necessary for resources administration;
ª To guarantee accurate and transparent financial reporting and administrative accounting;
ª To develop organizational and governance mechanisms that are coherent with strategic objectives;
ª To develop an organization that focuses on people, that is able to valorize professional skills and create a
stimulating and gratifying work environment;
ª To guarantee transparency in the raising and spending of funds, as well as the serious and rigorous transmission of scientific data.
To reach these objectives, numerous initiatives at various structural and service levels were planned and implemented during 2009:
PLANNING AND MANAGEMENT CONTROL
The planning and monitoring criteria and conditions for the economic-financial management of the Research
Divisions and Centers were identified through an improved definition of the budgets for each division together
with the criteria for monitoring the results in order to reach a true system of performance-based accountability
in the short-to-medium term.
ORGANIZATIONAL DEVELOPMENT & MANAGEMENT SYSTEMS
The organizational model and its implementation has further evolved through completion of the distribution
of the various scientific activities in the Research Divisions & Centers, as well as through organizational structuring and the activation of governance mechanisms within each research division and center.
In order to reach a coherent integration of the new organizational model of the Research Areas with other
models and management systems and/or regulations of the San Raffaele Foundation, measures have been taken
to revise the conditions and responsibilities linked to both the Security Management System and the Quality
Management System. A method has been introduced to revise processes and responsibilities in order to render
coherent the new organizational structure of research area with the ‘Model of Organization, Management &
Control’ as well as with the ‘Ethics Code’ of the Foundation.
XXIV - SAN RAFFAELE SCIENTIFIC INSTITUTE
HUMAN RESOURCES
A committee of professionals was appointed to define the new career paths of researchers with the aim to optimize the range of positions already available, to identify the most useful indicators, both from the point of
view of staff career progression and in the interests of the Institution, to reward virtuous paths of complete scientific and managerial development.
COMMUNICATION & MARKETING
For San Raffaele, communication is becoming indispensable to promote its strategic position, to be competitive in the Italian Health and Research environment, and to diversify its financial sources.
In order to promote its activities, results and projects, the Research Direction has strengthened its Marketing
& Fundraising Office that, since 2009, has been committed to the promotion of specific fundraising projects
and initiatives for various markets and reference targets: donations from individuals, companies, foundations &
organizations, and institutions.
Our priority for the future will be to define, according to the objectives highlighted in the Strategic Scientific
Plan, a strategic-operational plan with which to steer all research area activities towards the same goals, and to
control particularly critical development areas, such as fundraising, and creation of value for research and comunication.
It is highly desirable for a mission-oriented non-profit Institution such as ours that this strategic-operational
plan is on one hand oriented towards communication, and on the other, I would say above all, it aims to provide an efficient level of organizational governance, functional to the monitoring and strengthening of the relationships with our stakeholders, internal and external. If conceived in this way, this plan will be able to produce
noticeable and beneficial effects on the research organization in terms of alignment with and valorization of its
mission.
With the transformation underway, the effects of which will unfold in 2010, it seems right to take this opportunity to modify the approach towards the financial report, considering it not only as a legal necessity, but also
as a tool to measure the immeasurable – those activities with faded edges that make up the heart of San Raffaele’s ‘production of science’ and ‘production of value ’.
Maurizio Savi
Chief Operating Officer
INTRODUCTIONS - XXV
SAN RAFFAELE SCIENTIFIC RETREAT 2009
XXVI - SAN RAFFAELE SCIENTIFIC INSTITUTE
BEST POSTER AWARD
1st – Erica Butti
Cell fate analysis and selective killing of neural stem/precursor cells in
the adult mouse: potential application to study the role of the endogenous CNS stem cell compartment in neurological diseases
2nd – Emanuela Porrello
Csn5/Jab1 regulates Schwann cell-axon interaction and plays a role in
peripheral nerve development and function
INTRODUCTIONS - XXVII
3rd – Bruno Di Stefano
New procedures for genetic reprogramming of healthy and Parkinson’s
adult human cells and their differentiation into neural and dopaminergic
progenitors
BEST PAPER AWARD
1st – Giancarlo Comi
Comi, G; Pulizzi, A; Rovaris, M; Abramsky, O; Arbizu, T; Boiko, A;
Gold, R; Havrdova, E; Komoly, S; Selmaj, K; Sharrack, B; Filippi, M.
Effect of laquinimod on MRI-monitored disease activity in patients with
relapsing-remitting multiple sclerosis: a multicentre, randomised, doubleblind, placebo-controlled phase IIb study. Lancet: 2008; 371(9630):
2085-2092
XXVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE
2nd – Michele De Palma
De Palma, M; Mazzieri, R; Politi, LS; Pucci, F; Zonari, E; Sitia, G;
Mazzoleni, S; Moi, D; Venneri, MA; Indraccolo, S; Falini, A; Guidotti,
LG; Galli, R; Naldini, L. Tumor-targeted interferon-alpha delivery by
Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer
Cell: 2008; 14(4): 299-311
3rd – Stefano Biffo (in the photo: Valentina Gandin)
Gandin, V; Miluzio, A; Barbieri, AM; Beugnet, A; Kiyokawa, H; Marchisio, PC; Biffo, S. Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation. Nature: 2008; 455(7213): 684-688
INTRODUCTIONS - XXIX
I RAGAZZI DELLA VIA OLGETTINA
30 anni della storia del diabete al San Raffaele
October 31, 2009
Our President, don Luigi
Maria Verzè, and Guido
Pozza, Professor Emeritus
of Internal medicine,
Università Vita-Salute
San Raffaele
XXX - SAN RAFFAELE SCIENTIFIC INSTITUTE
Guido Pozza and Emanuele Bosi,
Head of the Department of internal
and specialistic medicine and
Associate director of the Diabetes
Research Institute
INTRODUCTIONS - XXXI
Health Care Directorate
HEALTH CARE SUPERVISOR: Gianna Zoppei
GENERAL DIRECTOR: Renato Botti
HOSPITAL DIRECTOR: Roberts Mazzuconi
PLANNING & CONTROL DIRECTOR: Alessandro Longo
INFORMATION SYSTEMS DIRECTOR: Carla Masperi
PROCUREMENT & LOGISTIC DIRECTOR: Alberto Russo
HEALTH AREA PROJECT DEVELOPMENT DIRECTOR: Maria Romano
CUSTOMER SERVICE DIRECTOR: Riccardo Pizzo
TECHNICAL SERVICE DIRECTOR: Andrea Roma
E-SERVICES FOR LIFE AND HEALTH DIRECTOR: Alberto Sanna
PROMOTION & DEVELOPMENT MANAGER: Alberto Galliani
ORGANIZATION & DEVELOPMENT MANAGER: Margherita Gambaro
LEGAL OFFICE MANAGER: Piergiorgio Sammartino
Renato Botti
XXXII - SAN RAFFAELE SCIENTIFIC INSTITUTE
Introduction by General Director Clinical Area
San Raffaele Hospital is a private no-profit Foundation certified as Istituto di Ricovero e Cura a Carattere Scientifico (Research Hospital). It is relentlessly pursuing its three interrelated activities of clinical care, research
and education since 1971, when it was established, and represented one of the first examples of a fully independent private hospital in Italy. In 1972 the Italian Ministry of Health granted to San Raffaele the status of IRCCS (Research Hospital), which favoured its development as a site for clinical research. Originally specialized
in diabetes and metabolic diseases, the status of research hospital was confirmed for the area of Molecular Medicine in the years 2004 and 2008.
San Raffaele IRCCS is a qualified hospital, well known in Italy for specific and relevant pathologies, as well as
for a highly specialized Emergency Center. It is a teaching Hospital linked with the Faculties of Medicine and
Surgery and Psychology of the San Raffaele Vita-Salute University.
Its high quality medical assistance and the availability of an extensive area of about 300.000 square metres has
led to a fast growth of the services provided by the Research Hospital.
San Raffaele Hospital is part of the Italian National Health Service: it has 1.397 beds accredited with the National Health Service, 75 of them dedicated to day surgery and day hospital treatments. In 2009 the hSR activity counts 56.870 in-patients, 62.835 patients admitted to the Emergency Room, more than 8.000.000 out-patients and diagnostic tests. The Hospital counts about 3.740 employees.
In January 2008, after the approval by the Board of Directors, the Hospital started to organize the medical areas in Clinical Departments. Due to the complexity of the Institution, this process required a great effort for the
analysis and definition of aggregation area, operational procedures and for the definition of the activity indicators. The process is still ongoing, but almost completed. The introduction of this new working model was
aimed to integrate and coordinate the resources and the processes of the different Clinical Units, to make them
more flexible, efficient with regard to the structural and management costs, to improve their specific role in patients’ management and to increase the quality of their medical activity.
From December 2009 to January 2010, Arrithmology Department has been absorbed by Cardio-ThoracicVascular Department, generating a total Departments reduction from 12 to 11.
1) CARDIO-THORACIC-VASCULAR DEPARTMENT
2) DEPARTMENT OF GENERAL AND SPECIALISTIC SURGERY
3) HEAD AND NECK DEPARTMENT
4) DEPARTMENT OF INFECTIOUS DISEASES
5) MATERNAL AND CHILD HEALTH DEPARTMENT
6) DEPARTMENT OF INTERNAL AND SPECIALISTIC MEDICINE
7) DEPARTMENT OF NEUROLOGY
8) DEPARTMENT OF CLINICAL NEUROSCIENCE
9) DEPARTMENT OF ONCOLOGY
10)DEPARTMENT OF RADIOLOGY
11)DEPARTMENT OF UROLOGY
There are six Cross Department Areas:
1. Imaging’s Laboratory (Services of Immuno-hematology and Transfusion Medicine, Laboraf, Pathological
Anatomy)
2. Imaging (Radiology, Neuroradiology, Nuclear Medicine)
3. Anaesthesia and Resuscitation (General Medicine, Cardiosurgery, Neurosurgery, Intensive Care Unit –
ICU)
4. Rehabilitation (Neurological, Cardiovascular, Orthopaedic)
5. Emergency
Such Areas, directly coordinated by the Health Direction, may enclose Units of different Clinical Departments and Units which do not belong to Departments (Emergency Medicine, Services of Transfusion Medicine,
Pathological Anatomy). The objective of the creation of these areas is to promote standardization of activities,
to realize common projects and synergies, to encourage the interexchange of the human and technological resources, to promote the communication between the Departments.
The activation of the Clinical Departments was made possible thanks to the strict collaboration between the
INTRODUCTIONS - XXXIII
medical areas and the hSR management. All the procedures and processes were discussed and approved jointly,
deriving from the common objective to increase the quality of the medical treatments and the efficiency of the
Institute. The project management has been played and is played by the Health Direction, supported by the
commitments of Board of Directors and General Direction.
The Clinical Departments are led by the Directors, appointed for three years and nominated by the President
of the Board of Directors, with the approval of the President of the Board of Director of the Università VitaSalute San Raffaele. Each Director has been assigned several measurable objectives included in the so-called Cruscotto Dipartimentale. The Cruscotto Dipartimentale is aimed to monitor yearly the reaching of the goals assigned and the proper enforcement of the Department processes.
The Departmental Director is assisted by a Director Management Assistant (DMA), a person with management background, with the function to co-ordinate the Department as far as the administrative issues are concerned and to facilitate the relationships between the Department and the hSR Health Direction and the Institute management. The Departmental Director is also supported by a so- called Department Area Coordinator
(DAC) that performs clinical activity and, in addition, is responsible for the coordination and the management
of a specific Departmental Area of activity (i.e. Research, Information Technology, Quality…). The clinical activity and resources management of the departmental Units is attributed to the Clinical Unit Leader (CUL).
The implementation Departmental Model of the San Raffaele hospital is progressively reaching its goals with
regard to economic efficiency and clinical effectiveness maintaining the central role of the patient through the
full integration and the co-sharing of the human, technologic and logistic resources.
Renato Botti
General Director Clinical Area
XXXIV - SAN RAFFAELE SCIENTIFIC INSTITUTE
2009 SEMINARS AND LECTURES
Division of molecular oncology
Division of neuroscience
Division of metabolic and cardiovascular sciences
Division of regenerative medicine, stem cells, and gene therapy
Division of immunology, transplantation, and infectious diseases
Division of genetics and cell biology
Center for genomics, bioinformatics, and biostatistics
January 20, 2009
Gene therapy trial for childhood cerebral
adrenoleukodystrophy
Natalie Cartier, INSERM U745, Faculté de
Pharmacie, Paris
Guest: Luigi Naldini
January 26, 2009
“Primo Levi Lectures”, nel giorno della memoria
Medicina e mondo ebraico nella storia
Giorgio Cosmacini, Università Vita-Salute
San Raffaele
Guest: Giorgio Parmiani
February 2, 2009
Regulation of Cell Polarity
Athar H. Chishti, Department of
Pharmacology, University of Illinois
College of Medicine
Guest: Alessandra Bolino
February 23, 2009
Local protein synthesis and spine
dysmorphogenesis: learning from the
Fragile X Syndrome
Claudia Bagni, Dept. of Experimental
Medicine and Biochemical Sciences, University
of Rome “Tor Vergata”, Developmental and
Molecular Genetics Section, Catholic
University of Leuven
Guest: Jacopo Meldolesi
February 25, 2009
Flexibility and alternative conformations: clues
to the operation of PDI as a protein folding
catalyst
Robert Freedman, Department of
Biological Sciences, Warwick University, UK
Guest: Roberto Sitia
March 11, 2009
Functions of PI3K in inflammation and cancer
Matthias Wymann, Inst. Biochemistry
and Genetics, Dept. for Biomedicine,
University of Basel
Guest: Ruggero Pardi
March 12, 2009
How to succeed in science without really
trying
Jonathan W. Yewdell, Cellular Biology
Section, Laboratory of Viral Diseases,
National Institute of Allergy and Infectious
Diseases, NIAID, Bethesda
March 13, 2009
Cysteine oxidation in catalysis and regulation
Leslie B. Poole, Department of Biochemistry,
Wake Forest University School of Medicine,
Winston-Salem, USA
March 16, 2009
The DNA damage response: a common
pathway regulating the expression of
different NK receptor activating ligands
on diseased cells
Angela Santoni, Università di Roma “La
Sapienza”, Dipartimento di Medicina Sperimentale
Guest: Angelo Manfredi
March 18, 2009
Making and using phage antibody libraries
Andrew Bradbury, Los Alamos National
Laboratory, B division, Los Alamos
INTRODUCTIONS - XXXV
April 3, 2009
The control of nerve development, pathology
and repair by c-Jun and Notch in Schwann cells
Kristjan Jessen, Research Department of
Cell and Developmental Biology, UCL, London
Guest: Lawrence Wrabetz
April 6, 2009
Functional Genomics of the Brain
Stefano Gustincich, The Giovanni ArmeniseHarvard Foundation Laboratory, International
School for Advanced Studies (ISAS)-SISSA
April 6, 2009
Manipulation of adaptive autoimmunity
Salvatore Albani, Arizona Arthritis Center
University of Arizona, Tucson
Guest: Maria Grazia Roncarolo
April 7, 2009
Polycomb repressors controlling stem cell
fate: implications for cancer and development
Maarten van Lohuizen, Division of Molecular
Genetics, The Netherlands Cancer Institute,
Amsterdam
Guest: Eugenio Montini
April 9, 2009
The Pathosystems Resource Integration
Center (PATRIC) at VBI: An Integrative
Resource on Host-Pathogen Interactions
Bruno Sobral, Virginia Bioinformatics
Institute, Virginia Tech Blacksburg, Virginia, USA
Guest: Elisa Vicenzi
April 22, 2009
Molecular battles between HIV and
macrophages
Gianfranco Pancino, Research Director
INSERM Regulation of Retroviral
Infections Unit Institute Pasteur, Paris
Guest: Lucia Lopalco
April 22, 2009
Epigenetic regulation of stem cell
differentiation
Niall Dillon, MRC Clinical Sciences Centre,
Faculty of Medicine, Imperial College, London
Guest: Marco E. Bianchi
April 27, 2009
Gene regulatory code
Alexander Kel, BIOBASE GmbH, Wolfenbuettel,
Germany
Guest: Angela Bachi
April 28, 2009
Neuronal physiology in animal models of
mental retardation
Yann Humeau, INCI, UPR3212 CNRS,
Université Louis Pasteur, Strasbourg
Guest: Patrizia D’Adamo
April 30, 2009
Death Receptors, Ubiquitin Editing &
Inflammasome function
Vishva Dixit, Early Discovery Research,
Genentech Inc, San Francisco
Guest: Marta Muzio
May 4, 2009
Probing how, when and where CD4 and
CD8 T cells influence antibody responses
Ian McLennan, MRC Centre for Immune
Regulation, University of Birmingham
Guest: Paolo Dellabona
May 11, 2009
SLAM-Family cell surface receptors also
control bacterial killing in phagosomes
Cox Terhorst, Professor of Medicine, Harvard
Medical School, and Chief, Division of
Immunology, Beth Israel Deaconess Medical
Center, Boston
Guest: Maria Grazia Roncarolo
May 13, 2009
Expanding AAV capacity for in vivo gene therapy
Alberto Auricchio, Dept. of Pediatrics,
“Federico II” University, Napoli & TIGEM
(Telethon Institute of Genetics and Medicine)
Guest: Vania Broccoli
XXXVI - SAN RAFFAELE SCIENTIFIC INSTITUTE
May 18, 2009
The influence of T cell avidity on the
differentiation of effector and memory T cells
Rose Zamoyska, Institute of Immunology
and Infection Research, University of Edinburgh
Guest: Anna Mondino
May 21, 2009
Studying monocyte functions in mouse and
human
Frederic Geissmann, Center for Inflammation
Biology & Dept of Rheumatology, King’s
College London School of Medicine
Guest: Luigi Naldini
May 25, 2009
Cellular and molecular mechanisms in
lymphoid organ formation in health and
disease
Reina Mebius, Dept. Molecular Cell Biology and
Immunology, VUMC, Amsterdam
Guest: Andrea Brendolan
May 25, 2009
Molecular Pathogenesis of Multiple Myeloma
P. Leif Bergsagel, Mayo Clinic Cancer Center
Scottsdale
Guest: Giovanni Tonon
May 29, 2009
ER stress signaling foci
Eelco van Anken, Dept. Biochemistry
& Biophysics, UCSF, San Francisco CA
June 8, 2009
Mitochondrial Medicine: A Therapy for
Muscular Dystrophies?
Paolo Bernardi, Department of Biomedical
Sciences, University of Padova
June 15, 2009
Charcot-Marie-Tooth disorder: from animal
models to therapy
Michel Fontés, Therapie des Maladies
Génétiques.Faculté de Médecine de la
Timone, Marseille
Guest: Lawrence Wrabetz
June 16, 2009
Modulation of inflammation by hepcidin
Ivana De Domenico, Internal Medicine
Department, Hematology Division, University
of Utah
Guest: Clara Camaschella
June 22, 2009
Unravelling “good” and “bad” Protein
Interactions
Franca Fraternali, Randall Division of Cell
and Molecular Biophysics, King’s College
London UK
Guest: Giovanna Musco
June 22, 2009
Claw paw meets the Adams family; a novel
signalling axis in nerve development
Dies Meijer, Department of Cell Biology and
Genetics, Erasmus University Medical Center,
Rotterdam
Guest: Alessandra Bolino
June 29, 2009
CD14 regulates the dendritic cell life cycle
through NFAT activation following LPS
encounter
Francesca Granucci, Department of
Biotechnology and Bioscience, University
of Milano-Bicocca
Guest: Anna Villa
July 3, 2009
What Targets ER Folding Enzymes to the
Mitochondria-Associated Membrane (MAM)?
Thomas Simmen, Department of Cell
Biology, University of Alberta, Edmonton
INTRODUCTIONS - XXXVII
July 6, 2009
Zebrafish visual system development and
function: imaging studies
Filippo Del Bene, Dept. of Physiology,
University of California, San Francisco
Guest: Gian Giacomo Consalez
October 15, 2009
Development of the Vertebrate
Musculoskeletal System: the Role of Muscle
and Connective Tissue Interactions
Gabrielle Kardon, Department of Human
Genetics, University of Utah
Guest: Giulio Cossu
July 15, 2009
Bacterial genomes as basis for the discovery
of vaccine antigens and novel virulence
factors: the MenB experience
Mariagrazia Pizza, Novartis Vaccines, Siena
Guest: Alessandra Bragonzi
October 15, 2009
Is it possible to correct the anergy of human
tumor-infiltrating lymphocytes?
Pierre van der Bruggen, Ludwig Institute for
Cancer Research, Belgium
Guests: Vincenzo Russo & Catia Traversari
September 8, 2009
Structural Roles of Laminins in Nerve and
Muscle
Peter Yurchenco, Department of Pathology
and Laboratory Medicine, UMDNJ, Robert
Wood Johnson Medical School, New Jersey
Guest: Maria Laura Feltri
September 21, 2009
Quantitative targeted proteomics for the
analysis of cellular networks
Paola Picotti, Institute of Molecular Systems
Biology, ETH, Zurich, Switzerland
Guest: Angela Bachi
September 28, 2009
Bone density measurements: the limitations
in pediatrics
Vicente Gilsanz, Childrens Hospital
Los Angeles, University of Southern California
Guest: Stefano Mora
October 12, 2009
The role of dendritic cell subsets in control
tolerance to islet antigens
Jonathan D. Katz, Diabetes Research Center,
Cincinnati Children’s Hospital Research Foundation
Guest: Paolo Dellabona
October 19, 2009
Are we ready for next-generation,
genome-driven systems bIology?
Elia Stupka, UCL Cancer Institute, London
Guest: Giorgio Casari
October 23, 2009
Searching for genes that induce myocardial
protection, myocardial repair or
neoangiogenesis by in vivo gene transfer
using AAV vectors
Mauro Giacca, International Centre for Genetic
Engineering and Biotechnology, (ICGEB), Trieste
Guest: Guido Poli
October 26, 2009
NK cells control of tumor progression
Ennio Carbone, University of Catanzaro Magna
Graecia and Department of Microbiology,
Cell and Tumor Biology, Karolinska Institutet
Guest: Giorgio Parmiani
November 6, 2009
Dendritic cells in bacterial handling in the gut
Maria Rescigno, Department of Experimental
Oncology, European Institute of Oncology
Guest: Marika Falcone
November 27, 2009
How viruses enter their host cells
Ari Helenius, ETH, Zurich, Switzerland
Guest: Daniela Talarico
XXXVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE
December 2, 2009
Sox2 is a mediator of FGF signaling that
regulates bone development
Claudio Basilico, Dept. of Microbiology, NYU
School of Medicine
Guest: Simone Cenci
December 15, 2009
From form to function: a role of Wnt signalling
at the synapse
Patricia Salinas, Department of Cell and
Developmental Biology, University College London, UK
Guest: Ivan De Curtis
December 14, 2009
Quiescent stem cells in intestinal homeostasis
and cancer
Riccardo Fodde, Department of Pathology,
Erasmus Medical Center, Rotterdam
Guest: Daniela Talarico
December 21, 2009
Innate mechanisms in the regulation of human
B cell physiology
Elisabetta Traggiai, Dipartimento di Scienze
Pediatriche, Laboratorio di Immunologia delle
Malattie Reumatiche, Istituto G. Gaslini, Genova
Guest: Marta Muzio
00intro 2
9 07 2010
16:45
Pagina XXXIX
SCIENTIFIC REPORTS
The Scientific Director, the Chief Operating Officer, the Directors and Associated Directors of the Research
Divisions, and the Directors of the Institutes and the Scientific and Technical Committee
DIVISIONS, CENTERS, INSTITUTES, AND RESEARCH PROGRAMMES
Microenvironment
and Genes in
Cancers of the Blood
(MAGIC Program)
Division of
molecular oncology
Division of
neuroscience
INSPE
Institute of
experimental
neurology
Human Brain
Invivo Mapping
with neuroimaging
(BRAINMAP Program)
Brain Regeneration
using medIcal Devices,
Gene vectors and stEm
cells (BRIDGE Program)
Division of
metabolic and
cardiovascular
sciences
Stem Cells
Program: from basic
research to clinical
experimentation
Division of
regenerative medicine,
stem cells,
and gene therapy
HSR-TIGET
The San Raffaele-Telethon
Institute for
gene therapy
Division of
immunology,
transplantation, and
infectious diseases
DRI
Diabetes
research institute
Division of
genetics and
cell biology
Center for
genomics,
bioinformatics and
biostatistics
Center for
imaging
Program in
Immunology and
Bio-immunotherapy of
Cancer (PIBIC)
Islet Trasplantation
Program (ITP)
Correlates of
HIV-Associated
Immune Response Modulation
program (CHARM)
Bone
Physiopathology
Program (BoNetwork)
DIVISION OF MOLECULAR ONCOLOGY - 1
DIVISION OF MOLECULAR ONCOLOGY
Director: Federico Caligaris-Cappio*
Associate Director: Giorgio Parmiani
Research Units
Lymphoid malignancies Unit
HEAD OF UNIT: Federico Caligaris-Cappio*,
POST-DOCTORAL FELLOWS: Maria Teresa Sabrina Bertilaccio, Carlo Calissano, Cristina Scielzo
PHD STUDENT: Giorgia Simonetti
FELLOW: Elisa ten Hacken
B-Cells neoplasia
GROUP LEADER: Paolo Ghia*
POST-DOCTORAL FELLOWS: Claudia Fazi**, Agnieszka Janus**
PHD STUDENT: Antonis Dagklis
FELLOW: Lydia Scarfò
Biology of multiple myeloma
GROUP LEADER: Marina Ferrarini
POST-DOCTORAL FELLOW: Daniela Belloni
Cell activation and signalling
GROUP LEADER: Marta Muzio
PHD STUDENTS: Benedetta Apollonio**, Stavroula Ntoufa
Dynamic fluorescence spectroscopy in biomedicine
GROUP LEADER: Valeria R. Caiolfa
POST DOCTORAL FELLOW: Christian Hellriegel
FELLOW: Moreno Zamai
GROUP LEADER: Andrea Brendolan
PHD STUDENT: Laura Castagnaro, Elisa Lenti
Preclinical models of cancer
GROUP LEADER: Rosa Bernardi
POST-DOCTORAL FELLOWS: Nadia Coltella, Benedetta Pozzi
PHD STUDENT: Ylenia Guarnerio**
TECHNICIAN: Marco Perego
Tumor microenvironment
GROUP LEADER: Elisabetta Ferrero
PHD STUDENT: Lorenzo Veschini
2 - SAN RAFFAELE SCIENTIFIC INSTITUTE
Immuno-biotherapy of melanoma and solid tumors Unit
HEAD OF UNIT: Giorgio Parmiani
RESEARCHER: Cristina Maccalli
PHYSICIAN: Lorenzo Pilla
POST-DOCTORAL FELLOW: Tiziano Di Tomaso
PHD STUDENT: Valeria Cambiaghi
TECHNICIAN: Gloria Sovena
Cancer gene therapy
GROUP LEADER: Vincenzo Russo
PHD STUDENTS: Raffaella Fontana**, Laura Raccosta
FELLOWS: Andrea Leiva, Claudia Lanterna**, Sara Tezza**
TECHNICIAN: Daniela Maggioni
Functional genomics of cancer Unit
HEAD OF UNIT: Giovanni Tonon
PHD STUDENTS: Aurora Negro**, Beatrice Rondinelli**
Model genetics of membrane trafficking Unit
HEAD OF UNIT: Ottavio Cremona*
POST-DOCTORAL FELLOWS: Simona Ferron, Karin Ferrari, Alessandra Zatti
Molecular histology and cell growth Unit
HEAD OF UNIT: Stefano Biffo
FORMER HEAD OF UNIT: Pier Carlo Marchisio*
POST-DOCTORAL FELLOWS: Daniela Brina, Stefano Grosso, Elia Ranzato, Viviana Volta
PHD STUDENT: Elisa Pesce
FELLOWS: Anne Beugnet, Marilena Mancino
TECHNICIAN: Annarita Miluzio
HEAD OF UNIT: Angelo Corti
RESEARCHERS: Flavio Curnis
PHD STUDENTS: Eleonora Dondossola**
FELLOW: Luca Crippa
TECHNICIANS: Barbara Colombo, Anna Gasparri, Angelina Sacchi
Digestive and pancreatico-biliary endoscopy Unit
HEAD OF UNIT: Pier Alberto Testoni*
PHYSICIANS: Lorella Fanti, Antonella Giussani, Alberto Mariani, Edi Viale
RESIDENTS: Milena Di Leo, Chiara Notaristefano, Cristian Vailati
FELLOWS: Antonella Putignano, Gemma Rossi, Sabrina Testoni
Endosonography: diagnostic and therapeutic endoscopic ultrasound
CLINICAL GROUP LEADER: Paolo Giorgio Arcidiacono
PHYSICIANS: Silvia Carrara, Gianni Mezzi, Maria Chiara Petrone
RESIDENT: Cinzia Boemo
Gastrointestinal surgical oncology Unit
HEAD OF UNIT: Carlo Staudacher*
PHYSICIANS: Paolo Aldo Raul Baccari, Paola De Nardi, Saverio Di Palo, Elena Orsenigo, Andrea Marco Tamburini,
Andrea Vignali
RESIDENTS: Maria Chiara Salandini, Ilaria Santagostino
FELLOWS: Michele Carvello, Paolo Gazzetta, Luca Ghirardelli, Shigeki Kusamura, Francesco Luparini, Alessio Mocci,
Jacopo Nifosi
Head and neck oncology Unit
HEAD OF UNIT: Mario Bussi*
PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Matteo Trimarchi
RESIDENTS: Chiara Bellini, Beatrice Fabiano, Pietro Limardo, Paola Recanati
TECHNICIANS: Daniela Gherner, Barbara Ramella
Multidisciplinary group for thoracic surgical oncology
HEAD OF UNIT: Piero Zannini*
PHYSICIANS: Alessandro Bandiera, Angelo Carretta, Paola Ciriaco, Giulio Melloni, Giampiero Negri*, Armando Puglisi,
Carlopietro Voci*
RESIDENTS: Michele Giovanardi, Annamaria Gremmo, Piergiorgio Muriana, Stefano Sestini, Antonio Tuoro
Oncogenesis in liver neoplasms Unit
HEAD OF UNIT: Gianfranco Ferla*
PHYSICIAN: Mvunde Mukenge
RESIDENT: Francesca Ratti
Onco-hematology Unit
HEAD OF UNIT: Fabio Ciceri
PHYSICIANS: Massimo Bernardi, Consuelo Corti, Elena Guggiari, Francesca Lunghi, Magda Marcatti
RESIDENTS: Alessandro Crotta, Fabio Giglio, Simona Malato
POST-DOCTORAL FELLOW: Michela Tassara
TECHNICIAN: Roberta Mattarucchi
Pancreatic cancer Unit: biology and new therapeutic approaches
HEAD OF UNIT: Valerio Di Carlo*
PHYSICIANS: Gianpaolo Balzano, Marco Braga*, Renato Castoldi, Walter Zuliani
RESIDENTS: Federica Milani, Cristina Ridolfi
FELLOW: Greta Grassini
Clinical lymphoid malignancies
HEAD OF UNIT: Federico Caligaris-Cappio*
CLINICAL GROUP LEADER: Andrés Jose Maria Ferreri
PHYSICIANS: Matteo Carrabba, Marco Foppoli, Silvia Govi, Silvia Mappa
RESIDENTS: Marta Bruno Ventre, Giovanni Donadoni, Giada Licata, Emerenziana Marturano, Chiara Francesca Verona
TECHNICIAN: Arianna Vino
Gynecologic oncology
HEAD OF UNIT: Massimo Candiani*
CLINICAL GROUP LEADER: Giorgia Mangili
PHYSICIANS: Patrizia De Marzi, Elisabetta Garavaglia, Micaela Petrone, Emanuela Rabaiotti, Riccardo Viganò
RESIDENTS: Cinzia Gentile, Serena Montoli, Francesca Pella
PHD STUDENTS: Jessica Ottolina, Cristina Sigismondi
Medical oncology Unit
HEAD OF UNIT: Eugenio Villa
Clinical trials
CLINICAL GROUP LEADER: Michele Reni
PHYSICIANS: Daniela Aldrighetti, Stefano Cereda, Elena Mazza, Monica Ronzoni, Giordano Pietro Vitali,
Patrizia Zucchinelli
CONSULTANTS: Monica Giovannini, Alessia Rognone
RESEARCH NURSE: Simona Longoni
Phase I and lung cancer clinical trials
CLINICAL GROUP LEADER: Vanesa Gregorc
PHYSICIANS: Giovanni Citterio, Maria Grazia Viganò
RESIDENTS: Luca Bergamaschi, Umberto Peretti, Cristina Sorlini, Paolo Strati
PHD STUDENT: Anna Spreafico
FELLOWS: Alessandra Bulotta, Chiara Lazzari, Gilda Rossoni
URI, Urological Research Institute
HEADS OF UNIT: Francesco Montorsi* and Petter Hedlund
PHYSICIANS: Roberto Bertini, Alberto Briganti, Nicolò Maria Buffi, Andrea Cestari, Renzo Colombo, Andrea Gallina, Luciano
Nava, Andrea Salonia, Vincenzo Scattoni, Nazareno Suardi, Antonino Saccà
RESIDENTS: Firas Abdollah, Marco Bianchi, Umberto Capitanio, Dario Di Trapani, Matteo Ferrari, Giovanni Lughezzani,
Carmen Maccagnano, Federico Pellucchi, Giovanni Petralia, Lorenzo Rocchini, Francesco Sozzi, Elena Strada,
Manuela Tutolo
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
Mission and vision - The Division’s
aim is to develop translational research
programmes and clinical research. The
tenet of this aim is that any significant
progress toward the cure of cancer can
only be based on an improved understanding of its pathogenesis, which, in
turn, will lead to the development of
improved diagnostics and more rationale therapeutic interventions. This will
be achieved by fostering extensive collaborations between basic scientists and
clinicians.
Organization - The Division of Research of Molecular Oncology entails 14
Federico Caligaris-Cappio
Basic Research Units (URB) and 15
groups of Clinical Research (GRC) that
are organizing themselves into Research Programs. The Personnel is close to 140 people. The Lab space
allocated to the Division is about m2 2500. We are working to develop infrastructure facilities that favour
the Division development (patient’s data base, bio-bank, mouse and cell lines registers).
Goals - The main goal is to join efforts with the Clinical Department of Oncology to create an internationally competitive Integrated Cancer Center (HSR-ICC) which integrates cancer research, treatment and education with the aim of curing cancer. While providing “State-of-the-art” clinical care for all cancers, we intend to become “Second to None” in selected areas of excellence.
The scientific aims of the Division are based on the approach “build
on strength”. Two major areas of excellence have been identified:
Cancer Microenvironment; and Cancer Immunology and Immunotherapy. The scientific aims within these areas have been funnelled into two specific Research Programs, Immunology and Bio-Immunotherapy of Cancer (PIBIC) and Microenvironment and Genes
in Cancers of the Blood (MAGIC), which span from basic science to
clinical application and focus on specific malignancies for which we are
Giorgio Parmiani
internationally renowned.
We are exploring the possibility of developing additional scientific
programs. One example is a program on Cancer Stem Cells in collaboration with the Division of Stem
Cells and Regenerative Medicine. Further novel Disease-Oriented Programs, focusing each on specific
cancer types, will be progressively developed following the main stream of Personalized Medicine, that is
to tailor treatment on the basis of the specific molecular characteristics of each individual patient’s malignancy. The Disease-Oriented Programs will involve Lymphoid Malignancies, Pancreatic Cancer, Thoracic Cancers, Genitourinary Cancers, Neuro Oncology, Melanoma.
Achievements - PIBIC represents the merging of two previous programs and is co-organized with the
Division of Immunology. PIBIC’s scientific theme is a historical strength of the Institution. Its investigations exploit the role of the immune system and of its manipulation in specific cancers, especially
melanoma and epithelial cancers. PIBIC aims at translating results of basic/pre-clinical studies into novel, proof of principle clinical trials.
MAGIC is developing through the expertise, network organization and multidisciplinarity of the
Lymphoid Tumor Unit, the Myeloma Unit and the Leukemia Unit which bridge the Division of Molecular Oncology with the Clinical Department of Oncology and also entails the participation of numerous
Research Divisions. The program spans from genomic and epigenomic studies to the characterization of
the interactions between genes and microenvironment in the development and progression of blood cancers. We expect to translate the findings into more comprehensive prognostic and predictive cards for the
risk stratification of individual patients and to develop novel therapeutic strategies based upon new molecular targets.
Training Opportunities - The Division hosts the Section of Biology and Biotherapy of Cancer which is
part of the Institutional PhD Program in Molecular Medicine and offers numerous post-doc opportunities. It is also prepared to host, train and mentor Physician Scientists.
Research Units
LYMPHOID MALIGNANCIES UNIT
The principal aim of our Unit is to to dissect the elements responsible for the clinical presentation and the
natural history of Chronic Lymphocytic Leukemia (CLL). It is plausible to consider that both “causal genes”
(including distinct microRNA, miR) and a number of other “influential genes” operate and that the products of
all these genes interact with the microenvironment inducing proliferation, survival and clonal expansion of
CLL cells within the tissues. The investigation of these elements will lead to the identification of molecules and
mechanisms that could be exploited as potential therapeutic targets. This has been approached in the current
year by analyzing different aspects in vitro and in vivo.
We investigated the functional relationships between miR-221/222 cluster and p27, a key regulator of cell cycle, in CLL. The enforced expression of miR-221/222 in the CLL cell line MEC1 induced a significant downregulation of p27 protein and conferred a proliferative advantage to the transduced cells. Accordingly, the expression of miR-221/miR-222 and p27 was found to be inversely related in leukemic cells obtained from the peripheral blood of CLL patients. Interestingly, when miR-221/222 and p27 protein were evaluated in different
anatomic compartments (lymph nodes or bone marrow) of the same patients, increased expression of the two
miRNAs became apparent as compared to peripheral blood. This finding was paralleled by a low expression of
p27. These data indicate that the miR-221/222 cluster modulates the expression of p27 protein in CLL cells
and that miR-221/222 and p27 may represent a regulatory loop maintaining CLL cells in a resting condition.
Easily reproducible animal models that allow for study of the biology of CLL have been very difficult to establish. We have developed a novel transplantable xenograft murine model of CLL by engrafting the CLL cell
line MEC1 into Rag2-/-γc-/- mice. The result is a novel in vivo model that has systemic involvement, develops
very rapidly, allows the measurement of tumor burden, and has 100% engraftment efficiency. This model closely resembles aggressive human CLL and could be very useful for evaluating both the biologic basis of CLL
growth and dissemination as well as the efficacy of new therapeutic agents.
B-CELL NEOPLASIA
The natural history of Monoclonal B Cell Lymphocytosis (MBL)
Our main research interest is on chronic malignancies of mature B-cells that are virtually incurable. These diseases have a long natural history that may be preceded by a pre-malignant phase as in the case of Chronic Lymphocytic Leukemia (CLL).
In the recent past, we and others have identified the presence of monoclonal B cells (MBL) resembling CLL
cells and circulating in the peripheral blood of otherwise healthy individuals that may progress to CLL at a rate
of 1.1%/year.
During 2009, we aimed at dissecting the relationship between the two entities (CLL and MBL), as it remained yet unclear and, in particular, we tested, in a prospective cohort, if CLL is always preceded by MBL.
Among 77,469 healthy adults who were enrolled in the US, Prostate, Lung, Colorectal, and Ovarian (PLCO)
Cancer Screening Trial, 45 subjects were identified in whom CLL was subsequently diagnosed up to 6.4 years
later, and for whom viable frozen cells were available for analysis. Using six-color flow cytometry and RT-PCR
assay for immunoglobulin heavy-chain gene rearrangement, we demonstrated that 44 of 45 patients with CLL
(98%) had a prediagnostic MBL clone. We analyzed the presence of somatic mutations in the immunoglobulin
heavy-chain variable (IGHV) genes in 35 of 45 prediagnostic clones (78%) and found that 27/35 of them
(77%) had mutations. These results indicated that, in virtually all CLL (both mutated and unumutated) cases,
the disease diagnosis was preceded by a prediagnostic MBL clone, up to 77 months earlier.
In the same cohort, 109 persons developed CLL and had serially collected prediagnostic serum samples avail-
able for analysis. We then studied the serum immune-related abnormalities preceding CLL diagnosis. We observed an abnormal κ/λ free light chains (FLCs) in 38% of the cases while immunoglobulins were diminished
in 13% of them and a monoclonal (M)-protein could be detected in 3% of all cases. Interestingly, in a total of
48 persons (44%), an abnormal FLC ratio and an M-protein could be observed up to 9.8 years before CLL diagnosis. In contrast, hypogammaglobulinemia was not present until 3 years before the diagnosis of CLL. These
findings support a role for chronic immune stimulation in CLL genesis.
These studies may help to better define ways to understand the mechanisms responsible for the evolution
from MBL to CLL.
Paolo Ghia
BIOLOGY OF MULTIPLE MYELOMA
Role of hypoxia in bone marrow angiogenesis associated with Multiple Myeloma
The main focus of our research is to dissect the role of bone marrow (BM) microenvironment in Multiple
Myeloma (MM) pathogenesis. MM is a tumor of fully differentiated plasma cells (PC) growing almost exclusively within the BM, which delivers pro-survival signals and confers chemo-resistance to neoplastic cells. BM
angiogenesis also deeply contributes to MM development and progression. The investigation of the mechanisms governing the interactions between the malignant PC and the milieu supporting its growth is expected to
identify new therapeutic targets for the disease, which remains ultimately incurable with available treatments.
We are currently investigating the mechanisms responsible for MM-associated BM angiogenesis. In solid tumors, hypoxia represents a major stimulus to angiogenesis. Exposure to a low-O2 environment triggers an evolutionary conserved hypoxic response in mammalian cells, based on the regulated expression of hypoxia-inducible- factor (HIF)-1α. HIF up-regulation results in the expression of genes that mediate glycolysis and angiogenesis, including VEGF and bFGF. BM is considered hypoxic by nature, but the role of hypoxia in supporting MM-associated, hypoxia-dependent angiogenesis has not been characterized so far.
During 2009, we initially compared different BM cellular components, including MM PC, endothelial cells
and BM stromal cells (BMSC), for their capability to release pro-angiogenic cytokines and chemokines. BMSC
were obtained from BM aspirates of MM patients, propagated and characterized as CD105positive, CD73positive, CD31negative adherent cells. BMSC were found to represent a major source of pro-angiogenic factors, including IL-6, VEGF, IL-8 and SDF-1 α. Moreover, exposure of BMSC to hypoxic conditions (5% O2), obtained by culturing cells in a hypoxic chamber, lead to a significant increase in VEGF release. In collaboration
with E. Ferrero, (Division of Molecular Oncology - HSR), we are currently assessing the function, in terms of
angiogenesis induction in vitro, of BMSC supernatants generated both in normoxia and hypoxia, as well as the
contribution of selected molecules. Final aim is to define biomarkers to be used to identify patients who can potentially benefit from anti-angiogenetic approaches, and to monitor the effect of therapy on angiogenesis.
Marina Ferrarini
CELL ACTIVATION AND SIGNALLING
The principal aim of our Unit is to dissect the molecular events which regulate cell activation and signalling,
in particular focussing our attention on the B-cell receptor (BCR) and Toll-like receptors (TLR) signalling pathways in normal and malignant B lymphocytes. The investigation of these elements is leading to the identification of molecules and mechanisms that could be exploited as potential therapeutic targets.
Toll-like receptors (TLR) are key players in host defence from infection. They recognize a specific set of molecular patterns of microbial origin, immediately trigger an innate immune response, and bridge innate and
adaptive immunity. TLR have also been shown to play a role in tumor development. In this context, chronic Bcell malignancies are an interesting example as clonal B lymphocytes remain responsive to and dependent on
stimuli originating from the microenvironment which then become crucial for maintaining and propagating the
disease. Emerging evidences suggest that, among other microenvironmental elements, TLR ligands may play a
role in the pathogenesis of chronic B-cell lymphoid malignancies.
In the current year, we studied fresh leukemic cells, freshly isolated from CLL patients, for the expression
pattern of TLR1 to TLR10, NOD1, NOD2, RP105 (also known as CD180) and TIR8 (also known as SIGIRR).
CLL cells were found to express, at different levels, distinct pattern recognition receptors including TLR1,
TLR2, TLR6, TLR10, NOD1, NOD2 and RP105. The specific TLR expressed by CLL cells were functional.
Leukemic cells, upon stimulation with TLR1/2/6 ligands, such as bacterial lipopeptides, activated several signalling pathways including the nuclear factor-κB cascade; cells stimulated with TLR ligands expressed more
CD86 and CD25 activation molecules, and were protected from spontaneous apoptosis. These findings further
support the hypothesis that CLL cells resemble antigen-activated B-cells and suggest a potential role of TLR in
modulating CLL cell response in the context of specific antigen recognition. Conceivably, their manipulation
may find a place in specific settings of treatment of these tumors.
Marta Muzio
DYNAMIC FLUORESCENCE SPECTROSCOPY IN BIOMEDICINE
Molecular dynamics of cell membrane receptors beyond multiphoton fluorescence microscopy
A crescent awareness of the need exists to replace static, “hard-wired” diagrams of receptor interactomes
(i.e., a schematic representations of signaling pathways), with real time dynamics of multi-protein complexes, as
they assembly, translocate and disassembly in living cells, governing the fundamental mechanisms of a cell.
These are the most demanding challenges in quantitative live imaging. State-of-the-art confocal, multiphoton
imaging technologies and even super-resolved fluorescence microscopies (STED, PALM) are far to fulfil these
tasks.
Our group has advanced in the development of molecular imaging tools that are sensitive and quantitative
and have the potential to follow the dynamics of whole protein complexes, in real time, in live cells and more
importantly with nanometric (i.e. molecular) resolution. They are based on time resolved fluorescence imaging,
image correlation and fluorescence fluctuation spectroscopy rather than on “colors” (which is normally what
microscopy does, in any fancy manner).
We have chosen to focus on three target systems, the urokinase plasminogen activator and its receptor
(uPA/uPAR), the epidermal growth factor and its receptor (EGF/EGFR) and the neural cell adhesion molecule
and fibroblast growth factor receptor (NCAM/FGFR). These systems have a relevant role in the coordination of
complex events leading to changes in cell growth, adhesion, movement and survival of the cell and their implication in cancer. Although they are structurally diverse, there are evidences of cross-talking between them. Applying the new N&B imaging, durning last year, we have been able to follow the interaction kinetics and stoichiometry of NCAM with FGFR and of ATF with uPAR, showing how binding leads to the receptor re-assembly on
the cell membrane, internalization of the ligand-receptor complexes and recycling on the membrane surface.
Valeria R. Caiolfa
LYMPHOID ORGAN DEVELOPMENT
The research in our laboratory focuses on identifying the molecular and cellular mechanisms underlying the
development and function of secondary lymphoid organs. Our long-term goal is to understand how the stromal
microenvironment regulates the function, survival and expansion of normal lymphoid and leukemia/lymphoma
cells. Concomitantly, we are translating our knowledge on how secondary lymphoid organs develop to construct a functional artificial lymph node that could serve as a novel approach to enhance anti-tumor immunity.
Over the past year, we have pursued the following research projects:
1. Elucidating the roles of oncogenic transcription factors in secondary lymphoid organ development.
By using DNA-microarray and chromatin immunoprecipitation analyses we are identifying the molecular
pathways controlled by oncogenic transcription factors during proliferation/differentiation of stromal progenitor cells. With this approach, we have recently uncovered several deregulated pathways associated with loss of
Tlx1, an oncogene required for spleen cell fate specification and proliferation. We are currently validating some
of these deregulated pathways.
2. Uncovering the differentiation pathways of stromal progenitors during lymphoid tissue development.
We have exploited a genetic approach in mice to label stromal progenitors within developing lymphoid organs. We are currently fate mapping the differentiation pathways of spleen and lymph node mesenchymal progenitors, identifying their contribution to the adult stromal cell pool and establishing functional relationships
with lymphoid cells.
3. Generating functional artificial lymphoid organs (aLOs).
By exploiting mesenchymal cell lines as a new source of stromal cells, we have succeeded in constructing
aLOs with features similar to normal lymphoid organs, including presence of T- and B-cell compartments as
well as stromal-cell networks. Over the year, we have also generated aLOs by using primary mesenchymal progenitors and found that primary mesenchymal cells are equally efficient in supporting the formation of artificial
lymphoid structures, thus opening to the possibility of using mesenchymal stem cells as a source of stromal progenitors.
Andrea Brendolan
PRECLINICAL MODELS OF CANCER
The main objective of this unit is to understand the role of pro-angiogenic factors and the efficacy of their targeting in leukemogenesis by creating mouse models.
Emerging data is suggesting that in addition to promoting growth and metastasis of solid tumors, angiogenesis may also promote leukemogenesis. Clinical studies indicate that leukemia patients express high levels of proangiogenic factors such as VEGF and have increased angiogenesis in their bone marrow. However, the molecular mechanisms leading to high VEGF production in leukemia have not been elucidated. Based on preliminary
data, we hypothesized that upregulation of the transcription factor HIF-1α, the main positive regulator of
VEGF expression in solid tumors, may cause high VEGF expression and may promote disease progression also
in some forms of leukemia. Therefore, inhibiting HIF-1α activity may be a useful molecular approach to restrain leukemogenesis.
In the past year we have:
1. Established lentiviral vectors to overexpress or silence HIF-1α and VEGF in primary mouse hematopoietic cells. We are currently co-transducing hematopoietic cells with leukemogenic fusion proteins and vectors
overexpressing HIF-1α and VEGF in order to verify in vivo whether these factors accelerate leukemogenesis.
2. Analyzed the expression of HIF-1α in hematopoietic malignancies.
3. We have analyzed a number of established cell lines representative of hematopoietic neoplasms and found
that the expression of HIF-1α is high prevalently in B cell malignancies. At the same time however, assays
that evaluate HIF-1α activity reveal that even in the absence of high levels of expression, HIF-1α activity is
high in certain myeloid leukemias. In collaboration with the Department of Pathology and the Hematology
and Transplantation Unit of San Raffaele Hospital, we are now planning to analyze bone marrow samples
of human leukemia for HIF-1α and VEGF expression.
4. Silenced HIF-1α and VEGF expression in cell lines and begun to investigate the outcome of inhibiting
HIF-1α as a means to inhibit leukemogenesis both in vitro, through co-culture experiments, and in vivo
upon injection into immunocompromised mice.
Rosa Bernardi
TUMOUR MICROENVIRONMENT
Multiple Myeloma angiogenesis: identification of biomarkers and use of 3-D cultures in bioreactor to
evaluate response to anti-angiogenic drugs
Bone Marrow (BM) angiogenesis contributes to Multiple Myeloma (MM) pathogenesis and progression and
BM microvessel density (MVD) has been associated with disease stage and response to therapy. Efficacy of an-
ti-myeloma drugs, including the proteasome inhibitor Bortezomib and the immunomodulatory drugs (IMiD)
could also depend on efficacy on MM vasculature. An emerging concept states that, besides the number of abnormal microvessels, their shape and structure may play a pivotal role in tumor growth and metastatization.
Lack of validated biological markers of angiogenesis and of animal models spontaneously developing MM, are
major biases to monitor angiogenesis in its multiple forms in the course of MM and to assess response to drugs,
in particular to anti-VEGF (Bevacizumab, Avastin) drugs, approved for treatment of solid cancers, but not currently used for MM. In collaboration with M. Ferrarini (Division of Molecular Oncology), we are now measuring, in the medullar and peripheral sera of patients with MM and MGUS, the concentration of selected cytochemokines involved in angiogenesis and vessel normalization, including VEGF, and Angiopoietin-1 and -2;
their relationship with MVD, presence of hypoxic areas and clinical data will be evaluated. The technology of
3-D culture model in bioreactor, by us validated for its ability to maintain viable and functional MM organotypic cultures, will be used to assess, through serial immunohistological examinations, MVD, vessel shape, presence of hypoxic areas and specific response to anti-angiogenic drugs, by means of a in-house developed, dedicated software.
Elisabetta Ferrero
IMMUNO-BIOTHERAPY OF MELANOMA AND SOLID TUMORS UNIT
Pre-clinical work. During the year 2009 our Unit has made substantial progress in the study of human colorectal cancer (CRC) antigens deriving from somatically mutated cancer driving genes, i.e. those genes that are
involved in the neoplastic transformation or in the maintenance of the neoplastic features like tumor progression and invasion. We have identified several of these genes by deep sequencing, then we have characterized the
mutated proteins containing potential epitopes recognized by T lymphocytes of the patient. These entirely new
and tumor specific antigens will then be tested functionally to assess their in vitro immunogenicity for peripheral blood T cells of colorectal cancer patients.
We have also expanded our study of cancer stem cells by an immunological characterization of their profile in
glioblastoma. A similar study has been initiated in colorectal cancer stem cells and we succeeded in generating
new tissue culture lines of pairs of CSC and non-CSC tumor lines that will be then analyzed for stemness features and immunogenicity in in vitro assays. Also the analysis of the role of NKG2D+ T cells as anti-melanoma
effectors has continued by acquiring new data on the association between release of soluble NKG2D ligands by
melanoma cells and patients’ prognosis.
During 2009, a new project has been also started to investigate biological mechanisms that may explain the
worse prognosis in melanoma patients bearing ulcerated vs. non ulcerated primary tumors. The network of
protein/cytokines that may be triggered by the ulceration (hypoxia, necrosis) will be studied in melanoma samples by immunohistochemistry and by in vitro assays. Genes that are activated by such process will be determined in comparison with melanoma cells obtained from non-ulcerated lesions and their gene products assessed functionally.
Clinical trials. Over 100 patients with melanoma have been visited and some of them enrolled in ongoing clinical studies. Meanwhile, the first part of the RNA-based vaccination in prostate cancer patients has been concluded; patients’ immune response to the vaccine is under evaluation. The new protocol of combination of the
anti-vascular agent NGR-hTNF and peptide-based vaccine has been approved by the Ethics Committee pending the approval of the Istituto Superiore di Sanità and it is planned to start shortly.
Giorgio Parmiani
CANCER GENE THERAPY
Pre-clinical and clinical studies have demonstrated the key role of the immune system in controlling tumor
growth. Nevertheless, the full clinical exploitation of these immune-based strategies is far from being successful, due to the limited clinical efficacy showed by current studies of immunotherapy. Among several reasons responsible for that, immune escape mechanisms perturbing the tumor microenvironment have recently been
demonstrated to play a relevant role in affecting antitumor immune responses. In fact, in some circumstances
the blockade of these mechanisms restores the antitumor immune response and induces an effective control of
tumor growth. Based on this, avoidance of immune surveillance has been proposed as the 7th hallmark of cancer (extrinsic oncogenic factors), and it should integrate with the six established intrinsic oncogenic factors to
fully explain tumor formation/establishment and metastasis. In recent years, several molecules and cells generating immune suppressive networks responsible for the inhibition of the antitumor immune response, have
been extensively investigated and identified.
The research of our group is focused on the investigation of cellular and molecular mechanisms increasing tumor antigen-presentation, and on the identification of new immune escape mechanisms, with the final goal to
identify new strategies to improve the antitumor immune response. In particular, we have recently developed a
novel strategy of active immunotherapy based on the in vivo loading of antigen presenting cells (i.e. dendritic
cells) with tumor antigens (Russo et al. J Clin Invest, 2007). The clinical translation of this approach has led to
the development of antitumor effectors correlating with a favorable clinical outcome in melanoma patients
(Fontana et al. Blood, 2009). Moreover, we have recently identified a novel mechanism of tumor immune escape, which dampens the spontaneous immune-mediated control of tumor growth by impairing the functional
expression of the lymphoid-organ homing receptor CCR7 on maturing dendritic cells. Of note, the use of drugs
interfering with this pathway, restores the spontaneous antitumor immune response and the control of tumor
growth in different mouse tumor models (Villablanca et al. Nat Med, 2010).
Vincenzo Russo
FUNCTIONAL GENOMICS OF CANCER UNIT
Transcriptomic, genetic and epigenetic reprogramming of cancer cells
Our laboratory is currently pursuing the following lines of research:
1. Role of histone methylation and demethylation in cancer development.
In the nuclei of eukaryotic cells, DNA is packed into chromatin. The basic constituent of chromatin, the nucleosome, is comprised of 147 bp of DNA wound around an octamer of core histone proteins. Post-translational modifications of the N-terminal tails of these core histone proteins, modulate chromatin configuration, resulting in changes in transcriptional regulation. These epigenetic modifications are controlled by complex enzymatic machinery that, when deregulated, disrupt normal transcriptional programs. Indeed, genomic alterations
of MLL, NSD1, CREBBP, WHSC1L1 and WHSC1, all encoding proteins involved in histone modification,
have been implicated in several cancer types.
Through genomic analysis and large-scale high-throughput sequencing, we have identified genetic lesions affecting histone methylases and demethylases and we are exploring the role of the genes implicated in these genomic rearrangements in the development of multiple myeloma, lung cancer and renal carcinoma.
2. Receptor tyrosine kinase receptors in the development of Multiple Myeloma.
The protein kinase is the most commonly represented Pfam domain encoded by cancer genes. Many carcinogenic tyrosine kinases are receptors, which are often overexpressed and/or mutated in a variety of tumors. Therapeutic agents targeting this class of receptors have proven to be highly effective in the clinical
setting. Multiple Myeloma (MM) is the second most frequent hematological cancer and remains incurable.
Several RTKs are expressed in MM and there is mounting evidence of their pathogenetic importance in this
disease.
We have conducted a genomic and proteomic survey of primary MM samples and identified two RTKs that
were overexpressed relative to levels present in plasma cells derived from normal donors. Strikingly, both RTKs
tap into developmental pathways that are highly relevant in cancer biology and demonstrated robust transforming activity.
The goal of this project is to elucidate the nature of the signaling mediated by these RTKs in MM, both in vitro and in vivo, with the final goal of identifying more effective drugs against MM.
Giovanni Tonon
MODEL GENETICS OF MEMBRANE TRAFFICKING UNIT
Epsins are endocytic adaptors with putative functions in housekeeping forms of endocytosis as well as in actin
dynamics, and neurotransmission. To test the role of the ubiquitously expressed Epn1 and 2 genes in vivo, we
generated KO mice for those genes (Chen H. et al., 2009 PNAS, 106:13838). While single epn mutants do not
show major phenotypic defects, Epn1/2 double KO (DKO) mutants are embryonic lethal at E9.5-E10, i.e., at
the beginning of organogenesis. Developmental defects observed in Epn1/2 DKO embryos recapitulated those
produced by a global impairment of Notch signaling. However, housekeeping forms of clathrin-mediated endocytosis were not impaired in cells derived from these embryos. Our findings support a role of epsin as a specialized endocytic adaptor of Notch ligands in mammals.
In collaboration with the laboratory of Kohji Takei (Okayama University), we studied amphiphysin1 function
in actin dynamics (Yamada H, 2009 J Biol Chem, 284:34244). We reported that amphiphysin1 interacts with NWASP and stimulates N-WASP- and Arp2/3-dependent actin polymerization. This association undergoes regulation and is enhanced by stimulating phosphatidylserine receptors on the cell surface that trigger ruffle formation. These results indicate that amphiphysin 1 is a key actin regulator and that such function cooperates with
the endocytic adaptor role of the protein during the endocytic reaction.
In collaboration with the laboratory of Pietro De Camilli (Yale University), we analyzed endocytic intermediates that accumulate in cells that lack dynamin expression (i.e. cells derived from dnm1/2 conditional DKO
mice; Ferguson S. et al., 2009 Dev Cell, 17:811). In these cells, actin-nucleating proteins, actin, and BAR domain proteins accumulate at the base of arrested endocytic clathrin-coated pits, where they support the growth
of dynamic long tubular necks. These results demonstrate a concerted action of these proteins prior to, and independent of, dynamin and emphasize similarities between clathrin-mediated endocytosis in yeast and higher
eukaryotes. Our data also demonstrate that the relationship between dynamin and actin is intimately connected
to dynamin’s endocytic role and that dynamin terminates a powerful actin- and BAR protein-dependent tubulating activity.
Ottavio Cremona
MOLECULAR HISTOLOGY AND CELL GROWTH UNIT
Translational control in cancer
Cancer cells are characterized by several metabolic anomalies. Among them, protein synthesis (translation) is
highly deregulated. Translation is controlled by defined factors known as eukaryotic initiation factors (eIFs).
Recent work has led to the identification of two initiation factors involved in tumorigenesis: eIF4E, and eIF6.
Our laboratory focuses on the biology of eIF6. Evidence produced in our lab has shown that eukaryotic initiation factor 6 (eIF6) is important in transformation, downstream of growth factors and oncogenic mutations of
ras. eIF6 is a rate-limiting factor in ribosome biogenesis and translation, and has the unique property to bridge
these two processes. eIF6 is necessary for cell growth and synthesis of 60S ribosomal subunits. Converging genetic and biochemical evidence indicates that eIF6 is rate-limiting for 60S ribosome assembly, by acting in a
multiprotein complex mostly composed of essential genes. eIF6 controls also translation. Briefly, eIF6 biochemical activity regulates 40S + 60S ribosomal joining in a mTORc1 independent fashion. Our lab has shown
that eIF6 is controlled by growth factors/mitogens and positively regulates translation. In this context, cells
with half levels of eIF6, compared to normal, have a normal basal level of translation, but insulin-stimulated
translation is blunted. Related to cancer, eIF6 is significantly upregulated during colon carcinoma progression,
and in other tumors.
In the last year we have progressed on the characterization of the role of eIF6 in tumor biology, by demonstrating that several classes of tumors are affected by eIF6 expression. The analysis of the molecular mechanism
by which eIF6 acts, is in progress.
Stefano Biffo
.
Figure 1. eIF6 in ribosome biogenesis and
translational control (from Miluzio et al., Embo
Reports, 2009). In the nucleolus, eIF6 associates with
immature large ribosomal subunits (pre-60S) and
other regulatory proteins (trans-acting factors). eIF6 is
found during pre-60S subunit maturation in the
nucleoplasm and is exported to the cytosol. Here, eIF6
release allows the 60S to join the 40S subunit, and the
active, translating 80S complex is formed. eIF6
shuttling between the nucleus and cytoplasm allows
the proper formation of pre-60S. eIF6, eukaryotic
initiation factor 6; PABP, polyA-binding protein.
TUMOR BIOLOGY AND VASCULAR TARGETING UNIT
Our studies focus on the development of new strategies for cancer therapy based on drugs that affect the tumor vasculature and microenvironment. For example, we have found that peptides containing the NGR, isoDGR and RGD sequences can be exploited for delivering Tumor Necrosis Factor α (TNF) and other cytokines
to tumor vessels. These compounds can induce vascular damage, can alter endothelial permeability and can increase the penetration of various chemotherapeutic drugs in tumors. Because of these properties, one of these
compounds, called NGR-TNF, is currently tested in several Phase II clinical studies, alone and in combination
with chemotherapy, with evidence of activity. A Phase III study in patients with malignant pleural mesothelioma started recently. Other lines of research are focused on the role of proteins containing the NGR, RGD
and isoDGR sequences in tumor vascular biology and angiogenesis. We have found that circulating CgA, an
RGD-containing protein secreted by many neuroendocrine cells and granulocytes, is elevated in patients with
cancer and other inflammatory diseases. This protein can regulate fibroblast and endothelial cell adhesion, can
inhibit TNF-induced vascular leakage, can inhibit angiogenesis and can inhibit tumor growth and metastasis
development in various animal models by affecting the tumor microenvironment. Regarding NGR (asparagineglycine-arginine) this sequence is present in many molecules of the extracellular matrix. We have demonstrated
that it can undergo rapid deamidation reactions generating the isoAsp-Gly-Arg (isoDGR) sequence in fibronectin. Peptides and fibronectin fragments containing the isoDGR motif can bind αvβ3, an integrin expressed in the angiogenic vasculature, can affect endothelial cell functions and can inhibit tumor growth. We
have hypothesized that the NGR-to-isoDGR switch in fibronectin and in other proteins of the ECM might
work as a “molecular timer” for generating new binding sites for integrins. Finally, we have shown that peptides
containing the isoDGR motif can be exploited for the delivery of TNF and nanoparticles to tumors.
Angelo Corti
DIGESTIVE AND PANCREATICO-BILIARY ENDOSCOPY UNIT
The Unit is involved in the development and clinical application of advanced endoscopic imaging and endoluminal therapy for recognition and treatment of high-grade dysplasia and early cancer of the gastrointestinal
tract (G.I.) and pancreatico-biliary system.
Advanced endoscopic imaging.
In the last years the research has been focused mainly on the use of Optical Coeherence Tomography (OCT)
for detecting and characterizing mucosal and submucosal lesions of the G.I. tract and for differential diagnosis
of structures of unknown aetiology of the main pancreatic and common bile duct. We first used OCT imaging
to investigate the layers of the main pancreatic and common bile duct in ex-vivo studies and in humans, by ERCP. Using this technique, we were able to characterize the intraductal tissue structure and differentiate between
neoplastic and inflammatory strictures, as documented by recent publications.
At present, surface and contrast enhanced endoscopic imaging is used to investigate mucosal flat lesions (preneoplastic and neoplastic); the technique appeared particularly useful in Barrett’s esophagus, gastric dysplasia,
and colonic flat adenomas.
Confocal endomicroscopy is currently used in clinical practice since the beginning of 2010. It is a new advanced imaging technique which enables in vivo microscopy with subcellular resolution during ongoing endoscopy. The technique is very effective in detecting neoplastic lesions at a very early stage, identifies pre-neoplastic lesions, and gives information about living cells in human beings. Confocal endoscopy can be carried out
also with probes that can be inserted into the pancreatico-biliary system, during ERCP procedures.
Endoluminal therapy.
Endoscopy is commonly used for treatment of neoplastic lesions of the G.I. tract confined within submucosa,
because the technique permits to remove tissue by mucosal resection, submucosal dissection, and radiofrequency ablation. Radiofrequency can also be delivered into the pancreatico-biliary ductal system to treat neoplastic strictures.
The Unit is involved in the development of new devices for tissue removal, including knife models and water jet probes for tissue lifting, and radiofrequency delivering devices for both G.I. tract and pancreatico-biliary ductal system. By using these devices, dysplastic epithelium and early cancer within Barrett’s esophagus,
as well as in the stomach and colon, can be completely removed, and neoplastic ductal strictures can be treated.
Pier Alberto Testoni
ENDOSONOGRAPHY: DIAGNOSTIC AND THERAPEUTIC
ENDOSCOPIC ULTRASOUND
The focus of our Endosonography Unit is to develop research programmes in diagnosis and treatment of premalignant and malignant pancreatic lesions. The importance of diagnostic Endoscopic Ultrasound (EUS), the
therapeutic and interventional applications of EUS are expanding and may become a major breakthrough in
the management of pancreatic diseases.
The diagnosis of premalignant lesions is necessary to avoid that most patients have advanced disease at the
time of diagnosis. Screening and surveillance for pancreatic cancer and its precursors is a new indication for endoscopic ultrasound. We are cooperating with John Hopkins Medical Institutions (Baltimore) for an international program of screening of patients with a strong family history of pancreatic cancer screened on a periodic
basis for pancreatic lesion. In the same way we are organizing a national screening program with the Italian Association for the study of the pancreas (AISP).
We are cooperating with Mayo Clinic Jacksonville for an international registry for multi-center collaboration
in Intraductal Papillary Mucinous Neoplasm (IPMN) research and clinical management, with the aim of identifying clinical and morphological predictors of cancer in patients with IPMN who undergo surgery, and to identify predictors of progression to cancer or high grade dysplasia among patients who are followed in surveillance
programs.
Patients with unresectable locally advanced pancreatic disease don’t have many chances and chemoradiation
confers them only a minimal symptomatic improvement. Radiofrequency ablation is a local thermal therapy
used for palliative treatment of solid tumours.
We have developed a new flexible bipolar ablation probe combining radiofrequency and cryotechnology applied under EUS-guided and we have demonstrated the feasibility and efficacy of this new treatment, using it in
a porcine model. We have also evaluated the efficacy of this new hybrid cryotherm probe (CTP) in destroying
neoplastic tissue of explanted pancreas of patients with pancreatic adenocarcinoma, analyzing both the tissue
histological changes and relationship between application time and long axis diameter of necrosis obtained.
The application provokes selective necrosis in neoplastic tissue, and there was a statistical significant correlation between necrosis diameter and application time. Now we are designing a clinical protocol for the treatment of local advanced carcinomas just after the first line of chemotherapy to study the capability of the CTP to
increase the number of patients to be resected.
Paolo Giorgio Arcidiacono
GASTROINTESTINAL SURGICAL ONCOLOGY UNIT
Our Unit’s research activity has been focused on several different relevant topics in gastrointestinal oncology:
1. Role of the induction of innate and adaptive antitumor immunity in nonmetastatic rectal cancer patients
treated with neoadjuvant CT-RT and its relationship with pCR and survival. The aim is to verify whether
innate factors influence the outcome of antineoplastic treatment, and whether they may predict in selected
patients the clinical response and survival.
2. Evaluation of the clinical significance of circulating Tumor Cells (CTCs) in blood from patients with gastrointestinal cancers. The aim is to determine and quantify CTCs in all patients with any stage of gastrointestinal malignancy, as well as correlate their presence with clinical and pathological factors. Our second
goal is to test the prognostic value regarding disease free overall survival.
3. Evaluation of parameters for tumor response to neoadjuvant chemotherapy in advanced gastrointestinal
cancers in an attempt to coin a new tumor regression grade system.
4. Evaluation of surrogate biological markers of oncological outcome in gastric cancer which includes the assessment of Cox-2 expression.
5. HIPEC in the treatment of locally advanced gastric cancer following preoperative chemotherapy and curative surgery. The purpose of the present protocol is to investigate the feasibility, morbidity, toxicity, mortality and oncological outcome of HIPEC in patients with locally advanced gastric cancer with a high risk for
peritoneal dissemination.
6. Cytoreductive surgery and HIPEC in the treatment of peritoneal carcinomatosis from colon cancer. The
purpose of the present pilot study is to investigate the feasibility, morbidity, toxicity, mortality and survival
of the cytoreductive surgery and HIPEC in colon cancer patients with primary/relapsing peritoneal carcinomatosis or at a high risk for peritoneal dissemination.
7. Sentinel node mapping during laparoscopic gastrectomy for gastric cancer. Laparoscopic modified surgery
based on sentinel node status would be the goal of a minimally invasive approach for pathologically node
negative early gastric cancer. The aim is to evaluate the feasibility in gastric cancer patients who underwent
laparoscopic detection of sentinel node.
Carlo Staudacher
HEAD AND NECK ONCOLOGY UNIT
Our Unit’s main research focus is the investigation on functional problems and outcomes of advanced larynx
cancer bearers.
A new technique of subtotal laryngectomy has been performed, in cooperation with other Ear, Nose and
Throat (ENT) oncological departments, to preserve the voice in advanced larynx cancers, extended to the subglottis. Phonatory and deglutition results have been studied, together with the satisfaction degree. As far as total laryngectomy concerns satisfaction and quality of life after voice prosthesis rehabilitation have been investigated. New functional surgical techniques and psychooncological studies will be carried on in the next period
to guarantee the best social outcome in subjects undergoing organ sacrificing surgery for advanced larynx cancer.
A series of 350 cases of parotidectomies performed in 7 years has been investigated from a clinical and statistical point of view.
Attention was paid to correlation between Fine Needle Aspiration Citology (FNAC) and definitive histological examination, to facial palsy, Frey’s syndrome and relapses; statistical analysis was performed on the grouped
data.
Over past 20 years, high risk human papilloma virus (HPV) infections has been established as a risk factor for
developing head and neck squamous cell carcinoma, independent of tobacco and alcohol use. Our unit is collaborating with the Laboratory of Tumor Immunology (M.D. Maria Pia Protti) with the aim of showing the
presence of viral genoma (HPV 16) in tumour cells. Besides we are investigating a specific immune response in
patients’ blood; in detail we are verifying the presence of CD4 + T cells with an immune response specific for
peptide sequences corresponding to E6 and E7 of HPV.
Further analysis and studies will be required to assess the feasibility and the efficacy of targeted HPV16 vaccination
Mario Bussi
MULTIDISCIPLINARY GROUP FOR THORACIC SURGICAL ONCOLOGY
Multidisciplinary approach for patients affected by non-small cell lung cancer and colorectal and renal cancer
lung metastases
Surgery remains the best treatment for patients affected by non-small cell lung cancer (NSCLC). Advanced
age, cardiorespiratory comorbidities and pathological mediastinal lymph nodes represent some contraindication to surgical resection. To extend possibility of surgical treatment, we undertook the following lines of research.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a potential alternative to mediastinoscopy to confirm or exclude lymph node metastases. Preliminary studies have
demonstrated that it may lead to an improvement in the results of N-staging decreasing the morbidity correlated to mediastinoscopy. The aim of this study is to assess the effectiveness and safety of EBUS-TBNA in staging
NSCLC patients.
Advanced emphysema is frequently associated with lung cancer and can impede surgical treatment. New
therapeutic strategies such as bronchoscopic lung volume reduction (BLVR) have been developed recently. The
goal of BLVR is to obtain a functional improvement by endoscopically-positioning one-way endobronchial
valves which divert ventilation from the emphysematous areas to more normal lung regions. The aim of this
study is to assess the results of BLVR in terms of post-treatment morbidity and improvement of respiratory
function aimed to perform surgery on patients affected by NSCLC.
Advanced age and associated cardiac and pulmonary diseases may however be a contraindication to surgical
treatment. The aim of the study is to assess the results of new treatment-strategies as percutaneous radiofrequency thermoablation and tomotherapy, a recently-developed radiotherapy technique, in patients with earlystage NSCLC with a contraindication to surgical treatment.
Surgical resection both for colorectal and renal cancer lung metastases are well-accepted treatment modali-
ties. Identification of new tumor markers to supplement clinical and pathological staging may allow to identify
those patients with lung metastases from colorectal and renal cancer at highest risk of recurrence following surgery. The aim of this study is to evaluate the use of immunohistochemical analysis to assess the prognostic value
of some tumor markers (microsatellite instability and S100a4 protein) in colorectal and renal cancer metastases.
Piero Zannini
ONCOGENESIS IN LIVER NEOPLASMS UNIT
The Hepatobiliary Unit is a multidisciplinary clinical unit where the traditional gap between physicians and
surgeons has been overcome to reach the optimal standards of patient care. Indeed, the medical staff includes
hepatologists and hepatobiliary surgeons who share their specific competences to treat in an unique environment both “internal” and “surgical” patients. Clinical activities are mainly focused on hepatobiliary tumors and
chronic liver diseases, including primary (hepatocellular carcinoma and cholangiocarcinoma) and metastastic
liver tumors (mainly liver metastases from colorectal cancer), liver cirrhosis and related complications (portal
hypertension, ascites, esophageal varices), benign and malignant diseases of the biliary tract, acute and chronic
hepatitis.
As far as concern liver tumors, the research activities are mainly focused on the outcome (in term of overall
survival and disease-free survival) of patients affected by liver metastases from colorectal cancer and treated by
surgery and adjuvant/neoadjuvant chemotherapy. Studies regarding the prognostic factors of survival after surgery and the impact of locoregional chemotherapy on the outcome after surgery have been published (World J
Surg, Ann Surg Oncol, J Gastroint Surg, J HBS).
Among the speculative studies about the liver metastases from colorectal cancer, the hepatobiliary unit have
been involved in cooperative protocols of study with the Unit of Immuno-biotherapy of Melanoma and Solid
Tumors (Prof. Parmiani). Surgical specimens have been collected after liver resection for colorectal liver metastases to characterize the expression of OX40 and 4-1BB on peripheral blood lymphocytes and in tumor and
lymphoid tissue of oncological patients. The study has ended the phase of case collection and it is still ongoing
as far as concern the final results. Further cooperative studies about carcinogenesis in patients affected by hepatocellular carcinoma and HCV infection are under evaluation at the present time.
Gianfranco Ferla
ONCO-HEMATOLOGY UNIT
The San Raffaele Onco-Hematology Group of Clinical Research is active in clinical research for acute
leukemias, myelodisplasia, mieloproliferative disorders, lymphomas and myelomas. Investigator-Initiated clinical trials are higly integrated in clinical care. To this purpose, the infrastructures comprise a clinical care facility
with ISO-9001 accreditation comprising all the requirements for care of patients affected by acute and chronic
leukemia, lymphoma and myeloma, a bone marrow transplantation unit and a dedicated Day Hospital Unit. We
participate and contribute to national and international disease networks (NILG, Gimema, Leukemianet, GITIL, IIL). Clinical research is organized in Diseases Units: Leukemia Unit and Myeloma Unit and we contribute to the Lymphoma Unit. During 2009 the clinical research activity has been focused on several diseasespecific master trials: NILG-AML master trial of the cooperative group NILG in AML at diagnosis; NILGALL 10/07 master trial of the cooperative group NILG in ALL patients at diagnosis with a systematic application of an MRD-oriented strategy to post remission therapies (www.nilg.it); salvage chemotherapy with clofarabine in relapsed AML; WT1 monitoring in bone marrow and peripheral blood at diagnosis to establish the predictive significance of disease persistence or relapse (MRD) to tailor adoptive immunotherapy strategies post allogeneic bone marrow transplantation; metabolomics profiling in patients with acute leukemia at diagnosis and
during treatment; metabolomics of MGUS and multiple myeloma. Several trials with new drugs (plerixafor,
romiplostim, eltrombopag, clofarabine, treosulfan), are ongoing for leukemias, myelomas and MDS.
Fabio Ciceri
PANCREATIC CANCER UNIT: BIOLOGY AND NEW THERAPEUTIC
APPROACHES
The Unit of Pancreatic Surgery during 2009 performed 162 resections, a surgical volume among the highest
in Europe. These cases are a great source of data and material for every type of research in this field. Pancreatic
ductal adenocarcinoma was the cause of resection in 95 patients. Pancreatic cancer is the fourth leading cause
of cancer mortality in the Western world and it has the worst prognosis among malignancies, with a 5-years survival < 5%. To improve discouraging present results, different new therapeutic strategies are under evaluation
at our unit. We are presently investigating in prospective studies different schemes and modality of perioperative chemotherapy. A randomised study on adjuvant chemotherapy has been completed: comparing standard
Gemcitabine with 4-drugs combination therapy we found a benefit in disease-free survival in favour of the new
combination therapy (1-year disease-free survival 65% versus 46%). In the basic science setting, a study on
pancreatic cancer stem cells (CSC) has been carried on. Putative CSC marker expression has been evaluated by
flow cytometry in cell lines (n=17) and in primary tumor of patients with pancreatic cancer (n=29). Only CXCR4 expression correlated to in vitro chemoresistance (p=0.028) and in vivo clonogenicity (p=0.042). Further,
CXCR4 positivity in primary tumor resulted a risk factor for recurrence (0.028; hazard ratio 1.31- CI 1.03-1.66;
cox regression analysis). No correlation has been noticed with other stem cell markers previously described.
Researches were focused also on pancreatic cancer neurotropism, that is a hallmark of this tumor and represents a major source of local tumor recurrence after surgery. Our study showed that the CX3CR1 receptor may
be involved in perineural growth and is a relevant and independent risk factor to predict an early local tumor
relapse in resected patients. We are presently investigating whether mutations in K-Ras, an early genetic lesion
in pancreatic adenocarcinoma, can play a role in the upregulation of CX3CR1.
Valerio Di Carlo
PATHOLOGY UNIT
Our research areas mainly focus on three major topics: hematopathology, pancreatic neoplasms and urologic
malignancies. Our hematopathology group is actively involved in two major fields. The first regards the link between infectious agents, mainly bacteria, and lymphoproliferative disorders. Following the model of the
etiopathogenetic relationship between gastric MALT lymphoma and Helicobacter pylori infection, we have discovered in collaboration with our Oncology Department and Aviano National Cancer Institute, the link between ocular adnexal lymphomas and Chalmydophila psittaci infection. This observation lead to an important
change in treatment strategies for these lymphomas and international collaboration have been established
both on clinical and pathobiological aspects. The second major field of investigation involves the relationship
between neoplastic cells and microenvironment in hematologic neoplasms, including indolent forms (such as
marginal zone lymphomas, chronic lymphocytic leukemia, follicular lymphomas, plasma cell dyscrasias, chronic myeloproliferative disordes and myelodysplastic syndromes) and aggressive hemopathies (such as high-grade
lymphomas, mantle cell lymphomas and acute leukemias). In this context several line of investigation are currently active and in particular the role of accessory cells –T lymphocytes subclasses, monocyte-macrophages
cells, dendritic and stromal cells-, in these heterogeneous malignancies. The other area of diagnostic and research interest are pancreatic neoplasms, deriving from the exocrine pancreas - the most frequent and lethal
ductal adenocarcinoma- and from the endocrine component. San Raffaele Scientific Institute is a leader hospital in the treatment of pancreatic diseases. Present interest is to establish primary pancreatic adenocarcinoma in
vitro cultures as a tool for research and for drug testing with the aim to develop a methodology able not only to
validate novel candidate drug targets but also to select the best available treatment for every Patient.
Another area of research involvement is in the field of urologic malignancies: active research projects are on
the identification of prognostic and predictive markers in renal cell carcinoma and in prostatic adenocarcinoma.
Claudio Doglioni
CLINICAL LYMPHOID MALIGNANCIES
In 2009 the Unit of Clinical Lymphoid Malignancies has continued the scientific activity with a specific interest in the extranodal lymphomas such as MALT lymphomas and primary and secondary central nervous system
lymphomas.
After studying the pathogenetic role of Chlamydia Psittaci and the effectiveness of eradicating antibiotic therapy with doxycicline in the treatment of ocular adnexal lymphomas (OAL), we have developed a phase II trial
to analyse activity and safety of high dose of Clarithromycin in relapsed or refractory EMZL patients and a
phase II trial about the use of intraocular rituximab in relapsed or refractory patients affected by lymphoma of
the conjunctiva. Furthermore, we are currently interested in studying the connection between the presence of
infection by other bacteria and the development of some forms of lymphomas such as OAL, mantle cell lymphoma and cutaneous lymphomas.
High dose methotrexate (HD-MTX)-based chemotherapy is the conventional first line therapy for primary
CNS lymphomas (PCNSL) and the addiction of HD-AraC to HD-MTX has recently demonstrated to improve
the outcome with acceptable toxicity. We have further developed an international multicentric randomized
phase II trial on PCNSL evaluating HD-MTX and HDAra-C with or without Thiothepa and with or without
Rituximab followed by whole brain radiotherapy (WBRT) vs autologous stem cell transplantation (ASCT).
CNS dissemination is often a lethal event in patients with aggressive lymphomas. In small retrospective series
high-dose chemotherapy supported by ASCT produced encouraging results. We designed a multicentric phase
II trial to evaluate a combination of methotrexate and cytarabine as induction therapy followed by R-HDS as
consolidation and thiotepa-BCNU-based conditioning supported by ASCT in patients with secondary CNS Bcell lymphomas. An interim analysis conducted on the first 13 registered patients has showed 9 (69%) complete
remissions and 3 partial remissions (OR rate 92%) with acceptable toxicity. At a median follow up of 15
months 4 patients experienced relapse/progression, with a 2-yr EFS of 46%; 9 patients are still alive with a 2-yr
OS of 54%.
This intensive approach shows encouraging preliminary results in this lymphoma, which has otherwise dismal
prognosis.
Andrés Jose Maria Ferreri
GYNECOLOGIC ONCOLOGY
In 2009 the gynecologic oncology unit has been involved in endometrial, ovarian and trophoblastic tumour
research in order to improve the quality of clinical activity. We studied biological and clinical prognostic factors
that may help the physician in decision making processes.
Endometrial Cancer.
We studied the role of FDG PET-TC examination in the management of high risk endometrial cancer. We also studied the surgical approach in the elderly patients with endometrial cancer. Finally we evaluated the adjuvant treatment with concomitant radiotherapy and chemotherapy in patients with high risk endometrial cancer.
Ovarian Cancer.
We took part in two clinical international multi-centric protocols: the first study involves the utilization of intraperitoneal (IP) catumaxumab with the primary objective to evaluate the safety of the three hour I.P. infusion
of this drug with or without prednisolone. The second study evaluates the efficacy of pazopanib in the treatment of ovarian cancer. Much effort has been invested in order to preserve fertility in young patients submitted
to gynaecologic surgery: we evaluated the role of the conservative treatment in patients with advanced ovarian
serous borderline tumour.
Trophoblastic tumour.
We introduced the intensive use of transvaginal ultrasound in the managment of trophoblastic tumor. We are
now able to riduce follow up period in patients with a desire of pregnancy.
Giorgia Mangili
MEDICAL ONCOLOGY UNIT - CLINICAL TRIALS
The Unit is involved in clinical trials addressing the role of antineoplastic drugs and strategies in the therapeutic management of pancreatic, central nervous system (CNS), prostate, renal, colorectal, gastric, biliary
tract, and breast cancer. Scientific activity regards also translational research and studies aimed at identifying
new prognostic and predictive biological markers.
Scientific activity on pancreatic cancer included: a) a phase II trial randomizing patients with stage IV disease
to receive maintenance therapy with sunitinib or observation and exploring the role of potential surrogate biomarkers; b) a study to identify a proteomic profile predictive of the outcome of patients with advanced disease;
c) a pharmacogenetic trial to assess the impact on the outcome of the SNPs involved in the metabolism of antiblastic drugs administered in advanced disease; d) a phase II-III trial randomizing patients with resectable disease to receive neoadjuvant or adjuvant chemotherapy.
In the topic of CNS tumors, ongoing trials are aimed at: a) identifying a proteomic profile able to predict the
outcome of newly diagnosed glioblastoma (GBM) treated with standard chemo-radiation (RT); b) assessing the
role of temozolomide (TMZ) associated to RT in newly diagnosed GBM in elderly patients; c) assessing the role
of TMZ concurrent to RT and adjuvant in non-1p/19q deleted anaplastic glioma; e) analyzing the role of primary chemotherapy with TMZ versus RT after stratification for 1p loss in low grade glioma; f) exploring the
role of salvage therapy with TMZ in pituitary neoplasms; g) exploring the role of salvage therapy with hydroxyurea alone or in combination with imatinib in meningiomas; h) investigating activity and safety of adjuvant
fotemustine and concomitant RT in anaplastic astrocytoma.
Research activity in gastric cancer is focusing on: a) feasibility of a new first-line chemotherapy combination
in metastatic disease; b) the role of laparoscopic hyperthermic intraperitoneal chemotherapy in advanced disease; c) clinical and pathological correlations of tumor regression grade and erb-B2 expression in resected disease after neoadjuvant chemotherapy; d) prognostic role of the expression of cyclooxigenase-2, Angiopoeitin2,
VEGF in resected gastric cancer.
Michele Reni
MEDICAL ONCOLOGY UNIT - PHASE I AND LUNG CANCER CLINICAL
TRIALS
The research activity of lung cancer group is divided into two main areas: pathogenesis of NSCLC and phase
I/II studies.
In the first area, we are focusing on improving knowledge on molecular mechanisms of new and standard
therapies, specific toxicities and pathways of drug resistance for defining personalized therapies. We developed
and validated a proteomic algorithm, VeriStratTM, Biodesix Inc., that classifies NSCLC patients according to
their outcome after EGFR-TKIs therapy in a good or a poor label. This algorithm may select those patients who
do not benefit from EGFR TKIs suggesting that the molecular species generating VeriStratTM classifier may
identify a primary resistance mechanism. In our study, four out of the 8 peaks composing VeriStratTM resulted
to be the secreted form of Serum Amyloid A1 (SAA1) and its truncated forms. Moreover, in the poor classified
patients different inflammatory proteins resulted up-regulated: SAA2, SAA4, haptoglobin, α1-antitrypsin and
α1-antichimotrypsin, suggesting that inflammation may play a role in the EGFR-TKIs resistance. It is not still
clear if SAA has a direct role in cancer pathogenesis and progression. SAA interacts with extracellular matrix
adhesion molecules and it induces the activation of metalloproteinase, that release of tyrosine kinase family ligands (EGF, IGF, VEGF) and this mechanism may bypass EGFR pathway or it may be involved in metastatic
development.
Our experience with regards to Phase I studies started in 2003, with a new anti-vascular targeting agent
(VTA), NGR-h-TNF which has been discovered and fully characterized at the San Raffaele Scientific Institute
(Dr. A. Corti, Division of Molecular Oncology) and then tested in clinical trials at Department of Oncology.
Since then four phase I/Ib studies have been conducted as single agent and in combination with chemotherapy.
In 2009, one phase Ib study in combination with cisplatin and three phase II studies with NGR-hTNF single
agent have been finished, one in hepatocellular carcinoma (HCC), one in colorectal carcinoma (CRC) and one
in malignant pleural mesothelioma (MPM). NGR-hTNF have shown a good toxicity profile, with evidence of
transient grade 1-2 constitutional symptoms (especially chills) during infusion. Promising results on antitumor
activity were observed in three phase II studies. A phase III study in mesothelioma started very recently and it is
currently ongoing.
Vanesa Gregorc
UROLOGICAL RESEARCH INSTITUTE (URI)
The Department of Urology, Vita-Salute San Raffaele, Milan, headed by Professor Patrizio Rigatti, represents
one of the most important international institutions for the diagnosis and the treatment of urological malignancies. The Department takes account weekly of 25 operating rooms, serving 110 beds for ordinary recovery.
Every year, about 1000, 500 and 250 surgeries are performed for prostate, bladder and kidney cancer, respectively.
The clinical investigations performed in the last years leaded to the publication of 623 scientific contributions
for a overall citation index of 6872 with a significant boost in the last three years (citation index last three years:
3113; h-index 40) [Source SCOPUS April 2010]. Every year, the Department substantially contributes with a
significant number of accepted abstracts to the most important international and national meetings. The main
clinical research areas consist of prostate cancer, kidney cancer, bladder cancer, infertility and andrology, female
sexual medicine, benign prostatic hyperplasia.
Ongoing and new translational researches has been starting after the birth of the Urological Research Institute (URI), headed by Professor Petter Hedlund. The main basic research areas consist of prostate and bladder
cancer, functional urology, reproductive and erectile dysfunction.
Francesco Montorsi
9 Arcidiacono, PG; Calori, G; Carrara, S; McNicol, ED; Testoni, PA. Celiac plexus block for pancreatic cancer pain in adults. Cochrane Database Syst Rev.: 2009; -1: CD007519 – Review.
IF 2008: 5,182
9 Breda, A; Finelli, A; Janetschek, G; Porpiglia, F; Montorsi, F.Complications of Laparoscopic Surgery for Renal
Masses: Prevention, Management, and Comparison with the Open Experience. Eur. Urol.: 2009; 55(4): 836850 – Review.
IF 2008: 6,512
9 Burger, JA; Ghia, P; Rosenwald, A; Caligaris-Cappio, F. The microenvironment in mature B-cell malignancies: A target for new treatment strategies. Blood: 2009; 114(16): 3367-3375 – Review.
IF 2008: 10,432
9 Capitanio, U; Karakiewicz, PI; Jeldres, C; Briganti, A; Salonia, A; Cestari, A; Guazzoni, G; Rigatti, P; Montorsi, F. Suspected Clinical T3 Prostate Cancer Is Associated with a High Rate of Negative Extended Biopsies:
Clinical Implications. Eur. Urol.: 2009; 55(1): 253-254 – Letter.
IF 2008: 6,512
9 Chen, H; Ko, G; Zatti, A; Di Giacomo, G; Liu, L; Raiteri, E; Perucco, E; Collesi, C; Min, W; Zeiss, C; De
Camilli, P; Cremona, O. Embryonic arrest at midgestation and disruption of Notch signaling produced by the
absence of both epsin 1 and epsin 2 in mice. Proc. Natl. Acad. Sci. U. S. A.: 2009; 106(33): 13838-13843 – Article.
IF 2008: 9,380
9 Ciceri, F; Bonini, C; Lupo Stanghellini, MT; Bondanza, A; Traversari, C; Salomoni, M; Turchetto, L; Colombi, S; Bernardi, M; Peccatori, J; Pescarollo, A; Servida, P; Magnani, Z; Perna, SK; Valtolina, V; Crippa, F;
Callegaro, L; Spoldi, E; Crocchiolo, R; Fleischhauer, K; Ponzoni, M; Vago, L; Santoro, A; Todisco, E; Apperley, J; Olavarria, E; Slavin, S; Weissinger, EM; Hertenstein, B; Stadler, M; Yannaki, E; Fassas, A; Anagnostopoulos, A; Bregni, M; Gallo Stampino, C; Bruzzi, P; Bordignon, C. Early and effective immunorecovery
after family haploidentical hemopoietic transplantation for leukemia by gene-engineered lymphocytes: the
TK007 study. Lancet Oncol.: 2009; 10(5): 489-500 – Article.
IF 2008: 13,283
9 Dagklis, A; Fazi, C; Sala, C; Cantarelli, V; Scielzo, C; Massacane, R; Toniolo, D; Caligaris-Cappio, F; Stamatopoulos, K; Ghia, P. The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring. Blood:
2009; 114(1): 26-32 – Article.
IF 2008: 10,432
9 Fanti, L; Agostoni, M; Gemma, M; Gambino, G; Facciorusso, A; Guslandi, M; Torri, G; Testoni, PA.
Remifentanil vs. meperidine for patient-controlled analgesia during colonoscopy: A randomized double-blind
trial. Am. J. Gastroenterol.: 2009; 104(5): 1119-1124 – Article.
IF 2008: 6,444
9 Ferreri, AJ; Reni, M; Foppoli, M; Martelli, M; Pangalis, GA; Frezzato, M; Cabras, MG; Fabbri, A; Corazzelli, G; Ilariucci, F; Rossi, G; Soffietti, R; Stelitano, C; Vallisa, D; Zaja, F; Zoppegno, L; Aondio, GM; Avvisati,
G; Balzarotti, M; Brandes, AA; Fajardo, J; Gomez, H; Guarini, A; Pinotti, G; Rigacci, L; Uhlmann, C; Picozzi, P; Vezzulli, P; Ponzoni, M; Zucca, E; Caligaris-Cappio, F; Cavalli, F. High-dose cytarabine plus highdose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised
phase 2 trial. Lancet: 2009; 374(9700): 1512-1520 – Article.
IF 2008: 28,409
9 Gregorc, V; Santoro, A; Bennicelli, E; Punt, CJA; Citterio, G; Timmer-Bonte, JNH; Caligaris-Cappio, F;
Lambiase, A; Bordignon, C; Van Herpen, CML. Phase Ib study of NGR-hTNF, a selective vascular targeting
agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours. Br.
J. Cancer: 2009; 101(2): 219-224 – Article.
IF 2008: 4,846
9 Miluzio, A; Beugnet, A; Volta, V; Biffo, S. Eukaryotic initiation factor 6 mediates a continuum between 60S ribosome biogenesis and translation. EMBO Rep.: 2009; 10(5): 459-465 – Review.
IF 2008: 7,099
9 Ponzoni, M; Dolcetti, R; Doglioni, C; Ferreri, AJM. Bugs and marginal zone lymphoma of the ocular adnexae:
Is the future already here? Blood: 2009; 114(16): 3499 – Letter.
IF 2008: 10,432
9 Reni, M; Cereda, S; Balzano, G; Passoni, P; Rognone, A; Zerbi, A; Nicoletti, R; Mazza, E; Arcidiacono, PG;
Di Carlo, V; Villa, E. Outcome of upfront combination chemotherapy followed by chemoradiation for locally
advanced pancreatic adenocarcinoma. Cancer Chemother. Pharmacol.: 2009; 64(6): 1253-1259 – Article.
IF 2008: 2,740
9 Vago, L; Perna, SK; Zanussi, M; Mazzi, B; Barlassina, C; Stanghellini, MTL; Perrelli, NF; Cosentino, C; Torri, F; Angius, A; Forno, B; Casucci, M; Bernardi, M; Peccatori, J; Corti, C; Bondanza, A; Ferrari, M; Rossini,
S; Roncarolo, MG; Bordignon, C; Bonini, C; Ciceri, F; Fleischhauer, K. Loss of mismatched HLA in
leukemia after stem-cell transplantation. N. Engl. J. Med.: 2009; 361(5): 478-488 – Article.
IF 2008: 50,017
9 Villablanca, EJ; Raccosta, L; Zhou, D; Fontana, R; Maggioni, D; Negro, A; Sanvito, F; Ponzoni, M; Valentinis, B; Bregni, M; Prinetti, A; Steffensen, KR; Sonnino, S; Gustafsson, JA; Doglioni, C; Bordignon, C; Traversari, C; Russo, V. Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat. Med.: 2010; 16(1): 98-105 – Article.
IF 2008: 27,553
Immuno-biotherapy of melanoma and solid tumors Unit
Pancreatic cancer Unit: biology and new therapeutic approaches
DIVISION OF NEUROSCIENCE - 27
DIVISION OF NEUROSCIENCE
Director: Gianvito Martino
Associate Director: Flavia Valtorta *
Research Units
HEAD OF UNIT: Flavia Valtorta*
POST-DOCTORAL FELLOW: Francesca Botti
PHD STUDENTS: Serena Bellani**, Eugenio Fornasiero**
FELLOW: Fabrizia Guarnieri
TECHNICIAN: Elena Monzani
Cell adhesion Unit
HEAD OF UNIT: Ivan De Curtis*
POST-DOCTORAL FELLOW: Roberta Pennucci
PHD STUDENTS: Claudia Asperti**, Antonio Totaro**
FELLOWS: Veronica Astro, Luisa Micheletti
TECHNICIANS: Sara Corbetta, Diletta Tonoli
HEAD OF UNIT: Jacopo Meldolesi*
RESEARCHER: Paola Podini
PHD STUDENT: Ilaria Prada**
FELLOWS: Rosalba D’Alessandro, Joanna Mikulak, Sara Negrini
TECHNICIANS: Anna Lorusso, Gabriella Racchetti
HEAD OF UNIT: Fabio Grohovaz*
RESEARCHER: Daniele Zacchetti
PHD STUDENTS: Barbara Bettegazzi**, Romina Macco**, Ilaria Pelizzoni**
FELLOW: Alessandra Consonni**
TECHNICIAN: Franca Codazzi
Developmental neurogenetics Unit
HEAD OF UNIT: Gian Giacomo Consalez
PHD STUDENTS: Ilaria Albieri**, Valeria Barili**
FELLOWS: Sara Dentali, Luca Massimino, Rosina Paterra
TECHNICIANS: Aurora Badaloni, Laura Croci
Neurobiology of learning Unit
HEAD OF UNIT: Antonio Malgaroli*
RESEARCHER: Vincenzo Zimarino
PHD STUDENTS: Marcello Belfiore **, Mattia Ferro, Maddalena Ripamonti
Proteomics of iron metabolism Unit
HEAD OF UNIT: Sonia Levi*
RESEARCHERS: Anna Cozzi, Paolo Santambrogio
PHD STUDENT: Alessandro Campanella**
FELLOW: Elisabetta Rovelli
Molecular genetics of mental retardation Unit (Dulbecco Telethon Institute)
GROUP LEADER: Patrizia D’Adamo
POST-DOCTORAL FELLOW: Maila Giannandrea
PHD STUDENT: Veronica Bianchi
FELLOWS: Maria Lidia Mignogna, Elena Carlotta Vismara
Neural degeneration Unit (Dulbecco Telethon Institute)
GROUP LEADER: Manolis Fanto
PHD STUDENTS: Piera Calamita**, Ilaria Nisoli**, Simona Occhi
FELLOW: Francesco Napoletano
GROUP LEADER: Vania Broccoli
PHD STUDENTS: Gaia Colasante**, Serena Giannelli**, Sara Ricciardi**, Alessandro Sessa**
FELLOWS: Giorgia Colciago, Bruno Di Stefano, Sara Lopalco, Federica Ungaro
Acute brain protection, Acute post-operative pain, Drugs and central nervous system Unit
HEAD OF UNIT: Luigi Beretta*
PHYSICIANS: Massimo Agostoni, Maria Rosa Calvi, Assunta De Vitis, Marco Gemma, Davide Poli
Eye repair Unit
HEAD OF UNIT: Paolo Rama
CONSULTANTS: Federica Ferrario, Chiara Insacco, Stanislav Matuska, Giorgio Paganoni, Maurizia Viganò
HEAD OF UNIT: Stefano F. Cappa*
RESEARCHERS: Jubin Abutalebi*, Nicola Canessa, Andrea Moro*
PHYSICIANS: Maria Cristina Giusti, Sandro Iannaccone, Marco Lacerenza, Alessandra Marcone, Michele Zamboni
POST-DOCTORAL FELLOW: Pasquale Della Rosa,
PHD STUDENTS: Federica Alemanno**, Eleonora Catricalà, Rosa Manenti**
Experimental neurosurgery Unit
HEAD OF UNIT: Pietro Mortini*
PHYSICIANS: Stefania Acerno, Lina Raffaella Barzaghi, Nicola Boari, Camillo Ferrari da Passano, Alberto Franzin, Lorenzo Gioia,
Marco Losa, Carlo Mandelli, Piero Picozzi, Micol Valle
PHD STUDENT: Silvia Snider**
RESIDENTS: Paola Castellazzi, Elena Colombo, Angelica Dipinto, Filippo Gagliardi, Lucio Aniello Mazzeo, Marzia Medone,
Davide Milani, Alda Rocca, Carlo Serra
Functional neuroradiology Unit
HEAD OF UNIT: Andrea Falini*
PHYSICIANS: Nicoletta Anzalone, Cristina Baldoli, Valeria Blasi, Silvia Pontesilli, Roberta Scotti, Paolo Vezzulli
PHD STUDENT: Monia Cabinio**
RESIDENTS: Antonella Castellano, Elisa Scola
TECHNICIAN: Antonella Iadanza**
In vivo Human molecular and structural neuroimaging Unit
HEAD OF UNIT: Daniela Perani*
RESEARCHER: Marco Tettamanti
PHD STUDENT: Monica Consonni**
POST-DOCTORAL FELLOW: Cristina Saccuman
FELLOWS: Elena Maria Andreolli, Danilo Spada
Neuroothology Unit
PHYSICIAN: Lucia Oriella Piccioni
CONSULTANTS: Fabrizio Ferrario, Annalisa Meli, Roberto Teggi
Psychiatry and clinical neurosciences Unit
HEAD OF UNIT: Francesco Benedetti
Psychiatry and clinical psychobiology
HEAD OF UNIT: Francesco Benedetti
PHYSICIANS: Ilaria Aina, Sara Angelone, Cinzia Arancio, Barbara Barbini, Laura Bellodi*, Alessandro Bernasconi,
Laura Bianchi, Marta Bosia, Stefania Cammino, Marco Catalano, Roberto Cavallaro, Maria Cristina Cavallini,
Mara Cigala Fulgosi, Federica Cocchi, Cristina Colombo, Michele Cucchi, Sara Dallaspezia, Stefano Erzegovesi,
Linda Franchini, Marta Henin, Laura Liperi, Marco Locatelli, Adelio Lucca, Fausto Panigada, Ernestina Politi,
Adriana Pontiggia, Laura Sforzini, Enrico Smeraldi*, Raffaella Zanardi
PHD STUDENTS: Elisa Galimberti, Sara Poletti
POST DOCTORAL FELLOWS: Francesco Fresi, Daniele Radaelli.
FELLOWS: Margherita Bechi, Vittoria Bottelli, Paola Canali, Ursula Catenazzi, Daniele Cavadini, Emma Fadda, Marcello
Florita, Chiara Gavinelli, Stefania Ozino, Giulia Paredi, Adele Pirovano, Roberta Riccaboni, Tomaso Siccardi
RESIDENTS: Giampiero Bottero, Dario Del Monte, Clara Locatelli, Alessia Malaguti, Chiara Ruffini, Irene Vanelli
TECHNICIAN: Cristina Lorenzi
Sleep medicine
CLINICAL GROUP LEADER: Luigi Ferini-Strambi*
RESEARCHERS: Vincenza Castronovo, Mauro Manconi, Alessandro Oldani, Marco Zucconi
PHD STUDENT: Sara Marelli
TECHNICIANS: Massimo Antonio, Daniele Bizzozero, Elisa Dallabà, Cristina Martinelli
Clinical psychology
CLINICAL GROUP LEADER: Cesare Maffei*
RESEARCHERS: Marco Battaglia*, Andrea Fossati*, Mariagrazia Movalli, Anna Ogliari*, Laura Vanzulli, Raffaele Visintini
RESIDENTS: Roberta Alesiani, Silvia Boccalon, Naima Coppolino, Maria Chiara Fiorin§, Gianluca Franciosi, Laura
Giarolli, Valeria Parlatini, Paola Pesenti-Gritti§, Chiara Spatola§, Martina Testa.
§EXTERNAL RESIDENTS
Motor function rehabilitation
CLINICAL GROUP LEADER: Roberto Gatti
PHYSICAL THERAPIST: Andrea Tettamanti
INSPE, Institute of Experimental Neurology
Director: Giancarlo Comi*
Research Units
Experimental neurology Unit
HEAD OF UNIT: Giancarlo Comi*
Experimental neuropathology
GROUP LEADER: Angelo Quattrini
PHD STUDENTS: Federica Cerri, Nilo Riva**
TECHNICIAN: Giorgia Dina
Experimental neurophysiology
GROUP LEADER: Letizia Leocani
BIOENGINEER: Marco Cursi
PHD STUDENTS: Ninfa Amato**, Marco Cambiaghi**, Alberto Inuggi, Sinem Kara, Svetla Velikova
FELLOW: Javier Gonzalez-Rosa
RESIDENTS: Mariangela Bianco, Raffaella Chieffo, Francesca Spagnolo, Laura Straffi
TECHNICIAN: Samantha Guzzoni
Molecular genetics of behaviour
GROUP LEADER: Riccardo Brambilla*
PHD STUDENTS: Raffaele D'Isa**, Daniel Orellana**, Alessandro Papale**
FELLOW: Stefania Fasano
TECHNICIAN: Marzia Indrigo
Neuromuscular repair
GROUP LEADER: Stefano Carlo Previtali
POST-DOCTORAL FELLOW: Domi Teuta
PHD STUDENT: Emanuela Porrello**
RESIDENT: Ignazio Diego Lopez
TECHNICIAN: Isabella Lorenzetti
Neuroimmunology Unit
HEAD OF UNIT: Gianvito Martino
RESEARCHER: Luca Muzio
POST-DOCTORAL FELLOW: Erica Butti
PHD STUDENTS: Cecilia Laterza**, Cinzia Marinaro**, Annamaria Nigro**
TECHNICIANS: Andrea Bergamaschi, Elena Brambilla
GROUP LEADER: Roberto Furlan
PHD STUDENTS: Giuseppe De Santis, Livia Garzetti, Chiara Maiorino
RESIDENT: Dacia Dallalibera
TECHNICIANS: Alessandra Bergami
CNS repair
GROUP LEADER: Stefano Pluchino
PHD STUDENTS: Chiara Cossetti, Melania Cusimano, Elena Giusto, Lucia Zanotti
RESIDENTS: Marco Bacigaluppi, Luca Peruzzotti Jametti
TECHNICIAN: Giuliana Salani
Neuroimaging research Unit
HEAD OF UNIT: Massimo Filippi
BIOENGINEERS: Elisabetta Pagani, Paola Valsasina
RESIDENTS: Martina Absinta, Sebastiano Galantucci
FELLOWS: Federica Agosta**, Elisa Canu**, Giulia Longoni**, Michela Pievani**, Paolo Preziosa**, Stefania Sala**, Lidia Sarro**
TECHNICIANS: Luca Dall’Occhio, Alessandro Meani, Melissa Petrolini, Ilaria Taffi, Roberto Vuotto
Neuroimaging of CNS white matter
GROUP LEADER: Maria Assunta Rocca
PHD STUDENT: Gianna Riccitelli**
TECHNICIANS: Paolo Misci, Mauro Sibilia
Human inherited neuropathies Unit (Dulbecco Telethon Institute)
HEAD OF UNIT: Alessandra Bolino
PHD STUDENTS: Annalisa Bolis, Silvia Coviello, Ilaria Vaccari
FELLOWS: Patrizia Cassella, Enrico Fragasso, Lara Piantoni
Axo-Glia interactions Unit (FISM)
GROUP LEADER: Carla Taveggia
POST-DOCTORAL FELLOW: Amelia Trimarco
TECHNICIAN: Rosa La Marca
Inflammatory CNS disorders Unit
HEAD OF UNIT: Vittorio Martinelli
RESEARCHERS: Filippo Martinelli-Boneschi, Lucia Moiola, Mariaemma Rodegher
PHYSICIAN: Paolo Rossi
PHD STUDENTS: Federica Esposito**, Marta Radaelli**
RESIDENTS: Elda Judica, Elisabetta Stefania Perego
Cerebrovascular disorders
CLINICAL GROUP LEADER: Maria Sessa
RESEARCHER: Francesco Corea
PHYSICIANS: Silvia Mammi, Antonella Poggi, Luisa Roveri
PHD STUDENT: Grazia Nuzzaco**, Maria Carmela Spinelli**
RESIDENTS: Chiara Ghidinelli, Sara La Gioia
Memory disorders
CLINICAL GROUP LEADER: Giuseppe Magnani
RESIDENTS: Francesca Caso, Elisabetta Coppi, Chiara Vismara
Movements disorders
CLINICAL GROUP LEADER: Ubaldo Del Carro
PHYSICIANS: Stefano Amadio, Roberta Guerriero, Stefania Medaglini, Maria Grazia Natali Sora, Maria Antonietta Volontè
RESIDENTS: Calogera Butera, Luisa De Toni Franceschini, Habtom Tesfaghebriel, Daniela Ungaro
Neuromuscular disorders
CLINICAL GROUP LEADER: Raffaella Fazio
PHYSICIANS: Fabio Formaglio, Patrizia Dacci
PHD STUDENT: Daniela Privitera**
Paroxysmal events
CLINICAL GROUP LEADER: Fabio Minicucci
PHYSICIANS: Bruno Colombo, Giovanna Franca Fanelli, Fabio Formaglio, Paolo Marchettini
RESIDENTS: Maria Grazia Deriu, Giulia Pavan
The brain is by far the most complex organ in our body, and, in addition, it
is one of the least accessible. These two facts, together with the fact that neurons are post-mitotic cells and therefore cannot be expanded in vitro, have
hampered neuroscience research, which for a long time has been lagging behind research in other fields.
The mission of the Division of Neuroscience is to be able to integrate morphological with functional and biochemical aspects of the nervous system in
Gianvito Martino
healthy and pathological conditions, from the molecular to the clinical level.
This integration, which requires a strong basic research, will also have important consequences for translational research, allowing the development of new therapies and new diagnostic markers. Integration among morphology, function and neurochemistry – in both healthy and
diseased nervous system – will be first of all pursued in the following prioritized research areas:
1. evaluation of the physiological maturation and aging processes of the CNS and the assessment of the
different pathological substrates (inflammation vs. degeneration) of the main neurological and psychiatric diseases;
2. combination of powerful new stem cell isolation and gene transfer approaches to state-of-the-art neuroimaging, immunological and neurophysiological readouts to test new therapeutic strategies in relevant animal model of neurodegenerative diseases;
3. understanding how a functional nervous system is generated during development to better understand the basis of neurological and psychiatric
pathologies linked to developmental defects (e.g. mental retardation,
schizophrenia, and bipolar disorders);
4. investigation of cellular and molecular mechanisms sustaining neurodeFlavia Valtorta
generation to identify new therapeutic targets to be translated into new
neuroprotective therapies.
An important role in bridging the gap between advancements in our understanding of the mechanisms
of brain functioning and our understanding of the pathogenesis of human neurological disorders (and the
development of novel therapeutic strategies) will be played by the development of animal models which
are amenable to studies ranging from the molecular to the neurophysiological and behavioural level.
This will be coupled with efforts finalized at integrating neurophysiological and neuroimaging tools at
both the micro- and macro-scopic levels, developing novel therapeutic tools, and performing phase I and
phase II trials.
The vision of the Division of Neuroscience is to achieve, within three-five years the followings aims:
1. to accomplish the cultural integration between basic and clinical research in the above-mentioned
neuroscience areas;
2. to continue to support a gold standard educational program for graduate students in the field of neuroscience and experimental neurology;
3. to consolidate the current research areas of scientific excellence such as nervous system regeneration,
brain imaging, cognitive neuroscience, cell biology of the neuron and glial cells, and neuroinflammation;
4. to build a competitive research in the fields of neurodegeneration and of developmental neurobiology;
5. to develop strong pre-clinical research in psychiatric and behavioural disorders.
To reach the ambitious aims we are proposing we plan to systematically assess the progress of existing
staff and the achievement of the proposed milestones. Furthermore, we plan to recruit excellent investigators in selected key fields and the continuous implementation of technological platforms and facilities.
Research Units
NEUROPSYCHOPHARMACOLOGY UNIT
Comprehensive goal of our research is the elucidation of the molecular mechanisms which underlie communication between cells of the brain, both in the adult and during development. The main form of communication between neurons is achieved through regulated secretion of neurotransmitter occurring at synapses. This
process is therefore of paramount importance for information processing in the central nervous system and is
known to be deranged in a number of pathological states.
In the past year research in our group has focused on two main topics:
Diseases of synaptic origin.
1) Synapsins are a family of brain phosphoproteins involved in neurotransmitter release through regulation of
synaptic vesicle availability. Synapsin KO mice develop an epileptic phenotype, and a mutation in the human
synapsin I gene has been recently associated with epilepsy. We have found that mutant synapsin I is subject to
nonsense-mediated mRNA decay (NMD). However, the protein which escapes NMD exhibits neurotoxic
properties.
2) α-synuclein is a cytosolic protein highly abundant in the brain whose overexpression or mutation participate in the pathogenesis of Parkinson’s disease. We have found that wild type and A30P mutated synuclein profoundly affect actin cytoskeleton dynamics in a differential manner. Since the actin cytoskeleton regulates several aspects of synaptic function, its disorganization may be responsible for the synaptic pathology which is an
early hallmark of neurodegeneration.
Membrane trafficking in neuronal development.
The establishment of a polarized cellular organization is required from the earliest steps of neuronal growth
to achieve proper differentiation. We have found that a number of dynamic membrane paths including directional traffic, high-capacity exocytosis and endocytosis are polarized already in morphologically undifferentiated neurons and their presence correlates with the emergence of the axon. Our data suggest that these membrane paths might regulate a set of adhesion molecules required for the polarized migration of neurons.
Flavia Valtorta
CELL ADHESION UNIT
Molecular mechanisms for the regulation of cell migration, invasion, and neuronal development
Rho GTPases are implicated in cell motility and neuronal differentiation. We have shown that two Rac
genes are needed for neuronal and mammalian brain development. The analysis of the 3 lines of mice with
mutation in the Rac3 gene (Rac3KO), conditional mutation of Rac1 in neurons (Rac1N), or mutation of both
GTPases (Rac3KO/Rac1N) has shown that while single mutant mice develop normally, double KO mice are
heavily impaired neurologically. Recent analysis of these mice has revealed alterations also in the interneuronal network, with strong decrease in the number of specific populations of cortical and hippocampal
GABAergic cells, important for normal brain function. This defect may contribute to the epileptic phenotype
observed in double KO mice, and supports the requirement of two Rac genes for neuronal development in
mammals.
The multi-molecular GIT complexes are involved in the regulation of cell migration. These complexes are assembled by the multi-domain GIT1 or GIT2 proteins, which interact functionally with Arf and Rac GTPases.
We have analyzed the function of the GIT/PIX complexes in the early neuronal development. We observed a
specific inhibition of neuritogenesis by depletion by RNA interference of either GIT2 or αPIX, while silencing
of GIT1 or βPIX, respectively, did not induce an appreciable effect.
Liprin-α1 belongs to a family of adaptor proteins involved in the assembly of neuronal synapses and in the or-
ganization of focal adhesions. We found that Liprin-α1 positively regulates motility, while its downregulation
prevents spreading and formation of lamellipodia. Further analysis has shown the requirement of Liprin-α1 for
the invasive behavior of breast cancer cells, and the high expression of this protein in human tumors. Interestingly, liprin-α1 affects the behavior of invasive cells not only by regulating their motility, but also by affecting
the degradation of the extracellular matrix associated to invadopodia. The comprehensive molecular/cellular
analysis performed by us is establishing Liprin-α as an essential regulator of migration and invasion, and as a
novel candidate marker of tumor progression.
Ivan De Curtis
CELLULAR AND MOLECULAR NEUROBIOLOGY UNIT
Role of REST in the physiology and pathology of nerve cells
The interest of the Unit is focussed on the transcription factor REST and on its role in the functional cell
biology of nerve cells. In previous studies we had demonstrated that REST governs the expression of neurosecretion since many genes coding for the proteins of the secretory vesicles and of their exocytosis are repressed as long as REST is high, a condition typical of non-nerve cells, and are expressed only when REST
drops, as it occurs during nerve cell maturation. In the last year we have shown that, in addition, high REST
governs positively the expression of another type of exocytic vesicle that we discovered years ago, the enlargesome, and that exocytosis of this vesicle sustains a new form of growth of neurites that occurs not only
in neurosecretory cell lines, but also in neurons of the embryonal brain and in primary neuronal cultures
shortly after their seeding. This result demonstrates that the membrane traffic processes that sustain neurite
outgrowth are at least two, one (occurring at an early phase) sustained by the exocytosis of enlargesomes, the
other (predominant later on) by the exocytosis of vesicles rich in VAMP7, as reported previously by others.
The second line of research concerns the role of REST in the transformation of nerve cell tumors, in particular medullo and neuroblastomas. Here we have discovered that high REST induces a decrease of another important factor, TSC2. Interestingly, low TSC2 induces the increase of β-catenin and of its transcription (with
TCF) of several genes, including REST. Therefore, the three factors are strictly linked to each other and their
interaction seems to govern the transformation. Finally we have tackled the problem of astrocytes, a type of
non-excitable cells that appear to be competent for neurosecretion. We have found that in those cells the levels of REST are variable, from low as in neurons to high as in non-nerve cells. Only the low REST astrocytes
appear to be neurosecretory, as suggested also by the appearance of specific neurosecretory vesicles in cultured astrocytes transfected with a dominant negative construct of the repressor. These results explain mechanistically a problem that has been intensely investigated and discussed in the astrocyte field during the last
15 years.
Jacopo Meldolesi
CELLULAR NEUROPHYSIOLOGY UNIT
Physiopathological mechanisms in neuroprotection and neurodegeneration
The research of our unit is aimed to understand the molecular mechanisms of neurodegeneration and neuroprotection. We mainly focused on Alzheimer’s disease, the most frequent form of dementia, and on iron-mediated oxidative stress, a harmful condition observed during aging and shared by several diseases of the central
nervous system, including stroke and Parkinson.
Regarding Alzheimer’s disease, we investigated BACE1, the β-secretase responsible for the production of the
neurotoxic amyloid-β peptides that accumulate in the brain of the patients. In particular, we studied how
BACE1 expression is controlled in neurons and astrocytes, with special attention to the translational mechanisms. A parallel project on the effects of amyloid-β revealed that fibrillar amyloid targets microglial cells and
that activation of these cells triggers the release of various molecules that might harm neurons. For this reason,
we performed a characterization of the molecular mechanisms of glia activation by investigating: different pro-
tocols of stimulation leading to specific phenotypes; the underlying intracellular pathways; the upregulation of
proteins and the release of molecules in the extracellular milieu.
As for iron-mediated oxidative stress, we studied the pathways of Fe2+ entry in neurons and the consequences of iron accumulation in terms of ROS accumulation, Ca2+ changes and cell death. We demonstrate
that Fe2+ can enter neurons through both Voltage Operated Calcium Channels and, during strong synaptic activity, NMDA receptors. Our results show that neuronal death is due to iron-mediated ROS production and
point to mitochondria as the main target of iron toxicity. In a related project we are also studying the effects
mutations in the ferritin light chain (inherited in the hereditary neuroferritinopathy disease) have in iron control and overall neuronal survival (in collaboration with the Proteomics of iron metabolism Unit).
Fabio Grohovaz
DEVELOPMENTAL NEUROGENETICS UNIT
The cerebellum as a model for the study of neurogenesis and CNS regeneration
The cerebellum as a model for the study of neurogenesis and CNS regeneration. The cerebellum is a highly
plastic system. Recent observations show that exogenous Purkinje cells (PCs) integrate productively and establish proper synaptic connections with their afferents and post-synaptic targets, when grafted to a host cerebellum. Several neurodegenerative cerebellar ataxias feature a selective, cell-autonomous loss of PCs, warranting
the development of experimental cell replacement strategies in model organisms. Our laboratory, in collaboration with F. Rossi’s lab (U. of Turin) is setting up protocols for Purkinje cell transplantation in wild type mice
and murine models of neurodegenerative ataxias (SCA2). In parallel, we are continuing our analysis of regulatory pathways involed in normal cerebellar development.
Factors controlling early stages of cerebellar neurogenesis. The neurogenetic cascades controlling PC development are still poorly understood, partially hampering the design of rational protocols for cell replacement.
Through the analysis of mutant mouse lines featuring genetic defects in cerebellar development, our group is
contributing to the analysis of pathways regulating early and late stages of cerebellar neurogenesis. A study just
completed has revealed that one gene, Zfp423, whose mutation causes a severe cerebellar malformation, works
at the intersection of Notch and BMP signaling pathways, regulating their interaction in neural cells (Masserdotti, Badaloni et al., in revision). In a parallel study, taking advantage of a knock-in line generated in our lab,
we are applying genetic inducible fate mapping to characterize the eventual fate of progenitors positive for neurogenin 2 (Neurog2), a proneural gene expressed in the cerebellar ventricular zone during developmental neurogenesis. These studies have revealed that Neurog2+ progenitors give rise to a specific subset of cerebellar
GABA neurons (Leto et al., in preparation). Further functional studies will clarify the specific role of this transcription factor in cerebellar neurogenesis. These studies will permit the isolation of a highly enriched population of committed PC progenitors for use in experimental cell replacement.
➥
Figure 2. Progenitors tagged during early embryogenesis by a
genetic inducible fate mapping approach develop into mature
Purkinje neurons in the adult cerebellar cortex.
Factors controlling PC survival in development. Insulin-like growth factor 1 (IGF1) is an anabolic factor
playing important roles in the context of neuronal development, physiology, survival and degeneration. Mice
carrying a null mutation in the Ebf2 gene, encoding an helix-loop-helix transcription factor important for cerebellar development (Croci et al., 2006; Chung et al., 2008; Chung et al., 2009), lose IGF1 expression in PCs at
birth. We have characterized the regulation of local IGF1 transcription and its role in antagonizing PC apoptosis, regulating their metabolism and signal transduction (Croci et al., accepted). At birth, PCs initiate a series of
major changes in their morphology, connectivity and function, sharply upregulating their protein synthesis activity. The acute requirement for locally produced IGF1 by PCs in the transition between pre- and postnatal life
warrants further studies of this factor’s specific role(s) in the regulation of PC homeostasis and survival.
Gian Giacomo Consalez
NEUROBIOLOGY OF LEARNING UNIT
A novel family of indicators to monitor synaptic activity in vivo
Every human behavior depends on an activity change in one or more brain areas, often with the contribution
of very small subgroups of cells and synapses. Conversely, when a brain disease modifies a behavioral aspect, inevitably this effect arises from a change in neural activity. Hence, viewing the fine structure of the brain by the
most advanced imaging techniques is certainly important but it would be more important to find some effective
way to detect changes in neuronal and synaptic activity during both physiological and pathological processes.
Unfortunately techniques available today to monitor brain function, such as E.E.G., fMRI, fNIRS, etc., either
sample brain activity very indirectly, through changes in metabolism and blood flow, or do not have the resolution which is required to reveal changes in small networks of neuronal cells and synapses. For the above reasons, the demand for a methodology that could yield a more direct readout of in vivo neuronal and synaptic activity is extremely high.
We have recently developed a methodology that provides a very direct and sensitive readout of brain activity.
This is based on a family of recombinant molecules which were designed in our lab to detect synaptic activaton
via the uptake of small exogenous markers. This methodology is capable of revealing the physiological activation of brain synaptic networks with very high sensitivity and resolution. In collaboration with the Unit of Developmental Neurogenetics directed by Gian Giacomo Consalez we are generating a series of transgenic animal
models that will be used for the selective probing of specific subgroups of neuronal cells and pathways in the
in-vivo brain.
Antonio Malgaroli
PROTEOMICS OF IRON METABOLISM UNIT
Ferritins and iron in neurodegenerative disorders
The brain expresses virtually all the proteins involved in the iron regulatory mechanisms, and it is characterized by limited iron exchanges. Excess iron is thought to catalyze the formation of reactive oxygen species and
induce oxidative damage, to which the brain is particularly sensitive, and that is a common denominator in
many neurodegenerative disorders. In these disorders, local alterations of levels of iron or of the proteins of
iron metabolism (particularly ferritins) have been often reported, but it is unclear whether this is the cause or a
consequence of the degeneration processes. Neuroferritinopathies, genetic defects connected with neurodegeneration and brain iron accumulation, is due to altered L-ferritin, a molecule that is central to the regulation of
cellular iron homeostasis. We have developed cellular and animal models of this disease with the aim to study
the relationship between brain iron misregulation and neurodegeneration The cellular models include HeLa
and neuroblastoma cells lines that overexpress L-ferritin wild type (FTL-wt) and two different pathogenic variants (FTL460InsA and 498InsTC). They showed some characteristics found in the patients tissues, including
the formation of ferritin aggregates. Characterization of these models suggested that the pathogenicity of the
variants acts through iron imbalance and consequent oxidative damage, while the ferritin aggregates does not
seem to be toxic. Transgenic mice expressing human wt-FTL and two mutants (460InsA and 498InsTC) were
obtained and their preliminary characterization indicated that high levels of transgene expression were detected
in brain and peripheral organs, suggesting that they may represent a model for the human disorder.
We also continued the characterization of the physiological role of the mitochondrial ferritin (FtMt), demonstrating its protective effect against iron-mediated oxidative damage in Friedreich ataxia patient’s fibloblasts.
Futhermore, analyzing human substantia nigra (SN) and putamen autoptic samples from Restless Legs Syndrome (RLS) cases and controls, we detected the increase of FtMt levels and number of mitochondria in the SN
of RLS respects the controls samples, suggesting that it may be involved in the pathogenesis of RLS.
Sonia Levi
MOLECULAR GENETICS OF MENTAL RETARDATION UNIT
Our research is focused on the understanding of the molecular mechanisms responsible for X-linked Mental
Retardation (XLMR), a common cause of inherited intellectual disability in the human population, with a reported prevalence of about 0,9-1,4/1000 males.
In the last years, we have showed that mutations in GDI1, one of the protein controlling the recycling of small
RAB GTPases, are responsible for XLMR. The that lack of αGDI in animal models alters cognitive functions
and the biogenesis and recycling of synaptic vesicles.
We were able to reverse the specific short-term memory deficit of Gdi1 KO mice by using a “spaced” instead
to “massed” cognitive training protocol, suggesting that the lack of Gdi1 alters steps controlling the formation
and maintenance of the SV pools possibly through changes in the Rab cycle and interfering with the efficiency
of mental processing (Bianchi et al., HMG 2009).
The association of GDI1 mutations with XLMR led us to test the hypothesis that X-linked RAB genes highly
expressed in brain could also be involved in XLMR. This was confirmed by the discovery of mutations in
RAB39B in XLMR patients and of a novel role for this RAB GTPase of unknown function in normal neuronal
development and synapses formation and maintenance (Giannadrea et al., AJHG 2010).
Genetic, biochemical, functional and behavioural approaches will be used to unravel the pathogenetic role of
RAB39B. From these studies we expect to gain novel insights into the molecular mechanisms regulating
synapse formation and to link them to learning and memory processes.
Patrizia D’Adamo
NEURAL DEGENERATION UNIT
Dentatorubropallidoluysian Atrophy (DRPLA) is a neurodegenerative disease caused by the expansion of a
polyglutamine tract in the Atrophin-1 gene. As for the other diseases of the polyglutamine family the precise
mechanisms through which neurodegeneration and the neurological manifestations arise are not clear. To address these issues we have generated several Drosophila models for DRPLA by expressing wt and mutated
forms of human Atrophin-1 and Drosophila Atro.
We have used the fly retinal neurons to analyse the cellular mechanism of neurodegeneration by polyglutamine Atrophins. We have reported (Nisoli et al. Cell Death Diff. 2010) that Atrophins interefere with the autophagic flux blocking digestion of the autophagic organells after fusion with the lysosomes. Thus in our models DRPLA shares toxic mechanisms proper of lysosomal storage disorders, which set it apart from other polyglutamine diseases like huntington. This has also important therapeutical consequences as it predicts that pharmacological therapies currently considered that woul stimulate further autophagy to rescue neurodegeneration
would not be effective for DRPLA.
We also continue our investigations on the role of Fat and its pathway in mediating neurodegeneration by
polyglutamine Atrophin focusing on the role of cell size control as an event which precedes neurodegeneration.
Finally in collaboration with Dr. Muzio at INSPE we are developing a model for Blood Brain Barrier (BBB)
breakdown in Drosophila which would allow to use flies to identify critical components for BBB homeostasis.
Manolis Fanto
STEM CELLS AND NEUROGENESIS
Exploiting genetic reprogramming to generate human iPS cells for modeling genetic disorders and for
therapeutic cell transplantations
A formidable approach named genetic reprogramming has been recently devised to generate embryonic
stem-like cells (iPS) from mouse and human fibroblasts cells by stable retroviral expression of a cocktail of ES
specific genes. iPS cells offer remarkable promises as a new source of stem cells with the following features (a)
autologous stem cells from donor patient fibroblasts, (b) extensive self-renewal in vitro, (c) ability to differentiate into a wide spectrum of functional cell types relevant for therapy, (d) generation of embryonic stem-like cells
without using preimplantation embryos. Furthermore, iPS technology offers also an unprecedented opportunity to recapitulate both normal and pathologic human tissue formation in vitro, thereby facilitating disease investigation and drug development. Our group has established all the procedures for a reliable and efficient generation of mouse and human iPS cells starting from a variety of somatic mature cells. Various reprogramming
vectors have been tested including a single vector containing three genes fused with 2A peptide sequences and
flanked with loxP sites. This last vector has allowed to generating effectively factor-free human iPS cell lines after its removal trough Cre expression. We have generated iPS cell lines from somatic cells of a variety of genetic diseases including Parkinson and Rett Syndrome. In particular, we have established iPS cell lines from Rett
syndrome patients with mutation in the Cdkl5 gene. Our lab has shown that Cdkl5 is influencing gene splicing
rate as well as synapse establishment in mouse neurons. Thus, we are assessing whether similar impairments are
notable in patient-specific iPS cells. Further, we showed that iPS cells can be efficiently differentiated into neural precursor cells, giving rise to neuronal and glial cell types in culture. Furthermore, iPS cells were induced to
differentiate into dopamine neurons of midbrain character and were able to improve behavior in a rat model of
Parkinson’s disease upon transplantation into the adult brain. These results offer the scientific ground for further exploring human iPS cells for transplantations in Parkinson’s disease.
Vania Broccoli
Figure 3. Rosettes-like structures organized by
neural progenitors derived by direct in vitro cell
differentiation of human iPS cells. ZO-1
immunofluorescence staining (purple) highlights the
apical cellular domains where cell junctions are
specifically localized lying on the most internal side
of the rosettes. DAPI nuclear staining is in blue.
ACUTE BRAIN PROTECTION, ACUTE POST-OPERATIVE PAIN, DRUGS
AND CENTRAL NERVOUS SYSTEM UNIT
Anesthesia and intensive care: head and neck
Clinical research areas
• Prognosis of diffuse axonal injury after trauma by MRI (prospective observational study).
• Cerebral perfusion before and after cranioplasty in patients previously submitted to osteo-dural decompression to control high intracranial pressure (prospective observational study).
• Troponine and BNP after major elective neurosurgery (prospective observational study).
• Cerebral perfusion after major elective neurosurgery in patients submitted to normo- or hyper-ventilation
during surgery (randomized controlled study).
• Partecipation to the multicenter prospectic database “Neurolink” of patients admitted to neurosurgical Intensive Care Units after severe head injury.
• Partecipation to the multicenter prospectic study “Neuromorfeo” (randomized comparison between total
intravenous and inhalation anesthesia during major elective neurosurgery).
• Effects of propofol on “functional MRI” in 4-8 ys old children submitted to sedation to accomplish neuroradiological examination (prospective observational study).
• Effects of propofol and thiopental on “functional MRI” in 1-4 ys old children submitted to sedation to accomplish neuroradiological examination (randomized controlled study).
• Physiopathology of mechanical ventilation during ENT surgery with laser-proof endotracheal tubes
(prospective observational study).
• Systemic complications during catharact surgery under local anesthesia (prospective observational study).
Luigi Beretta
EYE REPAIR UNIT
Clinical and basic research in ophthalmology
Analysis of neurogenic and regenerative potential of Müller Glial Cells in both the healthy and diseased mammalian retina
Our Unit, in collaboration with the Stem Cell Research Department, has been extensively studying Müller
Glial Cells in-vitro and in-vivo. We established procedures for isolation of Müller cells from murine and human
retinas and for their promotion into neuronal and photoreceptor lineages. We plan to improve in-vitro growth
of our cells in order to obtain lines of stably growing Müller Glia cells. On the other side, our methods for neuronal and photoreceptor differentiation will be further improved in order to obtain a higher percentage of photoreceptors for possible future cell therapies. Finally, a mouse model for Müller Glia genetic tracing has already
been established and will be used for the study of in-vivo Müller Glia regenerative potential in scenarios of retinal damage or degeneration.
Retrospective study to evaluate the efficacy and safety of autologous cultivated limbal stem cell transplantation for
restoration of corneal epithelium in patients with limbal stem cell deficiency due to ocular burns.
The primary objective of this observational study is to evaluate the success of transplantation based on stable
corneal epithelium without significant recurrence of neo-vascularisation at 12 months post-intervention.
Retrospective evaluation of the clinical management of patients affected by Acanthamoeba keratitis.
The primary objective of this study is to retrospectively evaluate the clinical outcome in patients affected by
Acanthamoeba keratitis treated with PHMB 0.02% alone or in combination with other anti-amoebal drugs.
Multicentric, randomised, double masked, controlled trial on the safety and efficacy of Cyclosporine A eye drop
treatment on patients with ocular cicatricial pemphigoid.
The primary aim of the study is to evaluate the efficacy of Cyclosporine A 0.05% eye drop treatment in controlling conjunctival inflammation in patients with ocular cicatrical pemphigoid, in addition to conventional
immunosuppressive systemic therapy. The study compares patients using CyA 0.05% eyedrops versus placebo
and evaluates the percentage of patients showing more than two relapses of conjunctival inflammation during
the two years of treatment.
Paolo Rama
COGNITIVE NEUROSCIENCE UNIT
The Unit applies a multi-disciplinary approach, combining expertises from many different areas (neurology
and neuroscience, linguistics, cognitive psychology, philosophy, economics), with the general aim to investigate
the neural basis of cognitive function in health and disease. The experimental approaches include behavioural
studies in normal subjects and in neurological patients, brain imaging using magnetic resonance techniques and
positron emission tomography, and neurophysiological investigations based on evoked responses, transcranial
magnetic and electrical stimulation. The main lines of investigation are:
• the neural basis of knowledge representation (semantic memory), with a special emphasis on the mechanisms underlying the acquisition and processing of abstract concepts
• the neurological mechanisms of syntacitc processing, in terms of their specificity and relationship to other
aspects of cognition
• the representation of multiple languages in the polyglot brain and their impact on other cognitive functions
• social cognitive neuroscience, with a special emphasis on decision making in conditions of uncertainty, and
on the impact of social contexts on complex choices.
These studies involve normal volunteers, and are applied also to populations with special levels of expertise.
These areas of “basic” cognitive neuroscience research are fully integrated with a clinical research program,
which focuses on model-based behavioural testing of patients affected by cognitive disorders due to acquired
focal and degenerative brain damage. The main conditions investigated using this approach are Alzheimer Disease, the fronto-temporal dementia spectrum, movement disorders, such as Parkinson Disease, as well as the
consequences of focal brain damage due to stroke or trauma. The patients are studied using innovative testing
procedures, typically derived from experimental paradigms applied to normal subjects, and the results correlated with those derived from the application of functional and structural imaging methods, allowing the correlation of behavioural findings with their neural underpinnings at different levels (gray matter, white matter, neurotransmission), as well as with the results of genetic analyses.
Stefano F. Cappa
EXPERIMENTAL NEUROSURGERY UNIT
• Results of Gamma Knife Radiosurgery in the treatment of pituitary adenomas. Collaboration with Prof. Comi, Dott. Martino, Dept. of Neurology, INSPE, Dott. Ciceri Dept. of Hematology HSR, in the design of
clinical trial regarding cell therapy with blood monocytes in traumatic spinal cord injury.
• Role of cancer stem cells in brain tumours biology (in collaboration with Dott. Galli, SCRI HSR).
• Cerebral MRI perfusion study in the follow-up of patients treated with Gamma Knife Radiosurgery for
brain metastases (in collaboration with Dott. Politi, Dep. of Neuroradiology).
• Study of pathogenetic mechanisms involved in human pituitary adenomas (in collaboration with Prof. G.K.
Stalla, Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany).
• Molecular biology and genetics of chordomas (in collaboration with Prof. P. Riva, Department of Biology
and Genetics, Medical Faculty, University of Milan).
• Molecular biology and genetics of craniopharyngiomas (in collaboration with Prof. P. Riva, Department of
Biology and Genetics, Medical Faculty, University of Milan).
• Microanatomical studies for new skull base approaches and relative reconstructive techniques (in collaboration con Prof. AJ Caputy, Prof. F. Roberti, George Washington University Neurological Institute, Washington DC, USA).
• Study of microcerebral blood flow (in collaboration with Prof. Agabiti Rosei, Prof. D. Rizzoni, Dott. G.
Boari, Clinica Medica, Department of Medical and Surgical Sciences, University of Brescia).
Pietro Mortini
FUNCTIONAL NEURORADIOLOGY UNIT
The Unit is composed by different groups that apply conventional and advanced MR techniques to investigate brain structure and function during physiological and pathological development, during normal and
pathological aging, in neuro-oncology and neurovascular diseases. The neuropediatric group focused on the
process of myelination in normal and preterm neonates; diffusion techniques have been employed to follow the
modification of white matter over time. Functional MR techniques have been used to test the possibility to investigate auditory and language areas in same subjects. Functional MRI has been used to investigate lateralization of the mirror neuron system in normal adult subjects and to verify the influence of experience on some specific motor functions, like digit skill, in musicians (in collaboration with Experimental Neurophysiology U).
Volumetric techniques (VBM analysis) and diffusion based techniques have been employed to study subjects
affected by neurodegenerative diseases like MCI, Alzheimer Disease and the Fronto-Temporal Dementia. Aim
of the project was to identify functional MR markers for an early diagnosis of MCI and of those changes associated with the conversion of MCI to dementia. Similar techniques have been employed to characterize the selective involvement of different brain areas in fronto-temporal dementia (in collaboration with Cognitive Neuroscience U.). The neurodegenerative changes related to motor neuron disease have been studied in Patients with
ALS and PLS. The vascular group applied new high resolution techniques to identify vulnerability characteristics in patients with severe carotid stenosis and their correlation with cerebral ischemia and to test new contrast
media. Finally, the neuro-oncology group focused on the clinical validation and utility of tractography, a new
diffusion based MR technique and on the development of new algorithm based on tensorial diffusion, potentially useful to better characterize the different cellular and extracellular components of brain tumors. Other
topics like the study of inflammatory diseases or optic nerve degeneration have been performed in collaboration with Neuroimaging Research Unit, Neuroimaging of CNS White Matter Unit, Eye Repair Unit.
Andrea Falini
Figure 4. Spectroscopy shows reduction of N-Acetyl aspartate in
the motor area (top left), normal spectra from the sensitive area
(bottom left) and frontal area (top right) in patients with
Amyotrophic Lateral Sclerosis
IN VIVO HUMAN MOLECULAR AND STRUCTURAL NEUROIMAGING
UNIT
Researches were aimed at investigating using PET and SPECT the brain functional parameters and neurotransmission systems in neurological and psychiatric diseases: 18F-FDG for the evaluation of glucose metabolism, 11C-Raclopride and 11C-Fe CIT for the dopaminergic system, 11C FMZ for the gabaergic system, 11CMP4 for AchE activity and 11C-PK for measuring neuroinflammation. These researches include Alzheimer’s
disease and MCI, fronto-temporal dementia and its variants, early and late onset of Parkinson’s disease, both
sporadic and genetically determined, primary dystonia (genetic and sporadic), and rare conditions such as Fatal
Familial Insomnia, an inherited prion disease. Depending on the pathological condition, PET and specific radiotracers reveal functional and neurotransmission changes which are also correlated with clinical symptoms
and their severity. Among the psychiatric disease, obsessive compulsive disorders (OCD) were studied with
PET and 11C-Raclopride for the evaluation of dopaminergic system, and 11C- MDL for the evaluation of
5HT2 serotonin receptors.
MRI structural studies were also used to address functional changes and morphometric changes (voxelbased-morphometry (VBM) and diffusion tensor imaging (DTI) techniques) in neurological and psychiatric
diseases that showed anatomical changes related to the underlying neuropathology. In OCD morphometric
DTI measurements showed fibre tracts changes that also correlated with clinical signs. We also addressed functional changes (fMRI), morphometric changes (VBM and DTI) in familial and in genetic association developmental dyslexia that were also correlated to reading disabilities and neuropsychological deficits.
Researches on the neural basis of the cognitive functions addressed a) language processes in monolingual and
bilingual individuals, showing the role of control mechanisms and critical variables such as exposure and proficiency in influencing dynamic changes in the neural substrates b) emotion processes, showing the functional
connections between sensory and perceptual brain regions and emotional system, c) music related processing,
in adult and infants, by using fMRI, MRI and EEG that allowed fundamental aspects of the related networking.
Daniela Perani
Figure 5. Single subject tractography and DTI fractional
anysotrophy changes in Obsessive Compulsive Disorder
NEUROOTHOLOGY UNIT
Little is known regarding the cortical areas involved in human vocalization. The study aim is to investigate
larynx cortical area involved in phonation. A 3 Tesla Magnetic Functional Resonance is performed in 6 healthy
adults to evaluate voice production related brain activations, using 5 tasks involving laryngeal muscles motor
control. We analyzed cerebral network modifications caused by a damage to the laryngeal structures. The fMRI
is used to examine 12 patients underwent to laryngeal surgery from January 2007 to February 2008. The pts will
be evaluated with the same fMRI tasks used in the healthy population and the results obtained about the two
study groups (healthy and surgical group) will be compared in order to obtain informations about the neuronal
plasticity following the laryngeal surgery.
In a sample of 30 pts referring dizziness and migraine we found a higher prevalence of vestibular abnormalities than in a normal dizzy group. We found increased stabilometric parameters and visual dependence. We
compared the rate of vestibular anomalies and the presence of definite migrainous vertigo in a sample of 52 pts
with Panic Disorders and agoraphobia, 30 pts with Panic Disorders without agoraphobia and 20 pts with depression, all referring dizziness. Agoraphobic pts presented a higher rate of vestibular anomalies and definite
migrainous vertigo. Vestibular anomalies may play a role in the arise of agoraphobic symptoms. We demonstrated an increased body sway during non foveal visual stimulation in agoraphobic pts compared with normal
subjects. Establish a role of genetically determined alterations of ionic transporters in inner ear in predisposing
to develop Meniére Syndrome (MS). We demonstrated a higher rate of Adducin mutation in a sample of 30 pts
with definite MS than in 2 different normal control group. Pts with MS presented a lower serum levels of
ouabaine, an hormone controlling ionic transporters activity.
The results underline the possibility that an increased pump activity and a lack of feed-back mechanisms may
change osmolarity of endolymph. Establish the efficacy of low level laser therapy in tinnitus treatment. Our results on a sample of 30 pts with tinnitus did not demonstrate any therapeutic results.
Mario Bussi
PSYCHIATRY AND CLINICAL PSYCHOBIOLOGY
During the year 2009 we continued our research activities at the interface between neuroscience and behavioral disorders, with the aim of increasing scientific knowledge and developing effective diagnosis and treatment options in the broad field of Psychiatry and Clinical Psychobiology.
In the field of psychiatric genetics, we discovered new influences of gene variants in the monoaminergic pathways and in the biological clock on core feature of illnesses and on response to treatments. In particular, we
published the first reports on the influence of COMT variants on response to antidepressant drugs and on new
influences of 5-HT2A and 5-HTTLPR.
In the field of brain imaging we produced the first reports that changes in the levels of glutamate correlate
with successful antidepressant chronotherapeutics and that changes in medial prefrontal cortex neural responses parallel successful antidepressant treatment. We developed new methods for the study of brain correlates of
social cognition in schizophrenia, and defined functional and structural brain correlates of theory of mind and
empathy deficits in schizophrenia.
Moreover, we implemented computer-aided neurocognitive remediation as an enhancing strategy for schizophrenia rehabilitation, and transcranial magnetic stimulation to improve OCD treatment options; continued
the characterization of the psychopatological features of eating disorders and anxiety disorders; and published
guidelines on the chonotherapeutic options for mood disorders.
All these findings were obtained in the context of research activities that had been ongoing since 1988 and
have continued thereon.
Francesco Benedetti
SLEEP MEDICINE
Movement-related sleep disorders
The main objective of our research program is the evaluation of movement-related sleep disorders, as the
Restless Legs Syndrome and Periodic Limb Movements (PLMs) during sleep. RLS is characterized by disagreeable sensitive symptoms in the lower limbs occurring at rest and improving with movements. A genetic mutation and a dysfunction in the dopaminergic nervous system seem to contribute to the pathogenesis of the disease. We found a locus for RLS on chromosome 14q13-21 region in a large Italian family. We are extending the
genetic investigation to other large families. We have conducted an epidemiological/MRI study on a group of
patients affected by Multiple Sclerosis (MS) and we found a high prevalence of RLS in MS and a significant
correlation between RLS and cervical spinal cord damage. Another large multicenter study that we have conducted in 861 MS patients and 649 controls confirmed the previous data. We are evaluating by polysomnography the effects of dopamine agonists with different receptor selectivity on RLS and PLMs. We are evaluating
the periodicity/duration of PLMs in patients with RLS or other sleep disorders, as REM sleep behaviour disorder (RBD) and narcolepsy, in order to demonstrate a possible different etiopathogenesis.
RBD is a parasomnia with intermittent loss of REM atonia and violent behaviour associated with dream mentation. RBD may precede neurodegenerative disorders. We found specific neuropsychological deficits, as well
as olfactory dsyfunctions, in idiopathic RBD patients: these abnormalities are similar to those described in the
early stages of Lewy body disease. On-going projects are aimed at longitudinally assessing the neurocognitive
functions, EEG and motor activity during sleep, in idiopathic RBD patients.
Luigi Ferini-Strambi
CLINICAL PSYCHOLOGY
The Unit of Clinical Psychology developed research programs in different areas. The principal key words can
be summarized according to the characteristics of each Sub-Unit:
1. Personality and Personality Disorders: the project on mentalized affectivity, emotion instability, disorders
of the Self and aggression (Professor A. Fossati) aimed at assessing the role of deficits in mentalization and
emotion dysregulation in aggressive behaviors. A major result was the deficits mentalized affectivity significantly mediated the effects of attachment styles on impulsive aggressiveness, at least in nonclinical participants. A second major findings was the evidence of a dissociability of proactive aggression –from reactive
aggression based on measures of emotional instability. Interestingly, different manifestations of narcissistic
personality were shown to have distinct patterns of associations with reactive and proactive dimensions of
aggression. Finally, over narcissistic personality features were shown to mediate the relation between the
edonistic style of prosocial moral reasoning and proactive aggression.
2. The project on emotional dysregulation in Borderline Personality Disorder (BPD) (Professor C. Maffei)
aimed at studying the way Borderline subjects manage emotional activation raised by videoclips stimulating
specific emotions and how emotional activation interferes with cognitive capacities, mainly mind-reading,
that is the capacity to individuate behavioral intentionality.
3. The Development and Psychopathology Sub-Unit (Professor M. Battaglia) research programs aimed to explore the importance of gene and environment and their possible interplay in shaping individual differences in different problem behaviours, pertaining both to internalizing and externalizing areas. Different
approaches and strategies have been employed to determine the extent to which individual differences
could be due to genes and/or environment: general population approaches, family based approaches, and
multivariate twin designs. These programs have been conducted in collaboration with foreign Institutes
and Universities.
4. The research project on HIV infection (Doctor R. Visintini) was a part of a multicentric national study coordinated by the Health Ministry (National AIDS Center - Istituto Superiore di Sanità) concerning the vaccine for HIV infection (TAT). The psychological evaluation of all the voluntary subjects involved in this
project was coordinated by the Clinical Psychology Unit of our hospital.
Cesare Maffei
MOTOR FUNCTION REHABILITATION
The research activities of 2009 focused on: biomechanical analysis of coupled movements coordination,
measure of cortical activation during execution of motor tasks performed with cognitive facilitations and
anatomical localisation of painful muscles points.
Literature report that the association of the same movement in the two body sides is easier when they are executed in a symmetrical modality (in-phase coordination). This aptitude is represented by a better performance
both in speed of execution and coordination pattern. Moreover the symmetrical coupled movement association
is spontaneously chosen by subjects. The hypothesis of research is that described motor behaviour permit an
energy saving due to a mechanical stabilisation of body parts and centre of mass. We investigated whether the
centre of pressure displacement, the torque exerted to the ground and the electromyographic activity of muscles involved with a postural role, are lower during in-phase coordination compared to anti-phase one. This
study was realised in the Lab of movement analysis, where the gesture kinematics, the ground reaction forces
and the surface electromyography were recorded.
Moreover, a collaboration with the Functional Unit of Quantitative Neuroimaging of HSR, is allowing to
study the effect of cognitive facilitations during the execution of motor tasks. The acquisitions regarded the
study of cortical activations during a dual task involving both cognitive and motor performances. These acquisitions were executed prior to and after a cognitive training to analyze if a cognitive training could lead to a better motor performance during a motor-cognitive dual task. The idea of this study origins from described difficulty of some kind of patients with CNS disease (eg: Parkinson disease) to perform the dual task. The first part
of this study has been conducted with healthy subjects.
Finally, in collaboration with the Lab of neuromuscular system engineering of the Turin Polytechnic the muscles painful points were studied. Using the technology of the Turin Polytechnic is possible to localize the muscle innervations zone by surface electromyography executed with matrix of electrodes. The aim of the study is
to establish if the muscle painful points coincide with the innervations zone.
Roberto Gatti
INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE)
Director: Giancarlo Comi*
The Institute of Experimental Neurology (INSPE) constitutes
one of the major European institutes primarily dedicated to
translational research in the neuroscience field. The overall ambition is to conjugate high level of basic research with the specific competences in pre-clinical and clinical research. This is
achievable considering that INSPE includes both research laboratories and the Neurological Department of the San Raffaele
Scientific Institute. Multiple sclerosis, stroke, traumatic injuries
of the central and peripheral nervous system, and neuromuscular diseases do represent the primary targets of the INSPE reGiancarlo Comi
search although research in neurodegenerative disorders is also
in the pipeline of the Institute.
The primary goal is to better understand the molecular mechanisms that sustain inflammatory and degenerative pathogenic mechanisms underlying neurological disorders so to identify therapeutic targets,
validate in co-operation with third parties new treatments, develop new disease biomarkers for both
clinical trials and patients monitoring. The neurological department is deeply involved in the definition
of new treatment algorithms for stroke, inflammatory and neurodegenerative diseases. The molecular
and functional bases for central and peripheral nervous system recovery processes and the potential to
modulate them by cellular and gene therapy and by specific rehabilitation interventions are another area
of interest of INSPE.
The INSPE laboratories spans on three different levels in a newly established building within the DIBIT2. One floor is dedicated to neuropathology, experimental neurophysiology, neurogenetics of monogenic and complex diseases. Another floor is dedicated to basic and clinical neuroimmunology, neurobiology, neural stem cell research and neuroembriology. The third floor is focused on neuroimaging of neuroinflammatory and neuro-degenerative disorders. Other laboratories involved in behavioral research and
in signals that regulate myelination and in clinical neurophysiology are also part of the Institute.
Research Units
EXPERIMENTAL NEUROPATHOLOGY
Regenerating the peripheral nervous system. The role of HMGB1 in the repair of peripheral nervous system:
an in vivo and in vitro study. Motor nerve biopsy: clinical usefulness and histopathological criteria
Regeneration of the nervous system (PNS) is the primary target of nerve injuries. We have already demonstrated how collagen tubes (medical device, MD) enhance nerve regeneration in a model of peripheral nerve injury, restoring a normal nerve and performing better than other MD available in clinical practice. To evaluate
whether the environment in the MD can influence nerve regeneration, we will perform gene expression analysis
by Illumina platform. Thus, the main aim of this project is to evaluate the biological events underlying regeneration of the PNS. These informations will improve therapeutic strategies not only for traumatic injury of the
PNS but for disorders of PNS such as peripheral neuropathy, condition that affect many people in our Country.
We examined the role of HMGB1 in the nerve lesions of patients with neuropathies. We showed that
HMGB1 was expressed in a wide range of nerve cells in patients compared to normal nerve: macrophages surrounding vasculitic lesions expressed high levels of HMGB1 in the damaged nerves. However, the extent of endoneurial HMGB1 expression level in Schwann cells was closely related to the degree of axonal degeneration
and fiber loss in neuropathies. In addition, we will investigate in vitro the effect of HMGB1 on the proliferation, migration and apoptosis of SC. We showed, independently from pathogenesis, that HMGB1 expression
correlate with the degree of pathological abnormalities, in particular with the extent of fibrosis. We can assume
that, in addition to its role as a trigger of inflammation, HMGB1 could directly stimulate repair in the PNS
rather than regeneration. Thus, HMGB1 may serve as one potential target for therapeutic intervention in nerve
disorders.
Early differential diagnosis of Motor Neuropathies (MN) and Lower Motor Neuron Diseases (LMND) is important, as prognosis and therapeutic approaches are different. We evaluated the diagnostic contribution of the
biopsy of the motor branch of the obturator nerve in consecutive patients in which, after clinical and neurophysiological studies, the differential diagnosis was still open. At baseline, motor biopsy was performed; diagnostic confirmation was obtained by clinical follow-up. Our results support the usefulness of this procedure in
MN and LMND.
Angelo Quattrini
EXPERIMENTAL NEUROPHYSIOLOGY
We developed and validated neurophysiological methods for the functional-anatomical investigation of brain
circuitries in physiological and pathological conditions. One application has been the study of circuitries involved in motor programming and execution using non-invasive methods like EEG source analysis, functional
magnetic resonance imaging (fMRI) and focal transcranial magnetic stimulation (TMS). In a first validation
study of EEG methods for localizing the primary motor cortex (M1), multimodal functional neuroimaging by
combining fMRI and EEG in healthy subjects was studied to achieve high-resolution reconstruction of the spatiotemporal cortical current density (CCD) distribution of movement-related cortical potentials on EEG. We
found fMRI activations, EEG sources and TMS mapping corresponding to the anatomical landmark of the
hand area in all subjects with fMRI and TMS center-of-gravity and in almost all subjects using fMRI-CCD with
moderate constraint. A significant improvement was found using fMRI-CCD compared to CCD alone. We also
investigated the effects of healthy aging on the pattern of activation to self-paced movement using EEG CCD
and a realistic volume conductor. Aging was associated with recruitment of a larger cortical neuronal population in the presence of a significantly longer movement, which more likely suggest their reduced selectivity in
activating the motor cortex than a compensatory mechanism to produce an optimum performance. Movement
duration resulted negatively correlated with pre-SMA activity, suggesting its involvement in movement termina-
tion. We also examine the resting state brain rhythms in drug naïve obsessive-compulsive disorder (OCD) patients using power (coupling of EEG bands, low-resolution electromagnetic tomography-LORETA) and coherence. In OCD, increased frontal beta, hyperactivity of insular delta sources, together with rhythms decoupling
and reduced interhemispheric alpha coherence, are consistent with previous evidence of frontal dysfunction
and with additional involvement of cortico-subcortical functional connections. This approach may provide
functional measures on different levels of involvement of cortico-subcortical circuits in neuropsychiatric disorders.
Letizia Leocani
MOLECULAR GENETICS OF BEHAVIOUR
The role of Ras-ERK signalling in behavioural plasticity and brain diseases
Our laboratory has focussed for a number of years on the role of the Ras-ERK intracellular cascade in neuronal cell signalling and behavioural plasticity. Once neurotransmitter receptors are activated, specific guanine
exchange factors (GEFs) are able to catalyse the exchange of GDP for GTP on Ras proteins, thus activating
this class of small GTPases. Activated Ras proteins then stimulate the core element of the signalling pathway,
the Ras-MEK-ERK protein kinase cascade which is crucially involved in transducing signals to the nucleus,
hence controlling chromatin remodelling and gene expression, key steps involved in synaptic plasticity and in
the formation of long-term memories.
In recent years, it has become clear that deregulation of this signalling pathway in the brain may lead to brain
dysfunction. The work of our laboratory is focussing on three brain diseases associated to abnormally high RasERK activity: drug addiction, L-DOPA induced dyskinesia (LID) and the Ras-MAPK syndromes.
The key brain structure implicated in both drug addiction and LID is the striatum. We have recently completed the analysis of several mouse strains bearing mutations affecting striatum-dependent behavioural plasticity. For instance, we showed that expression in the dorsal portion of the striatum of a potent inhibitor of the
CREB family of transcription factors, which are nuclear substrates of the ERK pathway, results in significant alterations at the level of both cocaine and morphine dependent behaviour. In addition, mice deficient for RasGRF1, a neuronal specific activator of Ras proteins, show strongly attenuated cocaine-mediated cellular and
behavioural responses. Importantly, Ras-GRF1 deficient mice also appear to be protected toward abnormal involuntary movements (AIM), the behavioural correlate of dyskinesia in rodents, in a neurotoxic model of LID.
Finally, we showed that a conditional, forebrain specific gain of function mutation in K-Ras (K-RasG12V)
largely recapitulates the cognitive impairments found in the Ras-MAPK syndromes, a recently identified class
of gain of function genetic diseases which are characterised by mental retardation.
Riccardo Brambilla
NEUROMUSCULAR REPAIR
We are currently interested in the mechanisms that sustain neuromuscular tissue repair. In particular, we are
interested in the role of adhesion in such a mechanism, which relies on the interaction between extracellular
matrix, cell surface adhesive receptors and cytoskeleton constituents. In 2009 we identified a role for vimentin,
an intermediate filament that belongs to the cytoskeleton of neurons and Schwann cells, in peripheral nerve development, myelination, and nerve regeneration. Loss of vimentin results in painful peripheral neuropathy and
distal motor denervation. Myelination is controlled with cell extrinsic mechanism, as is modulated by loss of vimentin in neurons and not in Schwann cells. Future studies will clarify how vimentin modulates myelination.
Loss of function experiments in transgenic mice have been also performed to investigate the role of Jab-1,
which is a signaling molecules likely downstream to the laminin pathway. Preliminary experiments show that
loss of Jab-1 results in abnormal axon sorting and myelination, consistent with a defective laminin pathway.
Finally, we are also investigating the efficacy of stem cell therapy to rescue muscle and nerve degeneration in
Congenital Muscular Dystrophy (CMD) and related neuropathy. Mesoangioblasts engineered to deliver a crosslinker molecule that re-connect myocytes to the basal lamina have been delivered in mouse models of CMD.
Treated mice showed delayed deterioration of motor performances and the amelioration of muscle tissue.
Stefano Carlo Previtali
Figure 6. Denervated neuromuscular junctions in vimentin
null mice
NEUROIMMUNOLOGY UNIT
Several recent data do indicate that an alteration of peculiar functions (e.g. proliferation, migration, differentiation) of sub-ventricular zone (SVZ)-derived neural stem/precursor cells (NPCs) might, over time, contribute
to the failure of the central nervous system (CNS). To assess this, we have generated transgenic mice, using recombineering and lentiviral vector technologies, in which we are able to trace (from their origin in the SVZ to
their final destination in the CNS) and/or to kill NPCs. Two founder lines have been generated by using two
NPC-restricted genes such as AspM and Nestin: (i) a transgenic mouse line in which the ligand-dependent
CRE-ERT2 gene was cloned under the control of AspM cis-acting regions, AspmCreERT2; (ii) a transgenic
mouse line in which the killing gene (TK) was under the control of Nestin regulatory regions, NestfloxGFPfloxTK-IRES-LacZ. On one hand, AspmCreERT2 mice were crossed with the reporter mice Rosa26R-YFP
(AspMCreERT2/Rosa26RYFP double transgenic mouse line) so to be able to trace and follow AspM descendants from early cortical development to post natal age. On the other hand, we crossed NestfloxGFPfloxTKIRES-LacZ mice with CMV-Cre mice to induce the activation of TK gene in SVZ cells (NestfloxGFPfloxTKIRES-LacZ/CMV-Cre mice). Beside, to assess the relevance of AspM precursor cells and to be able to selectively kill them a transgenic mouse line NestfloxGFPfloxTK-IRES-LacZ has been generated by crossing AspmCreERT2 line with the NestfloxGFPfloxTK-IRES-LacZ double transgenic mice. Tracing and killing experiments so far performed do indicate that the transgenic tools we generated can be considered solid and reproducible enough to trace NPCs from embryonic to adult life. This should led us to define the proliferative, differentiation and migratory, as well as reparative, capacities of SVZ-NPCs in inflammatory and degenerative
conditions of the CNS.
Gianvito Martino
Figure 7. The SVZ is morphologically deranged during
acute and the chronic CNS inflammation. The panel shows
the SVZ from mice with experimental autoimmune
encephalomyelitis (EAE), the animal model of MS. The
vast majority of microglia (Iba-1+ cells in blue) show a
ramified ‘quiescent’ morphology while many astrocyte-like
cells (GFAP+ cells in green) remain associated to vessels
(CD31+ cells in red) (arrows). Scale bar 200 micron.
CLINICAL NEUROIMMUNOLOGY
The Unit of Clinical Neuroimmunology is currently active in both experimental and clinical neuroimmunology with the aim to have a bi-directional transfer of scientific questions and experimental data between the two.
Concerning our work on mice, during 2009 we have completed a study concerning therapeutic effectiveness of
the interference with chemokine signaling, i.e. CCL2, in experimental neuroinflammation. Further, we have
characterized in two distinct papers the kinetic of FoxP3+ T regulatory cells, and their role in disease suppression using rapamycin, during experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple
sclerosis (MS), posing a serious note of caution in the use of FoxP3 as tout court marker of T cells with suppressive functions. In two relevant collaborative efforts, we have contributed to elucidate a novel mechanism of
intercellular communication used by glial cells to propagate pro-inflammatory signals in the brain, and we have
characterized early damage, affecting glutamatergic synapses, already present in EAE mice during a pre-clinical
stage of the disease. Both findings have lead to further, very relevant studies in both experimental and clinical
settings, leading to the characterization of novel biomarkers, insight into pathogenesis of MS and especially in
the relation between inflammation and neurodegeneration. Concerning clinical research, we have published a
comparative study describing 5 different protocols to detect anti-aquaporin IV antibodies, typical of neuromyelitis optica (NMO) patients, posing a note of caution on currently used detection techniques, and on interpretation of data from the literature. Further, we have conducted a large study, that is still ongoing, determining immunological markers in patients affected by major psychoses, with the aim to determine the possible
contribution of the immune system to pathogenesis. Finally, we contributed to a European consensus on how
cerebrospinal fluid samples should be collected and stored for biomarker analysis in MS.
Roberto Furlan
CNS REPAIR
Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates
The development of cell-based therapies aimed at promoting tissue repair in central nervous system (CNS)
diseases, represents one of the most challenging areas of investigation in the field of regenerative medicine. Indeed, cells play a critical role in reparative regeneration, as regenerating structures depend on a) proliferation of
cells surviving to the injury; b) de-differentiation of cells in the remaining tissue, or by c) influx of cells originating outside the damaged tissue. As such, the central role of stem cells and progenitors in regeneration has motivated a number of experimental approaches for CNS diseases with neural tissue repair being achieved after
stem cell transplantation. Recent evidence from our own and other labs indicates that undifferentiated neural
stem/precursor cells (NPCs) might very efficiently protect the CNS from chronic degeneration induced by inflammation, such as that occurring in experimental autoimmune encephalomyelitis (EAE) and stroke (Nature
2003, 422: 688-694; Nature 2005, 436: 266-271). Yet, a comprehensive understanding of the mechanisms by
which NPCs exert their therapeutic impact is lacking.
To address this, This study was designed as a preclinical test of the feasibility of human NPC transplantation
in an outbreed non-human primate EAE model approximating the clinical and complex neuropathological situation of human multiple sclerosis (MS) more closely than EAE in the laboratory rodent.
We examined the safety and efficacy of the intravenous (i.v.) and intrathecal (i.c.) administration of human
NPCs in common marmosets affected by myelin oligodendrocyte glycoprotein-induced EAE. Treatment commenced at the occurrence of detectable brain lesions on a 4.7T spectrometer.
NPC-injected EAE marmosets accumulated lower disability and displayed increased survival, as compared to
controls. Transplanted NPCs persisted within the central nervous system (CNS), but also in draining lymph
nodes, for up to three months after transplantation and exhibited remarkable immune regulatory capacity.
Herein, we provide the first evidence that human CNS stem cells ameliorate EAE in non-human primates
without overt side effects. Immune regulation is suggested as the major putative mechanism by which NPCs
ameliorate EAE in vivo. Our findings represent a critical step towards the clinical use of human NPCs in MS.
Stefano Pluchino
NEUROIMAGING RESEARCH UNIT
Major results:
Normal functioning of the human brain
Cognitive and motor learning results in short-term structural GM changes of brain neuronal networks.
Assessment of MS pathophysiology using structural and functional MRI
In relapse-onset MS, cortical lesions accumulate over 3-year follow up and are associated with disability progression and cognitive impairment; a dysfunction of the anterior components of the default mode network may
be among the factors responsible for the accumulation of cognitive deficits in progressive MS; tactile-associated
cervical cord fMRI activity is increased in relapse-onset and PP MS, and is more prominent in patients with severe locomotor disability.
Assessment of treatment efficacy in MS clinical trials
500 µg interferon β-1b was not more effective than the standard 250 µg dose, and both doses had similar clinical effects to glatiramer acetate; 1 g oral methylprednisolone (MP) x 5 days is not inferior to 1 g IV MP x 5 days
in reducing the gadolinium-enhancing lesions over 1 week.
MRI Assessment of CNS damage in migraine and optic neuropathies
Abnormalities of the resting-state visual and motor networks occur in cluster headache patients outside the
acute attack; brain damage in patients with Leber’s optic neuropathy is not limited to the anterior visual pathways, but extends posteriorly to the optic radiations and primary visual cortex.
MRI Assessment of CNS damage with aging and neurodegenerative diseases
Different patterns of microstructural and volumetric abnormalities occur with aging in WM tracts from
healthy subjects; in MCI, the severity of microstructural damage within and beyond the medial temporal lobe
was associated with an increased risk to develop AD; in ALS, more severe CST damage predicts greater disability progression rate and individual survival after 3.4 years; in depressed PD patients the pattern of brain atrophy overlaps with key regions involved in major depressive disorders, suggesting an increased vulnerability of
this neural circuit in PD.
Massimo Filippi
NEUROIMAGING OF CNS WHITE MATTER
In vivo assessment of pathophysiology of MS and other white matter diseases using MR-based techniques
Using functional magnetic resonance imaging (fMRI) and quantitative MR-based techniques, we found that:
1) during the performance of a simple motor task, patients with primary progressive multiple sclerosis (PPMS)
had more significant activations of several areas located in the fronto-parietal-occipital lobes. Compared with
PPMS patients, controls had increased functional connectivity between the left primary SMC and the ipsilateral inferior frontal gyrus. Conversely, PPMS patients showed increased functional connectivity between the left
primary SMC and the right cuneus. Moderate correlations were found between functional activations and damage to WM fiber bundles critical for motor network function; 2) during the performance of a cognitive task,
cognitively preserved PPMS patients, compared to cognitively impaired patients had increased activations of
the caudate nucleus, prefrontal cortex (PFC), and inferior parietal lobule. The opposite comparison showed increased activations of the SII, cerebellum, and insula in CI patients. In PPMS, a decreased composite cognitive
score correlated with increased activity of the cerebellum, insula, and SII, as well as decreased PFC activity. T2
lesion volume correlated with decreased PFC recruitment and increased SII recruitment; 3) we investigated effective connectivity changes of the sensorimotor network in pediatric relapsing remitting (RR) MS patients in
comparison with adult patients with clinically isolated syndromes (CIS) suggestive of MS or RRMS. Coefficients of effective connectivity of the sensorimotor network were similar in control subjects and pediatric MS
patients. In adult patients with CIS and even more evidently in those with RR MS, an increase of intra- and in-
terhemispheric strengths of coefficients of effective connectivity was found. The increases in such coefficients
were correlated with corpus callosum and corticospinal tract damage; 4) we found that compared with healthy
controls, patients with benign (B) and secondary progressive (SP) MS had increased activations of the left primary SMC. SPMS also showed increased activations of several areas in the fronto-temporo-occipital lobes and
reduced activations of the supplementary motor area, putamen, and cerebellum.
Maria Assunta Rocca
HUMAN INHERITED NEUROPATHIES UNIT
Impairment of endosomal dynamics in neurodegenerative disorders of the central and peripheral nervous
system
Polyphosphoinositides (PPIs) phospholipids represent important second messengers that govern a variety of
cellular functions including endosomal sorting and membrane trafficking. PPIs have a restricted distribution
within the cell, and their concentration is tightly regulated by the concerted action of specific kinases and phosphatases. In the nervous system, intracellular trafficking is a key event in basically all steps of development and
differentiation of both neurons and glial cells. However, relatively little is known on the regulation of endosomal trafficking by phospholipids in these cells.
The MTMR2 (Myotubularin-related protein 2) and FIG4 genes encode phospholipid phosphatases whose
loss causes autosomal recessive demyelinating Charcot-Marie-Tooth neuropathies, CMT4B1 and CMT4J, respectively. Hallmark of CMT4B1 are myelin outfoldings, redundant folds of excessive myelin. We previously
reported that CMT4B1 is caused by loss of MTMR2 in human and created a faithful mouse model of the disease. MTMR2 is a 3-phosphatase acting on PtdIns(3)P and PtdIns(3,5)P2, with a suggested role in intracellular
trafficking. However, why altered phospholipid levels leads to CMT4B1 remains to be assessed. CMT4J is a severe demyelinating neuropathy due to loss of the FIG4 phosphatase. Loss of FIG4 in mice provokes the Plt
phenotype, characterized by massive degeneration of the central and peripheral nervous system. In the Plt
mouse, extensive vacuolization of neurons has been observed as a consequence of decreased levels of PtdIns(3,5)P2, which is the substrate of FIG4. To elucidate endosomal dynamics and its regulation by phospholipids in both neurons and Schwann cells, we took advantage of the Mtmr2-null and Plt mouse mutants. We already generated a double knock-out mouse which has been preliminarily characterized. We revealed for the
first time a role of MTMR2 in neurons, since loss of MTMR2 exacerbates neuronal degeneration of Plt mouse.
On the contrary, haploinsufficiency of FIG4 rescued myelin outfoldings in Mtmr2-null mice, suggesting that
MTMR2 and FIG4 have opposite functions in Schwann cells. The preliminary analysis of this new model suggested strategies to rescue the disease phenotypes, aimed at restoring phospholipid levels and endosomal dynamics.
Alessandra Bolino
AXO-GLIA INTERACTIONS UNIT
Myelin is a multilamellar structure deriving from the spiral wrapping around the axons of oligodendrocytes in
the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). In the absence of
glial cells neurons die, demonstrating that the survival of these two cell types in developing nerves is strictly
linked. Similarly, axons promote the proliferation, survival and differentiation of myelinating glia. In addition,
axons also determine the amount of myelin formed. Alteration in myelination can have dramatic consequences
that can span from reduction of the conduction of the nerve impulses to neuronal cell death, with a significant
impairment of normal functionality in patients affected by demyelinating disorders.
Neuregulin1 (NRG1) is a key axonal signal that controls many aspects of PNS development, including glial
cell survival and proliferation. We have previously demonstrated that NRG1 type III is an essential instructive
signal for PNS myelination. We have also showed that in the CNS, type III NRG1 is not essential for OL myelination and the regulation of myelination in PNS and CNS is distinct.
We are now investigating how type III NRG1 is expressed on the axon and the regulation of the signal transduction pathway activated in glial cells during myelination. NRG1 are proteolytically cleaved in their extra and
intracellular domains. Upon cleavage in the juxtamembrane region, type III NRG1 remains tethered on the axonal surface and acts as a juxtacrine signal. We are now investigating the identity of the secretases involved in
NRG1 cleavage and their role in myelination. Our results suggest the ADAM 17 participates in type III NRG1
cleavage and, in vitro and in vivo studies, indicate that this cleavage inhibits myelination. Our results underscore the existence of several components controlling myelination and implicate secretases as key determinants
in controlling type III NRG1 expression on the axon.
The identification of the neuronal proteins regulating myelination are likely to provide important insights into the mechanisms required for its generation and maintenance and could be effective to develop therapies for
demyelinating diseases in which disability is correlated to myelin and axonal loss.
Carla Taveggia
INFLAMMATORY CNS DISORDERS UNIT
Our Clinical Unit was involved in many International RCTs (phase II, III or IV) to evaluate the safety and efficacy of newly-developed immunosuppressive or immunomodulatory (DM) drugs (Fingolimod, Laquinimod,
Cladribine, Teriflunomide, Ocrelizumab and Alemtuzumab) and to asses the efficacy of symptomatic therapies
(Sativex in refractory spasticity due to MS).
We coordinated a multicentre RCT on the long term benefits of a sequential therapy with Mitoxantrone
(MTX) followed by β-Interferon (IFN) on patients with bad prognostic factors in the early phase of the disease.
We were the promoting centre of an Italian multicentre study to evaluate the safety and efficacy of Natalizumab
in clinical practice. We published the data on a short-term MRI study comparing high dose oral versus iv
Methylprednisolone (MP) in MS relapses: oral high dose MP resulted as effective as iv MP with a similar safety
profile. Finally we were involved in 3 multicentre RCTs planned to asses the efficacy of conventional treatments
in delaying the convertion to MS after a first demyelinating clinical event (CIS). The PRECISE’ results have
been recently published, confirming the beneficial effects of the early use of Glatiramer Acetate.
We collected and analyzed clinical and laboratory data on more than 3000 MS patients, treated with DM
drugs, to identify the predictors of clinical efficacy or safety. In particular, we conducted a retrospective analysis
on the efficacy of MTX treatment in patients with RR and SP MS and we were the promoting centre of a multicentre retrospective study to evaluate the incidence of Acute Leukaemia (AL) in patients treated with MTX.
The risk of AL was 0.93 %, which represents a global risk of 1 AL every 107 MTX treated MS patients.
We conducted a study with a whole-genome case-control approach using the Illumina platform, to identify allelic variants associated with the risk to develop MS and its variant “primary progressive”.
Finally, we evaluated the efficacy of different aspects of intensive rehabilitation in MS patients with and without fatigue, and the clinical, immunological, and MRI characteristics of “atypical” forms of MS, to define an algorithm able to differentiate CNS demyelinating diseases from other primary CNS inflammatory diseases.
Vittorio Martinelli
CEREBROVASCULAR DISORDERS
The cerebrovascular patient: from bedside to bench and vice versa
The Stroke Team is involved in:
a)
Optimization of diagnostic/therapeutic management. Within a multicentric project aimed at the definition of outcomes of efficacy and efficiency in the management of cerebrovascular pts, we recruited 891
consecutive pts. Preliminary evaluation indicates that thrombolysis and vascular imaging correlate with
better outcome.
b)
International clinical trials evaluating therapeutic strategies in primary and secondary prevention.
c)
Individuation and validation of diagnostic/prognostic markers: Biochemical markers – within a collaborative project funded by the Ministry of Health we are collecting samples from patients undergoing
thrombolysis to study the prognostic role of markers of haemostasis and inflammation. Cognitive
markers – all consecutive patients admitted to the Stroke Unit are evaluated in the acute phase and
with repeated neuropsychological testings. Preliminary results indicate that executive dysfunctions are
one of the most relevant consequences of stroke/TIA and that Frontal Assessment Battery is a good
measure of these dysfunctions and a good predictor of long-term cognitive outcome. Markers of
carotid plaque instability - in collaboration with the Cardiovascular Department, we studied 76 patients with asymptomatic and symptomatic carotid stenosis by Color/Power Ultrasonography (US) before thromboendoarterectomy. A correlation between diagnosis of instability by US and histology (McNemar test p=0,02) was found.
d)
Characterization of genetic determinants of ischemic stroke risk with a whole genome approach using
Illumina® Bead Station 500. We have recruited 250 cerebrovascular pts and we plan to reach 500 pts
by 2011: genetic characterization and association with phenotype will follow. We are involved in an international collaborative study on whole-genome genetic association with clinical characteristics of almost 1,000 patients affected by cervical arterial dissection.
e)
Evaluation of the physiopathological role of patent forame ovale in patients with migraine and/or
stroke. 48 subjects were screened for the persistence of right-to-left shunt (RLS) with transcranial
Doppler and for the presence of white matter lesions (WMLs) using a 3.0 Tesla MRI. Preliminary results indicate that RLS does not increase WMLs.
Maria Sessa
MEMORY DISORDERS
The main task of our unit is the recruitment and proper diagnostic classification of patients with memory disorders and dementias respecting international diagnostic criteria: the correct identification of patients with dementia is the cornerstone of any type of study (neuroradiological, epidemiological, neurophysiological, genetics). Our Unit works in close collaboration with the Neuroimaging Research Unit (M. Filippi and F. Agosta)
and Functional Neuroradiology Unit (A. Falini) to identify structural and functional MR markers for the early
diagnosis of the mild cognitive impairment (MCI), to define the structural and functional CNS changes associated with the conversion of MCI to Alzheimer’s disease (AD) and to characterize the structural and functional
substrates of the non-AD dementia (frontotemporal dementia). Additional approaches in close collaboration
with the Experimental Neurophysiology Unit (L. Leocani) have been based on studies on programming of voluntary movement and motor control in aged normal subjects, MCI and AD patients. Our interest is also focused on the genetic components of AD. The Centre is engaged in the collection of blood samples to create a
clinical database and biological bank of subjects suffering from dementia with the aim to identify genetic factors involved in the risk of developing dementia and in the individual response to drugs, for which a genomewide study has been recently completed on 183 AD patients treated with Acetylcholinesterase inhibitors
(AChI) (F. Martinelli-Boneschi; Laboratory of neurological complex disorders). Recently we evaluated effectiveness of donepezil in 342 AD patients with a retrospective study during a follow-up of three years. We are also involved in clinical pharmacological trials to provide to AD patients innovative drugs (γ-secretase inhibitor,
anti β-amyloid monoclonal antibody).
Giuseppe Magnani
MOVEMENT DISORDERS
The Movement Disorder Unit of San Raffaele Institute arises from two different experiences: the first that
grows around the Parkinson and correlate diseases Clinical Center and, by now, long lasting practice in deep
brain stimulation (DBS); the second one that developed inside the Clinical Neurophysiology Unit. In these
years the group has been working on different fields of interest, like the clinical and neurophysiological study
on safety and efficacy of botulinum toxin type A (BT-A) therapy in different muscular fiber hyperactivity disorders. Notably we are studying the functional recovery after BT-A therapy in patients with focal spasticity in
multiple sclerosis (MS) as well as the identification of guidelines for the treatment with BT-A in MS patients
with neurogenic bladder without urine retention. In progression are the transcranial magnetic stimulation
(TMS) study of the exteroceptive suppression (“geste antagoniste”) in cervical dystonia, which started the last
year; the research of new targets and optimization of the procedures of surgical neurostimulation in Parkinson
disease and correlate disorders with particular focus on the mechanisms of action of the neurostimulation
through functional studies of cerebral metabolism and on the neuropsychological and behavioral modifications;
the adjustement of the interoperating monitoring (IOM). Still at the start is the protocol: ‘clinical and neurophysiological study of the efficacy and safety of the repetitive transcranial magnetic stimulation (rTMS) in
chronic neurogenic pain (CNP)’. We are also keeping on our animal neurophysiological studies in several model of experimental peripheral neuropathy, like the nervous regeneration after crush, in the aim of verifying
whether the association of classical neurophysiological tests and stimulated single fiber electromyography
(SFEMG) may contribute to better describe axonal and muscle fibers regeneration.
Ubaldo Del Carro
NEUROMUSCULAR DISORDERS
My group is working on two different topics: Neuromuscular diseases and Clinical Neuroimmunology.
About clinical studies in Neuromuscular Diseases addressed to give the best medical supports to our patients:
1. we participated in validation of the Italian version of the neuropathic pain symptom inventory in peripheral nervous system diseases
2. we has been involved in a nationwide retrospective analysis on the effect of immune therapy in patients
with chronic inflammatory demyelinating polyradiculoneuropathy
3. we completed multicentric clinical trial with talampanel in pts with ALS
4. we completed the study of brain fMRI in pts with acquired / familiar peripheral neuropathies in order to
evaluate the origin of symptom “fatigue”.
5. we completed an open multicentric international study (phase III) about the efficacy of subcutaneous Ig in
treatment of patients with MMN.
We are working on:
1. evaluation of FKT long term efficacy in pt with peripheral ataxia
2. efficacy of long term therapy with IVIg versus corticosteroids
3. a clinical multicentric randomized double blind trial for the efficacy of lithium carbonate in ALS patients
4. a clinical multicentric randomized double blind trial for the efficacy of EPO in ALS
About Clinical Neuroimmunology:
1. We critically evaluated the different techniques for the detections of AQP4 antibodies (involving in pathogenesis of Devic disease) in order to give to clinicians the more specific and sensitive technique and we are
directly involved in the creation of a Italian network for the standardization of these immunological testes.
2. we are involved in collection of clinical and immunological data of paraneoplastic patients (PNSEuronetwork)
We are working on:
1. detection of new antigens as target of immune-mediated neuropathies
2. detection of new antigens in movement disorders diseases
3. detection of new antigens in neuritis/retinitis of immune-mediated origin
4. implementation of immunological diagnostic testes for detection of CNS neuoromediated diseases
Raffaella Fazio
PAROXYSMAL EVENTS
Our unit is principally involved in the evaluation of epileptic patterns during status epilepticus and single
seizures. Status epilecticus is a medical emergency and the times for its identification and treatment influence
the prognosis of the patient. The current limits are especially connected to the possibilities of access of instrumental diagnosis and to the lack of therapeutic protocols universally acknowledged. For a correct diagnosis of
non convulsive status epilepticus and to verify the effects of the therapies is essential the contribution of neurophysiological diagnostic and, in particular, the electroencephalographic one. Long term EEG monitoring
(LTM) is a well-established procedure in the evaluation of epilepsy patients. The analysis of EEG recordings is
necessary to determine the seizure onset zone. LTM is also particularly useful in the evaluation of critically ill
patients, in which seizures are frequently silent, and in the pre-surgical evaluation of patients with pharmacorefractory epilepsy. Main goal of our studies is related to the automatic analysis of seizures EEG pattern in order
to obtain a 24 hours of monitoring of patiens.
We are also involved in the neurophysiological evaluation of mechanisms mediating epileptogenesis in Tuberous Sclerosis Complex in mice and in the human evaluation of therapy with Rapamycin. This drugs has no documented properties as an anticonvulsant agent but it has strong efficacy for preventing epileptic encephalopathy in animal model of Tuberous Sclerosis. Before starting with a human trials we need some more information
about the risks of withdrawal and we are actually involved in these part of the study. A multicentre study of efficacy of Rapamicyn in human may be plan for the next year.
Fabio Minicucci
9 Arcidiacono, PG; Calori, G; Carrara, S; McNicol, ED; Testoni, PA. Celiac plexus block for pancreatic cancer Asperti, C; Astro, V; Totaro, A; Paris, S; de Curtis, I. Liprin-α1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins. J. Cell Sci.: 2009; 122(18): 3225-3232 - Article
IF 2008: 6,247
9 Benedetti, F; Bernasconi, A; Bosia, M; Cavallaro, R; Dallaspezia, S; Falini, A; Poletti, S; Radaelli, D; Riccaboni, R; Scotti, G; Smeraldi, E. Functional and structural brain correlates of theory of mind and empathy
deficits in schizophrenia. Schizophr Res: 2009; 114(1-3): 154-160 - Article
IF 2008: 4,174
9 Bianchi, V; Farisello, P; Baldelli, P; Meskenaite, V; Milanese, M; Vecellio, M; Muhlemann, S; Lipp, HP; Bonanno, G; Benfenati, F; Toniolo, D; D’Adamo, P. Cognitive impairment in Gdi1-deficient mice is associated
with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training. Hum. Mol. Genet.: 2009; 18(1): 105-117 - Article
IF 2008: 7,249
9 Castronovo, V; Canessa, N; Ferini-Strambi, L; Aloia, MS; Consonni, M; Marelli, S; Iadanza, A; Bruschi, A;
Falini, A; Cappa, SF. Brain activation changes before and after PAP treatment in obstructive sleep apnea.
Sleep: 2009; 32(9): 1161-1172 - Article
IF 2008: 4,475
9 Centonze, D; Muzio, L; Rossi, S; Cavasinni, F; De Chiara, V; Bergami, A; Musella, A; D’Amelio, M; Cavallucci, V; Martorana, A; Bergamaschi, A; Cencioni, MT; Diamantini, A; Butti, E; Comi, G; Bernardi, G; Cecconi, F; Battistini, L; Furlan, R; Martino, G. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J. Neurosci.: 2009; 29(11): 3442-3452 - Article
IF 2008: 7,452
9 Chiappalone, M; Casagrande, S; Tedesco, M; Valtorta, F; Baldelli, P; Martinoia, S; Benfenati, F. Opposite
changes in glutamatergic and GABAergic transmission underlie the diffuse hyperexcitability of synapsin i-deficient cortical networks. Cereb. Cortex: 2009; 19(6): 1422-1439 - Article
IF 2008: 5,907
9 Colasante, G; Sessa, A; Crispi, S; Calogero, R; Mansouri, A; Collombat, P; Broccoli, V. Arx acts as a regional
key selector gene in the ventral telencephalon mainly through its transcriptional repression activity. Dev. Biol.:
2009; 334(1): 59-71 - Article
IF 2008: 4,416
9 Corbetta, S; Gualdoni, S; Ciceri, G; Monari, M; Zuccaro, E; Tybulewicz, VLJ; De Curtis, I. Essential role of
Rac1 and Rac3 GTPases in neuronal development. FASEB J.: 2009; 23(5): 1347-1357 - Article
IF 2008: 7,049
9 Cunha, C; Angelucci, A; D’Antoni, A; Dobrossy, MD; Dunnett, SB; Berardi, N; Brambilla, R. Brain-derived
neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol. Dis.: 2009; 33(3): 358-368 - Article
IF 2008: 4,852
9 Fornasiero, EF; Bonanomi, D; Benfenati, F; Valtorta, F. The role of synapsins in neuronal development. Cell.
Mol. Life Sci.: 2009; 1-14 - Article in Press
IF 2008: 5,511
9 Franzin, A; Snider, S; Picozzi, P; Bolognesi, A; Serra, C; Vimercati, A; Passarin, O; Mortini, P. Evaluation of
Different Score Index for Predicting Prognosis in Gamma Knife Radiosurgical Treatment for Brain Metastasis.
Int. J. Radiat. Oncol. Biol. Phys.: 2009; 74(3): 707-713 - Article
IF 2008: 4,639
9 Losa, M; Bianchi, R; Barzaghi, R; Giovanelli, M; Mortini, P. Persistent adrenocorticotropin response to desmopressin in the early postoperative period predicts recurrence of Cushing’s disease. J. Clin. Endocrinol. Metab.:
2009; 94(9): 3322-3328 - Article
IF 2008: 6,325
9 Martinelli, V; Rocca, MA; Annovazzi, P; Pulizzi, A; Rodegher, M; Martinelli-Boneschi, F; Scotti, R; Falini, A;
Sormani, MP; Comi, G; Filippi, M. A short-term randomized MRI study of high-dose oral vs intravenous
methylprednisolone in MS. Neurology: 2009; 73(22): 1842-1848 - Article
IF 2008: 7,043
9 Paulesu, E; Vallar, G; Berlingeri, M; Signorini, M; Vitali, P; Burani, C; Perani, D; Fazio, F. Supercalifragilisticexpialidocious: How the brain learns words never heard before. Neuroimage: 2009; 45(4): 1368-1377 - Article
IF 2008: 5,694
9 Stefano, L; Racchetti, G; Bianco, F; Passini, N; Gupta, RS; Bordignon, PP; Meldolesi, J. The surface-exposed
chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J. Neurochem.: 2009; 110(1): 284-294 - Article
IF 2008: 4,500
Selected publications (INSPE)
9 Arcidiacono, PG; Calori, G; Carrara, S; McNicol, ED; Testoni, PA. Celiac plexus block for pancreatic cancer Bolis, A; Coviello, S; Visigalli, I; Taveggia, C; Bachi, A; Chishti, AH; Hanada, T; Quattrini, A; Previtali,
SC; Biffi, A; Bolino, A. Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination. J.
Neurosci.: 2009; 29(27): 8858-8870 - Article
IF 2008: 7,452
9 Cerri, F; Gavazzi, A; Previtali, SC; Franceschi, M; Lopez, ID; Scarlato, M; Podini, P; Comi, G; Quattrini, A.
Diffuse intraneural leiomyoma in a case of sensorimotor neuropathy. Acta Neuropathol.: 2009; 117(5): 595597 - Article
IF 2008: 5,310
9 Comi, G; Martinelli, V; Rodegher, M; Moiola, L; Bajenaru, O; Carra, A; Elovaara, I; Fazekas, F; Hartung,
HP; Hillert, J; King, J; Komoly, S; Lubetzki, C; Montalban, X; Myhr, KM; Ravnborg, M; Rieckmann, P;
Wynn, D; Young, C; Filippi, M. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet: 2009; 374(9700): 1503-1511 - Article
IF 2008: 28,409
9 Inuggi, A; Amato, N; Magnani, G; Gonzalez-Rosa, JJ; Chieffo, R; Comi, G; Leocani, L. Cortical control of
unilateral simple movement in healthy aging. Neurobiol. Aging: 2009; (): - Article in Press
IF 2008: 5,959
9 Pluchino, S; Gritti, A; Blezer, E; Amadio, S; Brambilla, E; Borsellino, G; Cossetti, C; Del Carro, U; Comi, G;
‘T Hart, B; Vescovi, A; Martino, G. Human neural stem cells ameliorate autoimmune encephalomyelitis in
non-human primates. Ann. Neurol.: 2009; 66(3): 343-354 - Article
IF 2008: 9,935
Molecular genetics of mental retardation Unit
Neural degeneration Unit
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 63
DIVISION OF METABOLIC
AND CARDIOVASCULAR SCIENCES
Research Units
Amino acid and stable isotopes Unit
HEAD OF UNIT: Livio Luzi
RESEARCHERS: Andrea Caumo, Stefano Benedini, Roberto Codella, Ileana Terruzzi
FELLOWS: Chiara Martinelli, Anna Montesano, Antonella Pagani, Pamela Senesi
Complications of diabetes
GROUP LEADER: Gianpaolo Zerbini
RESEARCHERS: Mara Lorenzi, Anna Maestroni
PHD STUDENT: Silvia Maestroni
CONSULTANT: Gemma Tremolada
TECHNICIAN: Daniela Gabellini
Obesity and metabolic related diseases
GROUP LEADER: Gianluca Perseghin
FELLOW: Guido Lattuada
TECHNICIAN: Francesca Ragogna
HEAD OF UNIT: Alessandro Rubinacci
RESEARCHER: Isabella Villa
POST-DOCTORAL FELLOW: Emanuela Mrak
FELLOW: Simona Bolamperti
CONSULTANTS: Giovanna Mignogna, Gianluigi Moro, Marcella Sirtori
TECHNICIAN: Ennio Leporati
Coagulation service & thrombosis research Unit
HEAD OF UNIT: Armando D’Angelo
RESEARCHERS: Luciano Crippa, Patrizia Della Valle, Annalisa Fattorini, Silvana Viganò
FELLOW: Giulia Pavani
TECHNICIAN: Elisabetta Pattarini, Francesca Sampietro
Cardiodiabetes & core Lab
HEAD OF UNIT: Emanuele Bosi*
GROUP LEADER: Lucilla D. Monti
FELLOW: Elena Galluccio
TECHNICIANS: Sabrina Costa, Barbara Fontana
Pediatric endocrinology research
HEAD OF UNIT: Giuseppe Chiumello*
GROUP LEADER: Stefano Mora
FELLOWS: Silvia Carlucci, Annalisa Donini, Silvia Genovese, Ilaria Zamproni
TECHNICIAN: Maria Puzzovio
Diabetes and endocrinologyUnit
PHYSICIANS: Alberto Davalli, Gabriella Galimberti, Roberto Lanzi, Marco Federico Manzoni, Alessandro Saibene
RESIDENTS: Chiara Cappelletti, Valentina Crippa, Valentina Doria, Ilaria Formenti, Manuela Fortunato, Andrea Laurenzi, Sara
Madaschi, Elena Peretti, Francesca Perticone, Cecilia Piani, Maria Grazia Radaelli, Alessandro Rossini, Annachiara
Uccellatore, Valentina Villa
TECHNICIAN NUTRITIONIST: Monica Marchi
RESEARCH NURSE: Eleonora Bianconi
TRIAL COORDINATOR: Pauline Grogan
Cardio-metabolic and clinical trials
CLINICAL GROUP LEADER: Piermarco Piatti
FELLOWS: Pietro Lucotti, Emanuela Setola
RESEARCH NURSE: Michela Stuccillo
Pediatrics Unit
CLINICAL GROUP LEADER: Giovanna Weber*
RESEARCHERS: Stefania Di Candia, Gabriella Pozzobon, Gianni Russo, Maria Cristina Vigone
Diabetes and metabolic diseases in children and adolescents
CLINICAL GROUP LEADER: Franco Meschi
RESEARCHERS: Karen Marenzi, Matteo Viscardi
Neonatology
CLINICAL GROUP LEADER: Graziano Barera
RESEARCHERS: Antonella Poloniato, Rosanna Rovelli
RESIDENT: Patrizia Corsin
Gynecology and obstetrics Unit
Fetal-maternal medicine
CLINICAL GROUP LEADER: Maria Teresa Castiglioni
RESEARCHERS: Susanna Rosa, Maddalena Smid, Luca Valsecchi
PHD STUDENT: Paolo Cavoretto
FELLOWS: Federica Pasi, Audrey Serafini
Infertility
CLINICAL GROUP LEADER: Enrico Papaleo
RESEARCHERS: Ilaria Cino, Lucia De Santis, Michela Molgora, Nicoletta Panacci, Simone Rofena
FELLOW: Elena Gismano
Cardiovascular interventions Unit
HEAD OF UNIT: Antonio Colombo
PHYSICIANS: Mauro Carlino, Alfredo Castelli, Alaide Chieffo, Cosmo Godino, Azeem Mohamed Latib, Matteo Montorfano
FELLOWS: Rasha Al-Lamee, Francesco Arioli, Economou Fotios, Alfonso Ielasi, Marco Mussardo, Kensuke Takagi
RESIDENTS: Filippo Figini, Daniela Piraino,
TRIAL COORDINATOR: Angela Ferrari
Clinical cardiovascular biology Unit
HEAD OF UNIT: Domenico Cianflone*
PHYSICIANS: Enrico Ammirati, Nicole Cristell
POST-DOCTORAL FELLOW: Norma Maugeri
RESIDENTS: Alessandro Durante, Anna Chiara Vermi
TECHNICIAN: Michela Banfi
RESEARCH NURSE: Barbara Pontiroli
Ischaemic heart disease, heart failure and echocardiography Unit
HEAD OF UNIT: Alberto Margonato
PHYSICIANS: Eustachio Agricola, Alberto Capelletti, Gabriele Fragasso, Andrea Macchi, Michele Oppizzi
RESIDENTS: Michela Cera, Irene Franzoni, Claudia Montanaro, Isabella Rosa, Anna Salerno, Massimo Slavich
POST-DOCTORAL FELLOW: Fabio Buzzetti
PHD STUDENTS: Francesco Maranta, Camilla Tarlasco
Organ protection in critically ill patients,
Advanced cardiac failure and mechanical supports Unit
HEAD OF UNIT: Alberto Zangrillo*
PHYSICIANS: Elena Bignami, Tiziana Bove, Luca Cabrini, Giuseppina Maria Casiraghi, Sergio Colombo, Remo Daniel Covello,
Giovanni Landoni, Giovanni Marino, Melissa Messina, Federico Pappalardo, Davide Salaris, Paolo Silvani
RESIDENTS: Laura Corno, Giulia Maj, Anna Maria Mizzi, Giacomo Monti, Laura Ruggeri, Stefano Turi
POST-DOCTORAL FELLOWS: Luigi Barile, Luca Buratti, Elena Frati
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Simona Massani, Lara Sussani, Paola Zuppelli
Structural heart disease Unit
HEAD OF UNIT: Ottavio Alfieri*
PHYSICIANS: Stefano Benussi, Michele De Bonis, Francesco Maisano
FELLOWS: Andrea Guidotti, Ylenia Privitera, Davide Schiavi
Study and treatment of aortic disease Unit
HEAD OF UNIT: Roberto Chiesa*
PHYSICIANS: Domenico Astore, Renata Clotilde Castellano, Efrem Civilini, Laura Dordoni, Gloria Esposito, Enrico Maria
Marone, Massimiliano Marrocco-Trischitta, Germano Melissano, Yamume Tshomba
RESIDENTS: Chiara Brioschi, Giovanni Coppi, Andrea Kahlberg, Davide Logaldo, Daniele Mascia, Daniele Psacharopulo, Sara
Spelta, Gianbattista Tshiombo
FELLOWS: Domenico Baccellieri, Luca Bertoglio, Barbara Catenaccio
Center for arrhythmia research
HEAD OF UNIT: Carlo Pappone
CLINICAL GROUP LEADER: Vincenzo Santinelli
POST-DOCTORAL FELLOWS: Giuseppe Augello, Alessia Pappone, Simone Sala, Nicoleta Sora, Pasquale Vergara
RESIDENTS: Giuseppe Ciconte, Andrea Radinovic, Massimo Saviano
TECHNICIAN: Giorgio Maida
Vision first Unit
HEAD OF UNIT: Francesco Bandello*
PHYSICIANS: Maurizio Battaglia Parodi, Paolo Bettin, Stefania Bianchi Marzoli, Gianluigi Bolognesi, Marco Codenotti, Francesco
Fasce, Antonio Giordano Resti, Ugo Introini, Rosangela Lattanzio, Francesco Loperfido, Gisella Maestranzi, Giulio
Modorati, Luisa Pierro, Alessandra Tavola
RESIDENTS: Maria Lucia Cascavilla, Umberto De Benedetto, Federico Di Matteo, Matteo Ghidoni, Silvia Giatsidis, Jacopo Milesi,
Laura Regali, Ilaria Zucchiatti
CONSULTANTS: Nicola Baccelli, Loredana Bonisolli, Elena Bruschi, Gabriella Cammarata, Carlo Ciampi, Paola Ciasca, Annalisa
Colucci, Marina Fiori, Maddalena Forti, Marco Gagliardi, Silvia Gomarasca, Lauretta Guarisco, Francesca Legorini,
Maria Pia Manitto, Angela Malegori, Elena Mantovani, Elisabetta Martina, Paolo Mauceri, Lisa Melzi, Elisabetta
Miserocchi, Veronica Odazio, Matteo Prati, Andrea Ramoni, Carmen Rojo, Michela Rossi, Marco Setaccioli, Monica
Stoppani, Fabrizio Scotti, Alessandra Spinelli
TECHNICIANS: Giorgio Alto, Alessio Buzzotta
Introduction
Mission and Vision - It is unquestionable that some of the most relevant diseases with high social, economic and clinical impact in developed societies link disorders of metabolism to chronic and acute alterations of cardiovascular function. Metabolic and cardiovascular diseases represent a major area of clinical
care and research at San Raffaele Research Institute. Thus, the Division of Metabolic and Cardiovascular Sciences will be devoted to planning an integrated approach to treat patients and understand mechanisms based on a structured view of the pathophysiological connections between metabolic and cardiovascular alterations. Such a vision could set a strong example of how to tackle complex problems with
beneficial outcomes. Aim of the Division is therefore not only to exploit the obvious possibility of synergy
at the level of basic research, but also the creation of clinical programs in which experts in the study of altered metabolism are integrated in the team of cardiologists, cardiac surgeons, vascular surgeons and cardiac emergency physicians treating acute or chronic cardiovascular diseases. Conversely, cardiovascular
specialists should be part of the clinical team evaluating and treating patients with metabolic disorders.
Organization - At this stage, the Strategic Committee for Research is involved with drawing the
guidelines for implementation of the Institutional Research Division of Metabolic and Cardiovascular
Sciences. The efforts of this work-in-progress are focused on facilitating interactions that will lead to creating a common research space for the investigators of the Division.
Goals - The biology of endothelium may be considered as a theme of unifying interest and particular
relevance to research bridging the metabolic and cardiovascular disease areas. This could easily be expanded to include the biology of other cellular components of the vessel wall – smooth muscle cells, fibroblasts, inflammatory cells and adipocytes – which play a concerted and fundamental role in controlling all responses to acute and chronic vascular injuries. Along with this unifying theme, areas of interest
span from the mechanisms of myocardial damage; thrombosis; hemostatic imbalance (post-surgery bleeding in emergency patients and patients with ventricular assisting devices); pathobiology of the atherosclerotic plaque; metabolic alterations leading to cardiovascular diseases, in particular insulin resistance and
type 2 diabetes; material sciences and bioengineering with respect to developing new devices; and cell
therapies. The outcomes of this integrated approach will lay new grounds for innovative treatments of established metabolic and cardiovascular diseases, personalized preventive medicine programs and new
generations of clinical and nutritional studies.
Achievements - Work performed in the Division is internationally recognized in several areas of excellence including arrhythmology, cardiac valve and aortic surgery, acute and chronic myocardial damage,
coronary revascularization, vascular inflammation, insulin resistance, diabetic macro- and microangiopathy, intermediary and energy metabolism, bone pathophysiology.
Training Opportunities - The Division, through the intertwined connections with several Clinical Care
Departments, gives ample support to the Postgraduate Schools in Anesthesia and Intensive Care, Cardiovascular Diseases, Cardiac Surgery, Vascular Surgery, Endocrinology and Metabolic Diseases, Obstetrics and Gynecology, Pediatrics, and Ophthalmology.
Research Units
AMINO ACID AND STABLE ISOTOPES UNIT
The group is pursuing several major research areas. In details we are studying: the association among gene
polymorphisms, DNA methylation and metabolism in diabetes, obesity and athletes. Diabetes and obesity are
conditions often associated with altered levels of plasma homocysteine (Hcy) concentrations. Recently the interrelation between physical exercise and higher Hcy plasma levels have been studied in athletes. We are investigating the effect of in vitro DNA demethylation on MyoD, Myogenin, MHC, PPARγ and leptin expression to
evaluate the effect of deficiency in DNA methylation by polymorphisms on cells myogenesis and adipogenesis
promotion. Metabolic outcome of islet transplantation: using clamp techniques combined with tracer infusions
glucose, lipid and amino acids metabolism are studied in type 1 diabetic individuals undergoing islet transplantation.
Mathematical modelling of metabolic and endocrine systems. The simultaneous assessment of insulin sensitivity and insulin secretion is of paramount importance to evaluate the metabolic status of a subject at risk of
becoming diabetic or to monitor the effect of therapies. Aim of our research is to develop methods to perform
the simultaneous assessment of insulin secretion and insulin sensitivity. The increasing need to keep the experimental costs as low as possible has given remarkable impulse to the use of indices of derived from an oral glucose tolerance test (OGTT). We are developing a suitable mathematical model that will allow us to reliably estimate these parameters in different physiopathological states from a 3-sample OGTT. Lastly, a nutraceutical line
of research was undertaken to discover metabolic effects of plant-derived proteins.
Livio Luzi
COMPLICATIONS OF DIABETES
Prevention, cure and remission of the complications of diabetes
Despite major efforts aimed to obtain the best possible control of glucose metabolism, microvascular complications of diabetes remain among the major causes of end stage renal disease and blindness in Europe. Whether
the complications of diabetes may be the result, in predisposed individuals, of the persistent toxic effect of glucose on specific progenitor cells localized in target organs of diabetes such as the renal glomerulus or the retina,
is presently unknown. To test this hypothesis we are presently involved in two major projects:
1. Identification of podocyte progenitor cells (PPCs).
In case of diabetes the podocytes, i.e. the glomerular cells responsible for the filtering capacity of the kidney,
tend to die and to detach from the basal membrane causing the onset of a progressive and irreversible proteinuria.
Searching for progenitor cells, we identified inside the human visceral glomerulus, clusters of cells characterized by the expression of podocyte markers on one hand and of stem cell markers on the other, suggesting the
presence of PPCs inside the adult human kidney. Experiments aimed to isolate and grow in culture PPCs are
presently under way. The characterization of PPCs may allow to understand the cellular bases of diabetic
nephropathy.
2. Endothelial progenitor cells (EPCs) and vascular disease in type 1 diabetes
The final stage of diabetic retinopathy, so called proliferative retinopathy (PDR), is characterized by the active proliferation, inside the retina, of incompetent new capillaries causing hemorrhages and retinal detachment. Whether EPCs might be involved in the pathogenesis of PDR is presently unknown. In collaboration
with the Vision First Unit of this Institute we have demonstrated that an increased activity of EPCs is found not
only in type 1 diabetic patients with PDR, but also in patients with initial signs of diabetic retinopathy despite a
short duration of diabetes. Conversely, EPCs activity is normal in patients without retinopathy despite a long
duration of diabetes. Altogether these findings suggest that increased activity of EPCs is not only a marker of
predisposition to develop PDR, but may also be directly involved in the pathogenesis of the complication.
Gianpaolo Zerbini
OBESITY AND METABOLIC RELATED DISEASES
Insulin resistance is the common alteration leading to deleterious metabolic effects at the level of the skeletal
muscle, liver, heart, adipose tissue and β-cells responsible of the pathogenesis of obesity and metabolic syndrome. The molecular mechanisms responsible of insulin resistance at the cellular level were largely identified
in animal models. Despite that, the understanding of the pathogenic events leading to their activation remains
unresolved, eluding the drug-related strategies of intervention. Our working hypothesis is that any perturbation
(genetic or acquired) that leads to an increase in intracellular fatty acids concentrations such as 1) acquired or
inherited defects in mitochondrial lipid oxidation, 2) defects in adipocyte fat metabolism 3) increased fat delivery to muscle/liver/heart/adipose tissue due to higher energy intake constitutes a detrimental factor predisposing to the onset of insulin resistance. With our research activity we were among the first to demonstrate that in
humans increased fat accumulation within the skeletal muscle and the liver has systemic deleterious metabolic
effects and that increased epicardial fat and intracardiac fat accumulation is a major factor involved in diabetesinduced heart alterations. At this stage, to identify the targets to be treated to reduce fat-induced insulin resistance is of paramount importance. The methodological approach that was developed to address this issue is
based on Magnetic Resonance Spectroscopy techniques in vivo in humans to study non invasively the alteration
of energy metabolism in single organs and tissues to assess the impact on the whole body system using 31PMRS. In particular the cardiac and hepatic applications are novel, promising and strategic tools in our field of
investigation to identify targets for potential treatments.
Gianluca Perseghin
BONE METABOLISM UNIT
Aging bone: gene expression and endocrine mileu
The Unit is engaged in the effort to characterize the microstructural parameters, biomolecular signaling and
endocrine milieu characterizing the bone undergoing to fragility fractures. To these purposes, three lines of research have been carried out.
1. A pQCT study of the femoral neck of the elderly undergoing to hip replacement for femoral fractures or
primary arthrytis was performed. Results suggest that a bone mechanical adaptation mechanism to the age
related loss of trabecular elements is preserved only in the arthrytis group that exibits an overall lower risk
of fragility fractures. The lack of this protective mechanism in the osteoporotic cohort is consistent with the
hypothesis that the aging process is accompanied by a disturbance of the mechanotransduction process.
2. Wnt signaling in bone samples of postmenopausal women have been evaluated. Results indicate that aging
induces an altered balance between Wnt agonists and antagonists, constituting an age dependent insufficiency state of the Wnt signalling pathway with a subsequent impairment of osteoblastogenesis. The gene
expression profile was consistent with the major features of aging bone. In order to investigate the cell targets potentially affected by the altered Wnt signalling, mesenchymal cell fraction availability has been evaluated by challenging their differentiation profile and markers expression in vitro. Preliminary results suggest that the mesenchymal cell pool is available despite age and might therefore constitute a direct potential
pharmacological target.
3. The modulation of the GH intracellular signaling after the GH receptor activation exerted by estrogens
has been evaluated in human osteoblast-like cells. 17β-estradiol is able to positively modulate GH signaling, by inducing an increase of STAT5 phosphorylation with consequent increase in the IGF2 gene transcription and protein production. Further studies are ongoing in order to characterize the molecular mechanisms involved in estrogen facilitatory action on GH signaling.
By collaborative efforts, the bone phenotypes of ADA deficiency, islets transplant recipients, MPS, adult GHdeficiency, genetic clusters, coronary calcification and Paget disease have been evaluated.
Alessandro Rubinacci
Figure 8. 3D reconstruction of human femural neck by an
originally developed software.
COAGULATION SERVICE & THROMBOSIS RESEARCH UNIT
More about hyperhomocysteinemia and poor folate status
Our group has been interested in the identification of thrombophilia markers since a long time. Moderate hyperhomocysteinemia, an indicator of poor vitamin status, is a risk factor for thrombosis, but its causative role
has not been yet defined. In collaboration with the University La Sapienza of Rome, we evaluated tHcy levels in
patients with chronic obstructive pulmonary disease (COPD), who are at increased atherothrombotic risk.
Compared to controls, COPD patients had higher plasma tHcy (median: 13.9 micromol/l vs 11.5 micromol/l, p
= 0.002) and lower circulating folate (median: 2.5 ng/ml vs 2.8 ng/ml, p = 0.03) also after adjusting for smoking, heart failure, renal function and C-reactive protein (OR 1.36, p = 0.01). Low levels of folate (p = 0.02), vitamin B12 (p = 0.04), and hypertriglyceridemia (p 2 = 0.52). Thus, COPD patients have a poor B vitamin status
and increased tHcy, possibly resulting in increased atherothrombotic risk.
Human chromosomes are capped by telomeres, which consist of tandem repeats of DNA and associated proteins. Telomere dysfunction has been associated with development of age-related pathologies (cancer, cardiovascular disease, Alzheimer’s disease, Parkinson’s disease). Folate provides precursors for nucleotide synthesis
thus affecting DNA integrity; it also modulates DNA methylation, which in turn epigenetically regulates telomere length. In collaboration with the Tufts University of Boston, we determined whether folate status and the
677C > T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene are associated with the
telomere length of peripheral blood mononuclear cells in healthy men. When plasma folate concentration was
above the median, there was a positive relationship between folate and telomere length. In contrast, there was
an inverse relationship between folate and telomere length when plasma folate concentration was below the
median. The MTHFR 677C > T polymorphism was weakly associated with increased telomere length at belowmedian folate status. Folate status may thus affect DNA integrity and influence the epigenetic regulation of
telomere length through DNA methylation.
Armando D’Angelo
CARDIODIABETES & CORE LAB
Genetic characterization of different pathways in the induction of the Cardio-diabetes Syndrome
Our previous clinical experience demonstrated a specific phenotype characterized by increased fasting nitric
oxide levels but reduced response after an insulin stimulus in patients with cardiovascular disease and in type 2
diabetic patients and their first degree relatives. At genetic level we found a strong association between eNOS
gene variants and type 2 diabetes and intra-stent restenosis. The polymorphism in intron 18 of eNOS gene affects the physiological mRNA splicing, with skipping of exons 19 and 20. As a result, the alternative transcript
does not encode an enzymatically active protein and, when co-expressed, it inhibits enzymatic activity of the
full-length, thus acting as dominant negative regulators of nitric oxide synthesis. This suggests that truncated
NOS polypeptides have diminished enzymatic activity and it will explain the presence of dramatically increased
presence of early restenosis in patients carrying the eNOS SNP in intron 18. Our project is aimed to evaluate
eNOS gene function and the mechanisms of gene expression and regulation in the presence of gene variants
and the impact at cellular levels both in arterial or platelet cells of patients carrying the polymorphism. The importance of metabolic factors, i.e. the presence of alterations of glucose or lipid metabolism will be taken into
account. Recent data seems to demonstrate, in healthy subjects, that eNOS gene variants correlate with a reduced number of endothelial progenitor cells. The presence of eNOS gene variants also correlate with increased IMT values, an index of early atherosclerosis. In 2009, we started the evaluation of the presence of new
candidate gene variants (ANP) in patients with mitral valve disease. Further, we will continue with the definition of the molecular mechanisms involved in early endothelial activation and inflammation in isolated endothelial cells and the evaluation of genes expression for inflammation and oxidative stress in endothelial progenitors cells and the search of new serological indices involved in the pathogenesis of Cardio-diabetes in strict
collaboration with the Cardio-Metabolic and Clinical Trials Unit. The group also collaborate with the Neurogenomics Unit, the Cardio-Thoraco-Vascular and the Neurology Departments.
Lucilla D. Monti
PEDIATRIC ENDOCRINOLOGY RESEARCH
Although osteoporosis is regarded as a condition of the elderly, it is now clear that it has its antecedents during childhood and adolescence. One of the key factors influencing the development of osteoporosis in adulthood is the bone mass gain occurring during growth. The concerted action of bone-forming cells (osteoblasts),
and bone-resorbing cells (osteoclasts) is crucial for the development of a healthy and competent skeleton.
Whenever bone metabolism is impaired during childhood and adolescence, bone mass accrual is deficient. The
study of bone physiology is thus important to identify the factors influencing a correct metabolism.
Our group is investigating these factors in healthy children and adolescents by the assessment of specific biochemical markers of bone metabolism and by measurements of bone mass using different techniques. We are
also actively involved in the study of bone health in several pediatric disorders. In particular, we are investigating the role of antiretroviral treatment on bone mass in HIV-infected youths, in collaboration with Alessandra
Viganò at Sacco Hospital in Milan. We are also studying bone mass and bone metabolism in young patients
with congenital adrenal hyperplasia, a disease leading to disturbances of sexual differentiation.
In collaboration with the Universities of Milan, Insubria, and Catania, our group is coordinating a research
aimed to the identification of genetic markers of a rare disorder of glucose metabolism: Congenital Hyperinsulinism of Infancy (CHI). We established a National Registry for this disease, and we enrolled and studied 35
families with CHI. Molecular studies lead to the identification of several novel mutations responsible for the
disease.
Hypophosphatemic rickets is a rare condition leading to impaired bone mineralization, skeletal deformities,
and metabolic disturbances. The cause of the disease have been described recently, but they remain unknown
in some patients. Our group is involved in a collaborative study with the group of Maria Luisa Brandi, University of Florence, to identify the genetic causes of this type of rickets.
Stefano Mora
DIABETES AND ENDOCRINOLOGY UNIT
The research of our unit focused on relevant clinical questions, such as self-monitoring of blood glucose,
lifestyle changes (diet and physical activity), disabling diabetic neuropathy:
1. Self-monitoring of blood glucose for the management of patients with type 2 diabetes is a controversial issue. We are conducting a Nationwide multicenter randomized clinical trial to study the impact of a program of lifestyle changes based on self-monitoring of blood glucose in patients with type 2 diabetes treated
with diet alone or oral agents. The trial will recruit 1000 participants in over 30 diabetes outpatient clinics
throughout Italy.
2. Physical activity is one of the cornerstone of diabetes treatment. However, only a small proportion of patients with type 2 diabetes walks at least 10,000 steps/day. Modern technology may help our patients
achieve this goal. We are conducting a randomized clinical trial to assess whether providing patients with
type 2 with a with a step counter with wireless connection to a cell phone helps achieving the walking goal
of 10000 steps/day.
3. Patients with type 1 diabetes need to adjust their pre-meal insulin bolus according to the expected carbohydrate content of their meal. The method of carbohydrate counting has become very popular in Northern
America and more recently in Europe. We are conducting a randomized clinical trial to study the impact of
carbohydrate counting on glucose control in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion using an external insulin pump.
4. Peripheral neuropathy is a frequent and disabling microvascular complication of both type 1 and type 2 diabetes. Pharmacological treatment of diabetic neuropathy is purely symptomatic and largely unsatisfactory.
As a novel and original non pharmacological treatment, a Frequency modulated Electro-Magnetic neural
Stimulation (FREMS) method, characterized by sequences of modulated electrical stimuli which vary automatically in pulse frequency, duration and voltage amplitude, has recently been developed by our group. In
a pilot trial FREMS proved to be safe and efficacious in the treatment of painful diabetic neuropathy, with
the evidence of associated enhancement of local tissue microcirculation.
Emanuele Bosi
CARDIO-METABOLIC AND CLINICAL TRIALS
New etiopathogenetic approaches and clinical trials in the prevention and cure of Cardio-diabetes Syndrome
The main hypothesis of CARDIO-DIABETES Project is that type 2 diabetes mellitus and ischemic cardiomyopathy are the same disease. Furthermore, in our opinion, the heart is not only a passive player being affected
by the negative effects of type 2 diabetes but is also an active player acting as an endocrine-metabolic organ able
to induce type 2 diabetes. To screen populations at higher risk to develop DM2, we initiated the characterization of the metabolic and endothelial differences between coronary and carotid atherosclerosis. Preliminary data in a small group of patients suggested that coronary atherosclerosis is characterized by decreased adiponectin
levels, insulin resistence and a more proatherogenetic profile than carotid atherosclerosis. Conversely, an increased prothrombotic state and higher platelet activation seem to be present in patients with carotid vasculopathy, suggesting the presence of a marked heterogeneity of coronary and carotid atherosclerosis. Further, in
patients with heart valve disease we demonstrated a high prevalence of DM2 associated with increased ANP
and FFA levels. In the light to evaluate innovative treatments to revert insulin resistance (IR) and endothelial
dysfunction (ED), as part of a nutritional planning, two studies with L-arginine were performed in CAD and in
obese type 2 diabetic patients. In both cases, we showed that chronic oral L-arginine therapy ameliorated IR,
ED, glucose tolerance and inflammation. In a new protocol, in collaboration with GPs of Milan area, we aim to
deepen insight in the the characterization of glucose tolerance and insulin resistance not only in CAD patients
but also in first degree relatives (CAD-R). We also plan to cross-integrate a therapeutic intervention by changes
in life style, diet and physical activity aimed to reduce the progression to type 2 diabetes with analytical research
procedures based on the evaluation of eNOS variants both in CAD and CAD-R. The Unit works in strict collaboration with the Cardio-Diabetes and Core Lab. Unit. The group also collaborate with the Neurogenomics
Unit, the Cardio-Thoraco-Vascular and the Neurology Departments. The group is also involved in the largest
and major world-wide sponsored Clinical Trials for the prevention and cure of DM2 and CAD.
Piermarco Piatti
CLINICAL PEDIATRIC ENDOCRINOLOGY
We evaluated the role of genetic alterations on etiopathogenesis of some paediatric endocrinopathies.
Congenital Hypothyroidism (CH): we identified in cooperation with Milan University, 7 mutations on gene
involved in iodine organification (DUOX2/ DUOXA2), and 3 mutations on TSH-receptor gene. We also performed genetic analysis in patients with CH and associated choreoathetosis, discovering two new mutations in
TTF1 gene. We are performing studies to identify interaction between genetic, epigenetic environmental, factors of pathogenesis of CH.
Congenital Hyperinsulinism: to date, 34 families have been recruited; we identified 13 mutations in ABCC8/
KCNJ11 genes (5 new mutations). Moreover one patient had a novel mutation of the HADH gene; two patients
showed an homozygosity strand on chromosome 1, containing the MCAD gene. Finally we identified new possible loci associated to CHI in families (by genome-wide SNP mapping). In the next years we will continue to
screen new patients.
Hypogonadotrophic Hypogonadism: we are studying these patients from clinical and genetic perspective. In
two patients a mutation in candidate genes has been found.
Overweight and obesity are increasing dramatically in children. A timely diagnosis of impaired glucose tolerance (IGT) is desirable in obesity. We assessed whether one or more biochemical indexes measured in fasting
conditions could be used to identify obese children at risk of IGT.
In order to assess less-invasive and more accurate methods for the diagnosis and follow-up of various forms of
Congenital Adrenal Hyperplasia (CAH), we determined salivary and urinary steroid profile through liquid
chromatography-mass spectrometry. In CAH due to 21-hydroxylase deficiency, a good differentiation between
heterozygotes and healthy subjects is obtained through urinary hormones 17-hydroxypregnanolone and pregnenediol.
Small for gestational age (SGA) children are at risk for obesity and Metabolic Syndrome (MetS). We continued the analysis of the intrahepatic fat, measured using localized hepatic 1HMRS, whole body energy homeostasis, insulin sensitivity, and body composition in SGA and born appropriate for gestational age adolescents.
Giovanna Weber
DIABETES AND METABOLIC DISEASES IN CHILDREN AND
ADOLESCENTS
The aim of the unit is clinical research in children and adolescents with type 1 diabetes. We have a large outpatients clinic attended by 750 pediatric subjects with diabetes.
We have 3 main lines of study: 1) technology in diabetes 2) prevention of micro and macrovascular complication of diabetes 3) obesity in diabetic children.
We study the different application of technology in pediatric diabetology. More than 140 children treated
with pump for continuous subcutaneous insulin infusion (CSII) are in follow-up for many years end monitoring
long term results in term of HbA1c, acute complications, quality of life. We took part in a multicenter italian
study named VIPKIDS in order to study results and quality of life in children with CSII. Moreover we use continuous glucose monitoring (GCMS) in children and adolescents and we follow in outpatients the first combined application of CSII and CGMS. We are comparing CSII and MDI in children < 6 yrs.
Regarding prevention of microvascular complication we have a database of patients with longlasting diabetes
in order to perform periodic assessment monitoring the microvascular complications and related factors. Moreover we perform a study with Dr Zerbini on effect of EPC cells in retinopathy and on level of C peptide and microvascular complications.
In order to study the prevalence of obesity in type 1 diabetic children we perform a study in a cohort of 7-14
year’s old children with diabetes compared with a cohort of normal children same age. We evaluate risk factors
for macrovascular complications, physical examination and laboratory results.
Moreover we try to study the effect of the introduction of carbohydrate counting in the metabolic control and
BMI change in diabetic children.
We are an active part of SIEDP’s group in pediatric diabetology and we participate in different multicenter
studies.
Our Unit is fully involved in research projects in cooperation with Childhood Diabetes Unit of Diabetes Research Institute in the following topics: secondary and tertiary prevention of type 1 diabetes, identification of
rare cause of monogenic insulin dependent diabetes.
Franco Meschi
NEONATOLOGY
Central nervous system and neuropsychological development in newborn
The study of central nervous system maturation and of neuropsychological development in term and preterm
newborn in different clinical conditions is one of the most important research area of our group. The collaboration with Neuroradiology Unit and Neuroscience Department is pivotal for such studies.
• A longitudinal study is ongoing in order to evaluate myelinization and maturation of brain by serial MRI scan
in preterm babies with gestational age less than 34 weeks at birth: different imaging tecniques, like diffusion
technique imaging (DTI) and functional MRI are performed with high field MRI. Clinical and psychomotor
follow up evaluations will be correlated to post-natal clinical data. Preliminary data are under evaluation and
analisis.
• We examine neuronal function understanding auditory development in the first week of life. We used functional MRI to study brain activity in melodic and language processing in a cohort of newborns.
• The Unit is involved in a multicentre study, with other Italian Neonatology Units, on quality of life in “wellbeing” preterm infants: the aim of this study is to evaluate quality of care, its perception from the baby, effect and consequence on neuropsychological development up to the age of seven years.
Graziano Barera
FOETAL-MATERNAL MEDICINE
Study of new predictors of pregnancy outcomes in women with high risk pregnancies
1. Study of markers of cellular and systemic inflammation
We are planning a prospective study of women at high risk of complications during pregnancy (Anti Phospholipids Syndrome, recurrent miscarriages, second trimester abortion or intrauterine fetal death, even in the
absence of detectable autoimmunity). The goal is to explore the markers of cellular activation, systemic inflammation and coagulation. The patients, all treated with low molecular weight heparins, will be matched with a
control group, free from pregnancy complications. An additional group of women with type 1 diabetes, a disease of autoimmune etiopathogenesis, will also be studied. We project to start patient recruitment in early 2010,
after Ethics Committee approval.
2. Study of early morphological markers of abnormal fetal development
Despite optimal pre-natal care pregnant patients with type 1 diabetes have an increased risk of macrosomia
and fetal distress compared to women without diabetes. Furthermore, the growth pattern of fetuses of diabetic
mothers and the timing of growth changes are poorly understood. Recent evidences are highlighting the relevance of events in the first trimester of pregnancy for the development of complications in the later phase of
pregnancy. We described a specific delay of early growth among diabetic pregnancies, and this finding may be a
predictor of the pregnancy outcome. By conventional and 3D ultrasound we are continuing the study of fetal and
placental volumes to document fetal and trophoblastic development during the first trimester and the correlation
of these measurements both with levels of maternal serum hormones (eg f-BhCG and PAPP-A) and with pregnancy outcomes in women with type 1 diabetes and women at high risk of complication during pregnancy.
3. Study of feto- placentar nucleic acids in maternal plasma in preeclampsia and intrauterine growth restriction
Our collaboration with the Genomic Unit for Diagnosis of Human Pathologies is ongoing and we are evaluating a panel of transcripts of fetal and placental genes potentially involved in the pathogenesis of preeclampsia
and intrauterine growth restriction. At this purpose we are collecting blood from patient at risk to develop this
pathologies at different gestational ages. The identification of early markers of these diseases is important for
early diagnosis and prevention.
4. New therapeutic option for gestational diabetes
We are designing a study of vitamin supplementation in pregnancies complicated by gestational diabetes mellitus (GDM). Myoinositol has been already been used for the treatment of Polycystic Ovarian Syndrome with
an improvement of insulin-resistance. Our hypothesis is that myoinositol in patients with GDM will improve
insulin resistance and decrease the proportion of women with GDM who will require insulin to control their
blood glucose during pregnancy. We are planning to start recruitment for this study in July 2010
Maria Teresa Castiglioni
INFERTILITY
The department is primarily involved in both clinical and laboratory (applied) research with the final aim to
increase pregnancy outcome in couples undergoing assisted reproductive technologies. Our team is testing the
clinical efficacy of different novel molecules on the outcome of ovulation induction protocols. Two multicentre
randomised control trials are on: the first on a novel method for subcutaneous progesterone administration, is
renewing interest on the importance of the luteal phase support; the latter, is testing the role of co-treatment (rFSH + r-LH) in the approach to “poor prognosis patients” such as aged women or patients with a compromised ovarian reserve. Actually we are the first Italian IVF (In-vitro Fertilization) department undergoing trials
on nutraceutical (i.e Inositol and Melatonin) in reproductive fields.
Optimization of gametes is part of a project aimed to improve the clinical outcome of IVF. The study involves
males undergoing ICSI (intra cytoplasmic sperm injection) for severe oligoastenozoospermia in the absence of
chromosomal abnormalities. Patients are divided into two groups undergoing ICSI or IMSI (High Magnification Sperm Injection). The same samples are also analyzed for DNA integrity. SCSA (Sperm Chromatin Structure Assay) via flow cytometry has been developed in collaboration with Dr. A. Palini - Laboraf. The study try
to determine if, independently from the rate of DNA damage, a severe oligozoospermic patient can benefit
from IMSI.
Cryoprotectants (CPAs) are essential for cryopreservation but potentially can cause disruption of cell function. Studies in the mouse suggest that exposure to CPAs can generate a transient increase in intracellular Ca2+,
thus leading to a disturbance of cell cycle or activation. Therefore, the recording changes of intracellular Ca2+
in oocytes during exposure to CPAs could help to identify more appropriate conditions to minimize the disruption of cell cycle and, ultimately, improve the entire process of cryopreservation. Aim of our study is to evaluate
the increase in the concentration of intracellular Ca2+ adding different types and concentration of cryoprotectants simulating conditions adopted for slow freezing or vitrification of human oocyte.
Enrico Papaleo
CARDIOVASCULAR INTERVENTIONS UNIT
Imaging/Intravascular Ultrasound (IVUS): New criteria for optimal DES were tested in the multicenter randomized AVIO study. APICE OCT is an ongoing multi-center, randomized trial evaluating the re-endothelization of 2 second generation (zotarolimus vs. everolimus) drug-eluting stents.
Complex Coronary Lesions: Outcomes following drug eluting stent (DES) implantation vs. CABG in unprotected left main coronary artery lesions and anatomical features of restenosis following bare metal stent and
DES implantation were reported from our center. Two randomized trials were conducted to assess the optimal
revascularization therapy in diabetics with multivessel disease (FREEDOM) and in triple vessel disease and/or
left main lesions (SYNTAX). RITMO, is an Italian registry evaluating prevalence, therapeutical choice and
prognosis of patients with angiographic stenosis of unprotected left main disease.
Paclitaxel-eluting balloons: two randomized studies evaluating drug-eluting balloons as compared to DES in
de novo coronary lesions are ongoing: DILATATION and BELLO.
Adjunctive therapy: The PARIS registry is a study evaluating dual antiplatelet therapy (DAT) after stent implantation. The duration of DAT is currently also being investigated in the SECURITY study. Adjunctive therapy trials are: AQUARIUS, evaluating the efficacy of aliskiren on the progression of atherosclerosis in patients
with coronary artery disease when added to optimal background therapy; BINDARIT, a pilot study to evaluate
the efficacy and safety of Bindarit dose in preventing bare-metal stent restenosis; and the SATURN trial, assessing the effects of high doses of atorvastatin vs. rosuvastatin.
Neoangiogenesis: evaluated through intramyocardial injection of autologous stem cells in patients with refractory angina despite optimal medical therapy or not eligible for further revascularization.
Structural Heart Disease/Transcatheter valve therapy: Two devices of our program received CE-mark approval: the balloon-expandable Edwards-Sapien valve, and the self-expanding CoreValve ReValving System.
The multi-center SOURCE registry is testing Edwards Sapien. The outcomes of a percutaneous edge-to-edge
repair approach for mitral valve regurgitation with the MitraClip system (Evalve) were reported.
Antonio Colombo
CLINICAL CARDIOVASCULAR BIOLOGY UNIT
WP1: Circulating inflammatory markers in ACS
Task 1 - The study of markers of activation of leukocytes during the very early phase (< 6 hours) of acute myocardial infarction (STEMI) has revealed the presence of fully degranulated neutrophils in circle. This observation allowed us show that platelets and leukocytes are activated and transiently express a pro-thrombotic and
proinflammatory phenotype. We observed that neutrophils phagocyte activated platelets in the circulation,
helping to eliminate circulating activated platelets and could help explain the transience of the phenomenon.
Blood. 2009, 113 (21): 5254-65
Task 2 - Biological phenotype of 1099 STEMI and 878 controls in three ethnic groups (Italy, Scotland, China).
We studied their metabolic and inflammatory profiles, the incremental value of inflammatory markers on top of
risk factors and the cytokine profiles in samples upstream of active coronary lesion and downstream into the coronary sinus. [Young Investigator Award XV International Symposium On Atherosclerosis 2009 (Boston), Young
Investigator Award Congress of the Italian Society for the Study of Atherosclerosis (Milan 2009)]
Task 3 - Blood levels and function regulating lymphocytes (Treg) in acute and chronic coronary syndromes
(ACS); identifying a possible differential role of Treg in different presentations of coronary artery disease.
WP2: Gene Profiles in acute coronary syndromes
We completed DNA extraction and quality control in our biobank of 1099 STEMI, 878 100 NSTEMI and
100 PVD. A first set of 48 SNPs for 100 STEMI, 100 NSTEMI and 100 controls was studiedand we have identified a subset of SNPs to be studied on the remaining patients and controls.
WP3: Study of other mechanisms that could explain the transience of the cellular activation observed in AMI
Task 1 - The role of pentraxin 3 an acute phase reactant produced by monocytes, macrophages and neutrophils. In vitro PTX3 modulates platelet adhesion and reduces the stimulating effect of activated platelets on
neutrophils.
Task 2 - Components of Coronary Thrombus. We showed that the neutrophil degranulation in ACS is not
due to atherosclerosis or to ischemic damage while coronary thrombi show neutrophil extracellular traps
(NETs) and that activated platelets induce NETs.
Domenico Cianflone
Figure 9. TEM imaging of the phagocytic clearance
of an activated platelet
ISCHAEMIC HEART DISEASE, HEART FAILURE AND
ECHOCARDIOGRAPHY UNIT
Our group is carrying out several lines of investigation in the 3 main fields of interest of the Unit: ischemic
heart disease, heart failure and echocardiography.
Heart failure
• Myocardial mytochondrial ferritin determination in patients with dilated cardiomyopathy of different etiologies - This study aims to compare mytocondrial ferritin expression in biopsies obtained from “healthy” subjects and patients with heart failure; in 2009 we performed 9 myocardial biopsies in “healthy” subjects during heart surgery.
• Metabolic modulation of left ventricular function and energy metabolism in patients with heart failure: role of insuline sensitizers and anti-oxidants - The aim of these two protocols is to study the profound metabolic modification occurring in heart failure, often enhanced by insuline resistance and increased xantine oxidase levels.
• Effects of acute manipulation of serum non esterified fatty acids concentration on left ventricular energy metabolism and function in patients with heart failure - We have completed the first part of the study which
tries out the hypothesis that acute variations of circulating metabolic substrates could negatively affect left
ventricle energetic homeostasis in heart failure patients.
• The role of essential aminoacid supplementation in chronic heart failure - This study evaluates the therapeutic
effects of essential aminoacids supplementation in counteracting the metabolic derangements occurring in
congestive heart failure.
Ischeamic heart disease
• Bone mass density, osteoprotegerin levels and severity of atherosclerotic coronary disease in unstable and stable
patients - During the last year, we have studied osteoprotegerin levels in 33 patients with stable coronary artery disease and 21 patients with ST elevation myocardial infarction.
• Assessment of Loxin Test in the evaluation of coronary risk - We have enrolled 100 patients with coronary artery disease and 100 healthy controls, in order to evaluate the usefulness of Loxin Test for the assessment of
coronary artery disease risk; the results will be soon available.
Echocardiography
In the year 2009 the echolab was actively involved in many research fields. 3d echocardiography has been applied in particular to mitral valve disease, often in functional mitral regurgitation in patients with left ventricu-
lar disfunction; other areas of research include the clinical application of contrast echocardiography, basic research of animal experiments, and the clinical application of new generation of contrast molecular agents.
Alberto Margonato
ORGAN PROTECTION IN CRITICALLY ILL PATIENTS, ADVANCED
CARDIAC FAILURE AND MECHANICAL SUPPORTS UNIT
Perioperative organ failure is associated to high morbidity and mortality. We are coordinating large multicentre randomized controlled studies at the Italian level on numerous topics. These studies are supported by the
two largest and most influential Italian scientific societies in the field of anesthesia and intensive care (SIAARTI
and ITACTA). All the studies have been approved by the Ethical committee of San Raffaele Hospital, have
been published on www.clinicaltrials.gov and include:
• early treatment of low cardiac output syndrome and of advanced heart failure with mechanical supports
(ECMO, VAD in scientific collaboration with the Berlin Hertz Centrum.) or with pharmacological support
(levosimendan vs placebo: 30 centres, 1000 patients, double blind RCT).
• prevention of dialysis dependent acute renal failure and mortality after cardiac surgery (20 centres, 1000 patients, fenoldopam vs placebo, double blind RCT)
• optimization of perioperative cardiac protection (esmolol vs placebo and volatile agents versus total intravenous anesthesia).
• safety and efficacy or recombinant activated factor VII, of desmopressin, factor XIII, protein C zymogen
and protein C activated in patients experiencing excessive bleeding or with sepsis after surgery in large multicentre randomized studies or in patients with severe sepsis admitted in the intensive care unit.
• anesthesiological challenges of the unfit patients, ideal candidate to transfemoral artery aortic valve implantation.
• non-invasive ventilation outside intensive care unit and the role of the Medical Emergency Team for a timely treatment of critically ill patients in the hospital ward.
• cardiac biomarkers (proBNP, cardiac troponin) and Renal biomarkers (ouabaine)
We are also publishing numerous original papers and systematic review of the literature on the above described topics. With almost 40 papers published in pubmed indexed journals in 2009 we’re the most prolific
Italian group publishing in anesthesia and intensive care journals.
We are also editing an international journal “HSR proceedings in Intensive Care and Cardiovascular Anesthesia”, freely available on www.itacta.org
Alberto Zangrillo
STRUCTURAL HEART DISEASE UNIT
Treatment of structural heart disease
Heart failure
Surgical strategies to treat patients with heart failure due to ischemic or idiopathic cardiomyopathies are investigated.
Original procedures to correct secondary mitral and tricuspid regurgitation have been developed and extensively applied with a rigorous long-term follow-up.
A multidisciplinary protocol for mechanical circulation assistance has been prepared and selection intense
have been established. Cell therapy (myoblast) has been used in patients with post infarction left ventricular
dysfunction, in the contest of a multicenter prospective monitorized placebo controlled study (MAGIC study).
Heart valve disease
Innovative techniques to repair mitral and aortic valve are systematically evaluated. New imaging modalities
are applied and correlated to the operative findings. In repair the tricuspid valve, a new prosthetic ring has
been developed and tested on the bench.
Ischemic heart disease
Active contribution has been given to the SYNTAX study and the FREEDOM study, both comparing PCI
and CABG in multivessel disease.
Atrial fibrillation
New surgical methods to increase the effectiveness of the atrial fibrillation ablation procedures, during open
heart surgery, have been developed. A program for the treatment of lone atrial fibrillation via a minimally invasive approach has been initiated, and new technologies have been introduced and meticulously tested. The left
atrial remodeling has been studied non only structurally but also at molecular and biochemical level.
Transcatheter valve therapy
A multidisciplinary program for transcatheter aortic and mitral valve therapy has been developed using a
wide spectrum of techniques and technologies. Guidelines have been prepared and extensive investigation in
this new area are ongoing.
Ottavio Alfieri
STUDY AND TREATMENT OF AORTIC DISEASE UNIT
Our group is conducting several clinical research studies regarding the treatment of aortic disease.
In particular, endovascular repair has emerged as an extremely valuable alternative modality for the treatment
of thoracic aortic diseases due to its reduced invasiveness as compared to open repair. We are studying technical and clinical outcomes of the thoracic endograft Zenith Cook TX2 for the treatment of the aneurysms of descending thoracic aorta participating at the pivotal multicentric (42 North American and European Centers)
non-randomized trial Zenith TX2 Thoracic Endovascular graft Clinical Study Protocol #03-536 (enrolment
2006 – 2011). We also analysed the outcomes of endovascular treatment of thoracic aortic disease with the thoracic endograft Bolton Relay participating at the RESTORE registry.
Regarding the outcomes of endovascular repair of aortic dissections we also participate at the multicentric (12
European Centers) non-randomized trial Zenith Dissection Endovascular System Clinical study Protocol # 07004 (enrolment 2008-2013) to evaluate the outcomes of the treatment of acute type B dissection with the thoracic endograft TX2 and the stent Zenith Cook TXD (Zenith Dissection Endovascular System).
We also participate at the study SAFROS: Patient Safety in Robotic Surgery (2010-2013) in order to develop
technologies for patient safety in robotic surgery. In particular the aim of the study is to demonstrate that a properly controlled robotic surgery can improve the level of patient safety currently achievable by traditional surgery.
We also deepened specific strategies for virtual angioscopy (figure 10) and for the preoperative detection of
the Adamkiewicz artery by multidetector computed tomography and post-processing with OsiriX software.
In addition, we updated early and long-term results of endovascular repair of traumatic thoracic aortic rupture, and conducted and analysed the outcomes from a National survey on endovascular repair of aorto-oesophageal and aorto-bronchial fistulas.
As a Nation referral Center, we are reviewing our large experience of open and hybrid repair of thoracoabdominal aortic aneurysms and dissections with the use of the more innovative technique of organ protection
and specific graft material.
Roberto Chiesa
Figure 10. Virtual angioscopy enables an endoluminal view of the aorta and
allows to navigate within the true (green box) and false lume (red box).
Navigating through the lumens allow to study the origin of renal and visceral
vessels and their relationship with the dissecting lamella.
CENTER FOR ARRHYTHMIA RESEARCH
The research activity of the Arrhythmology group of San Raffaele University-Hospital is focused on atrial fibrillation ablation, particularly on remote ablation using tip-irrigated magnetic catheters in 2008. In our center
catheter ablation of atrial fibrillation is safely performed in many patients with and without comorbidities. We
are conducting a large study in the elderly to assess both efficacy and safety in this patient population. Another
area of research is the pathophysiology of atrial fibrillation investigating the natural history of the arrhythmia
with its progression from the first symptomatic episode. We are also assessing the effect of catheter ablation on
atrial fibrillation progression by the APAF2 study which is a 3-year extension study of the previous 1-year
APAF trial. It was designated to compare the long-term outcome of catheter ablation versus conventional antiarrhythmic drug therapy in a large number of patients randomized to both strategies. At 3 years (2008) the results demonstrate a striking superiority of catheter ablation over antiarrhythmic drugs in terms of efficacy, arrhythmia progression and late complications. The identification of asymptomatic subjects at risk of sudden
death with either latent Brugada syndrome or Wolff-Parkinson-White syndrome represents another important
area of research in our center. Finally, the last area of research is the development of new technologies for
catheter design and 3D anatomical reconstruction of cardiac chambers for atrial fibrillation ablation.
Vincenzo Santinelli
VISION FIRST UNIT
The Research Unit “Vision First “ was started in November 2009 under the direction of Prof. Francesco Bandello. The following Research Lines (CR: Clinical Research BR: Basic Research) are part of the Unit:
Medical Retina
CR: New therapeutic options with intravitreal compounds (anti-VEGF agents or steroids) for Age-Related
Macular Degeneration (AMD), Diabetic Retinopathy (DR) and Retinal Vein Occlusion, are presently tested in
several multicentre clinical trials.
BR: Evaluation of the behaviour of Endothelial Progenitor Cells in DR and AMD in collaboration with the
Diabetes Complication Unit.
Surgical Retina
CR: Evaluation of new therapeutic options: Enzymatic Vitreolysis with Autologous Plasmin and use of neuroenhancement agents in patients with previous Retinal Detachment.
BR: Set up of a Vitreous Biobank.
Pediatric Ophthalmology
CR: Multicentre clinical trial to test efficacy and tolerance of Azytromicin vs Tobramicin in pediatric purulent
bacterial conjunctivitis.
Neuro-Ophthalmology
CR: Evaluation of structural and functional brain damage and visual network plasticity in Leber’s Hereditary
Optic Neuropathy, Hereditary Retinal Dystrophies and Ereditary Optic Neuropathies in collaboration with
Neuroradiology and Neuroimaging Research Units.
Evaluation of efficacy and safety of surgical decompression and Gamma Knife radiosurgery on Pituitary Tumors and Meningiomas compressing the anterior visual pathway in collaboration with Neurosurgery Unit.
Orbital Surgery
CR: Evaluation of new therapeutic strategies of ocular MALT lymphomas in collaboration with Pathology
and Oncology Unit.
Imaging
CR: Evaluation of the inter/intra operatory reproducibility of nerve fiber layer thickness and topographic
measurement of the optic nerve and cornea among different Spectral Domain OCT instruments.
Ocular Immunology and Uveitis
CR: Evaluation of new biologic agents for the treatment of intraocular inflammation.
Ocular Oncology
CR: Evaluation of treatment with Gamma Knife Radiosurgery of conjunctival and intraocular tumors in collaboration with Neurosurgery Unit.
Glaucoma
CR: Several clinical studies (multicentric and single center) to test new medical and surgical therapeutic options in glaucoma management are ongoing.
Francesco Bandello
9 Benedini, S; Perseghin, G; Terruzzi, I; Scifo, P; Invernizzi, PL; Del Maschio, A; Lazzarin, A; Luzi, L. Effect
of L-acetylcarnitine on body composition in HIV-related lipodystrophy. Horm. Metab. Res.: 2009; 41(11): 840845 - Article
IF 2008: 2,715
9 Blasi, V; Longaretti, R; Giovanettoni, C; Baldoli, C; Pontesilli, S; Vigone, C; Saccuman, C; Nigro, F; Chiumello, G; Scotti, G; Weber, G. Decreased parietal cortex activity during mental rotation in children with congenital hypothyroidism. Neuroendocrinology: 2009; 89(1): 56-65 - Article
IF 2008: 2,913
9 Castoldi, G; di Gioia, CRT; Bombardi, C; Perego, C; Perego, L; Mancini, M; Leopizzi, M; Gorradi, B; Perlini, S; Zerbini, G; Stella, A. Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic
rats. Clin. Sci.: 2010; 118(3): 211-220 - Article
IF 2008: 4,187
9 De Cobelli, F; Esposito, A; Belloni, E; Pieroni, M; Perseghin, G; Chimenti, C; Frustaci, A; Del Maschio, A.
Delayed-enhanced cardiac MRI for differentiation of fabry’s disease from symmetric hypertrophic cardiomyopathy. Am. J. Roentgenol.: 2009; 192(3): W97–W102 - Article
IF 2008: 2,940
9 Del Rio, D; Valtuena, S; Pellegrini, N; Bianchi, MA; Ardigo, D; Franzini, L; Scazzina, F; Monti, L; Zavaroni,
I; Brighenti, F. Intervention study with a high or low antioxidant capacity diet: Effects on circulating Î2carotene. Eur. J. Clin. Nutr.: 2009; 63(10): 1220-1225 - Article
IF 2008: 2,686
9 Di Candia, S; Gessi, A; Pepe, G; Sogno Valin, P; Mangano, E; Chiumello, G; Gianolli, L; Proverbio, MC;
Mora, S. Identification of a diffuse form of hyperinsulinemic hypoglycemia by 18-fluoro-L-3,4 dihydroxyphenylalanine positron emission tomography/CT in a patient carrying a novel mutation of the HADH gene. Eur. J.
Endocrinol.: 2009; 160(6): 1019-1023 - Case report
IF 2008: 3,791
9 Esposito, A; De Cobelli, F; Perseghin, G; Pieroni, M; Belloni, E; Mellone, R; Canu, T; Gentinetta, F; Scifo,
P; Chimenti, C; Frustaci, A; Luzi, L; Maseri, A; Del Maschio, A. Impaired left ventricular energy metabolism
in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging. Heart: 2009; 95(3): 228-233 - Article
IF 2008: 4,964
9 Lucotti, P; Monti, L; Setola, E; La Canna, G; Castiglioni, A; Rossodivita, A; Pala, MG; Formica, F; Paolini,
G; Catapano, AL; Bosi, E; Alfieri, O; Piatti, P. Oral l-arginine supplementation improves endothelial function
and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass. Metab.-Clin. Exp.: 2009; 58(9): 1270-1276 - Article
IF 2008: 2,920
9 Perseghin, G. Where does insulin resistance start? The liver. Diabetes Care: 2009; 32(Suppl2): S164-S167 Review
IF 2008: 7,349
9 Perseghin, G; Caumo, A; Lattuada, G; De Cobelli, F; Ntali, G; Esposito, A; Belloni, E; Canu, T; Ragogna, F;
Scifo, P; Del Maschio, A; Luzi, L. Elevated fasting plasma C-peptide occurs in non-diabetic individuals with
fatty liver, irrespective of insulin resistance. Diabetic Med.: 2009; 26(9): 847-854 - Article
IF 2008: 3,172
9 Perseghin, G; De Cobelli, F; Esposito, A; Belloni, E; Lattuada, G; Canu, T; Invernizzi, PL; Ragogna, F; La
Torre, A; Scifo, P; Alberti, G; Del Maschio, A; Luzi, L. Left ventricular function and energy metabolism in
middle-aged men undergoing long-lasting sustained aerobic oxidative training. Heart: 2009; 95(8): 630-635 Article
IF 2008: 4,964
9 Perseghin, G; Lattuada, G; Ragogna, F; Alberti, G; La Torre, A; Luzi, L. Free leptin index and thyroid function in male highly trained athletes. Eur. J. Endocrinol.: 2009; 161(6): 871-876 - Article
IF 2008: 3,791
9 Piemonti, L; Calori, G; Lattuada, G: Mercalli, A; Ragogna, F; Garancini, MP; Ruotolo, G; Luzi, L; Perseghin, G. Association between plasma monocyte chemoattractant protein-1 concentration and cardiovascular disease mortality in middle-aged diabetic and nondiabetic individuals. Diabetes Care: 2009; 32(11): 2105-2110 Article
IF 2008: 7,349
9 Sauer, AV; Mrak, E; Hernandez, RJ; Zacchi, E; Cavani, F; Casiraghi, M; Grunebaum, E; Roifman, CM;
Cervi, MC; Ambrosi, A; Carlucci, F; Roncarolo, MG; Villa, A; Rubinacci, A; Aiuti, A. ADA-deficient SCID is
associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance
and osteoblast insufficiency. Blood: 2009; 114(15): 3216-3226 - Article
IF 2008: 10,432
9 Setola, E; Monti, LD; Lucotti, P; Galluccio, E; Oldani, M; Bosi, E; Piatti, P. Fasting hyperinsulinemia associates with increased sub-clinical inflammation in first-degree relatives normal glucose tolerant women independently of the metabolic syndrome. Diabetes-Metab. Res. Rev.: 2009; 25(7): 639-646 - Article
IF 2008: 3,149
Neonatology
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 85
DIVISION OF REGENERATIVE MEDICINE, STEM
CELLS, AND GENE THERAPY
Director: Giulio Cossu
Associate Directors: Fabio Ciceri, Luigi Naldini *
Research Units
HEAD OF UNIT: Giulio Cossu
RESEARCHER: Graziella Messina
POST-DOCTORAL FELLOWS: Arianna Dellavalle, Hoshia Hidetoshi, Anna Pistocchi, Gonzalo Ugarte
PHD STUDENTS: Sara Benedetti, Ornella Cappellari, Simona Rolandi-Maciotta, Giuliana Rossi, Saverio Tedesco
FELLOWS: Chiara Bonfanti, Giovanni Maroli.
TECHNICIANS: Stefania Antonini, Diego Covarello, Anna Innocenzi, Stefania Monteverde, Laura Perani, Rossana Tonlorenzi
GROUP LEADER: Silvia Brunelli
POST-DOCTORAL FELLOWS: Stephanie François, Patrizia Pessina, Thierry Touvier, Paola Zordan
PHD STUDENTS: Emanuele Azzoni, Valentina Conti
FELLOW: Tiziana Fatone
Gene expression and muscular dystrophy Unit (Dulbecco Telethon Institute)
GROUP LEADER: Davide Gabellini
POST-DOCTORAL FELLOWS: Sergia Bortolanza, Cristina Godio, Mariaelena Pistoni, Alexandros Xynos
PHD STUDENTS: Daphne Cabianca, Valentina Casà, Claudia Huichalaf, Marie Victoire Neguembor
GROUP LEADER: Katharina Fleischhauer
POST-DOCTORAL FELLOW: Federico Sizzano
PHD STUDENT: Pietro Crivello, Cristina Toffalori
FELLOW: Cinzia Pultrone (from April 2009)
TECHNICIAN: Laura Zito
Neural stem cell biology
GROUP LEADER: Rossella Galli
PHD STUDENTS: Daniela Corno**, Laura Magri**, Stefania Mazzoleni**
FELLOWS: Sara Morosini, Mauro Pala
TECHNICIAN: Vivian Deidda Vigoriti
Autoimmunity & vascular inflammation Unit
HEAD OF UNIT: Angelo A. Manfredi*
PHD STUDENTS: Lidia Bosurgi**, Lucia Cottone
TECHNICIANS: Annalisa Capobianco, Antonella Monno
Innate immunity and tissue remodelling
GROUP LEADER: Patrizia Rovere-Querini
POST-DOCTORAL FELLOWS: Gianfranca Corna, Elena Rigamonti
PHD STUDENTS: Lara Campana, Alessandra Castiglioni, Michela Vezzoli
Cellular pharmacology Unit
HEAD OF UNIT: Emilio Clementi
POST-DOCTORAL FELLOWS: Clara De Palma, Sestina Falcone, Cristiana Perrotta
PHD STUDENTS: Laura Bizzozero, Roberta Buono, Denise Cazzato
FELLOW: Viviana Pisa
TECHNICIAN: Clara Sciorati
HEAD OF UNIT: Chiara Bonini
RESEARCHER: Attilio Bondanza
POST-DOCTORAL FELLOW: Luca Vago**
PHD STUDENTS: Monica Casucci**, Maddalena Noviello**, Elena Provasi**
FELLOW: Alessandra Forcina
RESIDENT: Sara Mastaglio
TECHNICIANS: Barbara Camisa, Zulma Magnani
Angiogenesis and tumor targeting
HEAD OF UNIT: Luigi Naldini*
GROUP LEADER: Michele De Palma
POST-DOCTORAL FELLOW: Roberta Mazzieri
PHD STUDENTS: Daniela Biziato**, Ferdinando Pucci**, Mario Leonardo Squadrito
TECHNICIANS: Davide Moi, Anna Ranghetti
Hematology and hematopoietic stem cell transplantation Unit
PHYSICIANS: Andrea Assanelli, Jacopo Peccatori
RESIDENTS: Valeria Calbi, Daniela Clerici, Raffaella Greco
POST-DOCTORAL FELLOWS: Maria Teresa Lupo Stanghellini, Annalisa Ruggeri
TECHNICIANS: Roberta Mattarucchi
Immunohematology and transfusion medicine Unit
HEAD OF UNIT: Silvano Rossini
RESEARCHERS: Laura Bellio, Oriana Perini
FELLOW: Irene Cuppari
PSIEP - Strategic Program of Pediatric Immunohematology
HEAD OF UNIT: Maria Grazia Roncarolo*
PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Barbara Cappelli, Sarah Marktel
RESIDENT: Sara Napolitano
The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET)
Director: Luigi Naldini*
Research Units
Gene transfer technologies and new gene therapy strategies Unit
HEAD OF UNIT: Luigi Naldini*
POST-DOCTORAL FELLOWS: Mario Amendola, Bernhard Gentner**
PHD STUDENTS: Francesco Boccalatte**, Alessio Cantore**, Pietro Genovese**, Alice Giustacchini**, Angelo Lombardo**,
Erika Zonari
TECHNICIANS: Giulia Schira, Lucia Sergi Sergi
Gene/Neural stem cell therapy for lysosomal storage diseases
GROUP LEADER: Angela Gritti
PHD STUDENTS: Chiara Cavazzin, Annalisa Lattanzi, Margherita Neri**, Sara Santambrogio**
FELLOW: Beatriz Alcalà-Franco
TECHNICIAN: Claudio Maderna
Hematopoietic stem cell gene therapy for lysosomal storage disorders
GROUP LEADER: Alessandra Biffi
POST-DOCTORAL FELLOWS: Alessia Capotondo, Ilaria Visigalli
PHD STUDENTS: Stefania Delai, Silvia Ungari**
FELLOW: Rita Milazzo
TECHNICIAN: Tiziana Plati
Safety of gene therapy and insertional mutagenesis
GROUP LEADER: Eugenio Montini
PHD STUDENTS: Daniela Cesana**, Marco Ranzani**
TECHNICIAN: Fabrizio Benedicenti
HEAD OF UNIT: Giuliana Ferrari*
POST-DOCTORAL FELLOW: Maria Rosa Lidonnici, Emanuela Anna Roselli
PHD STUDENT: Rossella Ierardi
TECHNICIANS: Giacomo Mandelli, Claudia Rossi, Francesca Tiboni
Immunological tolerance Unit
POST-DOCTORAL FELLOWS: Andrea Annoni, Georgia Fousteri, Kevin Goudy
PHD STUDENT: Maura Rossetti
TECHNICIANS: Grazia Andolfi, Claudia Sartirana, Eleonora Tresoldi
From FOXP3 mutation to IPEX syndrome
GROUP LEADER: Rosa Bacchetta
RESEARCHER: Barbarella Lucarelli
POST-DOCTORAL FELLOWS: Didem Aydin, Laura Passerini
PHD STUDENT: Sara Di Nunzio
Tolerogenic dendritic cells
GROUP LEADER: Silvia Gregori
PHD STUDENT: Giada Amodio, Chiara Magnani
TECHNICIAN: Daniela Tomasoni
Pathogenesis and therapy of ADA-SCID Unit
HEAD OF UNIT: Alessandro Aiuti
PHD STUDENTS: Luca Biasco, Immacolata Brigida, Aisha Vanessa Sauer
TECHNICIANS: Raisa Jofra Hernandez, Anna Ripamonti
Gene therapy for WASP/Omenn
GROUP LEADER: Anna Villa
POST-DOCTORAL FELLOWS: Marita Bosticardo, Renata Ilde Mazzucchelli, Samantha Scaramuzza
PHD STUDENTS: Marco Catucci, Michela Locci, Maria Carmina Castiello
TECHNICIANS: Elena Caldana, Elena Draghici
PCRU - Pediatric Clinical Research Unit
COORDINATOR: Alessandro Aiuti
PROJECT LEADERS: Alessandro Aiuti (ADA-SCID), Maria Grazia Roncarolo* (WAS), Maria Sessa and Alessandra Biffi (MLD)
RESIDENTS: Francesca Ferrua, Francesca Fumagalli
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Valentina Bergamante
FELLOWS: Federica Barzaghi, Marta Frittoli, Laura Lorioli
PHD STUDENT: Martina Cesani
RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi
Mission - The Division of Regenerative Medicine was established with the mission of exploiting results from basic and pre-clinical research to conduct a series of
Phase I/II cell and gene therapy clinical trials for monogenic disorders of the
hematopoietic system, skeletal muscle, and nervous system as well as to implement novel cell and gene therapy strategies for treating hematological malignancies.
Vision - The Division will develop or maintain strong and competitive research
activity in cell and developmental biology of these tissues; molecular pathogenesis
of the diseases under investigation; gene transfer and cell transplantation strategies; role of the inflammatory and immune response in modulating engraftment of the transplanted cells
and survival of the gene-modified cells.
Bringing together researchers with complementary skills and expertise will enable an effective synergy
between research projects that share common methodological approaches and face similar scientific/technological and regulatory hurdles, with the goal to ensure a robust pipeline of preclinical studies feeding
the clinical trial units. Recruitments in areas such as hematopoietic stem cell biology and translational medicine will complement the existing plan and increase the chance of achieving the ambitious goals of this plan.
Giulio Cossu
Organization - The Division is mainly comprised of three major pillars,
which represents the three major pre-existing structures that have now been
merged.
The first pillar is the San Raffaele-Telethon Institute for Gene Therapy
(TIGET; www.sanraffaele.org/research/tiget), directed by Luigi Naldini. This Fabio Ciceri
is a multi-disciplinary research Institute with strong emphasis on the development of gene transfer for the treatment of rare genetic disorders. The second pillar is the former SCRI
(Stem Cell Research Institute), originally founded to study muscle and neural stem cells and to design
novel cell therapies for these tissues, directed by Giulio Cossu. The third pillar is represented by the clinical HSC Transplantation (HSCT) Unit, directed by F. Ciceri, which has one of the largest HSC transplantation case records in EU
The Division currently comprises 11 Unit heads and 12 Group leaders for a total of approximately 200
researchers, graduate students and technicians. The governance format is based upon one Director (G.
Cossu) and two vice-directors (L. Naldini and F. Ciceri) and a Board also comprising four senior scientists
(A. Aiuti, C. Bonini, G. Ferrari and A. Manfredi).
Goals - Several genetic diseases will be targeted with cell and gene therapy approaches: these include
congenital immune deficiencies, hematologic disorders such as b thalassemia and hemophilia B, muscular
dystrophies, and several lysosomal storage disorders. Vector technology certainly represents one of the
strengths of our Division and will benefit most of the other projects. Basic research in areas mentioned
above will produce high quality results that in turn will support further developments in cell and gene
therapy.
Achievements - The Division is composed of several internationally recognized experts who contributed to: 2) the pioneering of successful gene therapy trials of hematopoietic stem cell (HSC) therapy
and of adoptive cancer immunotherapy; 2) the development and validation of new gene transfer technologies; 3) the identification and characterization of new stem cells, innate effector and immune regula-
tory cells; 4) a state-of-the-art clinical center for HSC transplantation in cancer and pediatric diseases; 5)
cutting edge results in basic reaseach. This is documented by numerous articles published in top tier journals (New England Journal of Medicine, Cell, Nature, Science etc.) and is supported by funding from
most competitive sources (NIH, ERC etc.). Many patents have been deposited securing the intellectual
property of this research activity.
Training opportunies - PhD programs, post-doctoral and resident fellowships.
Research Units
SKELETAL MUSCLE DEVELOPMENT AND THERAPY UNIT
The research activity of the unit focuses on the development and clinical translation of cell therapies for muscular dystrophies and on the study of skeletal muscle development. The first project aims at transplantation of
mesoangioblasts (pericytes) in primary myopathies and is currently dedicated to donor cell intra-arterial transplantation in pediatric Duchenne patients: a phase I/II clinical trial is foreseen to start early in 2011, while a preliminary trial to validate outcome measures in these patients started on June 2009 and will be completed by July
2010. Future protocols foresee autologous cell correction by either lentiviral vectors or human artificial chromosomes (HAC) respectively expressing either α sarcoglycan (for limb girdle muscular dystrophy 2D) or the whole
dystrophin locus for Duchenne, and have been tested in pre-clinical models. Specifically HAC-dystrophin have
been transferred in mouse dystrophic mesoangioblasts and have been shown to ameliorate structure and function of mdx dystrophic mice (Tedesco et al. submitted). Moreover protocols to derive mesoangioblasts from patients’ iPS are being developed aiming to make it available in the future an unlimited source of autologous cells.
The second project aims to understand the role of different cell populations in the histogenesis and regeneration of skeletal muscle, their origin, lineage relationship and the signals that control their differentiation. In particular we are focusing on the gene Nuclear Factor Ix that controls the transcriptional switch between embryonic and fetal skeletal muscle (Messina et al. Cell 2010). In addition, other experiments address the origin of
mesoangioblasts during fetal muscle histogenesis, their lineage relationship with skeletal myoblasts and their
fate using genetic lineage tracing.
Giulio Cossu
Figure 11. How can you mend a broken heart? The image shows
an explant culture from a heart biopsy with outgrowing cells.
Curiously, the explant has the shape of a heart.
FUNCTIONAL GENETICS OF MUSCLE REGENERATION
Molecular and cellular biology of muscle regeneration: role of necdin and of vascular endothelial precursors
Regeneration of muscle fibers, lost during pathological muscle degeneration or after injuries, is sustained by
generation of new myofibers. Necdin (Ndn) is a MAGE protein expressed in satellite cells derived myogenic
precursors during perinatal growth. Following muscle injury necdin null mice showed a significant defect in
muscle healing while mice over-expressing necdin showed significantly increased myofiber regeneration. We
elucidated the role of necdin in muscle showing that it increases expression of myogenin, by cooperating with
MyoD and accelerates differentiation (Deponti et al. JBC, 2007). We have also shown that necdin is selectively
expressed in the atrophic muscles of cachectic mice (tumor induced cachexia) and proved that its expression is
causally linked to a protective response of the tissue against tumor-induced wasting, inhibition of myogenic differentiation and fiber regeneration. Necdin plays this role mainly via interference with TNF-α signaling, including regulation of expression of TNFRI, of p53 and of the activity of caspase 3 and 9 (Sciorati et al., JCS, 2009).
Furthermore we were able to isolate a novel protein that interacts with Necdin, CCAR1/CARP1: the complex
Necdin/CCAR1/p53 appears to mediates the anti-apoptotic action of Necdin in myoblast precursor cells
(Francois et al, submitted).
These data prompted us to investigate whether Necdin could be exploited also to enhance myogenic differentiation and inhibit cell death of other types of stem cells, such as mesoangioblasts (MABs). Overexpression of
Ndn in vitro increases the differentiation ability of MABs, and inhibit cell death. In addition muscles of αSarcoglycan dystrophic mice injected with Ndn-MABs showed a greater reconstitution of stem cell derived
fibers respect to wt MABs (Pessina et al, submitted).
To investigate in vivo the role of endothelial derived myogenesis, we have generated a transgenic mouse expressing an inducible Cre recombinase (CRE-ERT2) under the control of an endothelial specific promoter
(Vascular Endothelial Cadherin). Lineage tracing experiments show that endothelial progenitors can give rise
to cells of the skeletal muscle lineage at fetal and perinatal stages and contribute to muscle regeneration following acute damage in the adult.
Silvia Brunelli
GENE EXPRESSION AND MUSCULAR DYSTROPHY UNIT
Our group is interested in elucidating the regulatory pathways controlling muscle-specific gene expression
and delineate how they become subverted in muscular dystrophy using facioscapulohumeral muscular dystrophy (FSHD) as a paradigm. FSHD is the second most common muscular dystrophy in adults. FSHD is an autosomal dominant disorder that is not due to a mutation within a protein-coding gene. Instead, FSHD patients
carry deletions of 3.3 kilobase macrosatellite, termed D4Z4, located at chromosome 4q35.
D4Z4 appears to regulate chromatin structure and its partial deletion causes an epigenetic alteration leading
to over-expression of the 4q35 gene FRG1. Importantly, transgenic mice over-expressing FRG1 display an
FSHD phenotype and are the first animal model of the disease.
The number of D4Z4 repeats is a critical determinant of the age of onset and clinical severity of FSHD. In
general, fewer repeats are associated with a more severe phenotype that presents in childhood. Paradoxically,
individuals completely devoid of D4Z4 are normal. This suggests that at least one copy of D4Z4 is required to
cause FSHD, possibly through a gain-of-function mechanism.
Our preliminary results indicate that an non-protein coding RNA (ncRNA) is generated starting from upstream of D4Z4 uniquely in FSHD patients. Interestingly, the ncRNA is nuclear because it remains associated
to the 4q35 chromatin. Notably, knockdown of this transcript causes a significant reduction of 4q35 gene de-repression. Hence, it is tempting to speculate that production of this ncRNA activates the epigenetic cascade culminating with 4q35 gene de-repression in FSHD. An attractive hypothesis would be that transcription of the
region proximal to D4Z4 may play a role in de-condensation of the 4q35 genomic region, setting the stage for
activation of 4q35 genes and, most importantly, preventing re-repression of the region.
We are characterizing the ncRNA to determine how it regulates 4q35 gene expression. These studies will provide a critical nexus for revealing the basis of ncRNAs in FSHD etiology and their possible use as therapeutic
targets.
Our analysis will generate novel insights into the biological role of DNA repeats and ncRNAs in regulating
chromatin structure in higher eukaryotes.
Davide Gabellini
MOLECULAR AND FUNCTIONAL IMMUNOGENETICS
The scientific activity of this Unit is aimed at characterizing new immunogenetic parameters relevant for the
clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT).
During the year 2009, the following main achievements were made:
Characterization of the loss of mismatched HLA by leukemia as a major mechanism of immune escape from allore-
active donor T cells in after haploidentical HSCT.
We characterized selective loss of the mismatched HLA haplotype through uniparental disomy (UPD) of the
short arm of chromosome 6, in 5 out of 17 patients (29.4%) of patients with leukemia relapse after haploidentical HSCT. This phenomenon was identified through comparative analysis of patient chimerism follow-up posttransplantation by short tandem repeat (STR) and by HLA typing. UPD of chromosome 6 was observed only in
leukemia at relapse and not in the same patient’s leukemia at diagnosis, showing that it was a de novo event. We
also showed that this event led to complete evasion of the mutated leukemia from recognition by donor T cells
alloreactive to the lost haplotype. These data underline the importance of an attentive cross-talk between the
laboratory and the clinics, and set the basis for searching for additional targets of post-transplant leukemia immunoediting.
Identification of non-permissive HLA-DPB1 disparities significantly associated with the clinical outcome of unrelated HSCT.
We refined a previously developed algorithm for definition of non-permissive HLA-DPB1 disparities, and
verified its predictivity in a collaborative study with the Italian Bone Marrow Donor Registry (IBMDR). In 537
consecutive transplants facilitated by the IBMDR from unrelated volunteer donors, we showed that the presence of non-permissive mismatches was significantly associated with the probability of overall survival, due to
non-relapse mortality. This was true not only in the cohort overall, but in particular in transplants presenting 0
or 1 additional mismatch at other HLA loci. These data set the basis for refining the guidelines for unrelated
stem cell donor selection. They are currently being tested in international collaborative studies, and functional
evidence for the underlying immunological mechanisms is being sought in the laboratory.
Katharina Fleischhauer
NEURAL STEM CELL BIOLOGY
Epidermal growth factor receptor (EGFR) is unevenly expressed in most of de novo glioblastoma multiforme
(GBM) specimens, suggesting that it might specifically label subsets of GBM cells that behave as tumor-initiating cells (TICs). Indeed, we purified different cell fractions from GBM patient’s specimens by fluorescence activated cell sorting (FACS), based on their relative expression of EGFR and of the putative TIC marker CD133
and demonstrated that all these subpopulations were endowed with tumorigenic potential, although to different extent. When subjected to whole-transcript microarray profiling, EGFR-expression TICs were characterized by a specific molecular signature, clearly distinguishable from that of EGFR-negative TICs and closely associated with highly malignant GBM subclasses.
➥
Figure 12. Cancer stem cells isolated from human
glioblastoma multiforme, stained for the Epidermal
Growth Factor Receptor (EGFR, green) and the
cytoskeleton protein F-actin (red).
Medulloblastoma (MB) is the most common brain tumor in childhood. We isolated several cancer stem cell
(CSC) lines from mouse MBs, aiming at the identification of CSC-specific genes by molecular comparison with
normal cerebellar neural stem cells (NSCs). Transcriptome analysis pinpointed several genes differentially expressed between CSCs and NSCs. One of them is Ebf3, a transcription factor involved in cerebellum development and neuronal commitment. We have assessed Ebf3 expression in human MB specimens both in silico and
by IHC and we observed that Ebf3 is highly expressed both at the mRNA and protein levels, thus suggesting a
relevant role of Ebf3 in human MB biology.
By targeting Tsc1 deletion to embryonic (e) and adult (a) NSCs, we generated Tsc1 mutant mice that display:
1) shortened life span; 2) alterations in cortical lamination and adult neurogenesis; and 3) spontaneous epileptic
seizures. During the last year, we established in vitro several eNSC lines from wt and mutant mouse cortex at
embryonic day 16.5. Mutant eNSCs are defective in their neurogenic potential, as they give rise to dramatically
low number of neurons. Most interestingly, mutant eNSCs overexpress several genes, involved in neural patterning and regionalization as well as in cell adhesion and motility, that are also expressed in patient-derived
cortical tubers (CTs) and subependymal giant cell astrocytomas (SEGAs).
Rossella Galli
AUTOIMMUNITY & VASCULAR INFLAMMATION UNIT
Threats to tissue integrity, including sterile injuries and infection, cause inflammation. Inflammation may lead
to eradication of invading pathogens and to the repair of damaged tissues. However, it may be deleterious,with
persistent inflammatory damage and degeneration. The pattern of cell death in situ and the features of leukocytes and antigen presenting cells that actually dispose of cell death remnants influence the outcome of the inflammatory event. Defects in the initiation and execution steps of programmed cell death such as in the clearance of cell debris contribute to systemic autoimmune diseases, in which the deregulated response to cell death
behaves both as an initiator and an amplifying circuit, contributing to the specific clinical features of each disease. Moreover, stem and precursor cells represent a potential target of the autoimmune response, which could
thus jeopardize their differentiation in the injured tissue. During vascular inflammation a self-sustaining circuit
attracts and activates inflammatory leukocytes in the wall of vessels of various size and anatomical characteristics. Vascular inflammation fulfils homeostatic roles and the activation of circulating leukocytes, platelets and
endothelial cells is under the control of humoral innate immunity. We are directly addressing the molecular
mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue injury, with specific attention to the role of injury-associated signals (Damage-Associated Molecular Patterns, DAMPS, or Alarmins)
and of acute phase proteins.
Angelo A. Manfredi
INNATE IMMUNITY AND TISSUE REMODELLING
Macrophages play a dual role in damaged tissues: they enhance local injury, through their effectors functions,
and they favour repair. Macrophage differentiate in polarized type I (classically activated) and type II (alternatively activated) macrophages in peripheral tissues, depending on environmental cues. The identification of the
molecular code that control macrophage fate, which can be partially mimicked or tampered with, will provide
novel strategies for the treatment of various immune-mediated diseases. The main goal of the group is to identify the events that determine the action of infiltrating polarized macrophages in in vivo models of acute (toxic)
and chronic injury of skeletal muscle (muscular dystrophies and inflammatory myopathies) and of the peritoneum, as a consequence of benign (endometriosis) and malignant (ovary carcinoma) ectopic cellular growth.
We specifically focus on the cross-talk between macrophages and stem/precursor cells in these models and are
actively investigating the molecular pathways by which the two cell populations influence and reciprocally control migration, survival and differentiation.
Patrizia Rovere-Querini
CELLULAR PHARMACOLOGY UNIT
Role of nitric oxide in myogenesis: physiological and pathological aspects
Mitochondrial dynamics in myogenesis: endogenous nitric oxide stimulates myogenic differentiation by inhibiting
mitochondrial fission
We elucidated the role of mitochondrial fission and fusion in skeletal muscle function. We found that inhibition of mitochondrial fission with formation of elongated mitochondria is required for myogenesis to occur and
that this event depends on endogenous generation of nitric oxide (NO) by the differentiating myogenic cells.
Blockade of NO synthesis enhanced activity, translocation and docking to mitochondria of the pro-fission GTPase dynamin related protein 1 (Drp1), inhibiting mitochondrial elongation and myogenic differentiation. A
dominant-negative Drp1 reversed the effects due to NO synthesis blockade on fission and myogenesis, establishing a causal relationship between these processes. Under NO synthesis blockade, myogenic precursors displayed a latent mitochondrial dysfunction, compensated under basal conditions but that rendered cells more
sensitive to apoptotic clearance. This indicates the existence of a quality control check for myogenesis, dependent on generation of NO and correct mitochondrial morphofunctional status.
Nitric oxide combined with non steroidal antiinflammatory drugs and the therapy of Muscular Dystrophyies
We developed a therapy of muscular dystrophies with clinical-grade drugs, without the severe side effect of
corticosteroids combining the non steroidal anti-inflammatory drugs (NSAIDs) ibuprofen or paracetamol and
the NO donor isosrbide dinitrate) Two murine models for muscular dystrophies (α-sarcoglycan null and mdx
mice) treated for one year showed significant amelioration of the morphological, biochemical and functional
phenotype in the absence of secondary effects. The mechanism of action of the treatment include cyclic GMPdependent enhancement of mitochondrial energy metabolism, and S nitrosylation of a specific type 2 histone
deacetylase. The new therapeutic strategy we propose is not selective for a subset of mutations and provides
ground for immediate clinical experimentation.
Emilio Clementi
EXPERIMENTAL HEMATOLOGY UNIT
T cell-based gene therapy for cancer
The immune system can be properly modified to eradicate cancer. Currently, effector molecules, such as monoclonal antibodies and cells such a tumor-reactive lymphocytes, able to selectively target and eliminate tumors,
may be isolated and/or engineered. The potency of cellular adoptive immunotherapy for the treatment of cancer has been clearly revealed by the persistent and complete clinical responses observed in patients undergoing
allogeneic hematopoietic stem cell transplantation (allo-HSCT) followed by the adoptive transfer of donor T
lymphocytes. However, several hurdles remain to be overcome before adoptive immunotherapy can become a
broadly applicable therapeutic approach to treat cancer. We exploited gene transfer technologies to overcome
these hurdles thus enbling the development of safe and effective immunotherapeutic approaches for cancer. In
allo-HSCT, most of the antileukemic potential resides in alloreactivity towards patient-specific antigens, such as
minor and major histocompatibility antigens, by donor lymphocytes. Unfortunately, alloreactivity is also responsible for the most serious and frequent complication of allo-HSCT: the Graft-versus-Host-Disease
(GvHD). In a phase I-II clinical trial enrolling 54 pts undergoing haploidentical HSCT, we showed that the
transfer of a suicide gene into donor lymphocytes, allows to provide rapid and effective immune reconstitution,
and control of GvHD. By taming the toxicity of allo-HSCT the suicide gene approach renders haploidentical
HSCT a feasible, safe and more effective option for cancer patients of all ages. Gene transfer technologies allow
not only to improve the safety profile of cancer immunotherapy, but also to increase its feasibility and efficacy:
the transfer of autologous tumor specific cytotoxic T lymphocytes (CTLs) in cancer patients is highly effective
for selected tumor. However, major hurdles such as the difficulty in expanding rare, high-avidity tumor-specific
CTLs limit this approach. We set up protocols to efficiently transfer into T lymphocytes gene encoding for tumor-specific molecules such as T-cell receptors (TCRs) or chimeric antigen receptors (CARs), to confer to T
cells tumor-specificity and activity.
Chiara Bonini
ANGIOGENESIS AND TUMOR TARGETING
Macrophage heterogeneity in the tumor microenvironment: implications for angiogenesis and antiangiogenic
therapy
Macrophages infiltrate developing tumors, where they seem to support angiogenesis by releasing factors that
stimulate the growth and expansion of new blood vessels from the pre-existing vasculature. However, tumor-associated macrophages (TAMs) may comprise functionally distinct subpopulations. Our recent studies suggest
that, in mouse tumors, only a specific TAM subset displays a profound pro-angiogenic phenotype, the TIE2-expressing macrophages (TEMs). TEMs are characterized by the high expression of mannose receptor-1 (MRC1)
and aptoglobin/hemoglobin scavenger receptor (CD163), and the low expression of several pro-inflammatory
and anti-angiogenic molecules, such as IL-1β, COX2, iNOS and IL-12 (as compared to other TAMs). In contrast, a substantial fraction of the TIE2-negative TAMs express CD11c and produce higher amounts of pro-inflammatory molecules and lower amounts of pro-angiogenic factors. Our studies further indicate that different
ratios of MRC1+ TEMs and CD11c+ TAMs are present in different tumor types, and that this may correlate
with the angiogenic features of tumors. Little is known of the tumor-secreted factors that regulate TEM’s
proangiogenic activity. Because TEMs express the angiopoietin (ANG) receptor TIE2 (ca. 20-50-fold more
than CD11c+ TAMs) and respond to ANG2 stimulation in vitro, we speculated that ANG2, which is secreted
by angiogenic blood vessels, could regulate the attraction and/or biological activity of TEMs in tumors. We
found that blocking ANG2 using a novel, humanized monoclonal antibody, delays tumor progression in the
MMTV-PyMT spontaneous breast cancer model and inhibits the growth of pulmonary metastases, both in early and late treatment trials. Furthermore, the specific knock-down of TIE2 in TEMs inhibits tumor angiogenesis and vessel perfusion in MMTV-PyMT mice. Together, these data support the notion that targeting the
ANG2/TIE2 angiogenic axis in tumors may represent a dual-target strategy that impairs both vascular cells
(i.e., angiogenic tumor blood vessels) and proangiogenic macrophages (TEMs) in the angiogenic process. Assessing the specific contribution of distinct TAM subpopulations to tumor angiogenesis and progression may
thus have important implications for the design of improved anticancer therapies.
Michele De Palma
HEMATOLOGY AND HEMATOPOIETIC STEM CELL
TRANSPLANTATION UNIT
The San Raffaele Hematology and Bone Marrow Transplantation (BMT) Unit is highly integrated with dr Bonini, Fleischauer and Cossu Research Units in translational research. The stem cell transplantation activity is integrated with the Blood Bank Unit (Director Silvano Rossini) in a Stem Cell transplantation Program as member of
European Group for Blood and Marrow Tranplantation, EBMT (www.ebmt.org), in the file for Jacie-EBMT accreditation. Overall, the Unit is the largest Italian Unit for allogeneic HSC transplantation, performing since 2006
around 100 allogeneic tranplants/year. The Unit has long-lasting experience in transplantation from family mismatched haploidentical donors, with programs of cell therapy with suicide-gene modified donor T lymphocytes
and cell therapy with IL-10 induced T-regulatory cells for the control of Graft-versus-Host disease. Our aim is to
develop new conditioning regimens based on treosulfan for allogeneic hematopoietic stem cells transplantation
(HSCT) to reduce transplant related toxicity (Allo-treo trial, Eudract 2005-005182-11), and to increase antileukemia activity (cofarabine-treosulfan, Clo3o trial, Eudract 2008-006972-31). New modalities of immune suppression has been developed based on rapamycin (TrRaMM trial, Eudract 2007 005477-54) for Graft-versusHost disease prevention in the context of T-repleted haploidentical SCT. The unit is involved in development of
mesoangiobalst cell-therapy treatment of Duchenne Muscle distrophy in collaboration with dr Cossu lab.
Fabio Ciceri
IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE UNIT
The Hospital San Raffaele (HSR) Immunohematology and Transfusion Medicine Service (ITMS) provides
clinical services to support HSR patients in need of blood component therapy, cellular therapy, therapeutic
apheresis, and specialized laboratory diagnostics. This ISO 9002 Certified unit collects and prepares the blood
components and cellular therapy products used in patient care at the HSR, and provides education in the field
of Transfusion Medicine.
A Radio Frequency Identification (RFID) project is underway with the goal of increasing safety by implementing radiofrequency identification technology in the daily management of transfusions and transfusion
products. This system is a model for process traceability from donor to patient, for automation in the identification of patients, blood units and/or cellular products.
The ITMS is subdivided into three distinct sub-units
The blood donation center sub-unit is responsible for the collection and testing of blood to be transfused into patients at the San Raffaele Hospital. The Therapeutic Apheresis and Cellular Therapy sub-unit is responsible for collecting and processing hematopoietic stem cells and performs the necessary diagnostic testing required for bone marrow transplantation procedures. The lab supplies hematopoietic stem cells and relevant
cells in support of clinical trials for allogenic bone marrow and peripheral blood transplantation and offers a
Stem Cell Cryo Banking service for autologous and allogeneic bone marrow products. Bone Marrow from qualified donors is collected in accordance and recognition of the Italian Bone Marrow Donor Registry (IBMDR).
Therapeutic apheresis procedures to treat patients with neurologic and blood diseases, including photopheresis, red cell and plasma exchange procedures are also performed routinely.
The Clinical Laboratory Diagnostics sub-unit includes the following specialized laboratories: Immunohematology, Hematology, Flow Cytometry, Hematological Molecular Biology and an EFI Certified and accredited
HLA tissue typing laboratory. New technologies such as genetic red blood cell typing are being investigated. A
special emphasis is given to oncohematologic malignancies. These pathologies are studied using a multi-disciplinary approach.
Silvano Rossini
PSIEP - STRATEGIC PROGRAM OF PEDIATRIC
IMMUNOHEMATOLOGY
The Strategic Program of Pediatric Immunohematology is a pediatric Unit dedicated to translational and
clinical research in children with immunological, hematological, autoimmune and other genetic disorders. In
this context children are offered in addition to the standard care also experimental therapeutic option, among
these cellular therapy and gene therapy.
Between 2005 and 2009 the Unit has performed more than pediatric 70 allogeneic stem cell transplantations
for thalassemia, sickle cell anemia, immunodeficiencies and acute leukemias. The clinical performance of the
Unit in was very high as demonstrated by an engraftment rate of 95% and a treatment related mortality of 5%.
The Program is collaborating with HSR-TIGET on the study of pathogenesis and therapy for genetic diseases, with particular regards to primary immunodeficiencies and autoimmune diseases with known or unknown genetic defect. In synergy with the Pediatric clinical research Unit of HSR TIGET, clinical studies for
gene therapy of Wiskott-Aldrich Syndrome and Metachromatic Leukodystrophy are ongoing and in preparation for gene therapy of thalassemia. Finally, the Program is implementing a cell therapy clinical study for
Duchenne muscular dystrophy (project leader Prof Cossu).
THE SAN RAFFAELE TELETHON INSTITUTE FOR GENE
THERAPY (HSR-TIGET)
Director: Luigi Naldini*
The San Raffaele Telethon Institute for Gene Therapy (TIGET, www.sanraffaele.org/research/tiget) is a multi-disciplinary research Institute with
strong emphasis on the development of gene transfer technologies, cell and
gene therapy strategies and their application to the treatment of rare genetic
disorders. It hosts approximately 100 researchers (5 Heads of Unit and 7
Group/Project Leaders). HSR-TIGET was created in 1995 as a joint-venture between the San Raffaele Scientific Institute and the Telethon Foundation with the mission to perform cutting edge research in gene and cell therapy and to promote its translation into therapeutic advances for rare inborn
diseases. The research projects span from basic to pre-clinical studies aiming
to: a) identify the genetic bases and the patho-physiological processes of the
inherited diseases under study, which include primary immunodeficiencies
Luigi Naldini
and autoimmune disorders, thalassemia and other blood disorders, leukodystrophies and other lysosomal storage disorders; b) develop new gene transfer
technologies for more efficient and safe genetic modification of target cells, c) establish procedures for isolation, gene transfer and transplantation of stem cells; d) modulate immune response to gene and cell
products to improve efficacy and stability of the therapy; e) test the new therapeutic strategies in pre-clinical disease models instrumental to design clinical trials. TIGET scientists, led by Luigi Naldini, have
made essential contribution to the original development and continued improvements of lentiviral vectors, which have become one of the most widely used tool in biomedical research today and hold the
promise of therapy for several human diseases. In parallel, TIGET scientists, led by Maria Grazia Roncarolo, have made significant advances in the field of immuno-tolerance mediated by regulatory T cells
and the potential application of these cells as cell therapy of immune-mediated diseases. Furthermore,
TIGET has established a Pediatric Clinical Research Unit (P-CRU) within the San Raffaele Hospital
that focuses on the diagnosis, treatment and follow-up of patients with primary immunodeficiencies,
hematologic and metabolic disorders, including those enrolled in the gene therapy trials. The TIGET
clinical trial for a severe form of primary immunodeficiency (ADA-SCID) has provided the most successful demonstration today that gene transfer into human hematopoietic stem cells (HSC) can result in
long-term correction of disease with an excellent safety record. Two new gene therapy trials for
Metachromatic Leukodystrophy and Wiskott-Aldrich Syndrome are expected to start in the P-CRU in
spring 2010. They will be among the first trials employing lentiviral vectors for HSC gene transfer. Towards this goal, TIGET has developed large-scale manufacturing of clinical grade lentiviral vectors in
close collaboration with MolMed, a biotechnology company within the San Raffaele Biomedical Science
Park, and has held several meetings on the subject with regulatory authorities in Italy (ISS) and Europe
(EMEA). Overall, this research environment provides world-recognized leading scientific expertise in
vector design and assays, genetic modification of HSC, pre-clinical models of HSC activity as well as in
the translational, regulatory and clinical issues associated with testing novel therapies for immune and
hematological diseases. It is clear that monogenic diseases that lack effective therapies offer the best setting to validate the therapeutic potential of gene therapy in an appropriate risk-benefit setting.
Research Units
GENE TRANSFER TECHNOLOGIES AND NEW GENE THERAPY
STRATEGIES UNIT
We have long pursued the development of new gene transfer technologies and exploited them to gain insight
into biological processes of high medical relevance, such as hematopoietic stem cell (HSC) activity and angiogenesis, and to provide proof-of-principle of new strategies for treating genetic disease and cancer. Throughout the
years we have made major contributions to the development of lentiviral vectors for efficient and safe gene transfer. Today, lentiviral vectors represent one of the most broadly used tools in biomedical research and their successful first clinical testing in HSC was listed by the journal Science among the scientific breakthroughs of 2009.
In 2010, we will launch two new clinical trials of lentiviral vector-based HSC gene therapy for Metachromatic
Leukodystrophy and Wiskott-Aldrich Syndrome. We recently applied microRNA regulation to vector design
and provided a new strategy to make transgenes and medically used viruses stringently responsive to cell type,
activation and differentiation. Using this approach, we could overcome the immunological barrier to stable gene
transfer, one of the major hurdles to successful gene therapy, and establish long-term correction of hemophilia in
the mouse and dog models. We are now investigating the microRNA network regulating hematopoiesis and exploiting this knowledge to develop novel vectors with stringently controlled expression throughout the lineages.
We have also pioneered the use of engineered Zinc-finger nucleases to target vector integration and edit the human genome. By this approach we can correct, rather than replace genes and insert the transgene with high efficiency and specificity downstream its own endogenous promoter or into a safe genomic harbor that allows for
robust expression without interference on endogenous transcription. By combining all these strategies we can
provide radically improved gene transfer platforms. Furthermore, we are exploiting these technologies for the
generation and genetic correction of induced pluripotent stem cells, providing a potentially unlimited source of
patient-derived vector free gene corrected multipotent cells for future applications of regenerative medicine.
Luigi Naldini
GENE/NEURAL STEM CELL THERAPY FOR LYSOSOMAL STORAGE
DISEASES
In lysosomal storage disorders (LSD) deficiency of specific lysosomal enzymes results in storage of undegraded macromolecules, functional impairment and cell death. Leukodystrophies (MLD, GLD) and GM2-gangliosidosis (Tay-Sachs and Sandhoff diseases) are “global” diseases affecting the central and peripheral nervous
system and peripheral organs. Bone marrow transplant and enzyme replacement therapy cannot reverse the
course of the disease and are unsatisfactory for treating the CNS. Our main goal is to develop novel gene- and
neural stem cell (NSC)-based approaches to correct the metabolic defect and to restore the widespread CNS
tissue damage in murine models of LSD. This is being addressed through different strategies: a) intracerebral
injection of lentiviral vectors encoding for the missing genes (Lattanzi et al., Hum Mol. Genetics 2010); b) heterologous NSC transplantation (naïve or enzyme overexpressing NSC. Our studies allowed us to establish optimal experimental protocols for NSC neonatal transplantation. We are currently optimizing neonatal intracerebral direct gene delivery. These CNS-directed strategies will be combined with available approaches able to
treat the PNS and visceral organs (i.e. hematopoietic stem cell transplantation), according to protocols that will
take into consideration both the biological features of the donor cells and those of the pathologic environment.
In order to better exploit the therapeutic potential of these strategies an important part of research activity is
devoted to study: a) the biology of NSC during the onset and progression of the neurodegenerative condition
(Martino et al., JNC, 2009) and b) the cell-autonomous and non-cell autonomous mechanisms regulating resident stem cell compartments and NSC migration and engraftment following transplantation. As a future project we aim to generate induced Pluripotent Stem Cells from skin fibroblasts of GLD and MLD patients, in or-
der to have patient-specific pluripotent cell lines that could be differentiated into neural cells by means of previously described protocols. Given the absence of a source of neural cells from patients, these cell lines might
constitute a valuable in vitro model to study the mechanisms underlying the pathogenesis of the diseases and to
further confirm the safety and efficiency of gene transfer.
Angela Gritti
HEMATOPOIETIC STEM CELL BASED GENE THERAPY FOR THE
TREATMENT OF LYSOSOMAL STORAGE DISORDERS
In most Lysosomal Storage Disorders (LSD) hematopoietic stem cell (HSC) transplantation is not or poorly
effective. HSC gene therapy could ameliorate the outcome of allogeneic transplant and thus provide an expectation of efficacious treatment for these LSD. HSC can be genetically modified to express supra-normal levels
of the therapeutic enzyme, and become a quantitatively more effective source of functional enzyme than normal
donor’s cells. Moreover, autologous HSC are immediately available, thus saving precious time in rapidly progressing forms, and, when employed in a transplant setting, significantly reduce transplant-related morbidity
and mortality. We are thus implementing an innovative approach based on the transplantation of autologous,
gene corrected HSC for the treatment of severe LSD lacking efficacious and safe therapeutic opportunities. To
this goal, we exploit the unique features of lentiviral vectors (LV), which are prime candidates for HSC gene
transfer. By using LV for HSC gene correction, we proved the therapeutic potential of HSC gene therapy in the
murine model of metachromatic leukodystrophy (MLD), a severe dysmyelinating LSD. Based on the results obtained in the preclinical model and on an extensive safety study, a clinical trial of HSC gene therapy for MLD
has recently been approved (patient’s recruitment open on March 15, 2010). The same approach has been applied with success to the murine model of type I Mucopolysaccharidosis (MPS I), a LSD characterized by visceral organ, skeleton and nervous system involvement. Thus, a clinical development plan for MPS I has recently started. In the case of globoid leukodystrophy (GLD), we recently demonstrated that the disease-causing enzyme (GALC) could not be over-expressed in HSC since it causes an unbalance in the content of bioactive
sphingolipids tightly controlling HSC survival. Interestingly, when using a LV in which GALC expression is
regulated by an HSC-specific microRNA we could obtain safe HSC transduction, GALC over-expression in
the transduced HSC progeny, and significant phenotypic amelioration in mice transplanted with the transduced
HSC. Therefore, an advanced LV design allows rendering HSC gene therapy a safe and efficacious approach to
be further developed also for GLD.
Alessandra Biffi
SAFETY OF GENE THERAPY AND INSERTIONAL MUTAGENESIS
In vivo models to assess the risk of insertional mutagenesis in the liver upon vector systemic delivery
Efficient liver gene transfer by lentiviral vectors (LV) may allow the treatment of hepatic and systemic diseases. However, evaluation of the safety of liver gene transfer is required, as vector integration may occasionally
lead to transformation of hepatocytes.
We setup sensitive assays for liver genotoxicity in vivo exploiting 2 tumor-prone mouse models and wild type
mice. LVs carrying in the LTRs ubiquitous (LV.SF.LTR) or hepatospecific enhancers (LV.ET.LTR) were systemically administered in newborn mice. LV.SF.LTR in Cdkn2a-/- mice induced early onset of histiocytic lymphomas with respect to uninjected mice (p<0.0001), showing that non-hepatocyte cells are the most susceptible
target for transformation upon systemic injection of a genotoxic LV. LV.ET.LTR induced high grade hepatocellular carcinomas (HCC) in 30% of Cdkn2a-/- mice (0 HCCs in controls). Moreover, LV.ET.LTR induced HCCs
in a mouse model of liver-specific Pten deficiency (incidence 25%, p<0.05), and in wild type mice in combination with a tumor promoting CCl4 treatment (incidence 75%, p=0.002).
We exploited these validated mouse models to test the safety of SINLVs developed for the therapy of hemophilia B. A SINLV that express factor IX transcript under the control of hepatospecific enhancer with target se-
quences for microRNA 142.3p (SINLV.ET.FIX.142T) was administered in newborn mice at dose matched with
LV.ET.LTR. Survival curves and HCC incidence readouts in Cdkn2a-/- mice injected with SINLV.ET.FIX.142T
did not show evidence of genotoxicity. Evaluation of SINLV.ET.FIX.142T genotoxicity is also ongoing in wild
type mice with CCl4 treatment. Our approach will be instrumental to establish vector designs with the best
biosafety profile for liver gene therapy.
Eugenio Montini
GENE TRANSFER INTO STEM CELLS UNIT
Gene therapy for β thalassemia
Thalassemias are globally the most common monogenic disorders, affecting thousands of newborn annually.
At present, the only definitive cure is allogeneic bone marrow (BM) transplantation, which is, however, available for a minority of patients. Gene therapy represents an attractive alternative for patients lacking a suitable
donor. The development of lentiviral vectors (LV) and the optimization of hematopoietic stem cells (HSC)
transduction have provided significant contributions to this field, leading to the application of LVs expressing
the human ß-globin gene in preclinical models. Extensive preclinical studies of biology, efficacy and safety in
human cells are mandatory to make a rigorous evaluation of a predictable successful trial.
We achieved long-term correction of thalassemia in the murine model using the novel GLOBE vector (Miccio
et al. PNAS, 2008). Following on from this successful result, the exploitation of the therapeutic efficacy of
GLOBE was investigated in BM-CD34+ cells from a large cohort of pediatric patients. We have shown correction of hallmark features of the thalassemic phenotype, such as synthesis of HbA and ineffective erythropoiesis.
We demonstrated that GLOBE efficiently transduces CD34+ cells, providing physiological levels of HbA in the
erythroid progeny with a low number of integrants/cell. In order to assess the risk of genotoxicity related to
GLOBE, we sequenced and mapped the GLOBE integration sites in thalassemic CD34+ cells. Analysis of integration events showed preference for intragenic regions, without hot spots in protoncogenes, tumor-supressor or
cell cycle related genes. The potential of globin LV in perturbing gene expression over a distance of 200 kb from
the integration site was tested in human erythroid cells transduced with GLOBE and with a derived vector carrying the cHS4 insulator in the LTR. We investigated changes in gene expression of 256 genes and generation of
cellular aberrant transcripts originating by splicing events between cellular and vector sites. The analysis was performed at clonal level in transduced cells before and after induction to terminal differentiation. Overall, these results will provide evidence of efficacy and safety for the use of GLOBE in clinical gene therapy of thalassemia.
Giuliana Ferrari
IMMUNOLOGICAL TOLERANCE UNIT
Ex vivo and in vivo induction of regulatory T cells to re-establish/induce tolerance in T-cell mediated
diseases
Regulatory T (Tr) cells represent specific T cell subsets that play a key role in inducing and maintaining tolerance. Most attention has been focused on the natural Tr (nTreg) cells and on the adaptive type 1 Tr (Tr1) cells,
which are developmentally and functionally distinct, and cooperate in suppressing immune responses and in
maintaining immunological homeostasis by inducing tolerance to self and foreign antigens.
We are exploring and developing different strategies to promote/maintain tolerance via Tr cells: adoptive cell
therapy with ex vivo expansion/induction of Tr cells and in vivo induction of Tr cells with tolerogenic compounds.
We validated GMP protocols to selectively expand nTreg cells using rapamycin, and to generate Ag-specific
Tr1 cells with exogenous IL-10 or IL-10-derived from tolerogenic dendritic cells. Clinical studies in hematopoietic stem cell transplantation using Tr-based cell therapy demonstrated that infusion of Tr1 cells is well-tolerated,
safe, and does not result in severe GvHD.
Alternatively to the use of ex vivo expanded/induced Tr cells, these cells can be induced directly in vivo. A
combination therapy with depleting agents (i.e. anti-CD45 mAb) and rapamycin/IL-10 treatment is highly effective in inducing tolerance in pre-clinical models of transplantation and type 1 diabetes. (T1D). Alternatively, a
small molecular weight (smw) compound that specifically activates the Aryl Hydrocarbon Receptor (AHR) is efficient for inducing transplantation tolerance via direct or DC-mediated effects on Tr cells. Preliminary data using a T1D mouse model show that this smw compound has distinct tolerogenic properties compared to other
AHR agonists since it is capable of controlling autoimmunity. In a model of gene therapy, including in LV vectors
target sequences for miR142, a microRNA exclusively expressed in hematopoietic lineage cells, results in suppression of transgene (tg) expression in professional APC. This strategy enabled stable delivery of tg (i.e. GFP
and F.IX) in immuno-competent mice by inhibiting immune responses and de novo inducing tg-specific Tr cells.
These approaches represent significant progress towards the definition of new therapeutic protocols aimed at
suppressing pathology and restoring peripheral tolerance in immune-mediated diseases.
FROM FOXP3 MUTATION TO IPEX SYNDROME
IPEX syndrome as a paradigm of monogenic autoimmune disease: genotype/phenotype correlation, immune
pathogenic mechanisms and novel therapeutic options
Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is due to mutations of
FOXP3 gene, the transcription factor driving the differentiation and function of regulatory T (Treg) cells. The
disease is characterized by early onset refractory and life threatening enteropathy, eczema, elevated IgE levels and
Type I diabetes. Genetic analysis of FOXP3 mutations should always be performed to ensure an accurate diagnosis and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX. Thanks to a wide collaborative network (www.ipexconsortium.org), we have collected data on the clinical presentation and immunological features of at least 20 unrelated affected males with different mutations. We have observed that FOXP3
mutated Treg cells in IPEX patients have normal FOXP3 demethylation but show impaired suppressive function.
FOXP3 mutated T effector (Teff) cells also seem to contribute to the immune dysregulation, with an increased
production of IL-17. However, we recently demonstrated that, in female carriers of the mutation, only the nTreg
cells bearing the active wt allele of FOXP3 are selected to give rise to a normal Treg cell population, whereas the
distribution of the two alleles was random in Teff cells. Differential gene expression profile analysis between
FOXP3 null and FOXP3 wt cells of the same individuals are ongoing to clarify the role of FOXP3 in Teff cells.
Since immunosuppressive drugs can only partially control the clinical manifestations of IPEX and
haematopoietic stem cell transplantation (HSCT), although curative, is accessible to a limited number of patients, we are defining the most appropriate gene transfer approach for IPEX. Results of FOXP3 gene transfer
into conventional Teff cells demonstrated that suppressive capacity is conferred to human T cells upon high
and stable lentiviral mediated FOXP3 expression even in the presence of FOXP3 mutations. Therefore, gene
transfer might represent a valid alternative to restore tolerance in IPEX patients.
Results obtained from these studies will provide new insights into the biology of immune regulation, and will
pave the way for expert diagnosis and more rationale therapeutic approaches not only for IPEX but also for
other autoimmune pathologies.
Rosa Bacchetta
TOLEROGENIC DENDRITIC CELLS
Requirements for the induction of Tr1-inducer monocyte-derived dendritic cells
Dendritic cells (DC) are the most potent APC of the immune system able to promote immunity or tolerance
based on their ability to secrete inflammatory or immunomodulatory cytokines, respectively. Several biological
or pharmacological agents have been used to generate tolerogenic DC in vitro. We identified a new subset of
tolerogenic DC, called DC-10, inducible in vitro in the presence of IL-10, which have a peculiar phenotype and
cytokine-production profile, and are powerful inducers IL-10-producing T regulatory (Tr1) cells. The molecular mechanism underlying Tr1 cell induction via DC-10 is the IL-10-dependent Ig-like transcript(ILT)4/HLAG1 pathway. G-CSF is used in the clinic for the mobilization of bone marrow hematopoietic stem cells into the
bloodstream. G-CSF has pleiotropic effects on adaptive immune responses, it alters T cell functions and modulates DC. Monocytes from G-CSF-treated healthy donors differentiate into tolerogenic DC in vitro (post GDC) in the presence of autologous serum, containing high levels of IL-10 and IFN-α, and induce Tr1 cells.
Based on these findings we postulated that G-SCF can replace IL-10 in promoting tolerogenic DC. Comparative analyses between monocytes differentiated with G-CSF (G-DC) and DC-10 demonstrated that both subsets are CD14+CD1a-, acquire a DC-like morphology, with mature myeloid phenotype. In contrast to DC-10,
G-DC express significantly lower levels of ILT4 and HLA-G. G-DC spontaneously produce IL-10, although at
lower levels compared to DC-10 and, in contrast to DC-10, secrete low levels of IL-12 upon stimulation. Both
G-DC and DC-10 display low stimulatory capacity and induce anergy in naïve T cells. However, DC-10, but
not G-DC, induce suppressor Tr1 cells. The inability of G-DC to promote Tr1 cell differentiation does not reside in their cytokine-production profile but rather in the low expression of ILT4 and HLA-G. These findings
demonstrate that in vitro differentiation of DC with G-CSF can replicate some but not all features of post GDC. Moreover, potent Tr1-inducers DC should secrete high levels of IL-10 in the absence of IL-12 and express
high levels of ILT4 and HLA-G.
Silvia Gregori
PATHOGENESIS AND THERAPY OF ADA-SCID UNIT
Pathogenesis of ADA-SCID and its correction by gene therapy
Genetic defects in the adenosine deaminase (ADA) gene are among the most common causes for SCID.
Available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT), enzyme replacement therapy (PEG-ADA) or hematopoietic stem cell gene therapy (GT). Our aim is to acquire
new information on the immune and organ alterations of this disease, and to investigate the ability of gene therapy cells to correct these manifestations.
From detailed studies on the bone phenotype in ADA deficient mice, we obtained evidence for specific skeletal
defects related to ADA-SCID. These alterations are the combined result of an imbalanced RANKL/OPG axis
and an intrinsic defect of osteoblast function with subsequent low bone formation. Treatment of ADA-deficient
neonatal mice with PEG-ADA, BMT, or GT resulted in full recovery of the altered bone parameters. Remarkably,
untreated ADA-SCID patients showed a similar imbalance in RANKL/OPG levels alongside severe growth retardation. Retroviral gene therapy, but not PEG-ADA, improved serum RANKL levels and children’s growth,
Autoimmune manifestations are frequently observed in patients with milder forms of the disease or patients
on PEG-ADA. We found that untreated ADA-/- mice display alterations both in central and peripheral tolerance mechanisms. In PEG-ADA treated mice the percentage of nTregs significantly decreased and their suppressive function was completely abolished after long-term treatment. Subsequently, treated mice developed
multiple autoimmune manifestations, indicating long-term PEG-ADA treatment interferes with nTreg functions. To assess if defects in peripheral tolerance may be the consequence of an impaired development or function of human nTregs, we analyzed their frequency, the FoxP3 methylation profile and the suppressive function
of nTregs in ADA-SCID patients following ERT, GT or BMT as compared to controls. We found that the proportion and function of nTregs after GT mirrored that of controls, while nTreg from the ERT group showed a
reduced frequency and impaired function. This study provides new insights into a possible predisposition to
autoimmunity related to ADA-SCID and the underlying mechanisms causing immune dysregulation.
Alessandro Aiuti
GENE THERAPY FOR WASP/OMENN
Lentiviral-mediated gene therapy leads to B and dendritic cell reconstitution in Wiskott-Aldrich Syndrome
murine model
Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity and lymphomas. Transplantation of hematopoietic stem
cells (HSC) from HLA-identical donors is curative, but not available to all patients. We have developed a protocol of gene therapy (GT) for WAS based on the transplant of genetically corrected autologous HSC using an
HIV-based lentiviral vector encoding for WASp promoter/cDNA (w1.6W). We have previously demonstrated
long-term restoration of WASp expression and functional correction of T cells upon GT in was-/- mice. However, B cell and DC phenotypic and functional reconstitution in GT treated mice was not fully evaluated. We
then transplanted was-/- mice sublethally irradiated with Lin- BM cells wt, was-/- untransduced or transduced
with w1.6W LV. B cells expressing WASp were present in all tissues isolated from GT treated mice (bone marrow, spleen, peripheral blood and peritoneal cavity). WASp positive DCs were detected in spleen, lymph nodes
and thymus of GT treated mice. To test B cell functionality, we challenged mice with pneumococcal antigens
(P23 vaccine). Mice were challenged 4 months after GT by injecting i.p. P23 vaccine. GT treated mice showed
an improved antibody response, reaching levels comparable to mice transplanted with wt BM cells. Based on
preliminary results showing autoantibodies against dsDNA in majority of was-/- mice, we evaluated the presence of autoantibodies in treated mice. GT partially corrected the phenotype of was-/- mice, by decreasing the
frequency of mice positive for autoantibodies. To test the functionality of DCs from GT treated mice, we differentiated them in vitro from BM (BMDCs) or isolated DCs from spleen. We found that although only 20% of
BMDCs from GT treated mice expressed WASp, in vitro phagocytosis, in vivo migratory capacity and T cell
priming were ameliorated compared to was-/- BMDCs.
In conclusion, our data demonstrate that lentiviral vector-mediated gene transfer in was-/- mice restores
WASp expression and functionality in B and dendritic cells, providing further evidence of the efficacy of our
GT approach.
Anna Villa
PEDIATRIC CLINICAL RESEARCH UNIT - GENE THERAPY FOR
WISKOTT-ALDRICH SYNDROME
WAS is an X-linked immunodeficiency characterized by thrombocytopenia, infections, autoimmunity and
lymphomas. Transplantation of hematopoietic stem cell (HSC) from HLA-identical donors provides a complete cure for this disease but is not available for all patients and is still associated with risks of complications.
Gene therapy with HSC could represent an alternative for patients lacking an HLA-identical donor. We previously demonstrated that a lentiviral vector encoding for human WAS gene under the control of endogenous 1.6
kb long promoter efficiently transduced and corrected human and mouse cells. We set up a transduction protocol for CD34+ cells from the bone marrow or mobilized peripheral blood of healthy donors, which were exposed once or twice to GMP grade lentiviral vector encoding WASp. qPCR performed on transduced cells
showed a vector copy number per cell (VCN) of 0.4±0.1 (1 hit), and 0.6±0.2 (2 hits). The same protocol was
used to transduce HSC from WAS patients resulting in a VCN of 0.7±0.1 (1 hit) and 1.4±0.3 (2 hits) and
restoration of protein expression in differentiated cells. About 40% (1 hit) and 60% (2 hits) of CFC were positive for integrated vector. Transduced human HSC injected in sub-lethally irradiated Rag2/gc- deficient mice
showed a normal biodistribution into hematopoietic organs, with normal differentiation capacity into myeloid
and lymphoid cells (T and B) and no evidence of vector shedding or germline transmission. These data complete our previous preclinical studies performed in the mouse model demonstrating long-term safety and efficacy of gene therapy. A phase I/II gene therapy protocol based on infusion of transduced CD34+ cells combined
with a reduced intensity conditioning has been approved by the Ethical Committee and regulatory authorities
and will begin in 2010. The clinical trial is aimed at investigating: 1) the safety of the procedure and of the use
of lentiviral vectors; 2) the in vivo long-term engraftment and expression of vector-derived WASP; 3) the ability
of gene corrected cells to restore immune functions and increase platelet counts. If successful this study will
provide key results on the safety and efficacy of gene therapy for WAS with lentiviral vectors.
PEDIATRIC CLINICAL RESEARCH UNIT - ADA GENE TRANSFER INTO
HEMATOPOIETIC STEM CELLS FOR THE TREATMENT OF ADA-SCID
SCID due to adenosine deaminase (ADA)-deficiency is a fatal congenital disorder of the immune system associated with systemic toxicity. In the absence of an HLA-matched sibling donor, hematopoietic stem cell
(HSC) transplant from alternative donors is still affected by high morbidity and mortality, while enzyme replacement therapy (PEG-ADA) fails often to sustain adequate immune reconstitution. Our approach is based
on retroviral-mediated gene transfer into bone marrow CD34+ HSC combined to a nonmyeloablative
chemotherapy prior to cell reinfusion. Fifteen ADA-SCID children have been treated according to this experimental protocol, enrolled in 3 different clinical trials. No toxicity or adverse events related to gene transfer have
been observed after gene therapy. All patients are alive and 13 remain off PEG-ADA, with the longest follow
up at >9 years after gene therapy. Molecular analysis showed the presence of multilineage engraftment of gene
corrected HSC, confirmed by common vector insertions in lymphoid and myeloid cell subsets, derived from a
common stem/progenitor cell. Comparison of vector integration analyses from HSC-gene therapy patients with
those of ADA-SCID patients previously treated with infusions of mature lymphocytes revealed that MLV-vector insertions are cell-specific and linked to genetic-chromatin state of target cells in vitro. Immunological studies showed a progressive recovery in T-cell count and normalization of immune functions, leading to antigenspecific responses and effective protection from infections. Cell cycle and telomere length analyses showed that
T-cell homeostatic expansion contributes substantially to immune reconstitution, especially in the early months
after treatment, but this is not associated to senescence in the stem cell compartment. Finally, ADA expression
persisted long-term, resulting in efficient systemic detoxification and amelioration of patients’ growth. In summary, these studies have provided evidence that HSC gene transfer is a safe and efficacious therapy for ADASCID, resulting in correction of both the immunological and metabolic defects. These results have opened a
new perspective for the treatment of other life-threatening diseases of the hematopoietic system.
Alessandro Aiuti
PEDIATRIC CLINICAL RESEARCH UNIT - CLINICAL TRIAL OF GENE
THERAPY IN METACHROMATIC LEUKODYSTROPHY
Clinical trial of gene therapy in metachromatic leukodystrophy
In the last six years we have studied the natural history of Metachromatic Leukodystrophy (MLD) on a cohort of 28 patients. We demonstrated a quite precise genotype-phenotype correlation, confirming that patients
with 0/0 or 0/R genotype (late infantile and early juvenile) have a early onset disease and a rapid clinical progression, while patients with R/R genotype (late juvenile and adult) have a later onset and a more stable disease.
Moreover, this study allowed us to validate clinical (Gross Motor Function Measure) and instrumental (brain
Magnetic Resonance; ElectroNeuroGraphic recordings) tests to monitor disease progression.
The study has been designed in the perspective of the clinical translation of a gene therapy approach based on
autologous hematopoietic stem cells and lentiviral vectors. The clinical trial will be a Phase I/II study, in open,
non-randomized, perspective, comparative with the non-contemporary population of MLD patients studied
within a natural history study. To demonstrate efficacy, candidate patients should have an expected disease progression and survival time, which would allow evaluation of potential clinical benefits and safety of the proposed therapy. Therefore, either late infantile patients in pre-symptomatic phase, or early juvenile in pre- or early- symptomatic phase will be recruited. A myeloablative conditioning regimen based on IV Busulfan will be
administered. Together with safety end-points, efficacy will be assessed as reduction in the progression of the
clinical motor impairment in treated patients as compared to the progression in control patients, and as a significant increase of residual ARSA activity as compared to pre-treatment values. The clinical trial has been authorised by HSR Ethical Committee and Italian Superior Institute of Health (ISS). We plan to treat 8 patients,
recruited internationally, in a period of 3 years, who will be followed for the safety and efficacy endpoint measures for a period of 3 years within the clinical trial and thereafter life-long for monitoring of safety, according to
Italian legislation.
Maria Sessa
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Gene expression and muscular dystrophy Unit
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 111
DIVISION OF IMMUNOLOGY,
TRANSPLANTATION, AND INFECTIOUS DISEASES
Director: Ruggero Pardi*
Associate Director: Adriano Lazzarin*
Research Units
HEAD OF UNIT: Ruggero Pardi*
RESEARCHER: Monica Fabbri
POST-DOCTORAL FELLOWS: Raffaella Molteni, Martina Panattoni**
PHD STUDENTS: Carolina Lage Crespo**, Anna Lukacs**, Michela Palmisano, Michol Savio**
TECHNICIAN: Barbara Clissi
GROUP LEADER: Samuele E. Burastero
PHD STUDENT: Mona-Rita Yacoub**
TECHNICIAN: Daniela Breda
Human virology
GROUP LEADER: Mauro S. Malnati
RESEARCHER: Silvia Heltai
PHD STUDENT: Lia Vassena**
FELLOWS: Giulia Cassina, Emanuela De Martino
TECHNICIAN: Francesca Sironi
GROUP LEADER: Alessandra Bragonzi
POST-DOCTORAL FELLOW: Cristina Cigana
PHD STUDENTS: Irene Bianconi, Nicola Ivan Lorè, Moira Paroni
FELLOW: Elisa Pedretti
GROUP LEADER: Luca Vangelista
POST-DOCTORAL FELLOW: Massimiliano Secchi
γδ T cells in innate and adaptive immunity
RESEARCHER: Maria Raffaella Zocchi
FELLOWS: Paolo Canevali, Alessandra Musso
Infectious diseases Unit
HEAD OF UNIT: Adriano Lazzarin*
Immunobiology of HIV
GROUP LEADER: Lucia Lopalco
PHD STUDENTS: Lorenzo Diomede, Maria Luisa Visciano**
FELLOW: Valentina Merati
TECHNICIAN: Claudia Pastori
Immunological diagnostics of tuberculosis
GROUP LEADER: Claudio Fortis
HEAD OF UNIT: Guido Poli*
RESEARCHER: Massimo Alfano
PHD STUDENTS: Luca Cassetta, Giulia Della Chiara, Samanta Mariani
FELLOW: Livia Gobbo
TECHNICIAN: Chiara Rizzi
HEAD OF UNIT: Massimo Degano
POST-DOCTORAL FELLOWS: Beatrice Alfieri, Fabrizio Gangemi, Claudia Minici
PHD STUDENT: Stefano Vavassori**
FELLOW: Francesca Giannese
TECHNICIAN: Paola Tornaghi
HEAD OF UNIT: Matteo Bellone
PHD STUDENTS: Luca Generoso, Elena Jachetti**, Alessia Ricupito**, Nicolò Rigamonti**
TECHNICIAN: Matteo Grioni
HEAD OF UNIT: Daniela Maria Cirillo
PHD STUDENT: Paolo Miotto, Elisa Schena**
FELLOWS: Emanuele Borroni, Lucinda Furci, Paola Mantegani, Antonella Tuscano, Diego Zallocco
HEAD OF UNIT: Paolo Dellabona
RESEARCHERS: Giulia Casorati, Claudia De Lalla
PHD STUDENTS: Virginia Cecconi**, Maya Fedeli**, Nagabhooshan Hegde**, Marco Lepore, Anna Napoletano
FELLOW: Michele Cosmo Romano
TECHNICIANS: Marta Delogu, Claudio Garavaglia
Immunopathology Unit
HEAD OF UNIT: Luca G. Guidotti
RESEARCHER: Giovanni Sitia
POST-DOCTORAL FELLOW: Lara Ravanetti
PHD STUDENT: Matteo Iannacone
TECHNICIANS: Pietro Di Lucia, Marta Mainetti
HEAD OF UNIT: Anna Mondino
POST-DOCTORAL FELLOWS: Chaitanya Ekkirala, Rodrigo Hess-Michelini
PHD STUDENTS: Teresa Manzo**, Romana Tomasoni**
TECHNICIAN: Veronica Basso
Tumor immunology Unit
HEAD OF UNIT: Maria Pia Protti
RESEARCHER: Lucia De Monte
POST-DOCTORAL FELLOWS: Giulia Di Lullo, Diego Marescotti
PHD STUDENTS: Donato Calabrese**
TECHNICIAN: Giuseppe Consogno
HEAD OF UNIT: Gabriella Scarlatti
POST-DOCTORAL FELLOW: Mariangela Cavarelli
PHD STUDENTS: Stefania Dispinseri, Lara Mainetti
FELLOWS: Priscilla Biswas, Chiara Foglieni
TECHNICIAN: Monica Tolazzi
Viral pathogens and biosafety Unit
HEAD OF UNIT: Elisa Vicenzi
POST-DOCTORAL FELLOW: Anna Kajaste-Rudnitski
PHD STUDENT: Tiziana Coradin
FELLOW: Cinzia Pultrone (till March 2009)
TECHNICIAN: Silvia Ghezzi
Infectious diseases Unit
Management and antiretroviral treatment of HIV infection
CLINICAL GROUP LEADER: Antonella Castagna
PHYSICIAN: Nicola Gianotti
FELLOWS: Francesca Cossarini, Vincenzo Spagnuolo
STATISTICIAN: Laura Galli
TECHNICIAN: Andrea Galli
Neurovirology
CLINICAL GROUP LEADER: Paola Cinque
PHYSICIANS: Simona Bossolasco, Francesca Ferretti
POST-DOCTORAL FELLOW: Manuela Testa
TECHNICIAN: Arabella Bestetti
Study and treatment of hepatotropic viruses related diseases
CLINICAL GROUP LEADER: Caterina Uberti-Foppa
RESEARCHER: Giulia Morsica
POST-DOCTORAL FELLOWS: Sabrina Bagaglio, Hamid Ibrahim Hasson
FELLOWS: Alice Dadda, Camilla Granieri, Lucy Porrino
CLINICAL GROUP LEADER: Giuseppe Tambussi
PHYSICIAN: Silvia Nozza
FELLOW: Manuela Pogliaghi
RESEARCH NURSE: Liviana della Torre
TECHNICIAN: Andrea Galli
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Vega Rusconi
TRIAL COORDINATOR: Clara Ronchetti
Clinical immunopathology and advanced medical therapeutics Unit
HEAD OF UNIT: Maria Grazia Sabbadini*
PHYSICIANS: Elena Baldissera, Enrica P. Bozzolo, Giselda Colombo, Massimo Memoli, Luisa Praderio, Moreno Tresoldi
POST-DOCTORAL FELLOWS: Patrizia Aiello, Stefano Franchini
FELLOWS: Mattia Baldini, Emmanuel Della Torre, Barbara Guglielmi, Francesca Motta, Fulvio Salvo, Mirta Tiraboschi
CONSULTANT: Lorenzo Dagna**
HEAD OF UNIT: Antonio Secchi*
PHYSICIANS: Rossana Caldara, Chiara Gremizzi, Vera Paloschi
POST-DOCTORAL FELLOWS: Gabriella Cicenia, Alessandra Petrelli, Andrea Vergani
CONSULTANT: Paolo Fiorina
05immunology
9 07 2010
16:48
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Gynecological cancers immunology
CLINICAL GROUP LEADER: Massimo Origoni*
PHYSICIANS: Luigi Caputo, Guia Carminati, Davide Ferrari
RESIDENTS: Francesca Occhi**, Chiara Stefani**
Immunology in liver neoplasms
CLINICAL GROUP LEADER: Luca Aldrighetti
PHYSICIANS: Marco Catena, Renato Finazzi
RESIDENT: Federica Cipriani
Obesity
RESEARCHER: Michele Paganelli
Pancreatic tumors: immunotherapy and β-cell function substitution
CLINICAL GROUP LEADER: Alessandro Zerbi
PHYSICIAN: Marco Stella
RESIDENTS: Vanessa Capitanio, Giovanni Capretti, Federica Merlini
Gastroenterology Unit
Clinical hepato-gastroenterology
RESEARCHER: Mario Guslandi
Digestive pathophysiology
RESEARCHER: Sandro Passaretti
Transplant surgery
RESEARCHER: Carlo Socci
DRI, Diabetes Research Institute
Director: Luca G. Guidotti
Associate Director: Emanuele Bosi*
Research Units
Diabetes research Unit
HEAD OF UNIT: Luca G. Guidotti
Immune tolerance
GROUP LEADER: Manuela Battaglia
PHD STUDENTS: Alessandra Ferraro, Nicola Gagliani
FELLOW: Andrea Valle
TECHNICIANS: Tatiana Jofra, Angela Stabilini
05immunology
9 07 2010
16:48
Pagina 115
GROUP LEADER: Marika Falcone
POST-DOCTORAL FELLOW: Vera Usuelli
PHD STUDENT: Caterina Di Pietro**
FELLOW: Tamara Vorobjova
TECHNICIAN: Alessandra Caputo
β-cell biology
GROUP LEADER: Lorenzo Piemonti
POST-DOCTORAL FELLOW: Leda Racanicchi
PHD STUDENTS: Elisa Cantarelli, Valeria Sordi
FELLOWS: Antonio Citro, Erica Dugani
Cell imaging
HEAD OF UNIT: Alessandro Del Maschio*
GROUP LEADER: Maria Luisa Malosio
FELLOW: Cristina Brigatti**
Islet transplantation
CLINICAL GROUP LEADER: Paola Maffi
BIOLOGIST: Paola Magistretti
Prevention in Type 1 diabetes
CLINICAL GROUP LEADER: Luca Falqui
PHYSICIANS: Matteo Rocco Pastore, Sabina Martinenghi
RESIDENT: Laura Molteni
RESEARCH NURSE: Pauline Grogan
Epidemiology & data management
RESEARCHER: Marina Scavini
Childhood diabetes
RESEARCHER: Riccardo Bonfanti
PHYSICIAN: Andrea Rigamonti
RESIDENTS: Roseila Battaglino, Valentina Biffi, Giulio Frontino
SUPERVISOR: Lorenzo Piemonti
RESEARCHER: Rita Nano
FELLOWS: Raffaella Melzi, Alessia Mercalli
Mission and vision - Consistent with the Institutional mission of promoting a
strong integration between pre-clinical, mechanistic research and its potential exploitation for the diagnosis and cure of human disease, the comprehensive goal and
unifying mission of the DITID is to perform forefront mechanistic, translational and
clinical research eventually enabling us to harness the immune response for the benefit of patients. To achieve its ambitious goals, the DITID will profit from its own
potential, but will also aim at prospectively increasing such potential. This will be accomplished not only by systematically assessing progress of existing staff and estabRuggero Pardi
lishing defined operational plans and milestones, but also through the recruitment of
a few young, brilliant investigators, along with the implementation of shared technological platforms
and facilities. It is only through such a blend of inspired excellence, recruitment plans and advanced technology that the above statements will become realistic and feasible in the medium to long term.
Organization - As of January 2010, the DIDIT comprises 21 Basic
Research Units, with a total of 120 investigators and technicians (including graduate students) who have a primary affiliation to the
DITID, plus 11 Clinical Research Groups, which include 65 dedicated professionals. Future, coordinated research efforts will be focused on the existing Diabetes Research Institute, along with three
interdivisional Research Programs: The interdepartmental program
of immunology, immunobiotherapy and gene therapy of Cancer, copromoted with the Division of Molecular Oncology; the Islet TransAdriano Lazzarin
plantation Program; CHARM: Correlates of HIV-Associated Immune Response Modulation, merging efforts and promoting synergistic interactions between the DITID and the Department of Infectious Diseases). The scientific and Institutional goals of the DITID research programs are meant to promote coordination and synergies in research and clinical groups working on interdependent areas, but will by no means deter DITID members
from carrying out individual, curiosity-driven research and/or from generating spontaneous collaborative efforts both within the DITID and with outside investigators.
Goals - DITID teams, comprised of immunologists, pathologists, microbiologists, infectious disease specialists, experimental surgeons, scientists, and clinicians, are tackling this formidable challenge from
many different avenues, pooling their talents and pouring their energies into four interdependent and sequentially coordinated objectives:
1. To dissect sites, molecular networks and microenvironmental cues underlying antigen recognition,
immune cell differentiation, immunological memory and the acquisition of tolerance to self and foreign antigen;
2. To develop models and tools to manipulate the above responses;
3. To translate the most effective tools into proof-of-concept designs for phase I/II clinical trials in cancer, infection and chronic inflammation;
4. To develop novel and sensitive approaches to assess the immune status and monitor antigenic responses in clinical settings and in healthy subjects.
Achievements - Collectively, from 2007 to 2009 basic and clinical research groups or individual investigators affiliated with the DITID have published 421 papers in peer-reviewed journals, with an overall
Impact Factor of 2,503.93.
Training Opportunities - Higher education, and particularly Graduate education, has traditionally
been an asset of the DITID, which in the academic year 2002-2003 established a highly competitive basic and applied immunology PhD program under the auspices of San Raffaele University. Starting in
2004, the DITID has obtained funding exceeding 2 M€ to support the program. Furthermore, an interdepartmental post-doctoral program is currently being launched to host 3 to 5 young researchers, both
national and international.
Research Units
LEUKOCYTE BIOLOGY UNIT
Inflammatory cell migration in nonresolving inflammation: identification and validation of novel molecular
targets
Diseases underlying unresolving inflammation represent the greatest collective burden of suffering and economic cost in the developed world: collectively, one out of three individuals is estimated to be chronically affected at a certain time of her/his life span. In chronic inflammation, a variety of “inputs”, both exogenous and
endogenous, ultimately affect the recruitment and activation of immune and inflammatory cells, thereby amplifying and perpetuating the inflammatory state. Based on these premises, the general assumption and comprehensive goal underlying our recent work is that a thorough understanding of the mechanisms involved in persistent leukocyte migration and homing to the site of lesions will be germane to the discovery of novel therapeutic targets and more selective anti-inflammatory drugs that interfere with selected steps in this process. In
the last year we have unveiled a novel role of ubiquitous β arrestins in regulating the activation of signaling
pathways underlying discrete integrin-mediated steps in chemokine-driven leukocyte extravasation. By combining in vivo approaches in β arrestin knockout mice with in vitro studies in engineered cellular models we have
show that membrane-recruited β arrestin-2 is required for the onset and maintenance of shear stress-resistant
leukocyte adhesion mediated by both β-1 and β-2 integrins. We have subsequently identified intermediates and
effectors in the signaling cascade that qualify as “druggable” targets for the development of novel therapeutics
that selectively prevent inflammatory cell migration to the site of lesions in nonresolving inflammation. Additionally, we showed that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro,
which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A
concentrates in a polarized fashion at the leading edge and uropod. These data might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired. We are
currently testing the hypothesis that chemokines and integrins cooperatively control gene expression programs
in extravasating and infiltrating leukocytes.
Ruggero Pardi
CELLULAR AND MOLECULAR ALLERGOLOGY
Significant reduction of allergenicity by structurally-guided single point mutations
Recombinant allergens are entering clinical practice as highly performing diagnostic tools and have demonstrated efficacy and safety in controlled clinical trials. One of the advantages of immunotherapy with recombinant allergens is the possibility to mutate them in order to loose allergenicity while fully maintaining T-cell stimulatory potential, which is mandatory for the success of immunotherapy itself. Conventional strategies to generate “allergoids” include extended deletions of B-cell epitopes and multiple mutations of the allergen molecule.
Alternatively, we are investigating (in collaboration with the Department of Experimental Medicine of the University of Parma) the possibility to destroy crucial B cell epitopes with a single mutation approach. We are
working on the model of the Mus m 1.0101 major mouse allergen, belonging to the lipocalin protein family.
Preliminary data reveals that Tyr120 is particularly important for the overall stability of this protein. Mutations
at the level of this residue appear primarily responsible for alterations in the H-bonds network that stabilizes
this molecule and provide striking conformational modifications of the global protein architecture, as assessed
by nuclear magnetic resonance. We propose to investigate whether and to what extent this approach is capable
of significantly impairing allergen recognition by IgE from mouse-allergic patients, and its impact on T-cell epitopes. We are also interested to verify whether this strategy can be applied to recombinant panallergens. Panallergens, such as profilins, are promising tools to vaccinate a relevant proportion of allergic subjects who are
presently orphans of a specific immunotherapy. Previous data generated in this laboratory suggest that profilins
may play a crucial role in the epitope spreading of the immune response in polysensitized individuals, who represent approximately one third of the population allergic to pollen allergens. In principle, a specific vaccination
with immunogens clinically “easy to handle” due to low allergenicity could bring about a favorable interference
in this process for a large proportion of allergic individuals.
Samuele E. Burastero
Figure 13. Slab view of MUP2 crystal structure (1JV4,
displayed in topology cartoon): W19 is visible at the bottom of
the hydrophobic cavity of the b-barrel. The tryptophan side
chain is predicted to form a cation-p interaction, deemed
energetically significant by the CaPTURE web server, with
the atoms belonging to residue R122. The proximity of these
interacting residues to Y120 is appreciable; the side chains of
the cited residues are represented in sticks.
HUMAN VIROLOGY
The failure of anti HIV-1 vaccine strategy based on the induction of a broad T-cell response against structural antigens suggests that the most effective defence against HIV-1 transmission might require the combination
of HIV-1-specific T-cell responses and anti-HIV-specific antibody (Ab) responses. Our unit is mainly involved
on the development of an effective anti HIV-1 vaccine studying, on one side, the distinctive features of the Tcell mediated immune response towards structural and regulatory HIV-1 encoded antigens in particular cohorts of HIV-1 infected individuals who survive for long time without sign of immune deterioration (LTNP)
and/or naturally control viral replication below the level of detection of the clinical lab tests (Elite controllers=
EC). On the other side, we are conducting a deep characterization of the HIV-1 Envelope protein gp160 aiming to individuate structural modifications that render the gp160 a useful immunogen. Indeed, relevant epitopes of this oligomeric protein are shielded by “variable” loops that we are removing/modifying from the
gp160 scaffolds of two selected HIV-1 strains: the CCR5 dependent strain BaL and the R5X4 strain US077.
Results obtained in 2009
A strong response against the HIV-1 encoded antigen Tat is the hallmark of EC individuals being more frequent, higher and wider than in the other cohorts of HIV-1+ individuals. In addition, EC recognize selectively
particular regions of the protein that are critical for the trans-activating function of Tat. Interestingly, in silico
prediction of recognized epitopes matched with patients’ HLA, shows that targeted epitopes can be shared by
multiple HLA alleles.The deletion of the V2 region as well as the disruption of potential N-glycosilation sites
present in the V2 and in the V1-V2 stem-loop regions reduces fusion and modifies the recognition of mAbs directed against CD4-induced epitopes. Only the deletion of the V1 region is well tolerated by both gp160 proteins. Interestingly, the V1-deletion in the US077 gp160 increases the interaction with CD4/CCR5 complex allowing the binding of larger amounts of sCD4 and of the neutralizing CD4-binding site specific mAb B12, suggesting that this molecule might represent a potential candidate for vaccine development.
Mauro S. Malnati
INFECTION AND CYSTIC FIBROSIS
Pseudomonas aeruginosa-host interactions in Cystic Fibrosis: implications for pathogenesis and therapy
Persistent bacterial infections involving P. aeruginosa pose serious problems for human health including Cystic Fibrosis (CF) patients. After causing an initial acute disease state, which is kept in check by an immune response, P. aeruginosa establishes persistent infection and colonize the host by evading immune surveillance.
The goal of our program is to elucidate cellular and molecular mechanisms that are involved in the hostpathogen interactions during persistent infection with the aim of devising new therapeutic approaches to treat
respiratory infections.
Cellular and molecular mechanisms involved in P. aeruginosa-host pathogen interactions.
Life-long P. aeruginosa chronic infections in the airways of CF patients is established with patho-adaptive
variants, which are clonal with the initially acquired strains. We have taken two approaches of functional genomics, through trascriptomics and insertion mutagenesis, to obtain a genome scale picture of P. aeruginosa expression and strategies adopted by P. aeruginosa in the persistent lifestyle. By using a PCR-based signaturetagged mutagenesis (Pos-STM) based on positive selection screening in a murine model of chronic airways infection, we disclosed novel patho-adaptive mutations. Of particular interest was the finding that P. aeruginosa
virulence factors, relevant in the acute infection, were modified or selected against during chronic infection. In
particular, changes in P. aeruginosa PAMPs lead to escape host innate immune system and endorse pathogenesis. Our findings emphasize studies to define novel virulence determinants in adapted P. aeruginosa population
and novel targets which may lead to improved antimicrobial therapeutic strategies.
Evaluation of novel molecules for treating respiratory infection and inflammation.
Over the years, we have accumulated expertise on mouse model for acute infection, established a mouse
model for airway chronic infection and collected unique reagents such as a selection of highly virulent CF-related pathogens. Based on this expertise, we have established the Cystic Fibrosis Animal Core Facility (CFaCore)
to support investigations on candidate therapeutic molecules and to favor the translation of basic research projects into pre-clinical applications.
Alessandra Bragonzi
PROTEIN ENGINEERING AND THERAPEUTICS
Three major research fields are being exploited in our laboratory.
Main efforts are devoted to HIV-1 entry inhibitors based on engineered derivatives of RANTES and other
CCR5-binding chemokines, in an attempt to create CCR5 antagonists with potent anti-HIV-1 activity. Both fulllength RANTES mutants and short peptides are presently being developed as CCR5-antagonist anti-HIV-1 mucosal microbicides. The ‘live microbicides’ field is a promising and innovative approach based on the engineering of human commensal bacteria, such as lactic acid bacteria (LAB), to produce anti-HIV-1 protein therapeutics, a field in which we are involved and committed. A further aspect of HIV-1 entry inhibitor development
consists in the possible combination of different lead compounds. Both full-length and short peptide RANTES
derivatives presented full additivity or even slight synergism when tested in vitro in combination with different
HIV-1 inhibitors.
In a second research area, structure-function knowledge on IgE and its receptors is applied to the benefit of
human health. In this view, we devise IgE engineering in an attempt to combat both allergic manifestations as
well as cancer. In a research program co-directed with Prof. Antonio Siccardi, we found that IgE is a potent adjuvant in anti-tumor vaccination and Fc epsilon RI, the high affinity receptor for IgE, has a key role in the IgE
anti-tumor effect. The system has been evolved by engineering a recombinant modified vaccinia virus Ankara
to express a truncated version of human membrane IgE, capable to bind and activate human Fc epsilon RI.
This system, that includes the use of transgenic mice expressing the human receptor, has the advantage of being
safe and close to the clinics. In addition, we have strong evidence that endogenous IgE, in a transgenic mouse
engineered to produce high IgE levels, prevents tumor development in vivo.
Finally, we are planning to expand the commensal LAB engineering as a system to be exploited: a) for the de-
velopment of several live therapeutic applications, including human cytomegalovirus and allergy prevention; b)
for the use of LAB as a novel recombinant protein production system; and c) as a RANTES mutant screening
platform.
Luca Vangelista
Figure 14. Engineering commensal Lactic Acid
Bacteria (LAB) to screen new potent RANTES-based
anti-HIV-1 CCR5 antagonists, a system prompted to
provide live microbicide candidates
γδ T CELLS IN INNATE AND ADAPTIVE IMMUNITY
Role of γδ T cells in host defense against infections and lymphomas
Circulating Vδ2 T cells respond to mycobacteria and certain viruses, while the Vδ1 subset is resident in the
mucosal-associated lymphoid tissue and participate in the immunity against intracellular microrganisms. Vδ2 T
lymphocytes recognize non-peptidic phosphorylated molecules expressed by mycobacteria, while Vδ1 T cells
interact with stress-induced MHC-related antigens (MICA, MICB) and with the ULBPs, receptors for the
UL16 protein produced by CMV-infected cells. We showed that Vδ1 T lymphocytes are increased in HIV1 infected patients, express cytoplasmic interferon (IFN)γ and interleukin (IL)17, proliferate and produce both cytokines in response to C. albicans, while Vδ2 T cells respond to mycobacterial phosphate antigens. The
IFNγ/IL17 double producer γδ T cells express the Th17 RORC and the Th1 TXB21 transcription factors, bear
the CD27 memory T cell marker, the CCR7 homing receptor, the chemokine receptors CCR4 and CCR6 and
the CD161 marker of Th17 cells, that mediates transendothelial migration (Blood 2009, 113:6611-6618). We also found that circulating Vδ1 T lymphocytes are increased in patients with CLL and NHL, where they proliferate, produce TNFα,IFNγ or IL4 in response to autologous cells, provided they express MICA or ULBPs
(Blood 2007, 109:2078-2085). These ligands can be upregulated in vivo by the use of all-trans-retinoic acid or
sodium valproate (Leukemia 2009, 23:642-648). Of note, the number of circulating Vδ1 T cells in CLL and of
IL4 producing Vδ1 T lymphocytes infiltrating the lymph nodes in NHL correlates with disease stage and progression. Moreover, they are more resistant to apoptosis due to activation, via NKG2D, of the alternative pathway of NF-κB, leading to transcription and production of Bcl-xL antiapoptotic protein (in preparation). Thus,
specifically equipped circulating memory γδ T cells seem to be expanded in different pathological conditions,
being preferentially Th1/Th17 or Th2, probably depending on the antigen(s) encountered in lymphoid tissues
undergoing infections, chronic inflammation, or malignant transformation. We are investigating the microenvironmental factors driving γδ T cells towards one of these differentiating/effector pathway
Maria Raffaella Zocchi
IMMUNOBIOLOGY OF HIV
Natural immune responses to generate new vaccinal strategies against HIV transmission
HIV infection remains a major health burden worldwide and despite efforts and expectations, no effective
preventive HIV vaccine is available yet. Our Unit focuses on the structure-immunogenicity applied to the hostvirus relationship. In details, we have analysed and characterized both mucosal and systemic humoral immunity involved in HIV resistance. The last few years have provided documentary evidence of the existence of subjects who, despite multiple exposures to HIV-1, remain seronegative (referred to as ESN). The possibility that
some of these subjects may be “spontaneously vaccinated/cured” cannot be excluded, and so the study of their
antiviral response may reveal as yet unknown resistance mechanisms that may be reproducible in others. The
analyses the immune factors involved in immune controls could be extremely relevant to generate strategies
able to prevent and control HIV transmission.
CCR5 cellular protein is one the main coreceptors for HIV and CCR5 downregulating immunoglobulins
were found in sera and mucosal samples in ESN suggesting a role for such antibodies in controlling viral replication in vivo. Our findings suggest that natural mucosal anti CCR5 antibodies, at mucosal sites, bind receptor
and reach CCR5 intracellularly, thus preventing interaction with HIV and subsequent transcytosis. Thus, our
research is aimed at creating such immune barrier by targeting the host rather than the virus establishing a
durable elimination of CCR5. Proof of principle for this strategy has been provided by our team in mice.
Our Unit also focuses to create an immune barrier by targeting the highly conserved regions of gp41, which
could be an attractive target to prevent mucosal transmission. These regions are recognized by broad cross neutralizing antibodies which are rarely elicited potentially due to molecular mimicry o self-determinant and thus
the immunization is designed to break tolerance and force the immune system in raising such antibodies. Of interest is that, natural HIV neutralizing IgA has been associated to gp41 but not to other viral proteins in ESN.
Results from these studies are expected to provide novel direction for the development of durable HIV infection prevention measures not restricted to specific HIV isolates.
Lucia Lopalco
AIDS IMMUNOPATHOGENESIS UNIT
Central theme of our Unit is the regulation of HIV replication by exogenous host factors, primarily of immunological nature. In this scenario, we have been focusing our research primarily on the 4 topics listed below.
1. Role of macrophage polarization in HIV infection.
This project explores the potential role of M1 vs. M2 polarization of monocyte-derived macrophages (MDM)
infected in vitro with R5 HIV-1 in terms of virus replication. We have observed that both M1 and M2 polarized
MDM support less efficiently virus multiplication, although with differences in terms of potency (M1>M2), duration (M2>M1) of the effect and mechanism of action (M1: pre-integration; M2: post-integration).
2. Role of macrophage adhesion in controlling HIV replication.
Based on our published papers on the inhibitory effect of urokinase-type plasminogen activator (uPA), we
have addressed the role of static adhesion and of integrin-dependent signaling in impeding the release of mature virions from intra-cellular compartments from infected MDM and related cell lines.
3. Molecular pathogenesis of HIV infection, with specific regard to the role of the JAK/STAT signaling pathway,
and of STAT5 in particular, in HIV replication.
This project is the development of our paper published in 2007 (A. Crotti et al. Blood) in which we demonstrate a direct and functional binding of STAT5 and of its naturally C-terminus truncated variant STAT5∆ to
the HIV-1 LTR. In addition, we are pursuing the characterization of a transcriptome derived from primary
CD4+ T cells infected with either a CCR5-using (R5) vs. a CXCR4-dependent (X4) HIV infection.
4. Genetic studies in HIV long-term nonprogressors (LTNP).
Within a EC-funded consortium (“GISHEAL”), headed by Guido Poli, we have performed a genome-wide
association study (GWAS) using an ILLUMINA 550 HapMap platform to identify candidate alleles associated
with the LTNP condition. We have indeed identified LTNP-associated regions in HLA Class I, II and III loci.
Guido Poli
BIOCRYSTALLOGRAPHY UNIT
Our unit is interested in the structure-function relationship of biological macromolecules, in particular within
the processes of immune system recognition of pathogens and host-pathogen interactions. Our activities are
primarily focused on three main areas:
1. Target identification and structure-based drug design.
We demonstrated that enzymes with nucleoside hydrolase activity are essential for both Trypanosomes
(causative agents of tropical neglected diseases) and Stahpylococcus aureus. We determined the crystal structure of both isozymes, and used them as templates for the design of novel compounds that inhibit the enzymatic activity. These compounds are effective in infection models of Trypanosoma brucei, and will be similarly tested against Staphylococcus.
2. Molecular mechanisms involved in T cell and B cell physiology.
The APECED syndrome is a genetic autoimmune disease characterized by a loss of central tolerance to self
proteins due to lack of their thymic expression, leading to the absence of antigen normally driving the clonal
deletion of autoreactive T cells. The disease is caused by mutations in the AIRE gene, coding for a multidomain
protein of ~600 amino acids of largely unknown function. We are studying the structure of AIRE using a combination of NMR spectroscopy and X-ray crystallography to shed light on its complex function. The overall
goal of the project is to understand the molecular events underlying the expression of antigens in thymic selection, and to broaden our knowledge of the mechanisms of immunological tolerance.
3. Novel molecular tools in cancer suicide gene therapy.
We engineered a synthetic fluorouridine-activating enzyme (FAE) that efficiently converts FUR to a cytotoxic
metabolite. Expression of the gene in tumoral cells enhances their sensitivity to the prodrug, with EC50 reductions ranging from 50 to 98 % in different cell lines. Subcutaneous tumor models show a reduction in mass and
an enhanced survival when subjected to the FAE/FUR treatment. We plan to develop adequate vectors for a tumor selective delivery of the FAE gene, and to demonstrate its efficacy in spontaneous models of neoplastic diseases. This treatment could represent an alternative, lytic approach to the treatment of solid cancers.
Massimo Degano
Figure 15. Surface representation of the IG-NH from
Trypanosoma brucei brucei with the substrate inosine
modeled in the active site. Potent, competitive
inhibitors of the enzyme take advantage of aromatic
stacking interactions with residue Trp80.
CELLULAR IMMUNOLOGY UNIT
Harnessing the immune system against cancer
Our major goal is to achieve a deeper understanding of the molecular events regulating the interactions
among transformed cells, their surrounding stroma and the immune system during the different phases of tumor development and progression. This knowledge is then implemented to identify means whereby induce in
vivo a therapeutic tumor-specific immune response.
Monitoring the immune response against a tumor associated antigen (TAA) in the transgenic adenocarcinoma
of the mouse prostate (TRAMP) mice, a primary model of prostate cancer (PC), we have found that spontaneous tumor development and progression associates with the induction of a progressive state of selective immune tolerance. Indeed, tumor-bearing mice still harbor TAA-specific T lymphocytes that no longer respond to
a specific vaccination. So far, none of the best-characterized mechanisms of tumor escape [i.e. regulatory T cells
(Treg), myeloid derived suppressor cells (MDSC), and inhibitory enzymes] although existing in tumor-bearing
TRAMP mice, appeared to be relevant for the induction of TAA-tolerance.
Considering the profound state of TAA-specific immune tolerance that associates with PC progression in
TRAMP mice, we have hypothesized that alternative therapeutic strategies would be either the combination of
active or adoptive immunotherapy with tumor debulking approaches, or a “reload” of the immune system by
allotransplantation. Hence, on the one hand we are designing novel strategies that increase synergy between tumor debulking chemotherapy and immunotherapy. On the other hand, we are implementing allogeneic
hematopoietic stem cell transplantation and post-transplant tumor-specific vaccination in TRAMP mice. Preliminary data suggest that in both combined therapeutic approaches each single treatment act in synergy with
the others.
An additional complexity of the TRAMP model is the monitoring of tumor growth. Indeed, prostate masses
are detectable by abdominal palpation only in advanced phases of disease. In collaboration with the Department of Nuclear Medicine, we havedeveloped and validated PET imaging as a reliable tool for in vivo assessment of disease biology and progression in TRAMP mice using radioligands routinely applied in clinical practice: [18F]FDG and [11C]choline.
Matteo Bellone
EMERGING BACTERIAL PATHOGENS UNIT
Virulence and molecular epidemiology of drug resistant bacterial pathogens of community and nosocomial origin
Tuberculosis (TB): from public health to basic and applied research
We target some of the research priority areas in the TB field: new diagnostics for accurate and rapid DRTB
diagnosis and biomarkers for vaccine and treatment follow up.
We established a European consortium with extensive experience in basic and clinical research on MDR-TB,
TB control and epidemiology. TBPANNET and TM-REST FP7grants sustain this project. We implemented the
activities of our HSR-WHO TB Supranational laboratory and we are now collaborating with 9 middle-high
burden TB Countries world wide.
Host’s miRNAs and pathogen’s bacterial smallRNAs play a key role during host-pathogen interaction. We established an in vitro model for M. tuberculosis infection in human macrophages and monocytoid cell lines to
characterize host’s miRNAs response during infection. miRNAs expression profile was studied with a Taqman
medium-density arrays after infection with antigens and selected MTB strains.
smallRNA fraction from the pathogenic Mtuberculosis H37Rv and the avirulent strain Mbovis BCG were sequenced to identify unknown sRNAs in mycobacteria. Validation of candidates by expression analysis and target prediction are in progress.
Molecular epidemiology and virulence factors of nosocomial drug resistant pathogens.
Global epidemiology of S. aureus methicillin-resistant (MRSA) is evolving and the community-acquired (CA)
highly virulent US300-ST8 MRSA clone is the predominant clone in the US and is emerging in Europe. Studying
350 MRSA strains since 2005 we have identified: 1) a significant shift over time from clones bearing the scc mecI
to clones with scc mec IV; 2) two predominant clones, ST22 (EMRSA15) and HSR1 (Italian); 3) toxigenic US300
related strains causing severe infections. We are studying the expression of virulence factors in those clones.
C. difficile associated-colitis is increasing in nosocomial settings and highly virulent strains are spreading worldwide. C. difficile strains from symptomatic patients were fully characterized for virulence factors and we showed
the presence of epidemic strains with mutation/deletion in the tcdC gene coding for the negative regulator of toxinA/B. We are now investigating the association of virulence to mutations conferring antibiotic resistance.
Daniela Maria Cirillo
EXPERIMENTAL IMMUNOLOGY UNIT
We aim at gaining mechanistic insights into three aspects of the immune response that have direct relevance
to human health.
1. Development and function of CD1-restricted, lipid antigen-specific T cells.
CD1d-restricted invariant (i)NKT cells are a unique subset of T lymphocytes with innate effector functions
whose development relies on a distinct genetic program. We have shown that this program includes miRNAs
and identified an iNKT cell-specific miRNA signature. We are characterizing the molecular pathways regulated
by selected miRNAs. Following up our identification of the adjuvant function of iNKT cells for vaccine responses, we have defined a second mechanism by which iNKT cells can provide help to vaccine-specific B cells,
which relies on direct cognate interactions. We have also gained further insights into the mechanisms by which
mouse iNKT cells control prostate cancer in the TRAMP mouse transgenic model.
A second type of CD1 restricted T cells recognizes endogenous lipid antigens presented by CD1a, b, c. We
are testing the hypothesis that lipids synthesized by malignant cells may stimulate this T cell response. We have
identified a self-lipid molecule extracted from leukemia cells that stimulate CD1-restricted T cells, and we are
characterizing this T cell response in patients.
2. Tumor-specific CD4+ T cell responses.
We are optimizing the use of HLA-DR1101 tetramers to investigate the CD4+ T cell response specific for natural promiscuous epitopes derived from the frequent shared tumor antigen MAGE-3. Our study reveals the critical importance of the epitope binding registers into HLA-DR groove to generate functional HLA-DR tetramers.
3. Immunogenicity of the mutated tumor antigenome.
We are testing the hypothesis that somatic mutations in colorectal cancer genes (CRC CAN-genes) generate
strongly immunogenic antigens and specific immune responses in patients. By next generation sequencing of
the 40 most frequently mutated CAN-genes we are generating the atlas of unique or recurrent somatic mutations in 10 CRC samples. The immunogenicity of synthetic peptides encompassing the CAN-gene mutations is
being investigated with T lymphocytes from patients or healthy HLA-matched controls.
Paolo Dellabona
IMMUNOPATHOLOGY UNIT
Host-Virus interactions in the pathogenesis of viral hepatitis and viral hemorrhagic fevers
The hepatitis B virus (HBV) and hepatitis C virus (HCV) are noncytopathic viruses causing acute and chronic hepatitis of variable duration and severity. Over 700 million people worldwide are chronically infected by
these viruses and about 2 million of them die each year from the complications (i.e. cirrhosis and hepatocellular
carcinoma, HCC) of these infections. The main objective of our research is to define the cellular and molecular
mechanisms responsible for viral clearance and disease pathogenesis during HBV or HCV infection with the
expectation that our results will help to devise new therapeutic approaches to prevent and cure these diseases.
Our hepatitis program takes advantage of infected patients, unique mouse models of infection and new technological advances in the field of live imaging, tackling a number of unresolved issues that comprise the means by
which virus-specific T cells traffic and recognize viral antigens within the liver and how such processes are affected by the anatomical and hemodynamical changes that characterize the complications of chronic HBV infection. Having recently described a novel role for platelets in the pathogenesis of viral hepatitis (i.e. activated
platelets contribute promote the recruitment of virus-specific T cells into the liver), we are also currently dissecting the molecular basis of platelet/CTL interactions and the impact that pharmacologic inhibition of
platelet activation may have on the severity of immune-mediated chronic liver injury and HCC development. In
related studies aimed at testing the role of platelets in the pathogenesis of viral hemorrhagic fevers, we found
that mice infected with different isolates of hemorrhagic arenaviruses develop a mild hemorrhagic anemia,
which becomes severe and eventually lethal in animals depleted of platelets or lacking integrin β-3. Lethal hemorrhagic anemia is mediated by virus-induced interferon (IFN)- α/β that causes platelet dysfunction, mucocutaneous blood loss and suppression of erythropoiesis. Further, platelet-depleted mice fail to mount an efficient
T cell response and do not clear the virus. These studies indicate that IFN- α/β is required and sufficient to
cause the platelet dysfunction and the mechanism of this action is currently under investigation.
Luca G. Guidotti
LYMPHOCYTE ACTIVATION UNIT
On the cellular and molecular mechanisms controlling adaptive T cell immunity
Our goal is to gain a deeper understanding of the cellular and molecular mechanisms at the basis of adaptive
immunity, with emphasis on the role of CD4+ T lymphocytes in the establishment of immunological memory
and/or peripheral tolerance to tumors. We combine single cell-based in vivo analyses of T cell function with in
vitro biochemical and molecular characterization of the cells. We have developed several mouse models allowing the tracing of antigen- and tumor-specific CD4 and CD8 T cells in lymphoid and non lymphoid tissues. At
present we are focusing on: 1) the analysis of tumor-specific immune responses in mice with spontaneous and
transplantable tumor diseases and in the contest of active and adoptive immunotherapy, and 2) the definition of
the role of mTOR-dependent pathways in T cell tolerance and differentiation.
Ongoing scientific activities include:
• The study of the cooperation between minor histocompatibility antigen- and tumor-specific immunity in rejection of advanced prostate cancer in TRAMP mice. (R. Hess-Michelini, T. Manzo, M. Freschi, V. Basso,
M. Bellone and A. Mondino, 2010).
• The exploitation of transient TCR/CD28/IL-7 stimulation for the expansion of undifferentiated memory
CD4+ T cells. This has implication for adoptive cell therapy optimization. (V. Basso and A. Mondino, in
preparation)
• The study of dendritic cell-based vaccine immunogenicity in the context of allotransplantation. We found
that potent tumor-specific T cell priming can be induced in spite of concurrent potent minor histocompatibility antigen-specific responses. (T. Manzo, R. Hess-Michelini, V. Basso, J-G Chai, M. Bellone and A.
Mondino, submitted)
• This analysis of TSC-1 and mTOR in T cell biology. We find that TSC-1/mTOR-dependent signaling are
central to T cell development and the acquisition of transcriptional competence at genes involved in lineage
determination. (R. Tomasoni, V. Basso, S. Colombetti and A. Mondino, submitted)
Anna Mondino
TUMOR IMMUNOLOGY UNIT
Role of tumor antigen specific CD4+ T cells in tumor regression or promotion
Evidence for a role of CD4+ T cells in the antitumor immune response is established. However, along with
pro-inflammatory (Th1) anti-tumor immunity, it is now clear that CD4+ T cells may also exert regulatory and
anti-inflammatory (Th2) functions, eventually leading to tumor promotion through still not completely known
mechanisms. We set a strategy to study the quantity and quality of naturally occurring tumor antigen (TAA)specific CD4+ T cells in patients with cervical and pancreatic cancer.
Cervical lesions (CIN) are associated with infection by HPV. We focus on HPV-18 and found that low frequency of CD4+ T cells specific for the E6 and E7 proteins are present in the majority of HPV-18+ CIN patients. Surprisingly, we also found HPV-18-specific CD4+ T cells in 50% of patients tested, irrespective of the
presence of HPV-18 in their lesions, suggesting that the HPV-18- responsive patients might have cleared the infection. In agreement with this hypothesis, we found that a robust Th1/Th2 immune response against E7 but
not E6 was associated with the HPV-18- status. On the contrary, a robust Th1/Th2 immune response against
E6 but not against E7 correlated with lack of relapse. Our data demonstrate a positive role for anti-HPV-18 E6
and E7 CD4+ T immunity in CIN patients.
Pancreatic cancer (PC) is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which is believed to favor tumor progression. We previously reported a TAA-specific CD4+ Th2 immune-deviation in PC patients that correlated at the tumor site with a
predominant GATA-3+ over T-bet+ lymphoid infiltrate. We are currently testing the hypothesis that factor(s)
present in the tumor microenvironment activate dendritic cells with Th2 polarizing capability that in the draining lymph nodes would prime TAA-specific CD4+ Th2 cells. These cells will then home to the tumor, under the
influence of Th2 attractant chemokines, where they would exert effector functions on other immune cells with
the activation of a cascade of events affecting immune and tumor cells and further contribute directly by Th2
cytokine secretion to fibrosis, which is a hallmark in pancreatic cancer.
Maria Pia Protti
VIRAL EVOLUTION AND TRANSMISSION UNIT
Antigenic and phenotypic characterisation of HIV-1 variants in transmission and disease progression as
target for vaccine development
The intestinal mucosa is the main portal of entry of HIV-1 via all routes of transmission, and the site of major
immune subversion early after infection. HIV-1 was shown to transcytose through the epithelial intestinal mucosal layer but the pathways taken by the virus are still only mere speculation. Our results support the hypothesis that dendritic cells (DCs) mediate HIV-1 transmission from the lumen through the intestinal mucosa with a
process similar to bacterial sampling via a virus envelope-mediated mechanism with preferential transmission of
specific viral phenotypes to the underlying target cells. The cellular and molecular mechanisms driving the migration of HIV-1 through the intestinal epithelial barrier may be possible targets for mucosal vaccines. DCs mediating HIV-1 transmission may have important implications for inducing innate, non-specific defences and
promote adaptive immune response though to different degree in different intestinal sites. Indeed, in our experimental set-up DCs conditioned with epithelial cell-released factors change phenotype, and in turn restrict
viral replication. Understanding the cellular cross-talk and the type of immune responses promoted, will provide useful information on how to achieve an efficient anti-HIV immune responses in vivo.
Production of an broad neutralizing antibody (Nab) against multiple HIV-1 variants is a desired characteristic for HIV vaccines. We showed that those individuals who do control the disease progression (Long-term non
progressors) and/or control naturally the virus (Elite controllers) have mainly antibody against their own virus
but not cross-reacting against heterologous viruses, and thus are not of major interest for vaccine research. Instead our recent results indicated that an antibody response can raise shortly after infection and does not need
to follow the expected pattern of viral escape. The exquisite strong sensitivity of these viral variants to known
cross-reactive monoclonal antibodies make them an excellent antigen for vaccine development
Gabriella Scarlatti
VIRAL PATHOGENS & BIOSAFETY UNIT
Virus-host interactions: Human Immunodeficiency Virus (HIV), SARS Coronavirus (SARS-CoV) and
Influenza viruses
HIV. We have been studying HIV-infected individuals who naturally control HIV-1 infection maintaining a
healthy clinical state without the use of antiretroviral drugs (defined as LTNP). Among the nine HIV genes, the
integrity, variability and function of vif accessory gene have been analyzed in LTNP. Since most of HIV genes
exploit and manipulate cell host proteins, we are currently concentrating on host cell factors that restrict HIV
infection. In particular, we are interested in the role of the member 22 of the TRIparite Motif protein family
(TRIM22) on HIV replication. Previous observations have shown that overexpression of TRIM22 restricts HIV
infection. We have identified a model of U937 cell subclones in which TRIM22 endogenous expression correlates with poor HIV replication. Current studies are ongoing to define the precise mechanism of TRIM22 restriction.
A CoV is the etiological agent of the Severe Acute Respiratory Syndrome (SARS). Although the virus primarily infects the lungs, however, SARS-CoV causes a systemic infection since the virus has been found in blood,
urine and stool. We have been particularly interested in the kidney and intestinal tropism of the virus and identified human kidney cell lines that support SARS-CoV persistent infection. Such an infection leads to viral
adaptation sustained by the emergence of a single point mutation in the viral membrane glycoprotein that increases SARS-CoV replication in vitro and contributes to enhance its cytopathicity in a mouse model of SARSCoV infection. We have also identified the intestinal cell lines that supports SARS-CoV productive infection.
Influenza viruses. A currently believed dogma assesses that avian influenza viruses of H5, H7 and H9 subtypes
have the potential to be passed from animals, whether domesticated or wild, to humans. In contrast, H1 and H3
subtypes are devoid of such danger since the human population is endowed with cross-neutralizing antibodies
raised during seasonal infection and/or vaccination. By screening a panel of sera obtained from healthy volunteers who have responded to the seasonal influenza vaccine, we have demonstrated that humans do not have
cross-reacting antibodies against contemporary avian viruses raising concerns on future pandemic influenza.
Elisa Vicenzi
MANAGEMENT AND ANTIRETROVIRAL TREATMENT OF HIV
INFECTION
The Clinical Trial Unit (CTU) is a clinical research unit within the Department of Infectious Diseases, San
Raffaele Hospital, focused on addressing clinically relevant questions that may improve HIV patient care.
The activities of this unit are mainly concentrated on two areas: cohort studies and clinical trials.
As for the Cohort Studies, CTU participates to several national and international networks of HIV cohorts
(ICONA, ARCA, NEAT, EuroSida, D:A:D, COHERE, EURO CHAVI) collecting large amount of data on
HIV patients and addressing scientific questions (prognosis and outcome of adults HIV-infected subjects) that
single cohorts cannot answer individually. To be part of these collaborations, our internal database (the Infectious Diseases Database (IDD-HSR)) is regularly updated by fully-dedicated resources.
Moreover, CTU uses data from IDD-HSR for its own clinical studies mainly focused on long-term comorbidities associated with HIV infection and antiretroviral treatment such as diabetes, cancer, osteoporosis.
As for the Clinical Trials area, CTU is involved in the conduction and coordination of national and international industry sponsored phase II-IV clinical trials contributing to the:
• registration of new antiretroviral compounds,
• organization of early access program of experimental drugs for patients with limited therapeutic options.
CTU is also actively involved in proposing, coordinating and conducting investigator-driven independent,
no-profit, randomised and non-randomised clinical studies and committed to develop spin-off projects on new
strategies in salvage therapy.
In 2009, CTU activities were concentrated on the conduction of clinical studies providing insights on: 1) salvage strategies in patients resistant to all the standard therapies; 2) holding regimens in failing patients without
therapeutic options (T20 recycling, lamivudine monotherapy).
Antonella Castagna
NEUROVIROLOGY
Viral infections of the Central Nervous System (CNS): HIV infection of the CNS and Progressive Multifocal
Leukoencephalopathy (PML)
The importance of HIV CNS infection in the current era of suppressive antiretroviral treatment relates to the
role of the CNS as virus reservoir and the concern that persistent CNS immuneactivation may lead to neurocognitive impairment. We have observed a 42% frequency of neurocognitive impairment in treated and virologically suppressed patients with nadir CD4 cells
PML is a progressive demyelinating disease caused by JCV infection of oligodendrocytes. The mechanisms of
JCV reactivation leading to PML in patients with compromised immunity are mostly unknown. By sequencing
the JCV non coding control region (NCCR), we have identified identically highly “rearranged” patient-specific
sequences in CSF and plasma pairs, but not in urine, of PML patients. By sequencing the viral capsid protein-1
(VP1) coding gene we have identified mutations and deletions in both CSF and plasma of >90% of PML patients, but not in urine, corresponding to aminacid substitutions at critical sites for JCV binding to sialic acid
residues of the cell receptor, suggesting that, during reactivation, the virus may acquire adaptive mutations
within the patient that are associated with increased neurotropism. We have also characterized the CD8 T cell
responses by IFN-γ Elispot in both healthy subjects and PML patients, and identified an immunodominant
HLA-A*02-restricted JCV-VP1 epitope. By studying the IgG response against JCV-VP1, PML patients had low
antibody titres compared to immunocompromised controls. Altogether, the combined study of T and B cell responses could thus provide a tool to recognize persons at risk to develop PML.
Paola Cinque
STUDY AND TREATMENT OF HEPATOTROPIC VIRUSES RELATED
DISEASES
Treatment strategy against HCV in HIV/HCV coinfected individuals: HAART simplification, mechanism of
viral resistance to anti-HCV treatment
Current standard of treatment for hepatitis C virus infection (HCV) in HIV negative and positive individuals
involves a combination of pegylated-interferon-α (Peg-IFN) and the nucleoside analogue ribavirin. The efficacy of this combination is limited especially for genotype 1 infection for which less than one half of subjects
achieve sustained eradication of viremia. In HIV infected patients, chronic hepatitis C affects one third of HIV
positive individuals. These patients are less prone to maintain a sustained virologic response to anti-HCV treatment respect to HCV monoinfected individuals. The frequency of adverse events during anti-HCV treatment is
increased by concomitant highly active antiretroviral treatment (HAART). Additionally, HCV infection limits
HAART treatment because liver toxicity is more frequent in this setting. On the basis of this multifaceted scenario, we decided to focus two important issues: to improve the response to anti-HCV treatment in an intent to
treat fashion, to investigate the mechanism of viral resistance to antiviral treatment. We performed a prospective randomized study (KAMON 2) aimed to simplify HAART during standard anti HCV treatment. This
study demonstrated that simplification of HAART (one drug arm vs. HAART arm) during 48 weeks anti-HCV
treatment was effective as standard HAART treatment and response to anti-HCV treatment did not differ between patients included in the two arms.
The anti-HCV treatment response in HIV/HCV infected patients is lower than in HCV monoinfected
ones. This clinical evidence may be related to immune competence and unknown factors. To determine the
temporal dynamics of HCV infecting genotype in HIV/HCV infected patients under anti-HCV treatment
and their role in the treatment response was performed the molecular analysis of HCV viral strains in collected plasma samples of Kamon 2 study. A different virologic profile was shown between sustained virological
responders (SR) and non responders (NR) to anti-HCV treatment: SR were infected by a single HCV genotype, while NR were infected with more than one genotype, suggesting that viral resistance in HIV/HCV
coinfected patients is not only associated with infecting HCV genotype per se but also with the presence of a
mixed HCV infection.
Caterina Uberti-Foppa
VACCINE AND IMMUNOTHERAPY
Recombinant human interleukin-7 in HIV immunological non-responders to conventional antiretroviral
therapy
HIV infection is characterized by depletion of CD4 T cells and altered immune function, leading to severe
immune deficiency. CD4 cell depletion is the hallmark of HIV infection and occurs as a consequence of direct
viral replication and resulting cytolysis and apoptosis, but also as part of a general activation induced cell death.
The CD4 count is, with the HIV viral load, the strongest predictor of subsequent disease progression and survival. An adequate CD4 response for most patients on therapy is defined as an increase in the range of 50–150
cells/µL per year with an accelerated response in the first 3 months of treatment.
From 25% to 30% of HIV–infected patients who are receiving long term highly active antiretroviral therapy
do not exhibit a marked increase in the CD4 T cell count leading to an absence of recovery in the CD4 count,
despite achieving complete suppression of the HIV load. These patients are referred to as “immunological nonresponders.”
Apart from antiviral therapy for the infection, immunotherapies such as interleukin-7 (IL-7) that influence
Tcell homeostatic mechanisms are undergoing clinical evaluation. Because of its pleiotropic effects on developing and mature T cells, IL-7 may help to restore immune function during HIV infection.
At least 2 potential indications of rhIL-7 should be explored. Both correspond to unmet medical needs: to
rescue patients who experience immunological failure on HAART. First IL-7 will likely improve recovery of
CD4 T-cells in patients who remain lymphopenic under HAART, while HIV replication is at least partly suppressed. Despite recent progress, morbidity and mortality of these patients remain higher than in patients who
restore better their cell immunity. Second, this cytokine can be use to overcome the usual limitations of
HAART, observed in nearly all treated patients (i.e. the persisting insufficiency of the anti HIV T-cell response,
relatively toxic)
The clinical research activity of Vaccine and Immunotherapy Research Center is currently focused on the
conduction of multicentric, internantional phase I clinical trials employing IL-7 as immunotherapy on HIV
positive patients with poor CD4 recovery under conventional antiretroviral therapy.
GiuseppeTambussi
CLINICAL IMMUNOPATHOLOGY AND ADVANCED MEDICAL
THERAPEUTICS UNIT
Our interest focuses on the immunological features of systemic inflammatory diseases, with specific attention
to the identification of novel diagnostic and predictive markers of disease and disease activity, and to the dissection pathogenic mechanisms involved. We are specifically interested in:
• the pathogenesis of the prototypic systemic autoimmune disease, Systemic Lupus Erythematosus, with particular regard to the processes leading to kidney damage and pregnancy complications;
• the role of neuroendocrine mediators in vessel inflammation. In particular, we are carrying out a rather
comprehensive analysis of the factors underlying the enhanced cardiovascular risk of patients with sustained systemic inflammation;
• the immunopathogenesis of fibrosis and vascular damage in scleroderma and possible novel therapies;
• novel approaches in diagnosing and treating systemic vasculitides;
• the cytokine and chemokine network underlying the recruitment and activation of cells in systemic histiocytoses;
• the mechanisms of actions of biological agents used for the treatment of immune-mediated diseases (cytokines & anti-cytokines, monoclonal antibodies).
Maria Grazia Sabbadini
CLINICAL TRANSPLANT UNIT
Metabolic impact of portal venous drainage in pancreas transplantation
The veins of a transplanted pancreas are usually anastomozed to the external iliac vein of the recipient, leading to peripheral insulin secretion, while in physiological setting insulin is secreted within the portal system.
This leads to peripheral hyperinsulinization, a condition that was reported to be atherogenic. Pancreas transplantation can be performed with portal venous drainage, but requires a more complicated surgical procedure.
Furthermore portal drainage of the transplanted pancreas was considered less immunogenic than systemic
drainage.
The aim of this study is to evaluate the endocrine-metabolic impact and rate of rejection of portal venous
drainage in patients undergoing pancreas transplantation, compared to systemic venous drainage.
Open-label single center study comparing the efficacy and safety of tacrolimus vs cyclosporin in simultaneous kidney-pancreas transplantation.
The aim of the study is to evaluate the impact on patient survival, graft survival, rate of rejection, rate of complications and metabolic control of Cyclosporin vs Tacrolimus in kidney-pancreas transplantation.
Transplant Immunology
The transplant immunology activity is developed in collaboration with the Harvard Medical School in
Boston, US, in the context of the Transplantation Research Center at Children’s Hospital and it is coordinated
by Paolo Fiorina M.D.
The Lab is focused on two major topics:
1.
the regulation of anti pancreatic islet response both in term of autoimmunity versus self antigens in
type 1 diabetes and in term of alloimmunity in allogeneic islet transplantation.
Potential clinical application guides the development of our protocols. In particular it has been analyzed:
2.
a. B cell role and effect of depletion trough anti-CD22 immunotoxin on type 1 diabetes development
and anti-islet response maintenance.
b. Use of a combination treatment based on murine Thymoglobulin and CTLA4-Ig to modulate islet
rejection in NOD mice and to promote diabetes reversal.
c. Immunotherapy of diabetes trough the use of mesenchymal stem cells.
Use of new strategies to prevent or halting the curse of chronic rejection. Starting from the new murine
model available in our Lab (the bm12 into B6 minor mismatch model) we have developed new strategies with a high translational aim. Particularly, we are testing the effect of mobilizing endogenous
hematopoietic stem cells by targeting CXCR4-CXCL12 axis. These progenitors are known for their regenerative and immunological properties. We will take advantage of these characteristics to abrogate
the ongoing sub-acute alloimmune response evident in chronic rejection, as well as we will benefit from
their regenerative ability to repair damaged kidney.
Antonio Secchi
GYNECOLOGICAL CANCERS IMMUNOLOGY
Human PapillomaVirus (HPV) and cervical cancer
Main field of investigation of the Clinical Research Group is the correlation between Human Papillomavirus
(HPV) and the onset of cervical cancer. It is widely demonstrated that HPV infection is the causal factor for
neoplastic transformation of cervical cells; throghout viral DNA integration into cellular nuclei and viral protein expression, preneoplastic lesions (CIN) progress to invasive cancer.
In cooperation with the Tumor Immunology Unit we focused on HPV-18 and found that low frequency of
CD4+ T cells specific for the E6 and E7 proteins are present in the majority of HPV-18+ CIN patients. We also
found HPV-18-specific CD4+ T cells in 50% of patients tested, irrespective of the presence of HPV-18 in their
lesions, suggesting that HPV-18- responsive patients might have cleared the infection. Consistent with this hypothesis, we found that a robust Th1/Th2 immune response against E7 but not E6 was associated with the
HPV-18- status. On the contrary, a robust Th1/Th2 immune response against E6 but not against E7 correlated
with lack of relapse. Our data demonstrate a positive role for anti-HPV-18 E6 and E7 CD4+ T immunity in
CIN patients.
In a recent study we found a significantly higher relapse rate of preneoplastic lesions (CIN2 - CIN3) after surgical treatment in cases with reduced CD4,CD8,CD11C,T-bet and GATA-3 in the cervix. On the other side,
high levels of CD4+ and GATA-3+ in cervical tissues correlate with disease regression.
These data strenghten the tight correlation between immune response and HPV-related carcinogenesis.
Ongoing research projects deal with:
• Morphological study of cervical immune cells populations (mucosal immunity);
• Early biomolecular HPV 16-18 diagnosis and identification of “at risk” patients;
• HPV DNA identification as screening tool for cervical “high grade” lesions;
• Quantitative analysis of cervical immune sub-populations and correlation with HPV and HIV genital infection.
Massimo Origoni
IMMUNOLOGY IN LIVER NEOPLASMS
Evaluation of stress response in hepatobiliary surgery for liver neoplasms
The research programs of the Hepatobiliary Unit of the Department of Surgery are focused on the technical
aspects as well as the biological effects of the hepatic resections for liver neoplasms. In this setting, several studies are ongoing to reach the goals of optimizing the surgical techniques to minimize the biological postoperative
stress in terms of clinical outcome, inflammatory profile, and immunosuppression.
A prospective study (case-matched analysis) has been performed to investigate the short term outcome in pa-
tients undergoing laparoscopic and open liver resections, in terms of clinical outcome, inflammatory profile and
coagulation homeostasis. Thirty-two (=32) patients undergoing elective hepatic resections have been enrolled
in the study. Sixteen (=16) patients were non randomly assigned to the laparoscopic approach (LPS group),
while the further 16 to the traditional open procedure (LPT group). The two groups were matched for the extent of resection, and then for further parameters such as age, gender, preoperative liver function, tumor histology and size, and ASA score. We collected information about several indicators of postoperative clinical outcome, such as operating time, intraoperative blood losses and blood transfusions, tumor exposure at the transection surface and minimal surgical margin, hospital stay and overall morbidity rate, postoperative analgesic
therapy, mobilization recovery time and fasting duration.. We obtained plasmatic samples (collected preoperatively, in 1st, 2nd and 5th postoperative day) for the liver function assessment, measuring the Aspartate Aminotranspherase (AST), Alanina Aminotranspherase (ALT) and Total Bilirubin (BIL) levels. Moreover, we determined the serum levels of white blood cells count (WBC), C-reactive protein (CRP), Interleukin-6 (IL-6) and
Tumor Necrosis Factor (TNF) as markers of the inflammatory surgical stress response. Finally, we evaluated the
coagulation homeostasis measuring the serum levels of several parameters, such as prothrombin time (PT ratio), platelets count (PLT), fibrinogen (FG), antithrombin III (ATIII) and fibrin Ddimer (XDP).Postoperative
plasma levels of AST, ALT, WBC, CRP, IL-6, PT and XDP, along with blood losses, blood transfusions rate,
analgesic therapy amount, fasting duration, mobilization recovery time and overall morbidity showed a lower
rise in LPS group compared to LPT group. The decrease of PLT, ATIII and FG levels was lower in LPS group
than in LPT group. The laparoscopic technique for hepatic resections results in improved clinical outcome,
lower inflammatory stress response and lower coagulation alterations.
Luca Aldrighetti
PANCREATIC TUMORS: IMMUNOTHERAPY AND ß CELL FUNCTION
SUBSTITUTION
During 2009 the Unit of Pancreatic and Endocrine Surgery has focused its clinical research on pancreatic tumors. Surgical procedures performed represent the source of data and material necessary for every type of investigation and research.
Pancreatic cancer is a very aggressive disease with poor prognosis. Peculiar is the tumor microenvironment
characterised by an extensive fibrotic stroma which favors rapid tumor progression. A key-point is the assessment whether the Th2 polarisation of CEA-specific CD4 T cells from pancreatic cancer is stable or can be reverted by immunomodulating cytokines.
We found that only the combination of IL-12 and IL-27 modified the polarisation of Th2 effectors by both
reduction of IL-5, GM-CSF and IL-13 and induction of IFN-γ production, which lasted after cytokine removal.
Moreover, the combined treatment functionally modulated the Th2 polarization of CEA-specific CD4 T cells
and enhanced pre-existing Th1 type immunity.
The present results demonstrate that tumor antigen specific Th2 CEA-specific CD4 T cells in pancreatic cancer are endowed with functional plasticity. Hence, loco-regional cytokines delivery or targeted therapy based on
antibodies or molecules directed to the tumor stroma might improve anti-tumor immunity and ameliorate fibrosis without systemic toxicity.
Valerio Di Carlo
CLINICAL HEPATO-GASTROENTEROLOGY
Manipulation of the gut microbiota in the management of chronic intestinal disorders
The role of the gut microbiota in promoting and maintaining intestinal inflammation is now well recognized.
Antibiotics such as ciprofloxacin and metronidazole can be effectively employed in the treatment of inflammatory bowel disease, but side effects are common.
Both non-adsorbable antibiotics such as rifaximin and probiotics can represent a safer alternative. Probiotics
have been tested in the treatment of ulcerative colitis and Crohn’s disease (both in the acute phase and in the
maintenance of remission) with variable but promising results. The choice of the specific probiotic agent to is a
critical point because the mechanism of action of the various Lactobacillus strains, Bifidobacteria or yeasts such
as Saccharomyces boulardii is quite different.
To further our previous published experience in this area, we are currently evaluating the precise role of single probiotic agents, probiotic mixtures and rifaximin in the short- and long-term treatment of chronic intestinal disorders both of overt inflammatory nature (ulcerative colitis and Crohn’s disease) and where microscopic
inflammation may have a pathogenetic role (microscopic colitis, irritable bowel syndrome). Moreover, in co-operation with the recently established Probiotic Association (a multidisciplinary national society including gastroenterologists, paediatricians and microbiologists) we are endeavouring to identify and develop proper study
protocols in order to evaluate the efficacy of probiotic agents in clinical trials carried out according to a correct
methodology able to generate sound evidence-based data.
Mario Guslandi
TRANSPLANT SURGERY
The Area of Transplant Surgery focused its clinical research on Simultaneous Pancreas and Kidney Transplantation and Pancreas Alone Transplantation in IDDM patients regarding the following three fields: a) effect
of pancreatic transplantation with portal delivery of insulin secretion; b) effect of immunosuppressive protocols
on pancreas alone transplantation; c) efficacy of pancreas from pediatric donors to cure diabetes.
a)
25 patients underwent to pancreas transplantation with portal delivery of insulin secretion. Survival of
the pancreas was 82% and 63% at 1 and 5 years, respectively. Homa B% values which represent insulin delivery and insulin sensitivity recipients was no significantly different between patients with portal drainage transplant and normal individuals.
b)
From 2004 38 Pancreas transplantation alone have been performed; all of them received the whole organ with enteric diversion of exocrine secretion, 8 with portal-venous and 20 with systemic-venous
graft drainage. Two regimens of immunosuppressive therapy were used: in 2004 it was prednisone, mycophenolate mofetil, ATG (Anti-thymocyte globulin) and cyclosporine A, while from 2005 to 2009 was
prednisone, mycophenolate mofetil, ATG and tacrolimus. Cyclosporine A group included nine patients while tacrolimus group included nineteen. 1 year graft survival was 55% in the cyclosporine A
group while it was 80,7% in the tacrolimus group (p 0.12); after 5 years, graft survival was 33% in the
cyclosporine A group and 72,7% in the tacrolimus group (p 0.062).
c)
Pediatric donors could represent a novel source available for pancreas transplantation. From 2006 13
IDDM patients received pancreas transplants from pediatric donors (age between 12 and 17 years). After 1 year, patients survival rate is 92%, while pancreas graft survival is 61,5%, 40% for portal and
75% for systemic drainage. 2 patients with portal drainage developed graft thrombosis and one interrupted immunosuppressive therapy because of the onset of Moskowitz syndrome. 1 year after the operation mean HgbA1 was 4,9 (range 4,6 to 5,4) %; during OGTT mean basal glucose was 81,9mg/dl and
mean basal insulin was 9,1 µU/ml, at 120 minutes mean glucose was 88,3mg/dl and mean insulin was
42,4 µU/ml.
Carlo Socci
DIABETES RESEARCH INSTITUTE (DRI)
Director: Luca G. Guidotti
Associate Director: Emanuele Bosi*
Type 1 diabetes (T1D) afflicts nearly 150,000 people in Italy, most of them
children or young adults. Untreated, T1D is a fatal disease. Exogenous insulin, administered by multiple injections or by a continuous subcutaneous
infusion from an external pump, allows long-term survival in those who develop the disease, and most who are treated in this way will have a very good
health-related quality of life. However, insulin therapy does not provide normal glycemic control, and long-term survivors commonly develop vascular
complications such as diabetic retinopathy (the most common cause of adult
blindness) and diabetic nephropathy (the most common indication for adult
kidney transplantation).
Luca G. Guidotti
T1D results from the body’s inability to produce insulin, a hormone that is
needed to convert glucose into energy and regulate metabolism. The cause of insulin deficiency is the immune-mediated destruction of insulin producing β-cells located within the islets of the pancreas. The cellular and molecular determinants mediating this autoimmune process are still largely unknown.
Over the last 3 decades T1D has been one of the most relevant single areas of interest for patient care
and research at the San Raffaele Scientific Institute. With the objective of reinforcing and expanding its
commitment on diabetes research and care, in late 2007 a specialized and independent Research Institute
entirely devoted to T1D, denominated Diabetes Research Institute (HSRDRI), was launched at San
Raffaele.
HSR-DRI is part of the International DRI federation (DRI-NET), which includes 12 other DRI’s
around the world. HSR-DRI has an Executive Committee (Maria Grazia Roncarolo, Emanuele Bosi,
Luca G. Guidotti, Alessandro Del Maschio, Antonio Secchi) and a Scientific Advisory Board (Guido
Pozza, Camillo Ricordi, Giuseppe Chiumello, Massimo Trucco) and is composed of five Units of Basic
Research and four Groups of Clinical Research.
The Institute collaborates with nine groups of Basic Research (E. Bonifacio, Uni-Dresden; M. Von
Herrath, Uni-San Diego; M. Atkinson, Uni-Gainesville; P. Fiorina, Harvard; S. Gregori, Tiget; R. Bacchetta, Tiget; G. Zerbini, M. Lorenzi, V. Lampasona, HSR), six external Units of
Clinical Research (C. Ricordi, Miami; A. Ziegler, Uni-Munchen; F. Bertuzzi, Niguarda, Milan; PM. Piatti, G. Perseghin; M. Venturini HSR) and three external
Cores (L. Monti, HSR; E. Bazzigaluppi, Laboraf; A. Sanna, LaboRaf), which
closely interact with HSR-DRI scientists and actively contribute to the scientific
progress of the Institute.
The overall objective of HSR-DRI is to prevent and cure T1D.
To achieve this objective, two specific programs are pursued, both of which take
advantage of patients and animal models:
• Prediction and prevention of T1D: this program aims to define mechanisms of
Emanuele Bosi
induction and perpetuation of autoimmunity and at developing strategies for halting/reverting the
progression to T1D.
• β cell replacement and cell therapy in T1D: this program aims to develop novel immune tolerance-inducing, immunosuppression-lightening and islet-regeneration therapies to prolong the survival of native and/or transplanted β cells.
Research Units
IMMUNE TOLERANCE
Immunological tolerance in autoimmune type 1 diabetes: from problems toward solutions
Aims: Type-1 diabetes (T1D) is a chronic disorder mediated by self reactive cells that invade the pancreas and
destroy the insulin-producing cells. Peripheral tolerance results from a fine tuned balance between pathogenic
T cells and regulatory T cells (Tregs). Our goals are to: (1) characterize the immune responses occurring in the
target organ of T1D patients; (2) define new clinical grade protocols for the ex vivo expansion of human Tregs;
and (3) identify new therapies for re-establishing tolerance in pre-clinical animal models of T1D.
Achievements: (a) Pancreatic lymph nodes (PLN) were collected from T1D patients who underwent pancreas transplantation and were characterized phenotypically and functionally. We observed that FOXP3+ Tregs
of T1D patients are functional when they circulate in the peripheral blood but, within the site of auto-inflammatory drainage, they are environmentally modified towards a helper/effector phenotype despite being epigenetically imprinted to promote tolerance. (b) We previously demonstrated that rapamycin selectively expands
ex vivo Tregs while impedes the expansion of effector T cells. New studies have now delineated a good manufacturing practice (GMP) protocol for rapamycin-based human Tregs expansion Finally, (c) we showed that cell
therapy with Ag-specific Tr1 cells induced an IL-10–dependent tolerance in a stringent mouse model of islet
transplant. The therapeutic advantage of donor-specific Tr1 cells was due to their antigen-specificity.
Conclusions: (1) T1D patients do have Tregs in their target organ but they are unfit. It is still unknown
whether this finding is a cause or a consequence of the autoimmune disease. However, even if Tregs are not a
part of the problem they could still be part of the solution and treatments targeted at re-fitting Tregs may represent a solution for patients affected by T1D. (2) The definition of a GMP-grade protocol for the FOXP3+ Treg
expansion provides an additional justification for their clinical use. (3) The antigen-specific requirements for
Tr1 cells strongly point to the definition of clinical grade protocols for the generation of antigen-specific human
Tr1 cells to be used as cell therapy in T-cell–mediated diseases.
Manuela Battaglia
EXPERIMENTAL DIABETES
Pathogenetic mechanisms of autoimmune type 1 diabetes
Our research is focused on characterizing pathogenic mechanisms responsible for breaking self-tolerance and
generating autoimmune disease in animal models and patients with Type 1 Diabetes (T1D). The ultimate goal is
to identify novel targets for therapeutic intervention in T1D. Our two main projects are:
1. Study of gut immune regulation in T1D patients.
The gut is home of several immune regulatory cell subsets that contribute to maintain peripheral tolerance towards self-tissues. Specifically, tolerogenic dendritic cells (CD103+CD11c+ DCs) of the intestinal lamina propria are responsible for extrathymic differentiation of FoxP3+ Treg cells, a potent regulatory T cell subsets that
is crucial for prevention of autoimmune diabetes. Recently, thanks to collaboration with Clinical Units we received duodenal biopsies and study immune regulatory cells in the gut of patients with T1D and controls. Our
analysis revealed that T1D patients have a significant reduction of gut CD4+CD25+FoxP3+CD127- Treg cells
(P = 0.03) due to defective function of lamina propria tolerogenic DCs. Our future objective is to understand
whether the altered Treg cell differentiation in the gut of T1D patients is related to genetic or environmental
factors, e.g., microbiota alterations.
2. Restoration of immune regulatory iNKT cell function in pre-clinical models of T1D.
iNKT cells are immune regulatory cells crucial for prevention of autoimmune T1D. We recently demonstrated that iNKT cell inability to prevent autoimmune disease in T1D-prone NOD mice is due to lack of signals
driving their peripheral differentiation towards a regulatory phenotype, i.e., defective SLAM-SLAM homotypic
interaction with myeloid DCs (Baev et al. JI 2008). In 2009 we developed a gene therapy approach to restore
SLAM expression on NOD myeloid DCs. We cloned the murine SLAM gene into the MIGR1 retroviral vector
and used it to transfect myeloid NOD DCs of NOD mice and test their capacity to induce regulatory iNKT cell
differentiation. Our next goal is to test whether restoration of SLAM expression in NOD DCs and regulatory
iNKT cell differentiation prevents autoimmune diabetes. Moreover, we will assess whether a similar genetic defect of SLAM expression is present on DCs of T1D patients.
Marika Falcone
β CELL BIOLOGY
β cell replacement in diabetes
Background and unsolved issues. In principle, treatment for type-1 diabetes and many cases of type-2 diabetes, lies in the possibility of finding a β cell mass replacement capable of performing two essential functions:
assessing blood sugar levels and secreting appropriate levels of insulin in the vascular bed. Our project focuses
on creating conditions that favour β cell expansion and survival in transplanted and native environments Currently, the only available clinical therapy capable of restoring β cell mass in diabetic patients is the
allogeneic/autologous transplantation of β cells. Despite advances in recent years the somatic cell therapy is still
problematic.
Starting hypothesis and main results. The somatic cell therapy for T1D is a great platform to address mechanistic questions regarding type-1 diabetes. In the last years we were able to study the impact of β cell challenge
to the immune status of the patient and the efficacy of immunotherapeutics and their ability to control allogeneic and autoimmune responses. The results of these studies demonstrate (a) that survival of both syngeneic
and allogeneic islet grafts in the liver is sub-optimal, (b) that inflammatory reaction play a relevant role for the
survival and function of islets after transplantation, (c) that the actual immunosuppressive regimens do not control efficiently both allogeneic and autoimmune response.
Conclusions and future plans. To obtain the long term replacement of β cells in patients with diabetes we are
working on: (1) study bone marrow as site for islet transplantation, (2) develop novel islet survival strategies by
modulating inflammation specifically inhibiting pathways involving CCL2 or IL-8, (3) Improve islet transplantation outcome by cotransplantation of islets and feeder cells using mesenchymal stem cells, (4) determine
mechanisms of islet autoantigen immunization and destruction (5) to identify a renewable source of cells to be
used to increase the transplantable β cell mass.
Lorenzo Piemonti
CELL IMAGING
Non-invasive in vivo magnetic resonance imaging of Endorem®-labeled pancreatic islets in the liver following
transplantation in humans.
Non-invasive magnetic resonance imaging (MRI) of pancreatic islets is an attractive option for the “real-time”
monitoring of graft evolution in parallel to the measurement of metabolic parameters in T1diabetic patients.
We have previously optimized a labeling procedure for human islets using a clinically approved contrast
agent based on superparamagnetic iron oxide, Endorem®, assessing safety and in vivo MRI quality issues in a
preclinical model (Malosio et al, AJT 2009). Since 2009 a clinical study has started in collaboration with the
Islet Transplant Program and the Radiology Department, on T1diabetic patients, receiving intrahepatic transplantation of islet, of which the highly pure fraction is labeled with Endorem®. This allows to visualize by MRI
(T2*-weighted imaging) over time the presence of hypointese spots associated with labeled islets within the liver. This study is aimed at assessing how the MRI read-out correlates with the clinical measurement of islet function (glycemia; C-peptide; insulin need; HbA1c) and its usefulness in terms of prediction of functional success
or failure. Three patients have been transplanted so far and MRI monitoring over time (24h, 48h, 7d and once
every month for one year) is ongoing in parallel to the metabolic follow-up.
Identification of mechanisms underlying b cell functional failure.
Pancreatic β cell failure leading to cell death is a common feature of both T1 and T2 diabetes. The mechanisms involved remain largely unknown, though Endoplasmatic Reticulum (ER) and oxidative stress, mitochondrial insufficiency and up-regulation of inflammatory pathways have been implicated. The characterization of a rat insulinoma, the RIN-5AH line, by cell biology and fluorescence microscopy imaging approaches,
including the H2O2-sensing HyPervectors targeted to different intracellular compartments, is showing that
these cells display spontaneously many of the above mentioned stress features. Our studies aim at understanding: 1. the relationship between ER stress and oxidative stress, 2. mechanisms contributing to β cell survival or
death and their impact on β cell functional failure.
Maria Luisa Malosio
ISLET TRANSPLANTATION
The clinical Islet Transplantation Program activity has focused on the continuation of ongoing clinical trials
and the start up of new translational lines of research.
Continuation of ongoing studies:
2)
Study of the effect of exenatide on the dysfunction of transplanted islets. Two patients completed one
year treatment. No remarkable advantages of this treatment option were observed: one patient resumed subcutaneous insulin treatment at low doses, the other is continuing with exenatide administration.
3)
Pilot clinical trial (started in 2007) on a new immunosuppressive regimen without daclizumab and calcineurin inhibitors and with the potential of accomodating T regulatory cells expansion. This study was
completed. Two patients became insulin independent (insulin independence duration as of December
2009: 13 and 3 months); four patients had achieved partial islet function; three patients had early islet
failure, probably because of rejection.
4)
Effect of islet transplantation alone on long-term diabetes complications(i.e., early retinopathy, neuropathy, carotid artery disease) data are being collected prospectively and will be analyzed after the
completion of a 5 years follow-up.
5)
6)
7)
Prospective study of kidney function and incidence of cancer in patients who had received islet transplant alone.
Data entry in the Collaborative Islet Transplant Registry, supported by USA NIH and JDRF.
Safety and efficacy study of pancreatic islet autotransplant with total pancreatectomy. Three patients
received islet autotransplant and became insulin independent after one infusion of islet.
New studies:
1)
Pilot clinical trial on a new immunosuppressive regimen including ATG, MMF, tacrolimus during the
first 3 months after islet transplantation and sirolimus thereafter. One patients received the first islet infusion (9,185 IEq/kg) using this immunosuppressive regimen and achieved partial islet function.
2)
Safety study on intra bone marrow islet infusion in patients not eligible for islet infusion in the liver.
Three transplants have been completed [one autotransplant and two allotransplants (1 islet alone; 1
islet after kidney)]. C-peptide secretion was observed after islet infusion and no adverse events were
recorded.
3)
Study on in vivo magnetic resonance imaging of the transplanted islet. Three patients received Endorem-labeled islet into the liver; labeled islets were clearly recognized as hypo-intense spots scattered
into the liver. As for islet function, sustained C-peptide secretion was observed in two cases, early failure occurred in one case.
Paola Maffi
PREVENTION IN TYPE 1 DIABETES
This research program encompasses all studies aiming at the definition of pathogenetic mechanisms of induction and perpetuation of autoimmunity in humans and the identification of strategies for halting or reverting
the progression to clinically overt type 1 diabetes. In 2002, with the support of the Juvenile Diabetes Research
Foundation (JDRF), a Clinical Center infrastructure has been created at San Raffaele to host a TrialNet Center.
TrialNet is a NIH-supported network of clinical centres, investigators and core support facilities in the US
and Canada, United Kingdom, Italy, Germany, Finland and Australia. The goals of TrialNet programs are to:
further define epidemiology, natural history and risk factors of type 1 diabetes; support the development and
implementation of clinical trials of agents to slow the progression of type 1 diabetes in new-onset patients, and
delaying or preventing the emergence of type 1 diabetes in individuals found to be at risk of the disease.
Recently completed studies at the San Raffaele Centre include: the metabolic assessment of residual insulin
secretion in patients with type 1 diabetes and the Mycophenolate/Daclizumab clinical trial in recent onset patients; ongoing studies include: the natural history of development of type 1 diabetes; oral insulin for the prevention of diabetes in relatives at risk; studies under implementation include: s.q. GAD administration for the
prevention of diabetes in relatives at risk. An additional focus of the Clinical centre is the creation and expansion of a wide network of affiliate and satellite centres throughout Italy to support the enrolment into all the
TrialNet studies. Based on the same JDRF-funded infrastructure, other clinical trials, in addition to those performed within TrialNet, have been performed (e.g. anti-CD3 in new onset type 1 diabetes) or are expected to
be developed in the future, possibly including also phase I/proof-of-concept studies.
Emanuele Bosi
EPIDEMIOLOGY & DATA MANAGEMENT
The mission of the Epidemiology and Data Management Core is to provide methodological support to investigator-initiated clinical research and translational research projects within the Department of Immunology,
Transplantation and Infectious Diseases with special regards to those within the Diabetes Research Institute
(DRI). The Epidemiology and Data Management Core is currently providing support to the following major
projects within the Diabetes Research Institute and the Islet Transplant Program:
a)
studies of regulatory T cells in pancreatic and peripheral lymphonodes and of gut biopsies of patients
b)
c)
d)
e)
with type 1 diabetes. This studies use unique biological material collected through the collaboration of
clinicians and basic scientists.
a clinical trial testing safety, feasibility and efficacy of an immunesuppressive regimen that is compatible
with the use of T regulatory cells to induce immune tolerance. This study is part of a multicenter trial in
collaboration with the European Consortium for Islet Transplantation (ECIT).
a trial testing feasibility, safety and efficacy of the bone marrow as an alternative site for islet cell transplant in patients with type 1 diabetes in whom liver islet infusion is not feasible.
a randomized clinical trial to assess whether total pancreatectomy with islet autotransplantation is a superior alternative to pancreaticoduodenectomy in patients at very high-risk of complications of the
pancreatic anastomosis (soft pancreas and pancreatic duct diameter
a longitudinal study to identify and characterize the organ donor “inflammatory signature” and its potential to predict graft outcome. The study is conducted in collaboration with the Nord Italian Transplant program (NITp) and will involve over 1,000 cadaveric organ donors and 2,000 organ recipients
over the area served by NITp.
Marina Scavini
CHILDHOOD DIABETES
The Unit is involved in clinical trial aimed to secondary and tertiary prevention of type 1 diabetes in childhood. We have access to one of the larger cohort of newly diagnosed type 1 diabetes in children and adolescents
at italian level. During 2009 we collaborated with the Trialnet Center for the screening of family members of
children with Type 1 diabetes. We screened together 100 family members and we are part of the secondary prevention trial with oral insulin. Morover for tertiary prevention we participated to the Diamyd Trial an international multicenter phase 3 trial with GAD vaccination. We screened 9 patients in the trial end we enrolled 7 patients. We are following these patients for 2 years. Also for tertiary prevention we are involved in an italian multicenter trial sponsored by AIFA testing Metformine in patients at onset of disease. We are actually screening
patients at onset of diabetes in order to enrol in this trial.
The Unit is studying the characteristic of patients at onset of type 1 diabetes without immunologic cause of
type 1 diabetes: we try to identify unfrequent genetic mutation able to cause early onset diabetes (Mody, neonatal diabetes, insulin mutation, other rare mutation etc) in collaboration with Prof Barbetti in Rome. Moreover
in order to study T cells at onset of type 1 diabetes we setup a study in collaboration with Battaglia’s Lab and
Piemonti’s Lab, to study regulatory T cells and B cells at onset of diabetes and try to correlate phenothype and
genotype of these patients. In collaborations with others italian centers of SIEDP we participated in different
multicenter trial. In particularly we take part in a trial aimed to study concordance in italian twins for type 1 diabetes in collaboration with Istituto Superiore di Sanità aimed to discriminate between genetic and environmental factors in the pathogenesis of type 1 diabetes. We take part in a study aimed to clarify the history of potential celiac disease in diabetic patients.
Riccardo Bonfanti
ISLET PROCESSING ACTIVITY
Islet Processing Facility activity is devoted to islet of Langerhans isolation from human pancreas.
Allogenic transplant.
IPF mission is to provide isolated human islets for transplantation in type 1 diabetic patients as stated on the
Italian organ and tissues transplant regulation. Islets available for transplantation means that they have been determined to meet all release specifications and to be suitable for utilization. At this purpose, IPF organized
management with the target of ensuring that human islets have the quality required for transplantation in humans.
Autologous transplant.
We recently introduced islets isolation from segmental pancreas, obtained in the management of uncontrolled
fistula after Whipple resection. Islets re-infused in the same patient allow to reach a glycemic control also in patient with completion pancreatectomy.
ECIT – Islet for Research.
Human islet preparations not suitable for transplant in patients can be used as a mean to drive the isolation
procedures improvement, engraftment and its outcome, according to the local ethical committee decisions. IPF,
as a member of ECIT Consortium supported by JDRF, distributes islet preparation not suitable for transplant,
with the aim to improve the research activities in diabetes.
Different studies are currently in progress with the aim to increase the effectiveness of the islet transplant, to
achieve the immunological tolerance, define the best culture condition in terms of recovery before the transplant, and improve the islet transplant program with the stem cell base therapy.
Rita Nano
9 Abrams, D; Lévy, Y; Losso, MH; Babiker, A; Collins, G; Cooper, DA; Darbyshire, J; Emery, S; Fox, L;
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Human virology
Viral pathogens & biosafety Unit
Management and antiretroviral treatment of HIV infection
Study and treatment of hepatotropic viruses related diseases
Clinical immunopathology and advanced medical therapeutics Unit
Immune tolerance
β cell biology
DIVISION OF GENETICS AND CELL BIOLOGY - 149
DIVISION OF GENETICS AND CELL BIOLOGY
Director: Roberto Sitia*
Associate Director: Marco E. Bianchi*
Research Units
Protein transport and secretion Unit
HEAD OF UNIT: Roberto Sitia*
RESEARCHER: Tiziana Anelli
POST-DOCTORAL FELLOWS: Jose Garcia-Manteiga, Eva Margittai**
PHD STUDENT: Margherita Cortini**, Francesca Fontana
FELLOWS: Milena Bertolotti, Martina Brunati, Riccardo Ronzoni
TECHNICIANS: Claudio Fagioli, Elena Pasqualetto
Age related diseases
GROUP LEADER: Simone Cenci
POST-DOCTORAL FELLOW: Laura Oliva
PHD STUDENTS: Elisa Benasciutti, Enrico Milan**, Niccolò Pengo
FELLOW: Ugo Orfanelli
TECHNICIAN: Elisabetta Mariani
Molecular immunology
GROUP LEADER: Antonio Siccardi
FELLOWS: Rita Nunzia Fucci, Elisa Nigro
TECHNICIAN: Elisa Soprana
Chromatin dynamics Unit
HEAD OF UNIT: Marco E. Bianchi*
POST-DOCTORAL FELLOWS: Roberta Palumbo, Angela Raucci, Emilie Venereau
PHD STUDENTS: Antonella Antonelli, Jaron Liu, Tobias Pusterla**
FELLOWS: Lisa Trisciuoglio, Luca Sessa
TECHNICIANS: Francesco De Marchis, Alessandro Catucci
In vivo Chromatin and transcription
GROUP LEADER: Alessandra Agresti
PHD STUDENT: Barbara Celona**
HEAD OF UNIT: Lawrence Wrabetz
POST-DOCTORAL FELLOWS: Maurizio D’Antonio, Pietro Fratta, Francesca Florio, Ambra Zaghetto
PHD STUDENTS: Nicolò Musner**, Francesca Ornaghi**, Elisa Tinelli**, Domenica Vizzuso**
TECHNICIANS: Cinzia Ferri, Paola Saveri
HEAD OF UNIT: Angela Bachi
POST-DOCTORAL FELLOWS: Alfonsina D’Amato, Vittoria Matafora, Federico Torta
PHD STUDENT: Umberto Restuccia
FELLOW: Santosh Anand
TECHNICIAN: Angela Cattaneo
Gene expression Unit
HEAD OF UNIT: Fulvio Mavilio
RESEARCHERS: Maria Pannese, Alessandra Recchia
POST-DOCTORAL FELLOW: Claudia Cattoglio
PHD STUDENT: Valentina Poletti**
FELLOW: Simona Capossela
TECHNICIAN: Serenella Sartori
Genetics of common disorder Unit
HEAD OF UNIT: Daniela Toniolo
RESEARCHER: Silvia Bione
POST-DOCTORAL FELLOWS: Giorgio Pistis, Michela Traglia
PHD STUDENT: Tanguy Corre **
FELLOWS: Ivan Buetti, Salvatore Carrabino, Massimiliano Cocca, Corrado Masciullo
TECHNICIANS: Cinzia Sala, Fiammetta Viganò
Molecular basis of polycystic kidney disease Unit (Dulbecco Telethon Institute)
HEAD OF UNIT: Alessandra Boletta
POST-DOCTORAL FELLOW: Isaline Rowe
PHD STUDENTS: Maddalena Castelli**, Monika Pema
TECHNICIANS: Marco Chiaravalli, Gianfranco Distefano
Molecular genetics Unit
HEAD OF UNIT: Francesco Blasi*
RESEARCHER: Daniela Talarico
POST-DOCTORAL FELLOW: Silvia D’Alessio
PHD STUDENTS: Patrizia Marzorati, Silvia Mori
FELLOWS: Ambra Crippa, Laura Gerasi
TECHNICIAN: Massimo Resnati
Molecular dynamics of the nucleus
GROUP LEADER: Massimo Crippa
POST-DOCTORAL FELLOW: Nicola Micali
PHD STUDENT: Monika Wozinska**
FELLOWS: Andrea Boni**, Matteo Marinelli**
NeuroGlia Unit
HEAD OF UNIT: Maria Laura Feltri
POST-DOCTORAL FELLOWS: Silvia Bogni, Ernesto Pavoni, Yannick Poitelon
PHD STUDENTS: Cristina Colombelli, Monica Ghidinelli**, Marta Pellegatta**
FELLOW: Marilena Palmisano
TECHNICIANS: Stefania Saccucci, Desirée Zambroni
Regulation of iron metabolism Unit
HEAD OF UNIT: Clara Camaschella*
POST-DOCTORAL FELLOW: Laura Silvestri
PHD STUDENTS: Antonella Nai, Alessia Pagani
RESIDENT: Erika Poggiali
Molecular genetics of renal disorders Unit (Dulbecco Telethon Institute)
GROUP LEADER: Luca Rampoldi
POST-DOCTORAL FELLOW: Céline Schaeffer
PHD STUDENT: Ilenia Bernascone**, Martina Brunati
FELLOWS: Simone Perucca, Matteo Trudu
Dento-facial histopathology Unit
HEAD OF UNIT: Enrico Gherlone*
PHYSICIANS: Paolo Capparé, Carlo Alberto Cortella, Roberto Crespi, Massimo Pasi, Raffaele Vinci, Stefano Zandonella Necca
Genomics of renal diseases and hypertension Unit
HEAD OF UNIT: Paolo Manunta*
CLINICAL GROUP LEADER: Donatella Spotti
RESEARCHER: Laura Zagato
PHYSICIANS: Teresa Arcidiacono, Chiara Lanzani, Luisa Persichini, Maria Teresa Sciarrone Alibrandi, Giuseppe Vezzoli
RESIDENTS: Giovanna Bonavida, Irene Botticelli, Marialuisa Querques, Francesco Rainone, Marco Simonini
FELLOWS: Lorena Citterio, Simona Delli Carpini, Elisabetta Messaggio
TECHNICIAN: Nunzia Casamassima
RESEARCH NURSES: Elena Brioni, Marie Jankaricova
HEAD OF UNIT: Gianfranco Fraschini*
CLINICAL GROUP LEADER: Giuseppe M. Peretti
PHYSICIAN: Corrado Sosio
RESIDENTS: Laura Mangiavini, Alessandro Pozzi, Celeste Scotti
POST-DOCTORAL FELLOW: Daniela Deponti
FELLOW: Rosa Ballis
The Division of Genetics and Cell Biology (DGCB) consists of 14 basic
and 3 clinical research groups, totaling over 140 staff. It occupies laboratory space in Dibit 1 and 2 buildings.
Mission - DGCB aims at the mechanistic comprehension of biological
phenomena to acquire basic knowledge and fuel translational and clinical
research with novel concepts, tools and protocols. Understanding Physiology and Pathology in cellular and molecular terms is fundamental to cure
disease and create novel bio-technologies. Scientific training is another
DGCB priority.
Roberto Sitia
Organization - Scientists are free to engage
in competitive research projects: they are encouraged to join forces, data and equipment so as to foster synergies. Areas of
particular strength include bone and cartilage physiopathology, the physiopathology of stress responses and conformational diseases, chromatin dynamics and epigenetics, cell polarity, and the genetics of complex disorders.
DGCB staff is engaged in inter-Divisional Research Programs and Institutional Facilities.
Goals - Biology is becoming more and more a hard science. Surprising disMarco E. Bianchi
coveries are still made of course, but there is little doubt that quantitative aspects are now essential. This is especially true for an Institute like ours, which
expects basic and clinical research to synergistically flourish. In strict collaboration with the Center of
Genomics, BioInformatics and BioStatistics, DGCB develops state of the art technological platforms for
the scientific community.
DGCB aims at providing clinical sciences with novel concepts and protocols and develops robust cellular and animal models for their testing. As important is reverse translation, where the detailed analysis of
cohorts of patients can unravel physiological mechanisms. Identifying mutational hotspots in patients, for
instance, sheds light on the structure and function of the normal product.
The iterative process of translation is a key asset for DGCB.
Main achievements - The numerous scientific achievements in 2009 are described in the sections devoted to the single laboratories and are testified by the publication of about 70 papers on international journals.
Training opportunities - DGCB hosts both PhD and PostDoctoral training programs, where positions
are offered on a competitive basis for a minimum of 3 and 2 years, respectively.
Research Units
PROTEIN TRANSPORT AND SECRETION UNIT
Our Unit is exploring the processes of oxidative folding, quality control and degradation of proteins –antibodies in particular- in the early secretory compartment (ESC). Solving the structure of ERp44 revealed a novel
mechanism that regulates the binding and release of this chaperone to its client proteins (Wang et al., 2008),
likely governed by pH (Vavassori et al., in preparation). ERp44 interacts with ERGIC-53 and regulates the
transport and/or polymerization of Ero1, IgM and SUMF1 (Cortini and Sitia, 2010 a, b; Fraldi et al., 2008).
With Ero1, ERp44 also regulates IP3R1 channels (Bergamelli et al., submitted), thus integrating redox and calcium homeostasis/signaling (Anelli & Sitia, 2008; 2010). By manipulating the expression of key quality controllers in ESC, we could modify the fate of aggregation-prone mutant secretory proteins (Ronzoni et al., 2010).
Identifying potential targets for the wide family of ER storage disorders, these findings have profound implications in the pathogenesis of these and other protein conformational diseases Anelli and Sitia, 2010).
The lab analyses also the mechanisms that orchestrate the architectural (de novo biogenesis of the secretory
apparatus) and functional (onset of Ig secretion and eventually apoptosis) changes during B lymphocyte-plasma
cell differentiation. Our observation that proteasomal capacity declines in parallel to the massive increase in antibody production explains in part the exquisite sensitivity of normal and malignant plasma cells to proteasome
inhibitors (Nerini et al., 2008; Cascio et al., 2008, Cenci et al., 2008). Indeed, the proteasomal load vs capacity
ratio correlates with drug sensitivity and can hence provide a useful clinical indicator (Bianchi et al., 2009). The
tight connections between disulfide bond formation, protein secretion and oxidative stress identify novel targets for manipulating maladaptive stress responses (Masciarelli & Sitia, 2008; Rubartelli & Sitia, 2009a, b). The
possibility of modulating ER proteostasis, redox and stress could offer new therapeutic strategies not only in
ER storage and conformational diseases, but also in myeloma and other types of cancer.
Roberto Sitia
AGE RELATED DISEASES
We explore the basic cell biology of normal and malignant plasma cells, with implications for Ab responses
and Multiple Myeloma (MM, 2% of all cancer deaths).
Our discovery that differentiating plasma cells decrease proteasome activity and suffer from proteotoxic
stress (Cenci et al, 2006) provided us with a unique biological model linking protein synthesis to death, with
key immune and oncological implications, like the potential exploitation of proteasome inhibitors (PI) as humoral immunosuppressants in vivo (Cascio et al, 2008). Hence, our research activity aims at: understanding
how plasma cells cope with stress and proteasomal overload, investigating the mysterious mechanisms regulating mammalian proteasome biogenesis; exploiting proteotoxicity to identify novel targets against plasma cell
cancers.
Along these lines, we found that plasma cells deploy autophagy with potent regulatory effects on lifespan and
Ig secretion (Pengo et al, manuscript in preparation). In MM, proteasome expression and functional workload
are key determinants of apoptotic sensitivity to PI, providing potential molecular targets and prognostic indicators (Bianchi et al, 2009). Moreover, we are demonstrating an adaptive role for autophagy in MM (Fontana et
al, unpublished).
Parallel in vivo studies on the molecular mechanisms driving the differentiation of osteoclasts, unique boneresorbing cells, are unveiling novel links between adaptive immunity and bone biology, of potential therapeutic
interest against bone-wasting conditions (Cenci et al, 2003; Benasciutti et al, manuscript in preparation). Given
the vicious connection between MM and bone cells, this model will be of use to better understand the MM environment.
Simone Cenci
MOLECULAR IMMUNOLOGY
Two main projects are pursued.
1. Construction of recombinant poxviruses.
We developed novel methods that allow an extremely rapid production of recombinant poxviruses (MVA
and FPV). An interesting side product was the description of the sequence of homologous recombination
events that lead to the formation of markerless recombinants (Di Lullo et al., 2009; Di Lullo et al., 2010). Moreover, we developed a novel method for the parallel construction of MVA and FPV recombinants (Soprana et
al., submitted). MVA and FPV are immunologically not cross-reactive and can be employed for efficient
prime/boost strategies. Some of our influenza recombinant vaccine (M1, M2, Np, HA, of various H1 and H5
subtypes) are used in vaccination trials at the Robert Koch Institut in Berlin and at IZPS, Padova (Siccardi et
al., in preparation).
2. Exploiting the adjuvant role of membrane IgE in cell vaccines.
Owing to interactions between membrane IgE with specific receptors located on effector cells in a form of intercellular synapsis (Vangelista et al., 2005), tumor cells bearing membrane IgE are better vaccines than control
cells (Reali et al., 2001). The adjuvanticity is dependent upon the interaction with Fc-epsilion RI receptor bearing cell (as demonstrated in knock-out mice). The adjuvant effect of human membrane IgE is demostrable also
in mice which express only the human receptor (Nigro et al., 2009). A further demonstration of the IgE role in
tumor control in mice is that transplanted tumors grow much less in hyper IgE transgenic mice (Nigro et al., in
preparation).
Antonio Siccardi
CHROMATIN DYNAMICS UNIT
Our group studies chromatin organization and function, and in particular the role of one protein, High Mobility Group Box 1 (HMGB1). The state of chromatin determines how specific genes are expressed by different
cells in the same organism (that contain the same genome). Moreover, differentiated cells maintain their identity over time, and stem cells maintain their plasticity. When they fail in this, they can become tumors, or simply
start performing erratically (degenerative diseases of various kinds).
We are also very interested in a remarkable property of HMGB1. This nuclear protein can be leaked out of
necrotic cells and signal traumatic tissue damage, triggering inflammation, cell proliferation and migration, innate and adaptive immune responses, angiogenesis and eventually tissue repair. The connection between chromatin status in apoptosis and tissue repair is a particular focus of our group.
During 2009, we have been able to convince the “HMGB1-as-cytokine” field that by itself HMGB1 only acts
as a chemoattractant (essentially for all cells that can migrate), and can act as a cytokine (inducing the synthesis
of other cytokines, chemokines or immunological effector molecules) only when associated with other partner
molecules, via the receptor for the partner molecule. We have also shown that extracellular HMGB2 is functionally very similar to extracellular HMGB1.
➥
Figure 16. HMGB1 as a DAMP. Inflammatory
and immune responses are activated by
Pathogen Associated Molecular Patterns (parts
of bacteria, viruses etc) but also by endogenous
distress signals, or Damage Associated
Molecular Patterns, such as HMGB1.
We have also shown that the signal transduction pathways activated by extracellular HMGB1 include Srcfamily kinases and the non-classical NF-κB pathway, in addition to the already known MAPK and classical NFκB pathways.
Moreover, in collaboration with the group of Tadatsagu Taniguchi in Tokyo, we have shown that cytoplasmic
HMGB1 binds nucleic acids that happen to be outside of the nucleus, and therefore may represent viral
genomes. On doing so, HMGB1 presents the suspected viral genomes to specialized cytoplasmic virus detectors, and activates the antiviral responses of the cell.
Marco E. Bianchi
IN VIVO CHROMATIN AND TRANSCRIPTION
Our focus is on the quantitative analysis of NF-κB transcriptional dynamics in living cells, at single cell level.
Single cell analysis provides a sharper description of dynamic events and bypass the inherent limitation of kinetic studies in cell populations due to averaged results from standard biochemical approaches.
In resting cells, NF-κB is mainly cytoplasmic and translocates to the nucleus upon inflammatory stimuli. Activated gene transcription leads to the resynthesis of several negative feedback genes that cause the inactivation
of NF-κB and its re-localization to the cytoplasm. In the past, NF-κB nuclear cytoplasmic translocation has
been reported to have a biphasic pattern with a sharp first nuclear translocation peak followed by a prolonged
nuclear persistence with minor fluctuations. We demonstrated multiple consistent peaks of p65 nuclear localization (Sung et al, 2009) in single living fibroblasts from GFP-p65 knock-in mice that allow the detection of
physiological levels of endogenous p65. Fourier analysis demonstrated that oscillations are sustained in the majority of the cells (79%) with 2.2 hours period (median value). Furthermore, p65 in late translocations is capable of diffusing on and interacting with the genome as effectively as the first p65 molecules activated after TNFα by FRAP.
➥
Figure 17. Fine-tuning transcriptional output by NF-κB
oscillations. (A) When there are little or no NF-κB
oscillations, immediately accessible target genes are
continuously induced. Gene-specific mechanisms attenuate
the transcription of these genes over time, while a different
group of genes become responsive. In this model, overall
gene expression kinetics does not critically depend on
κB dynamics. (B) Sustained NF-κB oscillations allow only
pulses of expression for the immediate early genes, as the
transcription factor interacts transiently with the chromatin
at discrete times. In later signaling cycles, NF-κB returns
with characteristic genome-scanning competency and acts
on late-accessible genes, without having accumulated early
transcripts at a high level. Therefore, NF-κB oscillations,
which are strongly coupled with upstream signaling
kinetics, ensure balanced gene expression programs.
Mathematical modeling and computational simulations predicted that two different system perturbations
would abolish oscillations, constrain p65 in the nucleus and result in opposite functional consequences of p65
transcriptional activity. Leptomicyn and Cycloheximide (LMB and CHX) used to mimic high IKK inactivation
rate and low IkBα synthesis rate, respectively showed constitutive nuclear localization while p65 mobility increased with LMB and decreased with CHX suggesting different transcriptional activities. Indeed, expression
of NF-κB target genes was either inhibited (LMB) or profoundly enhanced (CHX) suggesting that NF-κB oscillations encode specific cellular signaling information.
These results suggest that the oscillatory mode of NF-κB action may be a cellular trade-off between efficient
pulses of expression and the need for NF-κB to monitor the signaling status for several hours to tune optimal
transcriptional responses (figure 17).
Alessandra Agresti
BIOLOGY OF MYELIN UNIT
Genesis and maintenance of myelin
We have a long-standing interest in myelin, the sheath that enwraps larger axons in the nervous system to permit rapid conduction of impulses and guarantee axonal health. We have explored the role of axonal signals, adhesion and transcriptional regulation in myelination. In particular, we have exploited inherited neuropathies,
which reveal important determinants of myelin formation.
Recently, we have produced/studied seven mouse models of Myelin Protein Zero (MPZ) neuropathies that
cause widely varying neuropathy phenotypes in patients. Mice overexpressing wildtype P0 develop congenital
hypomyelination; mice expressing P0 with a myc-epitope tag at the amino terminus unexpectedly model two
more severe subtypes of CMT1B neuropathy; and mice expressing P0 with any of five known human MPZ mutations model CMT1B or Congenital Hypomyelination Neuropathy. We validated these preclinical models (figure 18 shows onion bulbs and demyelination in peripheral nerve of MpzS63del mice), confirmed that the mutations operate through gain of function, and showed that the mutant proteins have their ‘toxic’ effect from various locations in the Schwann cell, many times away from myelin itself. For example, in MpzS63del mice, mutant P0 is retained in the endoplasmic reticulum and activates protein quality control pathways in myelinating
Schwann cells of peripheral nerve. Our recent data suggest that protein quality control unintentionally alters
translation of myelin proteins or impairs proteasome degradation of myelin proteins, thereby impairing myelin
stability in CMT nerves. More recently, we have strong evidence that endoplasmic reticulum stress activates inappropriate dedifferentiation of myelinating Schwann cells—this could explain the developmental defect seen
in S63del nerves. Another mutant P0 protein, P0Q215X, may be mistrafficked to the surface of Schwann cells
where it may interfere with appropriate signals from its extracellular matrix. Finally, P0S63C may form disulfide bonded dimers in trans in the myelin sheath, altering the fluidity of the myelin sheath. These continuing
studies reveal both the pathogenesis of neuropathy, and biological clues about the normal genesis and maintenance of myelin.
Lawrence Wrabetz
Figure 18. Onion bulbs and demyelination in peripheral nerve of MpzS63del mice
BIOMOLECULAR MASS SPECTROMETRY UNIT
Technological innovations have driven research in proteomics from single protein characterization to global
approaches, aiming to achieve a comprehensive qualitative and quantitative description of complex molecular
mechanisms. In this frame, we are developing novel approaches that can be applied to proteome analysis of
cells under physiological and pathological states. During 2009 we investigated how post-translational modifications affect protein function. In particular, to gain insights into the interconnection of the SUMO and the ubiquitin-proteasome pathway, we have studied, by a SILAC based quantitative approach, the effect of proteasome
inhibition on SUMO-conjugated proteins. 193 potential SUMO-1 substrates were identified, 78 of which are
upregulated upon proteasome inhibition. Among these, Histone H1, Histone H3 and p160 myb binding protein 1A have been further characterized as novel SUMO-1 substrates. Moreover, the analysis of the nature of
the SUMO-1 targets identified strongly indicates that sumoylation regulates the maintenance of nucleolar integrity acting in coordination with the ubiquitin-proteasome system (Matafora V. et al 2009).
One of the major challenges in the proteomic study of phosphorylation is the enrichment of substoichiometric phosphorylated peptides from complex mixtures. We have developed a novel TiO2 coated matrix assisted
laser desorption ionization plate that enables an efficient purification of phosphopeptides from complex mixtures (Torta F. et al 2009).
This new active surface is able to bind and enrich phosphopeptides from complex mixtures and make them
detectable for a standard MALDI-MS or MALDI-MS/MS analysis. The compatibility with a MALDITOF/TOF instrument could open the perspective of using it for the identification of phosphosites in complex
biological samples while its ability to retain also other kind of phosphorylated biomolecules could open a new
way of studying phospholipids.
Angela Bachi
Figure 19. SUMO-1 relocalization after MG132 treatment
GENE EXPRESSION UNIT
The rapidly expanding information on the structural and functional characteristics of the human genome allows the development of genome-wide approaches to the understanding of the molecular circuitry wiring stem
cell genetic and epigenetic programs. Transcription factors regulate gene expression and shape the epigenetic
state of chromatin by recruiting DNA methylation and histone modification complexes, playing essential roles
during commitment and fate determination. Most genome-wide studies on gene expression programs and epigenetic chromatin modifications come from easy accessible, homogeneous cell lines. Little is known on rare
stem cells that are defined only retrospectively by the nature of their progeny in culture or transplantation assays. We recently provided proof of principle for the use of retroviruses as genome “scanners” for active genes
and regulatory sequences, by deep sequencing analysis “integromes” in CD34+ human stem-progenitor cells.
We showed that retroviral vectors integrate in promoters, enhancers and other regions enriched in cell-type
specific subsets of transcription factor binding sites, and proposed that the viral integrase tethers pre-integration complexes to transcriptionally active regulatory regions by binding to general components of the Pol II
complex. We are currently applying retroviral scanning to the analysis of the genetic programs of human
hematopoietic, neural and epithelial stem cells.
Control of translation plays a critical role in development, growth, and differentiation. In eukaryotes, translation is mainly regulated at the level of initiation. The Wbscr1 gene encodes the eIF4H initiation factor. The human homolog of Wbscr1 is on chromosome 7, in a region commonly deleted in patients affected by the
Williams-Beuren Syndrome (WBS). We have generated knock-out mutant mice for Wbscr1, which are characterized by dwarfism, reduced fertility and impairment of sensorimotor coordination and cognitive functions, as
in WBS patients. To identify genes regulated at translational level by Wbscr1 we are performing micro array
profiling on total and polysomal mRNAs from embryonic fibroblasts and liver of wild-type and null mice, a
starting point to clarify the functions of this gene in human physiology and pathology.
Fulvio Mavilio
GENETICS OF COMMON DISORDERS UNIT
The large number of recently published GWAS has shown that only few common variants are implicated in determining the risk for complex disorder and that they only explain a small fraction of the genetic risk. Among the
cohorts used, the isolated populations appear particularly useful also in view of future approaches aimed at the
search for less common variants, expected to increase the risk in carriers at a substantially higher rate. We have
completed the first data collection of the isolated population of Val Borbera in North West Italy, including clinical data, with information on most common disorders and more than 60 serum and urine traits, genealogical and
genotyping data. This has allowed a large set of association and linkage analysis and identified a number of new
loci that have been replicated in different populations, in Italy, within the Italian Network of Genetic Isolates
(INGI) and in Europe, confirming the power of the special genetics of the population isolates. The availability of
genotyping data has also allowed the group to participate to several large consortia for meta analysis of blood
cells traits and iron, reproductive traits, urine and uric acid, blood pressure, thyroid disorders and others.
The genetics of premature ovarian failure (POF) is the second main topic of the unit. The association of the
DIAPH2 gene variants to POF was confirmed. A major role for the DIAPH2 gene in follicular maturation was
demonstrated by the finding that DIAPH2 is the main determinant of the cytoskeleton rearrangements induced
by FSH, The study of the POF in Val Borbera has highlighted new loci, including one in the Major Histocompatibility Complex on chromosome 6 that would very well explain the common finding of association of POF
and autoimmunity. Replicas of the results are ongoing using the other INGI populations as well as our large
Italian POF case-control cohort.
Daniela Toniolo
MOLECULAR BASIS OF POLYCYSTIC KIDNEY DISEASE UNIT
Unraveling the function of polycystin-1, the protein most commonly altered in Polycystic Kidney Diseases
The nephron is the filtering unit of the kidney and is formed by the glomerulus and the renal tubule. The diameter of the tubule needs to be tightly controlled for its proper function. Polycystic Kidney Diseases (PKD), is
a class of pathologies characterized by abnormally enlarged tubules eventually causing renal failure. Autosomal
Dominant Polycystic Kidney Disease (ADPKD) is the most common form of PKD and a very frequent genetic
disease affecting 1:1000.
ADPKD is caused by mutations in either the PKD1 (in 85% of cases) or the PKD2 genes (in 15%) encoding
for Polycystin-1 (PC-1), a large plasma membrane receptor, and Polycystin-2 (PC-2), a calcium channel, respectively. Our major interest is on studying the normal function of PC-1.
In the past we had found that PC-1 is a multi-tasking receptor involved in regulating several signaling cascades. PC-1 induces cell-cycle arrest in the G0/G1 phase of the cell cycle and concomitantly resistance to apoptosis. We have identified a novel domain in the PC-1 C-terminal tail, a polyproline motif mediating an interaction with Src homology domain 3 (SH3). A screen for interactions using the PC-1 C-terminal tail identified the
SH3 domain of nephrocystin-1 (NPHP1) as a potential binding partner of PC-1. NPHP1 is the product of a
gene that is mutated in a different form of renal cystic disease, nephronophthisis (NPHP). We performed in vitro pull-down assays and NMR structural studies to confirm the interaction between the PC-1 polyproline motif
and the NPHP1 SH3 domain. Furthermore, the two full-length proteins interact through these domains; using
a novel model system allowing us to track endogenous PC-1, we have confirmed the interaction between the
endogenous proteins. Finally, we have fund that NPHP1 trafficking to cilia does not require PC-1 and that PC-
1 requires NPHP1 to regulate resistance to apoptosis, but not to regulate cell cycle progression. Our data uncover a link between two different ciliopathies, ADPKD and NPHP, supporting the notion that common
pathogenetic defects underlie renal cyst formation.
Alessandra Boletta
MOLECULAR GENETICS UNIT
Characterization of the Prep1 gene.
We have characterized the apoptotic phenotype of Prep1. In the hypomorphic mice, apoptosis is due to the
absence of the anti-apoptotic gene Bcl-Xl, whereas under Prep1 overexpression apoptosis depends on the increase of p53, which is a direct target of Prep1.
We have demonstrated that Prep1 is a novel tumor suppressor. Indeed, Prep1 hypomorphic mice develop
spontaneous tumors and the haploinsufficiency of the Prep1 allele increases the death rate of EmuMyc transgenic myce. This appears to be true also in man, since over 30% of the over thousand tumors do not express
Prep1 (unlike the normal tissue) whereas 40% expressed it at very low level.
Characterization of the uPAR function.
We have demonstrated that uPAR KO mice have an hematopoietic phenotype. In particular, they are unable
to mobilize hamatopoietic stem cells upon treatment with 5-FU or with GCSF. This phenotype is linked to a retention function of uPAR in the bone marrow that is released upon activation of plasmin and solubilization of
uPAR. Retention is affected by uPAR through the interaction with the α4β1 integrin (VLA-1). In virtue of this
deficiency, mice treated with 5-FU succumb rapidly, unlike wild type.
uPAR is also involved in the formation of primary tumors, since uPAR Ko mice are protected in a skin carcinogenesis protocol. In this protocol, formation of primary papillomas, degeneration into squamous cells carcinoma and formation of metastasis is strongly and independently reduced. Therefore, uPAR is required for the
formation of tumors, the malignant conversion and for their metastatic activity. An important basis for this phenotype is the inability of the uPAR Ko skin stem cells to maintain the skin homeostasis under stress conditions.
Indeed the hair follicles stem cells are unable to respond to proliferative stimuli. The molecular mechanisms involved are now under investigation.
Francesco Blasi
Figure 20. Apoptosis in E9.5 wt embryos (left) and Prep1i/i
embryos (right), TUNEL reaction, whole mount.
MOLECULAR DYNAMICS OF THE NUCLEUS
As members of the Molecular Genetics unit we have characterized the apoptotic phenotype linked to the depletion of Prep-1 (an homeobox-containing transcription factor), using mouse embryo fibroblasts from Prep-1
hypomorphic mutant mice as a model system. We found that the Bcl-x gene is a direct transcriptional target of
Prep-1 and its downregulation affecs mitochondrial hoemeostasis and the apoptotic phenotyps of cells.As Mol-
ecular dynamics of the nucleus group we have characterized the effect of the overexpression of Prep1 in human
cells. The Prep-1 gene is located on chromosome 21 and cells from Down Syndrome patients “naturally” overexpress it. In parallel, we have also used a murine experimental model of Prep-1 overexpression. We found that
p53 is a direct transcriptional target of Prep-1 in overexpressing cells, which, in turn, are more sensitive to
apoptosis-inducing treatments (i.e. genotoxic stress) in both experimental systems.
Finally, we have identified novel nuclear structures called “poised transcription factories”, characterized by
the presence of transcriptionally competent, but inactive, genes and by the presence of the initiating form of
RNA polymerase II, typically phosphorylated at serine 5 of the C-terminal domain. Such structures allow the
“hosted” genes to rapidly respond to transcription-triggering stimuli. Interestingly, our results also show that
transcription occurs independently of the position of the active gene relative to the chromosome territory to
which it belongs and contribute to elucidate the functional organization of the nucleus.
Massimo Crippa
NEUROGLIA UNIT
Schwann cells myelinate peripheral nerves, and contribute to neuronal development, differentiation, integrity
and regeneration. Laminins, their receptors and the signals that they activate are required for many of these
functions. Indeed mutations in genes coding for laminins or components of laminin receptor complexes cause
hereditary neuropathies such as Merosin Deficient Congenital Muscular Dystrophy 1A, CMD1A, α dystroglycanopathies and Charcot-Marie-Tooth 4F.
One of the processes affected in the absence of laminins is axonal sorting, the process by which large axons to
be myelinated are segregated by a single Schwann cell. Using the Cre/LoxP system we have identified two α/β1
integrins and dystroglycan as the receptors important for radial sorting. All these are laminin receptors, so experiments are underway to determine if they bind to different laminins present in the Schwann cell basal lamina, and if they activate different signaling pathways. One signaling pathways that we had identified is the small
RhoGTPase Rac1. We are using primary co-coltures of sensory neurons and Schwann cells and proteomics to
identify Rac1 effectors relevant to myelination.
It is known that neuropathies due to laminin deficiency also have abnormal folding of myelin and short
myelin segments (internodes). This in turn leads to myelin instability and reduced nerve conduction velocity.
We have shown that this is due to lack of adhesion to α6β4 integrin and dystroglycan. In addition, regulated
proteolysis of dystroglycan by gelatinases (metalloproteinases 2 and 9) has a physiological role in organizing polarized compartments in the myelin segment. In hereditary and acquired neuropathies, metalloproteinases 2
and 9 are up-regulated, dystroglycan cleavage is augmented, and we showed that this can contribute to the formation of impaired myelin segments. Interestingly, this can be corrected by inhibiting cleavage of dystroglycan
in vitro. We are now exploring if inhibition of this activity in vivo can be beneficial in animal models of neuropathies. Thus, laminin receptors have important and diverse function in peripheral nerves, which are relevant
to the pathogenesis of neuromuscular diseases.
Maria Laura Feltri
REGULATION OF IRON METABOLISM UNIT
The aim of our research is to unravel the systemic iron regulation in mammals and the molecular pathogenesis of genetic iron disorders leading to both iron deficiency and overload. The key iron hormone hepcidin is upregulated in iron overload by a bone morphogenetic protein (BMP6)-SMAD-dependent pathway that uses as
co-receptor the hemochromatosis protein hemojuvelin. Hepcidin expression is also increased by an IL-6STAT3-dependent pathway in inflammation. Hepcidin expression is suppressed in iron deficiency/hypoxia by
multiple and partially understood mechanisms. The liver serine protease matriptase-2, encoded by TMPRSS6,
is a powerful hepcidin inhibitor, since TMPRSS6 inactivation leads to iron deficiency because of high hepcidin
levels both in mice and in humans. We have shown that matriptase-2 cleaves membrane hemojuvelin into proteolytic fragments and that this cleavage is suppressed in TMPRSS6 mutants lacking or mutated in the serine
protease domain. Matriptase-2 knock down by morpholino oligos in zebrafish causes anemia with high hepcidin levels, whereas the expression of matriptase-2 mutants results in a small anemic embryo, confirming the
matriptase-2 role in iron metabolism and indirectly its interaction with hemojuvelin. Matriptase-2 physically interacts with hemojuvelin through its ectodomain and the interaction is preserved in mutants devoid of the serine protease domain. We have defined the molecular mechanisms of mutants TMPRSS6 that occur outside the
serine protease domain, showing in in vitro systems that they are either unable to reach the cell surface and retained into the ER or unable to undergo auto-activation, as measured by the ability to release the serine protease domain in the culture media. In a Tmprss6-deficient mouse model we have shown that Tmprss6-haploinsufficiency confers susceptibility to iron deficiency in conditions of increased iron requests or following restriction of dietary iron, suggesting that heterozygous TMPRSS6 mutations may predispose patients to iron deficiency. Our results are relevant to understand the molecular pathogenesis and to implement innovative treatments of the two opposite disorders of iron metabolism: hemochromatosis and iron refractory iron deficiency
anemia (IRIDA).
Clara Camaschella
MOLECULAR GENETICS OF RENAL DISORDERS UNIT
Our interest is to understand the role of uromodulin in renal function and in chronic diseases of the kidney.
Uromodulin is the most abundant protein found in urine. It is exclusively expressed by epithelial cells lining
the thick ascending limb of Henle’s loop segment of the kidney nephrons and it plays a protective role against
urinary tract infections (Bates et al., 2004) and calcium oxalate crystals-induced urothelial damage (Mo et al.,
2004).
We have been studying the molecular mechanisms that regulate uromodulin shedding and polymerization.
We demonstrated that uromodulin is released in the urine through a conserved proteolytic cleavage (Santambrogio et al., 2008). Additionally, we recently demonstrated a functional link between protein cleavage and
polymerization. Indeed, we identified two conserved motifs that play an inhibitory role of protein assembly.
Proteolytic cleavage separating one of the two motifs from the mature monomer is needed to allow protein
polymerisation into filaments (Schaeffer et al., 2009).
Mutations in uromodulin lead to Medullary Cystic Kidney Disease/Familial Juvenile Hyperuricemic
Nephropathy (MCKD/FJHN), that are autosomal dominant kidney diseases characterized by alteration of urinary concentrating ability, frequent hyperuricemia, tubulo-interstitial fibrosis, cysts at the cortico-medullary
junction and renal failure. Through studies in transfected cells we demonstrated that mutations in uromodulin
lead to ER retention of mutant protein (Rampoldi et al., 2003; Bernascone et al., 2006). This is consistent with
the presence of uromodulin aggregates within the cytoplasm of tubular cells in kidney biopsies of
MCKD/FJHN patients (Dahan et al., 2003; Rampoldi et al., 2003) and the dramatic reduction of protein levels
in patient urine (Dahan et al., 2003).
Luca Rampoldi
DENTO-FACIAL HISTOPATHOLOGY UNIT
Our activity focused on biological features and clinical applications of bone substitutes in grafting procedures
and dental implants to allow implant-proshtodontics oral rehabilitations in edentulous patients.
The integration of grafted materials with the host tissue can initiate regenerative, inflammatory and apoptotic
response. Since molecular mechanisms exist at the basis of such response, we studied, by immunohistochemical
analyses, the expression of proteins involved in the graft integration process, in parallel to clinical and histological modifications, occurring on sites treated with extraoral autologous bone graft deriving from the parietal region of the calvaria (eAB), intraoral autologous bone graft deriving from mandibular ramus (iAB) and heterologous bone graft from swine (hB) in human patients. In our study, the immunohistochemical expression of BSP,
VEGF, eNOS in eAB samples was significantly higher (p < 0.05) compared to values recorded in iAB and hB
samples. The inflammatory response, investigated by iNOS expression, was found lower in all autologous samples (eAB and iAB) compared to hB, at statistically significant values. Moreover, the expression of the proapoptotic molecule, Bax, resulted significantly lower (p < 0.05) in eAB than in iAB and hB samples. These values, together with the low number of apoptotic cells detected in autologous samples, suggest a good regenerative response when extraoral autologous bone graft is used in comparison to the response from the other grafts,
and also suggest the use of calvaria graft as a predictable therapeutic procedure for repairing severe bone defects in oral and maxillofacial surgery, not only by clinical and biomechanical criteria, but also from a biomolecular aspect.
Moreover, we studied bone substitutes, in particular magnesium-enriched hydroxyapatite (MHA) and calcium sulfate (CS): they could allow bone grafting procedures with minimally invasive procedures. In clinical
studies by radiological, histological and histomorphometric examinations (percentages of mean vital bone, connective tissue and residual grafting material), both biomaterials, in particular MHA, demonstrated bone regeneration features to allow predictable implant positioning and oral rehabilitations (figure 21). Furthermore, we
studied MHA biological features in bone regeneration by ex vivo osteoblast expansion and highly sensitive gene
expression profiling by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In 25 bone specimens obtained from 15 patients, we demonstrated that gene expression profiling of an array of osteoblast specific genes is effective in certifying osteoblast identity and function.
Thus, we applied these findings in testing dental implants with innovative protocols: ‘platform switching’ implants, immediate loading in postextraction infected sites, implants in regenerated bone. In these studies, from
January to December 2009, we totally placed 444 implants in 147 patients, with a cumulative survival rate of
98,4%.
Enrico Gherlone
Figure 21. The graft material particles (GM) appeared wellincluded and showed continuity with the new bone (NB) tissue
and deposition of osteoid matrix
GENOMICS OF RENAL DISEASES AND HYPERTENSION UNIT
Genomics and pharmacogenomics of complex renal diseases
Hypertension.
Further analysis of our GWAS on salt-sensitive hypertension allowed to detect Myosin XVI, a non conventional myosin, significantly associated (p= 5.20E-06) to both systolic and diastolic blood pressure.
Evaluating the effects of a low sodium diet, we discovered the determinant role of NEDD4L and CYP11B2
genotypic combinations.
Pharmacogenomics.
A new anti-hypertensive drug, rostafuroxin, selectively inhibits the effect of Endogenous Ouabain (EO) and
460Trp mutated α-adducin (ADD1). The anti-hypertensive effect was markedly influenced by an allele combination (profile) of genes previously selected. The fall in SBP with rostafuroxin was -18.5; -23; -17 mmHg in
three different profiles, in placebo group was -2.0; -1.1 and -2.8 mmHg respectively. 23, 26 and 45% of total hypertensive population is included in the profiles. No profile effect was detected on the BP fall after losartan or
diuretic treatment.
Chronic Kidney Disease.
CKD progression displays great individual variability. Patients can be slow or rapid progressors. Genes involved in hypertension have been evaluated in patients with CKD. ADD1 and ADD2 play a role in the natural
history of ADPKD toward end stage disease by influencing the cyst formation. ACE and ADD2 affect proteinuria in chronic kidney disease and IgA nephropathy and, interacting with NCX1, display protective effects.
ADD1 and ADD2 variants have a predictive role on time to re-stenosis in renal artery stenosis.
Acute Renal Failure.
ARF is a frequent postoperative complication of major surgery and an independent risk factor of perioperative mortality. A correlation between EO and GFR was observed identifying EO as a new biomarker of renal
damage. Does plasma EO level increase precede or cause ARF? Since catecholamines and NT-proBNP have a
delayed increase compared to that of EO, we conclude that EO levels could be influenced by acute circulating
volume expansion.
Calcium kidney stone disease.
Polymorphisms of the calcium sensing receptor (CASR) gene located in the regulatory region were associated
to stones in idiopathic stone formers and in patients with primary hyperparathyroidism. Kidneys of normal subjects carrying variant alleles of these SNPs had lower CASR mRNA content suggesting a predisposition to stone
production.
Paolo Manunta
TISSUE ENGINEERING AND BIOMATERIALS
Tissue engineering and analysis for osteo-cartilaginous, meniscal and tendon tissue
One of the main goals of our group is the development of an engineered osteochondral composite for the repair of the cartilage lesion. In our studies, we focused on engineering in vitro a biphasic composite made of cellular cartilage scaffold and an osteo-bio-compatible material. Our studies have demonstrated the potential of a
gross integration between the two components and a cartilage-like quality of the newly formed matrix. In collaboration with other laboratories, we are testing different biomaterials as scaffold for the reparative cells. One
important aim of our research is also the importance of the in vivo maturation of the engineered cartilage. In
fact, the effect of the passage from in vitro to in vivo and the in vitro prolongation of the culture time before the
implantation represent important issues in the tissue engineering field. A series of studies are on their way for
the analysis of the effects of using fresh or expanded cells or the addition of growth factors in the culture medium.
We are also started a series of experiments with the attempt of characterizing the meniscal cells having the ultimate goal of developing an engineered meniscal substitute. We have demonstrated the presence of at least
three cell lines within the meniscus tissue and a different biochemical composition in the young and adult
meniscus.
We have also started a series of experiments with the goal of create a tissue engineered tendon. Tendons do
not repair spontaneously in the acute or chronic ruptures. We believe that a tendon engineered in vitro with a
biological scaffold seeded with autologous fibroblasts could represent an important solution. As possible cell
source we have tested tendon, ligament, and derma. We have also started a series of tests for the creation a lesion model in the rabbit patellar tendon. This would allow to test in vivo the efficacy of the engineered tendon
for repairing lesion defect in vivo.
Giuseppe M. Peretti
9 Bianchi, G; Oliva, L; Cascio, P; Pengo, N; Fontana, F; Cerruti, F; Orsi, A; Pasqualetto, E; Mezghrani, A;
Calbi, V; Palladini, G; Giuliani, N; Anderson, KC; Sitia, R; Cenci, S. The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood: 2009;
113(13): 3040-3049 - Article
IF 2008: 10,432
9 Bianchi, ME; Manfredi, AA. Dangers in and out. Science: 2009; 323(5922): 1683-1684 - Review
IF 2008: 28,103
9 Camaschella, C. BMP6 orchestrates iron metabolism. Nature Genet.: 2009; 41(4): 386-388 - Review
IF 2008: 30,259
9 Distefano, G; Boca, M; Rowe, I; Wodarczyk, C; Ma, L; Piontek, KB; Germino, GG; Pandolfi, PP; Boletta,
A. Polycystin-1 regulates extracellular signal-regulated kinase-dependent phosphorylation of tuberin to control
cell size through mTOR and its downstream effectors S6K and 4EBP1.. Mol. Cell. Biol.: 2009; 29(9): 23592371 - Article
IF 2008: 5,942
9 Gow, A; Wrabetz, L. CHOP and the endoplasmic reticulum stress response in myelinating glia. Curr. Opin.
Neurobiol. : 2009; 19(5): 505-510 - Article
IF 2008: 8,102
9 Manunta, P; Ferrandi, M; Bianchi, G; Hamlyn, JM. Endogenous ouabain in cardiovascular function and disease.. J. Hypertens.: 2009; 27(1): 9-18 - Review
IF 2008: 5,132
9 Matafora, V; D’Amato, A; Mori, S; Blasi, F; Bachi, A. Proteomics analysis of nucleolar SUMO-1 target proteins upon proteasome inhibition.. Mol. Cell Proteomics: 2009; 8(10): 2243-2255 - Article
IF 2008: 8,834
9 Micali, N; Ferrai, C; Fernandez-Diaz, LC; Blasi, F; Crippa, MP. Prep1 directly regulates the intrinsic apoptotic pathway by controlling Bcl-XL levels. Mol. Cell. Biol.: 2009; 29(5): 1143-1151 - Article
IF 2008: 5,942
9 Nigro, EA; Brini, AT; Soprana, E; Ambrosi, A; Dombrowicz, D; Siccardi, AG; Vangelista, L. Antitumor IgE
adjuvanticity: key role of Fc epsilon RI. J. Immunol.: 2009; 183: 4530-4536 - Article
IF 2008: 6,000
9 Rubartelli, A; Sitia, R. Chemo-metabolic regulation of immune responses by Tregs. Nat. Chem. Biol.: 2009;
5(10): 709-710 - Short Survey
IF 2008: 14,612
9 Schaeffer, C; Santambrogio, S; Perucca, S; Casari, G; Rampoldi, L. Analysis of uromodulin polymerization
provides new insights into the mechanisms regulating ZP domain-mediated protein assembly. Mol. Biol. Cell:
2009; 20(2): 589-599 - Article
IF 2008: 5,558
9 Silvestri, L; Guillem, F; Pagani, A; Nai, A; Oudin, C; Silva, M; Toutain, F; Kannengiesser, C; Beaumont, C;
Camaschella, C; Grandchamp, B. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6
mutations associated with iron-refractory iron deficiency anemia. Blood: 2009; 113(22): 5605-5608 - Article
IF 2008: 10,432
9 Sung, MH; Salvatore, L; De Lorenzi, R; Indrawan, A; Pasparakis, M; Hager, GL; Bianchi, ME; Agresti, A.
Sustained oscillations of NF-κB produce distinct genome scanning and gene expression profiles. PLoS ONE:
2009; 4(9): e7163 - Article
IF 2008: No Impact Factor
9 Traglia, M; Sala, C; Masciullo, C; Cverhova, V; Lori, F; Pistis, G; Bione, S; Gasparini, P; Ulivi, S; Ciullo, M;
Nutile, T; Bosi, E; Sirtori, M; Mignogna, G; Rubinacci, A; Buetti, I; Camaschella, C; Petretto, E; Toniolo, D.
Heritability and demographic analyses in the large isolated population of val borbera suggest advantages in
mapping complex traits genes. PLoS ONE: 2009; 4(10): art. no. e7554 - Article
IF 2008: No Impact Factor
9 Yanai, H; Ban, T; Wang, Z; Choi, MK; Kawamura, T; Negishi, H; Nakasato, M; Lu, Y; Hangai, S; Koshiba,
R; Savitsky, D; Ronfani, L; Akira, S; Bianchi, ME; Honda, K; Tamura, T; Kodama, T; Taniguchi, T. HMGB
proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature: 2009;
462(7269): 99-103 - Article
IF 2008: 31,434
Molecular basis of polycystic kidney disease Unit
NeuroGlia Unit
Molecular genetics of renal disorders Unit
CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS - 167
CENTER FOR GENOMICS, BIOINFORMATICS
AND BIOSTATISTICS
Director: Giorgio Casari *
Research Units
Neurogenomics Unit
HEAD OF UNIT: Giorgio Casari*
RESEARCHER: Giovanni Lavorgna
POST-DOCTORAL FELLOWS: Laura Cassina**, Francesca Maltecca**, Michela Riba, Riccardo Vago**
PHD STUDENT: Loredana Leo**
FELLOWS: Laura Corti, Sara Cottonaro
TECHNICIANS: Maurizio De Fusco, Celia Pardini
Theoretical biology
GROUP LEADER: Riccardo Fesce
Organelle biogenesis and motility Unit
HEAD OF UNIT: Maria Vittoria Schiaffino
POST-DOCTORAL FELLOWS: Rosa Lucia D’Ambrosio, Tiziana Daniele, Ilaria Palmisano
PHD STUDENT: Angela Palmigiano**
Genomic Unit for the diagnosis of human pathologies
HEAD OF UNIT: Maurizio Ferrari*
RESEARCHERS: Annapaola Andolfo, Sara Benedetti, Paola Carrera, Laura Cremonesi, Isabella Fermo, Vito Lampasona
PHD STUDENT: Angela Brisci**
FELLOWS: Viviana Bornaghi, Francesca Bruno, Emanuela Castiglioni, Vincenza Causarano, Chiara Di Resta, Alessandra Foglio,
Silvia Galbiati, Carlo Lombardoni, Chiara Redaelli, Francesca Rigo**, Elena Sommariva, Stefania Stenirri, Daniele Zeni
TECHNICIANS: Rose Mary Carletti, Cinzia Magagnotti, Nadia Soriani
HEAD OF UNIT: Massimo Alessio
POST-DOCTORAL FELLOWS: Barbara Comuzzi, Valeria Corti
PHD STUDENTS: Carlo Vittorio Cannistraci, Stefano Olivieri**
FELLOWS: Sara D’Annibale, Cristina Sensi
TECHNICIAN: Antonio Conti
Biomolecular NMR laboratory (Dulbecco Telethon Institute)
GROUP LEADER: Giovanna Musco
POST-DOCTORAL FELLOWS: Massimiliano Gaetani, Michela Ghitti, Silvia Mari, Luca Mollica, Andrea Spitaleri
PHD STUDENTS: Francesca Chignola, Valeria Mannella, Dmitrios Spiliotoupulos, Chiara Zucchelli
FELLOWS: Giacomo Quilici, Maria Elena Sana
Mission and vision - We want to become an internationally recognized
center in genomics, bioinformatics and biostatistics that, by taking advantage of the excellent clinical environment coupled to outstanding basic science, will allow the Institute as a whole to advance towards integrative
translational research. The Center will act as a catalyst for innovative research projects by complementing existing research lines across the Institute
with high throughput technologies, quantitative methods, and powerful data mining approaches.
Organization - At present five research units are included in the CGBB.
All units focus on the molecular pathogenesis of diseases from different and
Giorgio Casari
original points of view: from organelle perspectives (Neurogenomics and
Organelle Biogenesis and Motility Units), intimate protein-ligand interaction and metabolomics (Biomolecular NMR spectroscopy Unit), proteome (Proteome biochemistry Unit),
molecular diagnosis of diseases (Genomic Unit for the Diagnosis of Human Pathologies). Common to all
the units affiliated to the Center is the interest and involvement in developing bioinformatics and -omics
approaches as an inherent approach within their fields of investigation.
Goals - The overall goal of the center will be to provide HSR the skills and capacity to deliver high
quality genomics, bioinformatics and biostatistics research and support. This will be achieved by aggregating research groups already operating in these fields as well as investing in the technologies required.
In this light the main objectives of the Center for Genomics, Bioinformatics and Biostatistics are:
• To create synergies across and beyond HSR allowing research groups at HSR to integrate -omics approaches in current and future research.
• To produce original, high-impact research.
• To enhance research conducted at HSR by providing support to research groups through a genomics/bioinformatics/biostatistics core facility.
Achievements - CGBB Research Units have developed projects and expertise to deal with specific computational biological problems.
The Neurogenomics Unit is involved in the parallel analysis of the mitochondrial transcriptome and
proteome, as well as the systematic analysis of large non-coding RNAs, and the next generation sequencing of whole critical regions of Mendelian forms of disease. The Biomolecular NMR Spectroscopy Unit is
tackling the need for fast, robust, and reliable methods for sampling molecular 3D conformations by developing an innovative computational application to sample conformations of flexible ligands. Also, this
Unit is working on the characterization of receptor-ligand molecular interactions in their natural membrane environment using a ligand based NMR method.
High resolution 2D and 3D electrophoretic systems are routinely used for the identification of proteins
differentially expressed in different pathological and physiological conditions by the Proteome Biochemistry Unit, which developed a computational method for complex protein systems analysis.
The Genomic Unit for the Diagnosis of Human Pathologies is involved in the development of a labon-chip platform integrating a PCR amplification microreactor with a customable microarray for the detection of DNA sequence variations.
Mapping and dynamics of organelle movements are the main focus of the Organelle Biogenesis and
Motility Unit that is applying bimolecular fluorescence complementation to enlighten protein interactions and combine this approach with correlative light-electron microscopy.
Training Opportunities - The Coordinator of the Bioinformatics Core Facility will direct training and
dissemination activities aimed at showcasing to the HSR community the possibilities provided by the
new center. Examples of activities include: Bioinformatics Seminars, with local and invited speakers; one
day workshops on specific aspects, e.g. next-generation sequencing; regular training courses.
Research Units
NEUROGENOMICS UNIT
SCA28: a disease caused by inefficient mitochondrial calcium buffering?
The mitochondrial protease AFG3L2 forms homo-oligomeric and hetero-oligomeric complexes with its partner paraplegin (m-AAA proteases), which are in charge of protein quality control in the inner membrane. Mutations in AFG3L2 have been recently associated to a form of spinocerebellar ataxia (SCA28). We demonstrated that Afg3l2 haploinsufficient mouse recapitulates SCA28 phenotype, showing progressive ataxia due to dark
degeneration and loss of Purkinje cells (PCs), mediated by mitochondrial dysfunction. Our hypothesis for
SCA28 pathogenesis involves dysfunction of mitochondrial metabolism and inefficient Ca2+ internalization as
the starting events leading to aberrant accumulation of calcium in PCs, thus mimicking excitotoxic-mediated
dark degeneration.
PINK1, the mitochondrial kinase associated to Parkinson’s disease
Mutations of PINK1, a serine/threonine mitochondrial kinase, are responsible for a juvenile recessive form of
Parkinson’s disease. The project is focusing on the characterization of the PINK1 pathways through the identification of novel specific interactors and substrates. Preliminary data arose from yeast two-hybrid screening and
proteomic analysis resulted in a panel of candidates, belonging to microtubules-associated proteins, autophagic
factors and proteins involved in ubiquitin degradation pathway. These potential interactions are being confirmed by different and complementary experimental strategies.
Na,K ATPase and familial hemiplegic migraine
Familial hemiplegic migraine (FHM) is Mendelian severe form of migraine with aura caused by mutations of
the [alfa]2 subunit of the Na+/K+ pump, encoded by the ATP1A2 gene. In vitro models suggest a loss of function of FHM2 mutations. The project focuses on the characterization of two mouse models, a ATP1A2 knockin and a conditional mutants. At present, we demonstrate that cortical spreading depression (CSD), the molecular correlate of migraine aura, is facilitated in mutant mice. The astrocyte-specific expression of the [alfa]2
subunit of adult mice and the intense neuronal communication during CSD will be investigated by means of the
astrocyte conditional mutant.
Giorgio Casari
Figure 22. Aberrant mitochondria at Afg3l2 mutant
synapse
THEORETICAL BIOLOGY
1. Characterization of the effects of microgravity (simulated absence of gravity in a random positioning machine)
on the hair cell and cytoneural junction at the frog labyrinth.
Potassium and calcium conductances have been dissected in dissociated ampullar hair cells and relevant
changes have been observed following microgravity conditioning; then these changes have been correlated with
functional changes produced by the same treatment in junctional transmission in the intact labyrinth
2. Investigation of the ionic selectivity of the nicotinic acetylcholine receptor (nAChR) at the rat sympathetic ganglion
Having observed that the relative selectivity for potassium vs sudium ions was reduced by denervation, we set
out to examine les drastic treatments and were able to show that simple procedures such as changing membrane potential or chloride concentrations are able to produce similar effects. This suggests that ionic selectivity may be dynamically modulated at the nAChR, with possible relevant functional consequences for synaptic efficacy
Riccardo Fesce
ORGANELLE BIOGENESIS AND MOTILITY UNIT
The ocular albinism type 1 protein (OA1), an intracellular G protein-coupled receptor, regulates organelle
biogenesis and motility in pigment cells
We are focused into the study of secretory organelle biogenesis and transport in mammalian cells as alteration
of these processes represents an important cause of human disease. Our experimental model is ocular albinism
type 1, an X-linked disorder characterized by severe reduction of visual acuity, nystagmus, strabismus, photophobia, retinal hypopigmentation, foveal hypoplasia and misrouting of the optic tracts. The protein product of
the ocular albinism gene, named OA1, is a pigment cell-specific membrane glycoprotein, displaying structural
and functional features of G protein-coupled receptors (GPCRs), yet exclusively localized to intracellular organelles, i. e. lysosomes and melanosomes. Although the precise signaling pathway activated by OA1 remains
unknown, examination of the skin and eyes of patients with ocular albinism reveals the presence of giant
melanosomes (macromelanosomes); moreover, the analysis of Oa1-KO mouse melanocytes showed abnormal
number, size and distribution of melanosomes, which are less numerous, bigger and displaced toward the cell
periphery compared to wild-type melanocytes. These findings suggest that, as a resident intracellular GPCR,
OA1 might be activated by an intra-luminal ligand, regulating melanosome maturation and movement by interacting with downstream effectors on the organelle membrane. Consistently, L-DOPA has been recently found
to function as a ligand for OA1; however, this melanin by-product was found to activate OA1 when missorted
to the plasma membrane in a heterologous overexpression system, and to bind the receptor with low affinity.
Therefore, we set up an alternative assay to test for putative ligands, by taking advantage of protein-fragment
complementation assays, including bimolecular fluorescence and luciferase complementation, which lead to the
formation of fluorescent or enzymatic complexes, following specific interaction between two proteins under
study. This method will allow to test the interaction between OA1 and the most typical effectors common to
most GPCRs, G proteins and arrestins, in the physiological receptor context on intracellular organelles.
Maria Vittoria Schiaffino
GENOMIC UNIT FOR THE DIAGNOSIS OF HUMAN PATHOLOGIES
The Unit applied advanced methodologies to molecular analysis of genes involved in several pathologies, including neurologic and neuromuscular disorders, arhythmogenic disorders, pediatric surfactant deficiency,
macular degeneration, neurodegeneration, iron metabolism disorders, polycystic kidney disease, and myeloproliferative disorders. We developed high throughput SNP genotyping automated protocols and performed casecontrol association studies to correlate genome variation to disease predisposition.
Our approaches led to the identification of a variety of known and new sequence variations and made possible a genotype-phenotype correlation with particular respect in the field of both monogenic and multifactorial
traits. We also applied new genotyping devices and methodologies, such as pyrosequencing-based assays for the
identification of sequence variations in the CFTR gene and high-sensitive microarray substrates specifically designed to improve sensitivity for the identification of fetal paternally inherited sequences in maternal plasma.
In the frame of the International Human Variome Project we are involved in creation and maintenance of Locus Specific Data Bases and Clinical-Molecular Data Bases aimed to realize an accurate documentation of
genome variation related to disease.
Our Clinical Proteomics group is working out strategies for biomarker discovery in different pathologies:
prostate cancer, laminopathies, type-1 diabetes-related nephropathy, bronchopulmonary dysplasia. Our approach consists of identification of differentially expressed proteins in biological samples derived from patients.
We essentially use 2D-electrophoresis, image analysis and mass spectrometry, in order to clarify molecular
mechanisms of pathogenesis, indicate diagnostic tools or therapeutic targets to develop.
A further area of research is aimed at the development of novel assays for detection of autoantibodies associated with autoimmune diseases. Recently new assays were developed, based on expression of recombinant autoantigens, and applied to the diagnostics of type 1 diabetes and neuromyelitis optica. In particular these allowed the study and characterization of the immune responses respectively to the Zinc Transporter 8 and
Aquaporin 4 autoantigens.
Maurizio Ferrari
Figure 23. HRM analysis of normal (WT) and
mutated samples in the FGFR3 gene.
PROTEOME BIOCHEMISTRY UNIT
Onco-proteomics: serological proteome analysis of colorectal carcinoma
Immunologic tolerance to self-components is broken in pathologic conditions such as cancer. We performed
a screening of the colorectal tumor proteoma by exploiting auto-antibodies contained in the sera of patients to
identify colon specific tumoral antigens. Tumour-specific immunoreactive proteins have been found, the analysis demonstrated a modification in antigen recognition by patients B cells as a function of colon cancer progression. Autoantibodies directed against a surface metallo-protease have been found in patients, with higher frequency in patients with advanced disease.
Neuro-proteomics: Protein pattern changes in cerebrospinal fluid (CSF) of neurodegenerative diseases
CSF being in contact with the brain contains proteins released directly from the central nervous system following pathological conditions, thus CSF analysis is very important to understand the pathological processes
and for diagnostic purpose. Differential expression proteomics analysis applied to CSF of patients with Amyotrophic Lateral Sclerosis compared to healthy subjects showed that ceruloplasmin protein expression was increased in ALS patients, in particular the asialo-ceruloplasmin isoforms. We are working on CSF from patients
affected by Parkinson’s Disease. Proteins involved in the regulation of redox balance that might be a target of
oxidative stress damage have been found differentially expressed showing different post-translational modifica-
tions. Interestingly a control group of Alzheimer disease patients showed similar, but significantly less extent,
modifications. Also the enzymatic function of one of the target proteins has been found impaired.
Computational biology: development of computational methods for complex systems analysis
We developed tools based on linear and non-linear dimensional reduction approaches followed by automatic
clustering evaluation for the analysis of 2DE images aimed at the patients clustering and classification. This approach allowed us to discriminate patients affected by peripheral neuropathies with or without pain. We also
developed a new filter the Median-modified Wiener filter that provides efficient denoising, preserving spot
edge and morphology in 2-DE image processing.
Massimo Alessio
BIOMOLECULAR NMR LABORATORY
We study the structure and dynamics of biomolecular complexes in solution by NMR spectroscopy in combination with a wide range of biochemical, biophysical and computational techniques.Our activity is focused on
two main projects: 1) Structural characterization of the interaction of small drugs with extracellular cellular receptors; and 2) Structural and dynamic characterization of novel chromatin-interacting modules.
1. Integrin aVb3 is involved in many biological processes such as angiogenesis, inflammation, and cancer.
aVb3 exerts its role interacting with proteins containing an RGD motif. Recent drug design research has
therefore focused on the development of RGD-containing ligands for medical applications. A. Corti has recently shown that the isoDGR motif can compete with RGD in the binding to aVb3. By means of docking and
metadynamics simulations we have characterized the interaction isoDGR-aVb3. Using ligand-based NMR techniques we have characterized the interactions isoDGR ligands with surface-receptors localized on living cells
(in collaboration with Molmed)
2. Methylation of lysine residues on histone H3 tails regulates transcription.
A recent addition to known methylated histone binding modules is the PHD finger. AIRE protein contains
two PHD fingers and mutations in AIRE gene cause autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy. AIRE promotes the expression of tissue-specific antigens in the thymus. The mechanism by which
AIRE controls gene expression is currently unknown and the function of its PHD fingers is still elusive. We
have characterized the three-dimensional structure of AIRE-PHD1 in complex with H3K4me0 (collaboration
with P.Peterson tartu-University) providing a new link between the status of histone modifications and the regulation of tissue-specific antigen expression in thymus. We are currently characterizing PHD fingers from other
transcriptional activators.
The group collaborates to other projects aiming to characterize at molecular levels a) the interactions of the
protein HMGB1 with CpG rich oligonucleotides (M. Bianchi) and b) the interaction of the intracellular part of
PKD1 and the SH3 domain of NPHP1, two protein involved in renal genetic diseases (A. Boletta).
Giovanna Musco
Figure 24. Various ligand’s
receptor interactions in different
human cancer cell lines were
probed directly by twodimensional transferred-NOE
spectroscopy to prove recognition
specificity and determine an
affinity ranking of several ligands.
9 Bruno, F; Damin, F; Causarano, V; Galbiati, S; Di Carlo, G; Seia, M; Porcaro, L; Ferrari, M; Chiari, M; Cremonesi, L. High-sensitive microarray substrates specifically designed to improve sensitivity for the identification of fetal paternally inherited sequences in maternal plasma. Clin. Chem. Lab. Med.: 2009; 47(7): 818-823 Article
IF 2008: 1,888
9 Cannistraci, CV; Montevecchi, FM; Alessio, M. Median-modified Wiener filter provides efficient denoising,
preserving spot edge and morphology in 2-DE image processing. PROTEOMICS: 2009; 9(21): 4908-4919 - Article
IF 2008: 4,586
9 Chignola, F; Gaetani, M; Rebane, A; Org, T; Mollica, L; Zucchelli, C; Spitaleri, A; Mannella, V; Peterson, P;
Musco, G. The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation. Nucleic Acids Res.: 2009; 37(9): 29512961 - Article
IF 2008: 6,878
9 De Grandi, A; Volpato, CB; Bedin, E; Pattaro, C; Marroni, F; Pichler, I; Hicks, AA; Casari, G; Pramstaller,
PP. ParkScreen: A Low-Cost Rapid Linkage Marker Panel for Parkinson’s Disease. J. Mol. Neurosci.: 2009;
39(1-2): 235-241 - Article
IF 2008: 2,061
9 Innamorati, G; Giannone, F; Guzzi, F; Rovati, GE; Accomazzo, MR; Chini, B; Bianchi, E; Schiaffino, MV;
Tridente, G; Parenti, M. Heterotrimeric G proteins demonstrate differential sensitivity to ß-arrestin dependent
desensitization. Cell. Signal.: 2009; 21(7): 1135-1142 - Article
IF 2008: 4,305
9 Maltecca, F; Magnoni, R; Cerri, F; Cox, GA; Quattrini, A; Casari, G. Haploinsufficiency of AFG3L2, the
gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. J. Neurosci.: 2009; 29(29): 9244-9254 - Article
IF 2008: 7,452
9 Manfredi, I; Zani, AD; Rampoldi, L; Pegorini, S; Bernascone, I; Moretti, M; Gotti, C; Croci, L; Consalez,
GG; Ferini-Strambi, L; Sala, M; Pattini, L; Casari, G. Expression of mutant ß2 nicotinic receptors during development is crucial for epileptogenesis. Hum. Mol. Genet.: 2009; 18(6): 1075-1088 - Article
IF 2008: 7,249
9 Martinelli, P; La Mattina, V; Bernacchia, A; Magnoni, R; Cerri, F; Cox, G; Quattrini, A; Casari, G; Rugarli,
EI. Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration.
Hum. Mol. Genet.: 2009; 18(11): 2001-2013 - Article
IF 2008: 7,249
9 Monti, L; Cinquetti, R; Guffanti, A; Nicassio, F; Cremona, M; Lavorgna, G; Bianchi, F; Vignati, F; Cittaro,
D; Taramelli, R; Acquati, F. In silico prediction and experimental validation of natural antisense transcripts in
two cancer-associated regions of human chromosome 6. Int. J. Oncol.: 2009; 34(4): 1099-1108 - Article
IF 2008: 2,234
9 Myocardial Infarction Genetics Consortium; Kathiresan, S; Voight, BF; Purcell, S; Musunuru, K; Ardissino,
D; Mannucci, PM; Anand, S; Engert, JC; Samani, NJ; Schunkert, H; Erdmann, J; Reilly, MP; Rader, DJ;
Morgan, T; Spertus, JA; Stoll, M; Girelli, D; McKeown, PP; Patterson, CC; Siscovick, DS; O’Donnell, CJ;
Elosua, R; Peltonen, L; Salomaa, V; Schwartz, SM; Melander, O; Altshuler, D; Ardissino, D; Merlini, PA;
Berzuini, C; Bernardinelli, L; Peyvandi, F; Tubaro, M; Celli, P; Ferrario, M; Fetiveau, R; Marziliano, N;
Casari, G; Galli, M; Ribichini, F; Rossi, M; Bernardi, F; Zonzin, P; Piazza, A; Mannucci, PM; Schwartz, SM;
Siscovick, DS; Yee, J; Friedlander, Y; Elosua, R; Marrugat, J; Lucas, G; Subirana, I; Sala, J; Ramos, R;
Kathiresan, S; Meigs, JB; Williams, G; Nathan, DM; MacRae, CA; O’Donnell, CJ; Salomaa, V; Havulinna,
AS; Peltonen, L; Melander, O; Berglund, G; Voight, BF; Kathiresan, S; Hirschhorn, JN; Asselta, R; Duga, S;
Spreafico, M; Musunuru, K; Daly, MJ; Purcell, S; Voight, BF; Purcell, S; Nemesh, J; Korn, JM; McCarroll,
SA; Schwartz, SM; Yee, J; Kathiresan, S; Lucas, G; Subirana, I; Elosua, R; Surti, A; Guiducci, C; Gianniny,
L; Mirel, D; Parkin, M; Burtt, N; Gabriel, SB; Samani, NJ; Thompson, JR; Braund, PS; Wright, BJ; Balmforth, AJ; Ball, SG; Hall, AS; Schunkert, H; Erdmann, J; Linsel-Nitschke, P; Lieb, W; Ziegler, A; Konig, IR;
Hengstenberg, C; Fischer, M; Stark, K; Grosshennig, A; Preuss, M; Wichmann, HE; Schreiber, S; Schunkert, H; Samani, NJ; Erdmann, J; Ouwehand, W; Hengstenberg, C; Deloukas, P; Scholz, M; Cambien, F;
Reilly, MP; Li, M; Chen, Z; Wilensky, R; Matthai, W; Qasim, A; Hakonarson, HH; Devaney, J; Burnett, MS;
Pichard, AD; Kent, KM; Satler, L; Lindsay, JM; Waksman, R; Epstein, SE; Rader, DJ; Scheffold, T; Berger,
K; Stoll, M; Huge, A; Girelli, D; Martinelli, N; Olivieri, O; Corrocher, R; Morgan, T; Spertus, JA; McKeown, PP; Patterson, CC; Schunkert, H; Erdmann, J; Linsel-Nitschke, P; Lieb, W; Ziegler, A; Konig, IR;
Hengstenberg, C; Fischer, M; Stark, K; Grosshennig, A; Preuss, M; Wichmann, HE; Schreiber, S; Holm, H;
Thorleifsson, G; Thorsteinsdottir, U; Stefansson, K; Engert, JC; Do, R; Xie, C; Anand, S; Kathiresan, S;
Ardissino, D; Mannucci, PM; Siscovick, D; O’Donnell, CJ; Samani, NJ; Melander, O; Elosua, R; Peltonen,
L; Salomaa, V; Schwartz, SM; Altshuler, D. Genome-wide association of early-onset myocardial infarction
with single nucleotide polymorphisms and copy number variants. Nature Genetics: 2009; 41(3): 334-341 - Article
IF 2008: 30,259
9 Sitaram, A; Piccirillo, R; Palmisano, I; Harper, DC; Dell’Angelica, EC; Schiaffino, MV; Marks, MS. Localization to mature melanosomes by virtue of cytoplasmic dileucine motifs is required for human OCA2 function.
Mol. Biol. Cell: 2009; 20(5): 1464-1477 - Article
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leukemia after stem-cell transplantation. N. Engl. J. Med.: 2009; 361(5): 478-488 - Article
IF 2008: 50,017
Neurogenomics Unit
Genomic Unit for the diagnosis of human pathologies
Biomolecular NMR laboratory
CENTER FOR IMAGING - 177
CENTER FOR IMAGING
Director: Carlo Tacchetti
Associate Director: Alessandro Del Maschio*
Clinical and experimental radiology Unit
PHYSICIANS: Francesco De Cobelli*, Antonio Esposito, Pietro Panizza, Massimo Venturini
CONSULTANT: Claudio Losio
TECHNICIAN: Tamara Canu
HEAD OF UNIT: Nadia Di Muzio
PHYSICIANS: Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Aniko Maria Deli, Italo Dell’Oca, Andrei Fodor, Micaela Motta,
Marcella Pasetti, Paolo Passoni, Najla Slim
RESIDENT: Brigida Pappalardi
TECHNICIANS: Laura Longoni, Giovannella Salvadori, Simone Selli
Medical physics Unit
HEAD OF UNIT: Riccardo Calandrino
PHYSICISTS: Sara Broggi, Giovanni Mauro Cattaneo, Antonella Del Vecchio, Claudio Fiorino, Barbara Longobardi, Paola
Mangili, Lucia Perna, Patrizia Signorotto
RESEARCHERS: Veronica Ardu, Antonello Spinelli
Molecular imaging Unit
HEAD OF UNIT: Luigi Gianolli
PHYSICIANS: Elena Busnardo, Carla Canevari, Federico Fallanca, Claudio Landoni, Patrizia Magnani, Maria Cristina Messa,
Andrea Panzacchi, Maria Picchio, Ana Maria Samanes Gajate, Pietro Spagnolo, Paola Todeschini
RESEARCHERS: Sara Belloli, Valentino Bettinardi, Assunta Carpinelli, Isabella Castiglioni, Maria Carla Gilardi, Mario Matarrese,
Maria Grazia Minotti, Rosa Maria Moresco, Marco Rigamonti, Paola Scifo, Sergio Todde
POST-DOCTORAL FELLOWS: Ioana Florea, Manuela Giglio, Valeria Masiello
PHD STUDENTS: Francesca Gallivanone, Cristina Monterisi, Eugenio Rapisarda
TECHNICIANS: Antonia Compierchio, Andrea Fabro, Paola Lanzoni, Carlo Pizzamiglio, Pasquale Simonelli, Francesco Sudati,
Mauro Vaghi
Neuroradiology research group
HEAD OF UNIT: Giuseppe Scotti*
GROUP LEADER: Letterio Salvatore Politi
PHYSICIANS: Simonetta Gerevini, Claudio Righi, Francesco Scomazzoni, Franco Simionato
FELLOW: Sara Pizzi
Mission - The mission of the Experimental Imaging Center (CIS, Centro
di Imaging Sperimentale) is stratified into four different levels of intervention:
• Added value to HSR campus: to harness existing imaging expertise and
capabilities in the San Raffaele Scientific Institute, and develop them into a facility platform able to support the growth of multi-disciplinary research activities and speed the development of biomedical research discoveries in the campus.
• Technology development: to promote and
create an integrated platform for multidisCarlo Tacchetti
ciplinary activity in R&D, involving biologists, chemists, physicists, computer scientists
and clinician scientists, to develop tools and technologies in biomedical imaging.
• Competitive biomedical research: to support independent clinical and
pre-clinical research and to foster translational research.
• Partnerships with private research institutions: to provide a focal point of
interaction with pharmaceutical and biotechnology industries to explore
Alessandro Del Maschio
joint research collaborations or business ventures.
Vision - CIS aims at establishing an internationally recognized leading integrated center in biomedical
imaging. The goal is to foster the proper background to integrate facility, biomedical research and technology development.
CLINICAL AND EXPERIMENTAL RADIOLOGY UNIT
The main research projects encompass:
1) Breast Imaging. Screening and secondary oncologic prevention program of breast cancer in women of 4049 years old tailored and based on the personal risk factors.
2) Clinical trials with new contrast agents. Clinical trials on different contrast media have been conducted in
evaluation of breast lesions, cardiac, coronary and vascular diseases.
3) Cardiac magnetic resonance (CMR) Imaging and Spectroscopy and cardiac Computed Tomography (CT).
Understanding of pathophysiology and characterization of cardiomyopathies with gadolinium delayed-enhanced technique; evaluation of ventricular function and energy metabolism in different conditions such as
different type of exercise training, obesity and fatty liver or insulin-resistance; accuracy of CT in the evaluation of coronary artery stenosis and stents with a new low dose radiation exposure technique.
4) Diffusion-weighted Magnetic Resonance Imaging. DWI provides quantitative and qualitative evaluation of
gastric-esophageal, pancreatic and breast lesions, helping to differentiate between malignant and non-malignant lesions; moreover, DWI allows early information about response to chemotherapy also in patients
with Gastric Esophageal Neoplasms.
5) Cellular and molecular imaging. A non-invasive MR based method for in-vivo cellular tracking has been
developed and applied to cells labeling and imaging in order to follow the pancreatic islets fate, after their
transplantation in mouse model of type 1 diabetes.
6) Imaging of islet transplantation in Humans. Non-invasive visualization of pancreatic islet transplantation is
a major challenge. We developed new imaging techniques able to visualize labelled cells with MR and liverfocal-fatty changes with ultrasound as an early sign of altered graft function.
7) Implementation of radiotherapy planning by new imaging-techniques. Our aim has been to use different
techniques such as MRI, diffusion weighted MR and 4D-CT to improve target volume definition in
prostate cancer, rectal cancer and in pancreatic ductal adenocarcinoma.
8) Gastric Esophageal Tumors (GET) imaging. In the last year we focused our research on GET performing a
prospective study using MR, Endoscopic-ultrasound and MDCT in evaluation of wall and nodes invasion.
HIGH TECHNOLOGY IN RADIATION THERAPY UNIT
Prostate cancer
After a median follow-up of 4 years, the incidence of biochemical relapses in the first 150 patients (pts) submitted to hypofractionated Helical Tomotherapy (HTT) with both radical and early adjuvant intent is < 5%.
The gastroenteric toxicity profile is excellent, owing to the disappearance of Grade 3-4 rectal toxicity, while only < 5% patients experienced Grade 3 acute urinary toxicity.
The feasibility of dose escalation up to 100-120 Gy by means of HTT to tumoral subvolumes (Dominant Intraprostatic Lesions, DILs) identified with MRI was investigated: a theoretical model indicates that is possible
to escalate the dose to one or more DILs within the prostatic gland up to 100 Gy, with a risk of Grade 2-3 acute
and late rectal sequelae < 5%.
A multicentric, prospective, observational study investigating clinical and physico-dosimetric factors predictive of RT-induced urinary toxicity and erectile disfunction was designed and promoted by our group. The
study, supported by the AIRC Grant 8784, will be conducted in the next 5 years in 20 Italian and foreign Radiotherapy Centers.
Lung cancer
A Phase I-II study evaluating the feasibility of PET guided hypofractionated HTT for the treatment of inop-
erable locally advanced NSCLC delivering 52 Gy in 13 fractions (4 Gy/day) to the PET positive volume was
completed, indicating that this approach is feasible and shortens the overall treatment time; moreover, HTT
produces excellent toxicity profile and local control rate.
Rectal cancer
The feasibility of adaptive RT concomitant to CT as preoperative treatment was investigated: a precise estimate of rectal volume variations permits to better “guide” irradiation, allowing a significant tumour volume reduction and dose escalation in the second half of treatment..
Pancreatic cancer
A dose-escalation study with hypofractionated HTT on CT pretreatd pts showed that the delivery of 44.25
Gy/15 fractions + CT is associated with a low rate of G3 acute toxicity and provides stabilization/improvement
of local disease.
CNS
A thorough analysis on 373 patients treated with gamma-knife for SNC metastases from NSCLC indicated a
dose > 22 Gy (single fraction) as the covariates most predictive of longer overall survival in pts decesed for cerebral progression.
Nadia Di Muzio
MEDICAL PHYSICS UNIT
The main areas of interest of the Medical Physics Department (MPD) are the following:
1. Radiotherapy Physics
The backbone of the department is the knowledge of advanced methodologies for the optimization of the radiotherapy treatments. Sophisticated treatment units such as tomotherapy and rapid-arc are continuously monitored and tuned by the senior staff of the Department.
Novel treatment protocols and modalities for different cancer localization have been defined, in collaboration
with the medical staff. Results have been presented at international meetings and published on peer review
journals. The outcomes were monitored during patients follow up over several years.
Multi-modal images were acquired before and during the treatment in order to obtain: 1) a more accurate
definition of the real extension of neoplastic disease; 2) a better visualization of healthy tissues; 3) the evaluation
of breathing related tumor/organ mobility (4D technology); 4) the definition of adaptive strategies to modify
treatment plans. A number of investigations have been conducted evaluating the impact of multi-modal approach in treatment planning optimization for malignancies of different anatomical regions.
2. Physics for Imaging
The use of monochromatic x-rays will lead to a significant dose reduction and an improvement of the image
intrinsic contrast. In the next 3 years a compact inverse Compton scattering source (ICS) will be developed by
INFN and HSR. The ICS will be capable to generate monochromatic x-rays beam for research and diagnostic
imaging.
A second research topic is the CT dose reduction and image quality optimization by using iterative image denoising and recovery algorithms.
The MPD has recently to design and develop and optical imaging instrument in order to detect Cerenkov radiation (CR). The CR is a well-known phenomenon and is generated when charged particles travel through an
optical transparent material with a velocity greater than light velocity in the material. We realised that a similar
approach could also be applied in vivo in order to obtain small animal optical images.
3. Physics applied to Radioprotection, Laser and NMR Safety
At HSR is present one of the largest Italian Nuclear Medicine Department (NMD) with two Cyclotrons for
the preparation of PET radio-pharmaceuticals. The radiation protection of the NMD is carried out by the
MPD staff and requires the use of the most advanced methodologies for ionizing radiation monitoring. Since
the beginning of the 80s the MPD staff is also enrolled in the safety and quality assurance of Laser and NMR
equipments installed at HSR.
Riccardo Calandrino
MOLECULAR IMAGING UNIT
The main research activities are focused on:
1) Radiolabeling of ligands for in vivo PET imaging: a) activated microglia linked Translocator Protein ligand
19F-VC701; b) β amyloid complex ligand 11C-PIB and c) marker for cardiac sympathetic nervous system
11C-HED. The development of new tools for in vivo detection of angiogenesis and hypoxia and of an automatic system for the production of radiolabeled metals, such as 64/60 Cupper and 110 Indium are still
ongoing.
2) Development of a) a new fully 3D iterative (OSEM) reconstruction algorithm which accounts for the Point
Spread Function of PET and b) a computer-based method for Partial Volume Correction and Standard
Uptake Value quantification in PET/CT oncological studies
3) Preclinical imaging activities for: a) characterization of preclinical cancer models using 18F-FDG and tracer for the in vivo imaging of hypoxia; b) 18F-FDG evaluation of a mouse model of lung cancer based on
the subcutaneous implants of post surgery specimen from patients; c) in vivo characterization in rats of the
effect of acute stress on the regional cerebral uptake of 18F-FDG.
4) Assessment of the role of PET/CT in staging and re-staging of different cancers, by 18F-FDG and 11CCholine, also including cost analysis evaluations. In particular, 18F-FDG PET/CT has been shown as an
accurate diagnostic tool in the pre-surgical evaluation of pelvic nodes metastases in high risk endometrial
cancer patients. In addition, it has been established the role of 11C-Choline PET/CT in the treatment
planning of prostate cancer patients.
5) Clinical Imaging in Neuropharmacology and mathematical model were dedicated to the development of a
new voxel based methods for the in vivo quantification of the activity of acetylcholine esterase in patients
with dementia.
6) Prognostic value of SPECT/CTA in patients with an intermediate probability of CAD. Evaluation of a new
sequential scan protocol for CTA on image quality and radiation dose with a randomized trial. Initial experience with a ultra-low-dose iodinate CM using a new high flow injection protocol in CTA.
Luigi Gianolli
NEURORADIOLOGY RESEARCH GROUP
The Neuroradiology Research Group is committed to applying innovative imaging technologies toward more
comprehensive understanding of pathologies of the central and peripheral nervous systems at both preclinical
and clinical levels, and to developing new neuro-interventional procedures and protocols for minimally-invasive treatment of neurovascular diseases.
During 2009 the research activity of the Group was focused on 3 main areas: preclinical studies, clinical diagnostic research activity and neuro-interventional trials. In the first area, the Group has a well-established expertise in conventional and advanced MR-based imaging techniques of brain tumors and of inflammatory, demyelinating and dysmyelinating murine models of central nervous system diseases. Using a human-grade 3 Tesla Magnetic Resonance Imaging (MRI) apparatus equipped with a mouse-dedicated coil we evaluated and quantified
structural changes in the brains of murine models of several neurological pathologies, such as inherited or acquired demyelinating disorders and brain tumors. Further, innovative cellular and molecular imaging techniques
were developed for monitoring stem cell transplantation in neurological diseases and for tracking the recruitment of hematopoietic and stromal cells inside the tumors. We explored several cell labelling strategies based on
superparamagnetic iron oxides particles and on different MR reporter genes, allowing iron accumulation within
cells. Trangenic mice expressing a mutated form of the human L-ferritin chain were also analyzed.
In the field of clinical research, the Group worked on the vivo assessment of structural and functional aspects
of brain and orbital inflammatory, infectious and tumoral disorders. Specific fields of interest were HIV-related
infections and lymphomas. Additionally, MR-based imaging techniques were been applied also for studying peripheral nervous system disorders and neuromuscular diseases.
The research in the neuro-interventional area was focused at the optimization of new endovascular techniques and at the validation of new angiographic devices for treatment of intracranial aneurysms, vascular
stenosis/occlusions and artero-venous malformations or shunts. A clinical trial was carried out for the treatment
of acute stroke patients.
Letterio Salvatore Politi
9 Belloli, S; Jachetti, E; Moresco, RM; Picchio, M; Lecchi, M; Valtorta, S; Freschi, M; Hess-Michelini, R; Bellone, M; Fazio, F. Characterization of preclinical models of prostate cancer using PET-based molecular imaging.
Eur. J. Nucl. Med. Mol. Imaging: 2009; 36(8): 1245-1255 - Article
IF 2008: 4,532
9 Benedetti, F; Bernasconi, A; Bosia, M; Cavallaro, R; Dallaspezia, S; Falini, A; Poletti, S; Radaelli, D; Riccaboni, R; Scotti, G; Smeraldi, E. Functional and structural brain correlates of theory of mind and empathy
deficits in schizophrenia. SCHIZOPHR RES: 2009; 114(1-3): 154-160 - Article
IF 2008: 4,174
9 Boschi, F; Spinelli, AE; D’Ambrosio, D; Calderan, L; Marengo, M; Sbarbati, A. Combined optical and single
photon emission imaging: preliminary results. Phys. Med. Biol.: 2009; 54(23): L57-62 - Letter
IF 2008: 2,784
9 Broggi, S; Cozzarini, C; Fiorino, C; Maggiulli, E; Alongi, F; Cattaneo, GM; Di Muzio, N; Calandrino, R.
Modeling set-up error by daily MVCT for prostate adjuvant treatment delivered in 20 fractions: Implications for
the assessment of the optimal correction strategies. Radiother. Oncol.: 2009; 93(2): 246-252 - Article
IF 2008: 3,990
9 Castiglioni, I; Canesi, B; Schenone, A; Perani, D; Gilardi, MC. A Grid-based SPM service (GriSPM) for
SPECT and PET neurological studies. Eur. J. Nucl. Med. Mol. Imaging: 2009; 36(7): 1193-1195 - Letter
IF 2008: 4,532
9 Cinque, P; Koralnik, IJ; Gerevini, S; Miro, JM; Price, RW. Progressive multifocal leukoencephalopathy in
HIV-1 infection. Lancet Infect. Dis.: 2009; 9(10): 625-636 - Review
IF 2008: 13,165
9 De Cobelli, F; Esposito, A; Belloni, E; Pieroni, M; Perseghin, G; Chimenti, C; Frustaci, A; Del Maschio, A.
Delayed-enhanced cardiac MRI for differentiation of fabry’s disease from symmetric hypertrophic cardiomyopathy. Am. J. Roentgenol.: 2009; 192(3): W97–W102 - Article
IF 2008: 2,940
9 Esposito, A; De Cobelli, F; Perseghin, G; Pieroni, M; Belloni, E; Mellone, R; Canu, T; Gentinetta, F; Scifo,
P; Chimenti, C; Frustaci, A; Luzi, L; Maseri, A; Del Maschio, A. Impaired left ventricular energy metabolism
in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging. Heart: 2009; 95(3): 228-233 - Article
IF 2008: 4,964
9 Giovacchini, G; Fallanca, F; Landoni, C; Gianolli, L; Picozzi, P; Attuati, L; Terreni, M; Picchio, M; Messa,
C; Fazio, F. C-11 choline versus F-18 fluorodeoxyglucose for imaging meningiomas: an initial experience. Clin.
Nucl. Med.: 2009; 34(1): 7-10 - Article
IF 2008: 3,181
9 Marano, R; De Cobelli, F; Floriani, I; Becker, C; Herzog, C; Centonze, M; Morana, G; Gualdi, GF; Ligabue,
G; Pontone, G; Catalano, C; Chiappino, D; Midiri, M; Simonetti, G; Marchisio, F; Olivetti, L; Fattori, R;
Bonomo, L; Del Maschio, A. Italian multicenter, prospective study to evaluate the negative predictive value of
16- and 64-slice MDCT imaging in patients scheduled for coronary angiography (NIMISCAD-Non Invasive
Multicenter Italian Study for Coronary Artery Disease). Eur. Radiol.: 2009; 19(5): 1114-1123 - Article
IF 2008: 3,651
9 Pastorino, U; Landoni, C; Marchianò, A; Calabrò, E; Sozzi, G; Miceli, R; Picchio, M; Mariani, L; Messa, C;
Fazio, F. Fluorodeoxyglucose uptake measured by positron emission tomography and standardized uptake value
predicts long-term survival of CT screening detected lung cancer in heavy smokers. J. Thorac. Oncol.: 2009;
4(11): 1352-1356 - Article
IF 2008: 3,508
9 Perna, L; Fiorino, C; Cozzarini, C; Broggi, S; Cattaneo, GM; De Cobelli, F; Mangili, P; Di Muzio, N; Calandrino, R. Sparing the penile bulb in the radical irradiation of clinically localised prostate carcinoma: A comparison between MRI and CT prostatic apex definition in 3DCRT, Linac-IMRT and Helical Tomotherapy. Radiother. Oncol.: 2009; 93(1): 57-63 - Article
IF 2008: 3,990
9 Perseghin, G; De Cobelli, F; Esposito, A; Belloni, E; Lattuada, G; Canu, T; Invernizzi, PL; Ragogna, F; La
Torre, A; Scifo, P; Alberti, G; Del Maschio, A; Luzi, L. Left ventricular function and energy metabolism in
middle-aged men undergoing long-lasting sustained aerobic oxidative training. Heart: 2009; 95(8): 630-635 Article
IF 2008: 4,964
9 Signorelli, M; Guerra, L; Buda, A; Picchio, M; Mangili, G; Dell’Anna, T; Sironi, S; Messa, C. Role of the integrated FDG PET/CT in the surgical management of patients with high risk clinical early stage endometrial
cancer: Detection of pelvic nodal metastases. Gynecol. Oncol.: 2009; 115(2): 231-235 - Article
IF 2008: 2,919
9 Visigalli, I; Moresco, RM; Belloli, S; Politi, LS; Gritti, A; Ungaro, D; Matarrese, M; Turolla, E; Falini, A;
Scotti, G; Naldini, L; Fazio, F; Biffi, A. Monitoring disease evolution and treatment response in lysosomal disorders by the peripheral benzodiazepine receptor ligand PK11195. Neurobiol. Dis.: 2009; 34(1): 51-62 - Article
IF 2008: 4,852
FACILITIES - 185
FACILITIES
ALEMBIC, Advanced Light and Electron Microscopy Bioimaging Center
HEAD OF UNIT: Fabio Grohovaz*
RESEARCHER: Maria Carla Panzeri
FELLOW: Miriam Ascagni
TECHNICIANS: Cesare Covino, Andrea Menegon
CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis
HEAD OF UNIT: Marco E. Bianchi*
RESEARCHER: Lorenza Ronfani
FELLOWS: Ivana Benzoni, Rosanna Rinaldi
TECHNICIAN: Maria Luisa Pintonello
FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications
Laboratory
Research Cytometry Support Team
HEAD OF UNIT: Alessio Palini
BIOLOGIST: Chiara Villa
TECHNICIAN: Emanuele Canonico
CERMAC, Centre of Excellence of High Field Magnetic Resonance
PHYSICIAN: Valeria Blasi
RESIDENTS: Antonella Castellano, Elisa Scola
POST-DOCTORAL FELLOWS: Monia Cabinio, Sara Cirillo, Roberta Longaretti, Silvia Polverigiani
PHD STUDENT: Paolo Vezzulli
FELLOW: Paola Scifo
TECHNICIAN: Antonella Iadanza
Mouse histopathology
HEAD OF UNIT: Claudio Doglioni*
GROUP LEADER: Francesca Sanvito
TECHNICIAN: Martina Rocchi
ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center
Alembic is a resource for the scientific community by providing both access to sophisticated imaging techniques and innovation through the efforts of a small staff. The facility is designed to accommodate researchers
by providing instrumentation and instructing them in the most effective use of it, so that they may perform experiments independently. This is particularly true for access to optical microscopes for which those interested
are required to attend a course taught by the Alembic staff before being authorized to use the instrumentation.
The research activity of the staff also promotes technical updates on a regular basis to keep the local facility on
the forefront of available technology. In the course of the years, several new technologies have been integrated
into Alembic and new ones are being developed.
There is also an area in which the staff develops new methodologies and conducts research on techniques
with significant potential to enhance bioimaging research. This R&D activity has mainly converged around the
use of voltage sensitive dyes along two main directions:
• integration of optical recordings with a multi electrode system to monitor membrane potential changes in
complex neuronal networks (in collaboration with Politecnico di Milano and San Raffaele Units);
• use in drug discovery screening (patent application n. EP09165872 “Method for optical measuring variations of cell membrane conductance”, filed in collaboration with Optotec on July 20, 2009).
Main intrumentation at Alembic are:
LIGHT MICROSCOPY
• Leica TCS SP2 Laser Scanning Confocal
• BioRad MRC 1024 Laser Scanning Confocal
• Perkin Elmer UltraVIEW ERS Spinning Disk Confocal
• Widefield Imaging Setup for time-lapse imaging
• AIS2 automatic Microinjection/Imaging setup
• DeltaVision RT Deconvolution System
• Zeiss Axioplan2 with AxioCam MRc
• GElifesciences IN Cell Analyzer 1000 for high throughput/high content screening
ELECTRON MICROSCOPY
• TEM LEO 912AB with energy filter for microanalysis
• TEM Zeiss EM900
Our numbers in 2009 are: 607 registered users (411 active), 112 persons attending theorical/practical courses;
4560 hours of independent microscopes use.
Web resources: www.sanraffaele.org/research/alembic
Fabio Grohovaz
Figure 25. Neurons and astrocytes
isolated from rat hippocampus stained for
DNA (blue), neuronal-specific βIIItubulin (green) and astrocyte-specific
GFAP (red). Credits: Franca Codazzi,
Cellular Neurophysiology Unit. Image
acquired by GE Healthcare IN Cell 1000
- Miriam Ascagni, ALEMBIC.
FACILITIES - 187
CFCM, Core Facility for Conditional Mutagenesis
Transgenic and knock-out mice are widely used in the research because of their high impact in the understanding of the proteins functional role and because constitute models to study genetic diseases.
The San Raffaele-Telethon Core Facility for Conditional Mutagenesis (CFCM) is operative from 1999. During this time CFCM provided to the Scientific Community more than 300 murine models.
CFCM performs pronuclear injections and lentiviral infections to generate transgenic mice, offers the electroporation of Embryonic Stem cell (ES cells) and the blastocysts injection of recombinant clones. Moreover,
CFCM carries out rederivation of mice via embryo transfer. In addition, CFCM helps Researchers to plan experiments, to manipulate and genotype mice.
Other services provided by CFCM are the screening of resistant clones by Southern Blotting to identify gene
targeted clones and the production of lentiviral vectors to generate transgenic mice via oocytes infections.
Very important, CFCM is offering now the Embryo Cryopreservation. This is a basic service because Researchers spent time and moneys to maintain murine lines not necessary for their current studies. Moreover,
these murine lines occupy precious space in the Animal House.
CFCM is setting up the isolation of ES cells from wild type and mutant bastocysts. ES cells derived from
transgenic mice represent important tools for the analysis of mutant mice.
More information can be found at the site http://www.sanraffaele.org/CFCMn.html
Marco E. Bianchi
FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications
Laboratory
The Flow cytometry Resource and Analytical Cytology Technical Applications Laboratory is a core facility
that offers state-of-the-art instrumentation and analysis techniques to the scientific community. Flow cytometry
is an evolving field; it is continually being re-discovered by young scientists who approach this technology to
answer a multitude of questions in their discovery work. Cytometrists continue to find and develop new applications. So wide ranging is the applicability of this technology that practitioners may include, in addition to biologists, physicians, microbiologists, marine biologists, veterinarians and research chemists to name a few. Verifiable results can easily be obtained for such applications as Immunophenotyping, Cell division and Apoptosis,
Cell activation, Intracellular pH shifts, Phagocytosis, Oxidative burst and many more. In addition to the analytical capabilities of this technique, the core facility offers assisted cell Sorting services for characterizing, separating and purifying populations of particles as diverse as beads, bacteria, micro-particles, cells and chromosomes.
In 2009 the facility supported over 380 Researchers, performed more than 1450 cell sorts and logged over 9500
hours of analytical instrument time.
Alessio Palini
CERMAC, Centre of Excellence of High Field Magnetic Resonance
CERMAC is a Centre of Excellence financed by an original grant of the ministry of Education and Ministry
of health.
Different research groups have access to the centre and perform studies independently financed.
The core facility available is a 3Tesla magnet with post processing hardware and software facilities for advanced morphological and functional studies of the Central Nervous System.
The following research groups have access and develop their projects within the centre; Neuroradiology, Nuclear Medicine, Neurology, Psychiatry, Radiology, Cognitive neurosciences.
In 2008, 20 papers have been published in indexed journals.
The main fields of research are devoted to:
• Development and validation of MR advanced techniques and dedicated post-processing programs
• Application of conventional and advanced techniques in the study of the normal brain:
• Brain maturation in premature and terms neonates
• Aging
• Brain functions in paediatric and adult population (perception of music and sounds, language, memory and
other cognitive functions)
• Motor system function including mirror neurons system
• Application of conventional and advanced techniques in the study of the diseased brain:
• Brain inflammatory deseases, with a special focus on Multiple Sclerosis
• Mood disorders and other psychiatric deseases like schizophrenia
• Neuro-oncology (diffusion tensor imaging and tractography in brain tumors)
• Vascular diseases
• Degenerative diseases
Giuseppe Scotti
MOUSE HISTOPATHOLOGY
The principal aim of the Mouse Histopathology Unit is to support, complement and favour the advancement
of scientific projects, by providing conventional morphological analysis and immunophenotyping.
The facility is located in the Department of Pathology and offers the technical and the intepretative experience for the analysis of tissues from animal models, evaluating the best histological or immunocytochemical
procedures, based on the expected results.
The services provided include:
1.
macroscopic examination including perfusion and necroscopy
2.
microscopic analysis
• paraffin embedding and inclusion
• microtome sectioning and standard HE staining
• special histochemical staining (Perls, PAS, Masson, Gomori stain…)
• frozen tissues and cryostatic section preparation
• immunohistochemistry (commercial antibody and
• cytospin and paraffin cytoblock
• final report
3.
image analysis
The role of pathology in the field of experimental studies on laboratory animal is of interest for:
• indentification and evaluation of experimentally induced lesions
• setting of animal models of human diseases
• efficacy and safety studies
• phenotyping of transgenic mice
To date multiple collaborations within our Institute have been settled in order to analyze the morphological
and immunophenotipical patterns of murine models of diseases, treated with different therapeutic approaches
and to analyze the efficacy of genic therapy and safety of the use of viral vectors.
Francesca Sanvito
FACILITIES - 189
ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center
CFCM, Core Facility for Conditional Mutagenesis
CLINICAL DEPARTMENTS - 191
THE CLINICAL DEPARTMENTS
DEPARTMENT OF ARRHYTHMOLOGY
Head of Department: Carlo Pappone
DEPARTMENT AREA COORDINATOR: Vincenzo Santinelli
Electrophysiology and cardiac pacing
HEAD OF UNIT: Carlo Pappone§
RESEARCHER:Vincenzo Santinelli
PHYSICIANS: Giuseppe Augello, Cristiano Ciaccio, Simone Gulletta, Patrizio Mazzone, Gabriele Paglino, Alessia Pappone,
Simone Sala, Andreina Santagostino, Nicoleta Sora, Pasquale Vergara, Gabriele Vicedomini
RESIDENTS: Francesco Arioli, Maria Avitabile, Giuseppe Ciconte, Amarild Cuko, Enrico Frigoli, Emma Gelera, Alessandra Marzi,
Rita Naio, Andrea Radinovic, Stefania Sacchi, Massimo Saviano, Roberto Spoladore
BIO ENGINEERS: Simonetta Crisà, Giorgio Maida
FELLOWS: Ombretta Osnago, Francesca Zuffada
§ in 2010 the Cardio-Thoracic-Vascular Department will include Arrhythmology, which will be directed by Prof. Della Bella from
January 15th, 2010.
CARDIO-THORACIC-VASCULAR DEPARTMENT
Head of Department: Ottavio Alfieri*
DEPARTMENT AREA COORDINATORS: Stefano Benussi, Renata Clotilde Castellano, Domenico Cianflone*, Guglielmo Cornero,
Stefano Gerosa, Giovanni La Canna, Silvio Magrin, Giovanni Marino, Enrico Maria Marone, Germano Melissano, Stefano
Moriggia, Carlopietro Voci*
Cardiac surgery
HEAD OF UNIT: Ottavio Alfieri*
CLINICAL UNIT LEADERS: Michele De Bonis, Francesco Maisano, Alessandra Rossodivita
CLINICAL UNIT COORDINATOR: Alessandro Castiglioni
PHYSICIANS: Irina Arendar, Stefano Benussi, Andrea Blasio, David Ferrara, Andrea Fumero, Andrea Galanti, Antonio Grimaldi,
Giuseppe Iaci, Giovanni Laino, Elisabetta Lapenna, Stefano Moriggia, Simona Nascimbene, Maria Grazia Pala,
Alessandro Verzini
RESIDENTS: Maria Chiara Calabrese, Micaela Cioni, Egidio Collu, Paolo Denti, Enrica Dorigo, Andrea Giacomini, Mario Manca,
Maurizio Taramasso, Giorgio Viganò
FELLOWS: Andrea Guidotti, Ylenia Privitera, Davide Schiavi
Cardiac ultrasound imaging
HEAD OF UNIT: Giovanni La Canna
Cardiovascular rehabilitation and prevention
HEAD OF UNIT: Domenico Cianflone*
CLINICAL UNIT LEADER: Carlo Meloni
PHYSICIANS: Alice Calabrese, Nicole Cristell
Cath Lab
HEAD OF UNIT: Antonio Colombo
CLINICAL UNIT LEADERS: Mauro Carlino, Alaide Chieffo, Matteo Montorfano
PHYSICIANS: Alfredo Castelli, Cosmo Godino, Azeem Mohamed Latib
RESIDENTS: Filippo Figini, Daniela Piraino
FELLOWS: Rasha Al-Lamee, Francesco Arioli, Economou Fotios, Alfonso Ielasi, Marco Mussardo, Kensuke Takagi
TECHNICIANS: Gianfranco Accarino, Raimondo Bellanca, Salvatore Cannavale, Andrea Di Marco, Fanny Lavazza, Matteo
Longoni, Davide Maccagni, Massimo Angelo Messa, Marcello Murino, Vittorio Romano, Mario Squilla
Clinical cardiology
CLINICAL UNIT LEADERS: Fabrizio Bonetti, Alberto Cappelletti, Andrea Conversano, Gabriele Fragasso, Andrea Macchi,
Michele Oppizzi
PHYSICIANS: Eustachio Agricola, Fabio Buzzetti, Chiara Camesasca, Cristina Canciani, Barbara Demarchi, Stefano Gerosa,
Alessandra Mailhac, Cinzia Nitti, Alessandra Pancaldi, Marco Papa, Cristina Pedrigi, Patrizia Puccetti, Carmen Silipigni
Coronary Care Unit (CCU)
CLINICAL UNIT LEADERS: Carlo Ballarotto, Giuseppe Pizzetti
PHYSICIANS: Giorgio Bassanelli, Roberto Spoladore
Functional Rehabilitation
HEAD OF UNIT: Alessandra Raschi
Intensive Care Unit (ICU) and Post Operatory Care Unit (POCU)
CLINICAL UNIT LEADER: Giovanni Landoni, Giovanni Marino
CLINICAL UNIT COORDINATORS: Jaques N’Zepa Batonga, Andrea Carozzo, Guglielmo Cornero, Antonella Crescenti, Rossana
Fiori, Silvio Magrin
PHYSICIANS: Valeria Aldovrandi, Elena Bignami, Tiziana Bove, Maria Grazia Calabrò, Francesco Cama, Giuseppina Maria
Casiraghi, Domenica Carrieri, Francesca Cavenago, Remo Daniel Covello, Monica De Luca, Greta Fano, Annalisa
Franco, Giovanna Frau, Chiara Gerli, Giulio Melisurgo, Roberta Mennella, Melissa Messina, Fabrizio Monaco,
Massimiliano Nuzzi, Federico Pappalardo, Tiziana Giuseppa Quattrocchi, Anna Mara Scandroglio, Ornella Sottocorna,
Massimo Zambon
Thoracic surgery
HEAD OF UNIT: Piero Zannini*
CLINICAL UNIT LEADERS: Giulio Melloni, Giampiero Negri* Carlopietro Voci*
CLINICAL UNIT COORDINATOR: Angelo Carretta
PHYSICIANS: Alessandro Bandiera, Paola Ciriaco, Armando Puglisi
RESIDENTS: Michele Giovanardi, Annamaria Gremmo, Piergiorgio Muriana, Stefano Sestini, Antonio Tuoro
Vascular surgery
HEAD OF UNIT: Roberto Chiesa*
CLINICAL UNIT LEADERS: Efrem Civilini, Enrico Maria Marone, Germano Melissano, Yamume Tshomba
CLINICAL UNIT COORDINATOR: Renata Clotilde Castellano
PHYSICIANS: Domenico Astore, Laura Dordoni, Gloria Esposito, Massimiliano Marrocco-Trischitta
RESIDENTS: Chiara Brioschi, Giovanni Coppi, Andrea Kahlberg, Davide Logaldo, Daniele Mascia, Daniele Psacharopulo, Sara
Spelta, Gianbattista Tshiombo
FELLOWS: Domenico Baccellieri, Luca Bertoglio, Barbara Catenaccio
The clinical activity of the Department is devoted to the diagnosis and treatment of cardiac, thoracic and vascular disease.
New techniques and technologies have been introduced to offer to the patients the entire spectrum of the therapy options in a
multidisciplinary environment.
Patients-centered care is the philosophy behind the daily clinical practice.
The interaction among different specialists (anesthesiologists,
cardiovascular and thoracic surgeons, interventional and clinical
cardiologists) is favored by the contiguity of the areas devoted to
surgery, cath lab procedures and intensive care.
Patients with acute disease coming on emergency basis as well
as patients with chronic diseases admitted electively are submit
Ottavio Alfieri
ted to diagnostic investigation, treatment, an then rehabilitation
if needed. A well structured rehabilitation program is available
providing complete recovery even for the sickest patients. An active outpatient clinic is functioning for
new referrals and follow-up.
Clinical activity and Areas of excellence - In regard to cardiac diseases, the main pathologies are ischemic and valvular heart diseases, which are treated either with catheter based interventions or minimally invasive procedures or conventional surgery. Grown-up patients with congenital heart disease
have been increasing recently. A large number of patients with major aortic and vascular pathologies are
also increasingly referred as well as patients with complex oncological problems of the thoracic organs.
Transcatheter aortic valve implantation has been widely carried out to treat inoperable or high risk patients with severe aortic stenosis and today the largest experience in Italy has been accumulated in this
field by our multidisciplinary team.
The percutaneous treatment of mitral insufficiency is performed in patients with heart failure and our
series represents one of the very first in Europe.
Innovative modalities of medical treatment for patients with congestive heart failure have been recently introduced, particularly in the field of improvement of cardiac metabolism, achieving a significant increase of survival/quality of life as compared to figures reported in the literature.
A structurized program for the treatment of patients with end-stage heart failure has been developed.
Aim of the program is to provide a comprehensive treatment for the failing heart, including mechanical
circulatory support (short and long term) in different clinical settings: post cardiotomy cardiogenic shock,
acute myocardial infarction, bridge to transplant, destination therapy. Also treatment of acute hypoxia
and ARDS by ECMO is now offered as a life-saving procedure.
A wide spectrum of aortic pathologies, including aneurysms, dissection, traumatic injuries, coarctation
etc., are treated using both conventional and endovascular approaches. For high risk patients with complex aortic arch and thoracoabdominal pathology, hybrid open and endovascular strategies are selectively performed, and endovascular branch-technology is currently under evaluation. Both open and endovascular procedures are also used for carotid and lower limb revascularization.
A great recent achievement in thoracic surgery has been the treatment of lung cancer in patients with
emphysema. The respiratory impairment due to this disease used to be a surgical contraindication in the
past. Today different strategies have been introduced in our Department to extend surgical indication in
lung cancer including parenchyma-sparing bronchoplasty techniques, lung volume reduction surgery and
bronchoscopic lung volume reduction.
Finally, 3-D echocardiography has been introduced as a routine imaging modality to assess patients
with structural heart disease, with considerable enhancement of diagnostic capabilities.
Fields of research - Research is related to the clinical activity, as presented above.
Ottavio Alfieri
DEPARTMENT OF GENERAL
AND SPECIALISTIC SURGERY
Head of Department: Carlo Staudacher*
DEPARTMENT AREA COORDINATORS: Marco Braga*, Carlo Castoldi, Francesco Deni, Renato Finazzi, Emiliano Giorgi, Gilberto
Mari, Michele Paganelli, Danilo Parolini, Sandro Passaretti, Carlo Socci, Marco Stella, Walter Zuliani
Gastroenterologic surgery
CLINICAL UNIT LEADERS: Saverio Di Palo, Elena Orsenigo
CLINICAL UNIT COORDINATORS: Paolo Aldo Raul Baccari, Paola De Nardi
PHYSICIANS: Andrea Marco Tamburini, Andrea Vignali
RESIDENTS: Michele Carvello, Tiziana Casiraghi, Carmen Forestieri, Francesco Luparini, Alessio Mocci, Danilo Parolini, Carlo
Socci,Valentina Tomajer, Roberta Varale
General and pancreatic surgery
CLINICAL UNIT LEADERS: Marco Braga*, Marco Cristallo
PHYSICIANS: Gianpaolo Balzano, Renato Castoldi, Walter Zuliani
RESEARCHER: Lorenzo Piemonti
RESIDENTS: Massimiliano Bissolati, Vanessa Capitanio, Giovanni Capretti, Cristina Gilardini, Federica Merlini, Federica Milani,
Gregorio Stratta
FELLOWS: Alessia Mercalli, Cristina Ridolfi, Valeria Sordi
Hepatobiliary and week surgery
CLINICAL UNIT LEADERS: Luca Aldrighetti, Edoardo Beretta, Alberto Marassi
PHYSICIANS: Marco Catena, Enrico Fiacco, Renato Finazzi, Gilberto Mari, Mvunde Mukenge, Michele Paganelli
CONSULTANT: Veronica Zuber
RESIDENTS: Federica Cipriani, Ines Mulas, Carlo Pulitanò, Francesca Ratti
Orthopaedics
HEAD OF UNIT: Gianfranco Fraschini*
CLINICAL UNIT LEADERS: Francesco Camnasio, Maurizio De Pellegrin, Giuseppe Gioia, Crispino Grispigni, Eliseo Mainetti
RESEARCHER: Giuseppe M. Peretti*
PHYSICIANS: Arianna Banfi, Carlo Castoldi, Pietro Ciampi, Alessandro De Ponti, Dario Fracassetti, Davide Mandelli,
Umberto Mezzadri, Gianluigi Moro, Paola Rivoltini, Paolo Sirtori, Corrado Sosio, Matteo Vitali
RESIDENTS: Niky Mancini, Laura Mangiavini, Alessandro Pozzi, Celeste Scotti
POST-DOCTORAL FELLOW: Daniela Deponti
Gastroenterology-Endoscopy
CLINICAL UNIT LEADERS: Paolo Giorgio Arcidiacono, Mario Guslandi, Sandro Passaretti
PHYSICIANS: Silvia Carrara, Lorella Fanti, Alberto Mariani, Edi Viale
FELLOWS: Cinzia Boemo, Milena Di Leo, Chiara Notaristefano, Cristian Vailati
CONSULTANTS: Maura Corsetti, Antonella Giussani, Gianni Mezzi, Maria Chiara Petrone
Anaesthesiology
CLINICAL UNIT COORDINATORS: Massimo Agostoni, Massimo Caldi, Eleonora Colnaghi, Laura Comotti, Francesco Deni,
Emiliano Giorgi, Daniela Giudici, Carla Martani, Valeria Perotti, Roberto Valeri, Giovanna Valentini
PHYSICIANS: Barbara Airaghi, Felicia Adalgisa Antonino, Tania Capocasa, Mariela Decembrino, Daniela Larato, Renato Meani,
Francesca Presti, Lorenzo Quario, Raffaella Reineke, Monica Scarioni
CLINICAL UNIT LEADER: Sergio Colombo
PHYSICIANS: Paolo Federico Beccaria, Pier Carlo Bergonzi, Luca Cabrini, Carlo Leggieri, Daniela Mamo, Elena Moizo,
Silvia Marolina Morero, Milena Mucci, Davide Salaris, Federico Vinciguerra
*Professor at: Università Vita-Salute San Raffaele
The Department of Surgery and Specialized Units encompasses
Upper Gastrointestinal Surgery, Colorectal Surgery, Pancreas
Surgery, Breast Unit, Hepatobiliary Unit, Bariatric Surgery, Lymphatic Surgery, Endocrine Surgery, General Surgery, Transplantation, Gastroenterology & Endoscopy, Orthopedic Surgery, Anesthesiology, and Intensive Care Unit. The Department has three
core missions: excellent clinical care, outstanding research productivity and the delivery of state of the art educational programs. The
Upper Gastrointestinal Surgery Unit has a dedicated program in
treating cancers and benign diseases of the upper gastrointestinal
tract. Patients are treated by a multidisciplinary team of experts. A
research program is ongoing to improve the pre operative workup
of tumors of esophagus and stomach with the inclusion of Magnetic
resonance imaging, sentinel node identification in early cancer
stage and neoadjuvant chemotherapy and HIPEC in the advanced
Carlo Staudacher
ones. The high volume Colorectal Surgery Unit offers the most advanced surgical and minimally invasive options not only to eradicate the disease, but also to preserve patients’ ability to normal function. Among various programs there
are the sentinel node mapping in colorectal and cancer of the anal canal and the perioperative evaluation
of anorectal function a pelvic floor biofeedback rehabilitation method. The Pancreatic Surgery Unit has
one of the highest pancreatic surgery volume in Europe with more than 160 pancreatic resections performed/ year. In order to treat the post-surgical diabetes secondary to total pancreatectomy there is an
active program of islet autotransplantation. The Breast Unit applies the International Standard of excellence stated by EUSOMA (European Society of Mastology). In the Hepatobiliary Surgery Unit the activities are mainly focused on hepatobiliary tumors and chronic liver diseases, including primary and
metastastic liver tumors, benign and malignant diseases of the biliary tract, acute and chronic hepatitis.
Concerning the hepatic surgery the Unit is a high-volume unit for liver resections, performing 150-170
liver resection/year. A clinical program of laparoscopic liver surgery has been started on January 2007.
Data regarding the Bariatric Surgery Unit included a successful activity in the past years. The current
program foresees an activity increase, with special interest to the obese diabetic patient and metabolic
surgery. Lymphatic Surgery: the primary and secondary lymphoedema surgical therapy finds in the lympho-venous anastomosis, as well as in the lymphatic grafting the more reliable procedures. The Section of
Endocrine Surgery treats endocrine tumors in children and adults. Surgeons working in this section apply
the state-of-the-art technology, including minimally invasive parathyroid surgery with intraoperative
parathormone (PTH) assay determination , and laparoscopic adrenalectomy. The clinical activity of
Transplant Surgery area includes the following programs: Simultaneous Pancreas and Kidney Transplantation and Pancreas Alone Transplantation in IDDM patients; double kidney from marginal donors; laparoscopic living donor nephrectomy; islet transplantation. The clinical activity of the Division of Gastroenterology and Gastrointestinal Endoscopy includes four main sections: clinical gastroenterology and
hepatology, gastrointestinal and pancreatico-biliary endoscopy, ultrasound endoscopy, and digestive
motility. The division is a tertiary referral center for therapeutic pancreatico-biliary and G.I. tract endoscopy, as well as for endoscopic ultrasound, diagnosis and treatment of motility disorders (mainly
esophagus and rectum), and pancreatic diseases. Advanced endoscopic procedures, as ERCP, endoscopic
ultrasound, and therapeutic G.I. tract procedures are carried out under deep sedation and anaesthesiologist assistance; two anaesthesiologists are involved daily in two operatory rooms.The Division of Orthopedic Surgery cares for all injuries and diseases of the musculoskeletal system. The Division provides subspecialty clinics in the specific areas of major joint reconstruction, sports medicine, pediatric orthopedics,
foot, hand, spine, trauma, oncology, reconstructive microsurgery, and rehabilitation. The clinical activity
of the Orthopaedics and Traumatology Unit aims to cover all the needs related to traumatic, degenerative, oncologic, infectious and metabolic aspects of the musculo-skeletal system. The spine surgery, the
shoulder and elbow surgery, the treatment of the degenerative disease of the joints, the pelvis surgery, the
diagnosis and treatment of the pathologies of the bone metabolism represent areas of distinction of the
Orthopaedics and Traumatology Unit. The Orthopaedics and Traumatology Unit has also an intense basic research activity with the Laboratory for Tissue Engineering and Biomaterials. The Anesthesiology
and Intensive Care Unit reflects the comprehensive effort of a team of anesthesia physicians, nurses, and
staff to advanced patient care. Pre-admission diagnosis and staging program is ongoing in order to decrease hospital stay. The main fields of research are: Medical Emergency Team; Non-invasive Ventilation
in innovative fields; Percutaneous Tracheostomy in difficult cases; Activated or Zymogen Protein C in
sepsis; Use of Simulation in medical training; Extracorporeal support in ARDS patients (in particular in
influenza A H1N1-related ARDS). The team are editing an international journal “HSR proceedings in
Intensive Care and Cardiovascular Anesthesia”, freely available on www.itacta.org.
Carlo Staudacher
HEAD AND NECK DEPARTMENT
Head of Department: Giuseppe Scotti*
DEPARTMENT AREA COORDINATORS: Antonio Dell'Acqua, Andrea Falini*, Marco Gemma, Susanna Piccoli, Sandra Pieralli,
Claudio Righi, Francesco Scomazzoni
Neuroradiology
CLINICAL UNIT LEADERS: Nicoletta Anzalone, Cristina Baldoli, Andrea Falini*, Franco Simionato
PHYSICIANS: Simonetta Gerevini, Sandra Pieralli, Letterio Salvatore Politi, Silvia Pontesilli, Claudio Righi, Francesco Scomazzoni,
Roberta Scotti, Paolo Vezzulli
Head and neck anaesthesia and neurointensive care
CLINICAL UNIT LEADERS: Silvano Cozzi, Cristina Mattioli
CLINICAL UNIT COORDINATORS: Antonio Dell’Acqua, Marco Gemma, Susanna Piccoli
PHYSICIANS: Fabio Bernasconi, Maria Rosa Calvi, Marco Cerri, Antonella Cipriani, Assunta De Vitis, Cristina Frascoli, Luigi
Gioia, Elisabetta Grandi, Maurizio Mungo, Davide Poli, Alfredo Ravizza, Luisa Sacchi
Ophthalmology
HEAD OF UNIT: Francesco Bandello*
CLINICAL UNIT LEADER: Francesco Fasce
CLINICAL UNIT COORDINATORS: Gianluigi Bolognesi, Luisa Pierro
PHYSICIANS: Nicola Baccelli, Maurizio Battaglia Parodi, Paolo Bettin, Stefania Bianchi Marzoli, Elena Bruschi, Gabriella
Cammarata, Maria Lucia Cascavilla, Carlo Ciampi, Paola Ciasca, Marco Codenotti, Annalisa Colucci, Umberto De
Benedetto, Federico Di Matteo, Marina Fiori, Maddalena Forti, Marco Gagliardi, Matteo Ghidoni, Silvia Giatsidis,
Antonio Giordano Resti, Lauretta Guarisco, Ugo Introini, Rosangela Lattanzio, Francesca Legorini, Francesco Loperfido,
Gisella Maestranzi, Angela Malegori, Maria Pia Manitto, Elena Mantovani, Elisabetta Martina, Paolo Mauceri, Lisa
Melzi, Jacopo Milesi, Elisabetta Miserocchi, Giulio Modorati, Veronica Odazio, Matteo Prati, Andrea Ramoni, Laura
Regali, Carmen Rojo, Michela Rossi, Fabrizio Scotti, Marco Setaccioli, Alessandra Spinelli, Monica Stoppani, Gemma
Tremolada, Ilaria Zucchiatti
TECHNICIANS: Giorgio Alto, Adriana Angiolini, Alessio Buzzotta, Chiara Manclossi, Antonella Ribecca
Cornea and ocular surface Unit
HEAD OF UNIT: Paolo Rama
CONSULTANTS: Federica Ferrario, Chiara Insacco, Stanislav Matuska, Giorgio Paganoni, Elena Scandola, Maurizia Viganò
Otorhinolaryngology
PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Lucia Oriella Piccioni, Matteo Trimarchi
CONSULTANTS: Chiara Bellini, Beatrice Fabiano, Fabrizio Ferrario, Annalisa Meli, Andrea Muzza, Francesca Palonta, Rosaria
Taverna, Roberto Teggi
RESIDENTS: Pietro Limardo, Paola Recanati, Daniela Sarandria
SPEECH THERAPISTS: Daniela Gherner, Barbara Ramella
TECHNICIAN: Federica Mores
Neurosurgery
HEAD OF UNIT: Pietro Mortini*
CLINICAL UNIT LEADERS: Stefania Acerno, Camillo Ferrari Da Passano, Alberto Franzin, Marco Losa, Carlo Mandelli,
Piero Picozzi
PHYSICIANS: Lina Raffaella Barzaghi, Nicola Boari, Paola Castellazzi, Lorenzo Gioia, Silvia Snider, Micol Valle
CONSULTANT: Marzia Medone
The “head and neck department” develops, within a very busy and differentiated clinical practice, multiple fields of research, frequently integrated with other clinical departments or research divisions. Six clinical
units are integrated within the Department:
• Neurosurgery
• Otolaryngology
• Ophthalmology
• Cornea and Ocular surface
• Neuro intensive care
• Neuroradiology
Giuseppe Scotti
Fields of research
Neurosurgery
Neurosurgery: surgery of brain tumors and base of the skull tumors is one of the fields of excellence of
the unit. Surgery of the spine and peripheral nervous system is developed.
The neurosurgery unit is involved in research studies regarding brain gliomas, peripheral nerves regeneration, role of radiotherapy in treatment of vascular malformations.
Neurointensive Care
• Prognosis of diffuse axonal injury after trauma by MRI
• Cerebral perfusion before and after cranioplasty
• Troponine and BNP after major elective neurosurgery
• Cerebral perfusion after major elective neurosurgery in patients submitted to normo- or hyper-ventilation during surgery
• Database “Neurolink” of patients admitted to neurosurgical Intensive Care Units after severe head
injury.
• Multicenter study “Neuromorfeo” (randomized comparison between total intravenous and inhalation anesthesia during major elective neurosurgery)
• Effects of propofol on “functional MRI” in 14 and 4-8 ys old children submitted to sedation to accomplish neuroradiological examination
• Physiopathology of mechanical ventilation during ENT surgery with laser-proof endotracheal tubes
• Systemic complications during catharact surgery under local anesthesia
Ophthalmology
Retina
New therapeutic options with intravitreal compounds for Age-Related Macular Degeneration (AMD),
Diabetic Retinopathy (DR) and Retinal Vein Occlusion
Evaluation of the behaviour of Endothelial Progenitor Cells in DR and AMD
Evaluation of new therapeutic options: Enzymatic Vitreolysis with Autologous Plasmin and use of neuro-enhancement agents in patients with previous Retinal Detachment. Set up of a Vitreous Biobank.
Pediatric Ophthalmology
Multicentre clinical trial to test efficacy and tolerance of Azytromicin vs Tobramicin in purulent bacterial conjunctivitis.
Neuro-Ophthalmology
Evaluation of structural and functional brain damage and visual network plasticity in Leber’s Hereditary Optic Neuropathy, Hereditary Retinal Dystrophies and Ereditary Optic Neuropathies.
Evaluation of efficacy and safety of surgical decompression and Gamma Knife radiosurgery on Tumors
compressing the anterior visual pathway
Orbital Surgery
Evaluation of new therapeutic strategies of ocular MALT lymphomas
Imaging
Evaluation of the inter /intra operator reproducibility of nerve fiber layer thickness and topographic
measurement of the optic nerve and cornea among different Spectral Domain OCT instruments.
Ocular Immunology and Uveitis
Evaluation of new biologic agents for the treatment of intraocular inflammation.
Ocular Oncology
Evaluation of treatment with Gamma Knife Radiosurgery of conjunctival and intraocular tumors
Glaucoma
Studies on new medical and surgical therapeutic options in glaucoma management are ongoing.
Otolaryngology
• In collaboration with Neuroradiology fMRI studies are performed to evaluate plasticity and brain
cortical reorganization in patient submitted to major surgery of the larynx for neoplastic lesions.
• Research studies are performer to evaluate immune response in chronic rhinosinusitis and nasal
polips. The unit is part of an international research network that is involved in developing a worldwide database of tumors of paranasal sinuses.
• In collaboration with the Division of kidney diseases, studies are under way to evaluate genetically
determined anomalies of ion transportation in the inner ear responsible for Menière syndrome.
• In collaboration with the neeroscience division studies are performer on EEG anomalies in migraine
patients with auditory problems. Neurophysiological studies are performed in patients submitted to
laryngectomy fro head and neck cancer; evaluation of functional aspects and quality of life in laryngectomised patients with artificial prosthesis is under way. A new study regarding the role of viral
genoma of HPV virus in the pathogenesis of head and neck tumors has been initiated.
Cornea and ocular surface
• Evaluation of the efficacy and safety of autologous cultivated limbal stem cell transplantation for
restoration of corneal epithelium in patients with limbal stem cell deficiency due to ocular burns.
• Clinical outcome in patients affected by Acanthamoeba keratitis treated with polyhexamethylene
biguanide (PHMB) 0.02% alone or in combination with other anti-amoebal drugs .
• A multicentric, randomized, double masked, controlled trial on the safety and efficacy of Cyclosporine A (CyA) eye drop treatment on patients with ocular cicatricial pemphigoid.
• Research in different fields such as retinal pathology, in collaboration with the Stem Cell Research
Department. Müller Glial Cells are extensively studied. A mouse model for Müller Glia genetic tracing has already been established and will be used for the study of in-vivo Müller Glia regenerative
potential in scenarios of retinal damage or degeneration.
Neuroradiology
• Research in Neuroradiology addresses different fields with different research modalities.
• Studies of brain maturation and functional activity of the pediatric brain are performed with MRI,
functional MRI and brain activation techniques, both with 1.5T or 3.0 T magnets.
• Functional activation in brain tumors, studies of disruption of associative and projective tracts and fibres are performed with diffusion tensor imaging techniques and tractography. Degenerative and inflammatory diseases are studied in cooperation with the neuroscience research division.
• Ocular degenerative diseases and orbital lymphomas are studied in collaboration with ophthalmology and neuropathology units.
• Experimental and animal research projects are under development in the field of stem cells targeting
with MRI. Peripheral nervous system regeneration, and development of endovascular devices are
other fields of research. Evaluation of new contrast media for MR angiography and coordination of
multicenter international studies.
Giuseppe Scotti
DEPARTMENT OF INFECTIOUS DISEASES
Head of Department: Adriano Lazzarin*
DEPARTMENT AREA COORDINATORS: Nicola Gianotti, Paolo Scarpellini
Infectious diseases
CLINICAL UNIT LEADERS: Antonella Castagna, Massimo Cernuschi, Paolo Scarpellini, Giuseppe Tambussi, Caterina Uberti-Foppa
PHYSICIANS: Paola Cinque, Anna Danise, Luca Fumagalli, Nicola Gianotti, Monica Guffanti, Myriam Maillard, Roberto Novati,
Silvia Nozza
RESEARCHERS: Claudio Fortis, Laura Galli, Lucia Lopalco, Giulia Morsica, Claudia Pastori
CONSULTANTS: Simona Bossolasco, Giovanni Gaiera, Andrea Galli, Giulia Gallotta, Hamid Ibrahim Hasson, Annamaria Pazzi,
Cecilia Pizzocolo, Deborah Ratti, Clara Ronchetti, Vega Rusconi, Flavia Salmaso, Stefania Salpietro
FELLOWS: Laura Alagna, Sabrina Bagaglio, Francesca Cossarini, Manuela Pogliaghi, Lucy Porrino, Vincenzo Spagnuolo, Chiara
Tassan Din, Simon Tiberi, Giovanna Travi
TECHNICIAN: Arabella Bestetti
The aim of the Department of Infectious Diseases is to maintain
and improve excellence in the management of infectious diseases. In
particular, the Department aims at optimizing treatment of HIV infection by clinical trials and data analyses, infectious diseases other
than HIV, including tropical diseases, central nervous system infections and hepatitis, hospital-acquired infections, and opportunistic
infections in the immune deficient host.
The activity is organized in six Functional Units (ordinary admission, HIV-infected outpatient ambulatory, infectivology service at
San Raffaele main building, experimental therapies, day-hospital
plus gastroenterological fibroscopy and tropical diseases) and two Coordination Areas (quality and information technology). The Department includes three ordinary Admission Units, with 34 beds cumulatively (26 of which currently active), one day-hospital unit with six beds, and nine ambulatory rooms. About
4000 outpatients with HIV infection (80% on treatment with antiretroviral drugs) and 1000 with hepatitis B or C infection are currently followed-up, each of them attending about four visits per year.
Adriano Lazzarin
Two Clinical Trial Units have been set up and a clinical database (now containing information from
more than 7000 HIV-infected patients) has been implemented, which allows patients’ clinical data gathered during everyday activity to be used for clinical research and to be timely available for matching laboratory with clinical findings. During 2008, 41 clinical trials were ongoing at the Department, including
phase I, II and III clinical trials on new antiretroviral drugs, vaccines and immune-based therapies for
HIV infection. Research collaborations with European and NIH academic initiatives are also well established, particularly in the field of HIV infection: the Department is member of the following study
groups: Italian Cohort of Antiretroviral Naïve patients (ICONA), EUROSIDA (both of them taking
part in the intercontinental Data Collection on Adverse events of Anti-HIV Drugs - D:A:D: study
group), European AIDS Treatment Network (NEAT), and COHERE. The Department is also collaborating with Regione Lombardia to investigate treatment strategies for HIV infection aiming to reduce
health costs without jeopardizing treatment efficacy. In addition to clinical trials, the ongoing clinical research lines include: the pathogenesis and management of HIV drug-resistance, HIV encephalopathy,
metabolic disorders and cardiovascular complications of HIV disease, co-infection with hepatitis viruses,
HIV-associated tumors. The Department is also involved in the research of new diagnostic and management tools for the management of viral diseases different from HIV, particularly those affecting the central nervous system.
The Department also tightly collaborates with the Comitato per le Infezioni Ospedaliere in order to
survey, lower the incidence and improve the management of hospital-acquired infections, as well as with
the transplantations units for the prevention and treatment of opportunistic infections in patients with
treatment-related immune deficiencies. In this context, it is committed to the development and implementation of guidelines to assist other Departments in the management of infectious diseases. Furthermore, the Department participates to national initiatives aiming at studying and preventing the widespread of emerging and re-emerging diseases, such as tropical diseases and tuberculosis. In this context it
is also involved in projects aiming at improving the cures in low-income countries, in collaboration with
AISPO.
Due to its high ranking in the management of HIV infection, the Department organizes residential
stages in this field for doctors coming from all over Italy.
Adriano Lazzarin
MATERNAL AND CHILD HEALTH DEPARTMENT
Head of Department: Giuseppe Chiumello*
DEPARTMENT AREA COORDINATORS: Alessandro Aiuti, Ferdinando Bombelli, Riccardo Bonfanti, Guido Candotti, Moreno
Dindelli, Stefano Ferrari, Maria Pia Guarneri, Stefania Luchini, Massimo Origoni*
Pediatrics and neonatology
CLINICAL UNIT LEADERS: Graziano Barera, Franco Meschi, Gianni Russo, Giovanna Weber*
PHYSICIANS: Riccardo Bonfanti, Stefania Di Candia, Margherita Franco, Gisella Garbetta, Maria Pia Guarneri, Karen Marenzi,
Antonella Poloniato, Gabriella Pozzobon, Rosanna Rovelli, Paola Sgaramella, Maria Cristina Vigone, Matteo Viscardi
RESEARCHER: Stefano Mora
RESIDENTS: Valentina Biffi, Maddalena Bove, Bruna Cammarata, Giuseppe Cannalire, Ilaria Colombo, Francesca Cortinovis,
Valentina Donghi , Matilde Ferrario, Giulio Frontino, Alessandra Giardelli, Barbara Parma, Arianna Passoni, Alessandra
Perduca, Maria Antonietta Piscopo, Marco Pitea, Andrea Rigamonti, Elisa Rizzato, Paola Sogno Valin
FELLOWS: Maria Puzzovio, Ilaria Zamproni
Gynaecology and obstetrics
CLINICAL UNIT LEADERS: Ferdinando Bombelli, Claudio Brigante, Maria Teresa Castiglioni, Enrico Conti, Giorgia Mangili,
Daniele Spagnolo, Luca Valsecchi, Riccardo Viganò
CLINICAL UNIT COORDINATORS: Guido Candotti, Gabriella Colombo, Moreno Dindelli, Stefano Ferrari, Francesco Fusi,
Stefania Luchini
PHYSICIANS: Anna Cardani, Davide Ferrari, Luca Gandini, Elisabetta Garavaglia, Guido Marelli, Elena Marsiglio, Micaela
Petrone, Maria Teresa Potenza, Emanuela Rabaiotti, Susanna Rosa, Maddalena Smid
RESEARCHER: Massimo Origoni*
CONSULTANTS: Giada Almirante, Luigi Caputo, Paolo Cavoretto, Patrizia De Marzi, Rossana Favia, Susanna Filippis, Paolo
Giardina, Fabio Mauro, Michela Molgora, Nicoletta Panacci, Enrico Papaleo, Simone Rofena
RESIDENTS: Lara Di Piazza, Francesca Di Puppo, Cinzia Gentile, Serena Montoli, Francesca Occhi, Federica Pasi,
Francesca Pella, Paola Persico, Serena Pirola, Anna Redaelli, Audrey Serafini, Chiara Stefani
Pediatric immuno-hematology Unit
CLINICAL UNIT LEADER: Sarah Marktel
PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Alessandra Biffi, Barbara Cappelli
RESIDENTS: Costanza Evangelio, Francesca Ferrua, Valentina Finizio, Marco Fossati, Sara Napolitano, Anna Noè
CHARGE NURSE: Clara Soliman
RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi
Giuseppe Chiumello
The obstetrical outpatient management focuses on the clinical control
of physiological and pathological pregnancies, with particular attention
to gestational and pre-gestational diabetes, hypertension, autoimmune
diseases, thrombophilia and recurrent abortion. In 2008, 3300 outpatient evaluations have been performed. A complementary first and second level ultrasound service and prenatal diagnosis is available, with
nearly 3600 examinations performed in 2008. The obstetrical inpatient
activities are mostly dedicated to delivery assistance (in 2008, 1910 deliveries) of which 66% are vaginal deliveries and 34% caesarean sections. The obstetrical admissions for medical complications of pregnancy represent less than 10% of total admissions underlining the predominant outpatient management of high risk pregnancies.
Other activities include Day surgery procedures, conservative and demolitive laparotomy, laparoscopy,
vaginal surgery, and surgical treatment of urogenital prolapse and stress incontinence. Diagnosis, radical
surgery, and chemotherapy for genital tumors, treatment for trophoblastic diseases, and diagnostic/operative hysteroscopy are also performed.
Pilot center for the diagnosis and treatment of endometriosis with a multidisciplinary approach and the
use of the most advanced minimally invasive surgical techniques.
Infertile couples are managed with the most advanced treatments and assisted reproduction techniques
such as intra uterine insemination (IUI), in vitro fertilization & embryo transfer (IVF), and intra cytoplasmic sperm Injection (ICSI) with fresh or frozen-thawed ejaculated semen or spermatozoa from surgically retrieved testicles.
The activities of pediatric unit include involve general pediatric diseases, neonatology ,endocrinopaties
and diabetes. Nearly 750 children are admitted yearly in the emergency room. Neonatal care is inspired
by the most modern criteria of assistance for healthy newborns, and particular importance is given to the
relationship between the mother and the newborn. Specialized assistance is provided to both premature
and unhealthy newborns.
Approximately 700 patients with congenital hypothyroidism are followed by an integrated multidisciplinary approach involving the pediatric endocrinologist and neuropsychologist. In these patients genetic
studies have demonstrated 7 mutations on gene involved in iodine organification (DUOX2/
DUOXA2), and 3 mutations on TSH-receptor gene
More than 750 cases of Type 1 Diabetes Mellitus are currently followed and 80 patients are newly diagnosed each year, representing one of the broadest case records in Italy and Europe. Particular focus is given to new technologies for continuous insulin infusion and glucose monitoring. Three trials are ongoing
for secondary and tertiary prevention. The Unit is studying unfrequent genetic mutations able to cause
early onset diabetes
The management of Willi-Prader Syndrome involves a medical-psychological evaluation, close relationship with the family and motor-skills intervention, all of which have determined improvements in
the prognosis of this disease.
The case records of children with genital ambiguity is the greatest in Italy, and its management includes a collaboration with surgeons and psychologists. In order to assess less-invasive and more accurate
methods for the diagnosis and follow-up of various forms of Congenital Adrenal Hyperplasia (CAH), we
determined salivary and urinary steroid profile through liquid chromatography-mass spectrometry.The
number of patients with GH disorders under growth hormone treatment is one of the greatest in Italy.
Small for gestational age (SGA) children are at risk for obesity and Metabolic Syndrome (MetS); we are
performing the analysis of the intrahepatic fat, measured using localized hepatic 1HMRS, whole body
energy homeostasis, insulin sensitivity, and body composition in SGA and born appropriate for gestational age adolescents.Other main fields are bone diseases and hyperinsulinemic hypoglicemia.
The field of pediatric hematology and immunology is dedicated to research, diagnosis and cure of children with genetic disorders of the blood. In this context children are offered in addition to standard care
also experimental therapeutic options, among these cellular therapy and gene therapy. Our Institute has
an ongoing clinical program for hemoglobinopaties, immunodeficiencies, autoimmune diseases with
known or unknown genetic defects, metabolic disorders and muscular dystrophies. Concerning hemoglobinopaties, between 2005 and 2009, 68 bone marrow transplantation procedures were performed in patients with thalassemias or sickle cell anemias. In parallel, a research project of gene therapy in thalassemia is going and in 2012 a clinical trial will hopefully start. Regarding immunodeficiencies and autoimmune diseases with known or unknown genetic defects, our Institute regularly performs allogeneic
stem cell transplantation and gene therapy of ADA-SCID and Wiskott-Aldrich Syndrome. Concerning
metabolic disorders, a clinical trial of gene therapy in Metachromatic Leukodystrophy is ongoing. Finally,
a cell therapy clinical study for Duchenne muscular dystrophy will start in 2011.
Giuseppe Chiumello
DEPARTMENT OF INTERNAL
AND SPECIALISTIC MEDICINE
Head of Department: Emanuele Bosi*
DEPARTMENT AREA COORDINATORS: Giselda Colombo, Matteo Rocco Pastore, Moreno Tresoldi
General medicine, diabetes, endocrinology and metabolic diseases
CLINICAL UNIT LEADERS: Luca Falqui, Gabriella Galimberti, Roberto Lanzi, Matteo Rocco Pastore, Piermarco Piatti
CLINICAL UNIT COORDINATOR: Marco Federico Manzoni
PHYSICIANS: Alberto Davalli, Alessandro Saibene, Maurizio Storti
RESIDENTS: Chiara Cappelletti, Valentina Crippa, Valentina Doria, Ilaria Formenti, Manuela Fortunato, Andrea Laurenzi, Sara
Madaschi, Laura Molteni, Francesca Perticone, Cecilia Piani, Elena Peretti, Maria Grazia Radaelli, Alessandro Rossini,
Annachiara Uccellatore
NUTRITIONIST: Monica Marchi
Clinical transplantation
CLINICAL UNIT LEADERS: Rossana Caldara, Paola Maffi
PHYSICIAN: Sabina Martinenghi
CONSULTANTS: Chiara Gremizzi, Vera Paloschi
RESIDENTS: Gabriella Cicenia, Andrea Vergani
General medicine, clinical immunology and rheumatology
HEAD OF UNIT: Maria Grazia Sabbadini*
CLINICAL UNIT LEADERS: Giselda Colombo, Luisa Praderio, Moreno Tresoldi
PHYSICIANS: Enrica P. Bozzolo, Massimo Memoli, Chiara Salmaggi, Nicoletta Saporiti, Raffaella Scotti, Magda Vecellio
CONSULTANTS: Elena Baldissera, Lorenzo Dagna, Teresa D’Aliberti, Stefano Franchini, Mona-Rita Yacoub, Patrizia Aiello
RESIDENTS: Mattia Baldini, Emmanuel della Torre, Barbara Guglielmi, Alessandro Marinosci, Francesca Motta, Fulvio Salvo,
Mirta Tiraboschi
Nephrology and dialysis
HEAD OF UNIT: Donatella Spotti
CLINICAL UNIT LEADERS: Paolo Manunta*, Giorgio Slaviero, Giuseppe Vezzoli
PHYSICIANS: Teresa Arcidiacono, Chiara Lanzani, Marco Melandri, Luisa Persichini, Rita Quartagno, Maria Teresa Sciarrone
Alibrandi, Paola Stella
RESIDENTS: Irene Botticelli, Lino Merlino, Marialuisa Querques, Francesco Rainone, Marco Simonini
Emanuele Bosi
The Department of Internal Medicine incorporates all the areas and clinical activities of General and Specialized Medicine of the San Raffaele Hospital and Scientific Institute. Within the Department, physicians, nurses, technicians, students and
volunteers are dedicated to the compassionate practice of medicine, with a continuum of care encompassing preventive medicine, acute care, palliative therapies and
rehabilitation. The objective of the Department is to integrate clinical care, research
and education with the aim of assisting patients at the best of current medical
knowledge and technological expertise.
Clinical activity and Areas of excellence - The Department of Internal Medicine is composed of four inpatient Clinical Units and many Outpatient Clinics and Services covering General Medicine and the
medical specialties of Allergology, Clinical Immunology, Clinical Transplantation, Diabetes, Dialysis,
Endocrinology, Hypertension, Metabolic Diseases, Nephrology, Nutrition and Rheumatology. Moreover,
the Department of Internal Medicine works in close interaction with the Emergency Department, representing the main structure for hospitalization of patients presenting at the Emergency Medicine. The Department of Internal Medicine offers a complete range of teaching for students at the Medical School and
hosts the Post Graduate Medical Schools of Allergology and Clinical Immunology, Endocrinology,
Nephrology and Emergency Medicine, being also recognized as a centre of excellence in these specific
fields.
Fields of research - Integration between clinical care and research is a general theme across the Department. Relevant activities include: phase II/III clinical trials on novel pharmacological treatments and diagnostic tools in the fields of diabetes, rheumatoid arthritis, metabolism, hypertension, cardiovascular
and immune-mediated diseases; and some important projects of translational medicine in the fields of
islet transplantation and immunotherapies of type 1 diabetes and other autoimmune diseases. The Department is embedded in a remarkable clinical and scientific environment at San Raffaele, which offers
unique opportunities for interdisciplinary collaboration and translational research. The scientific production by physicians and clinical investigators from the Department is remarkable, with internationally
recognized areas of excellence in diabetes and metabolism, clinical immunology, hypertension, islet and
pancreas transplantation.
Emanuele Bosi
DEPARTMENT OF CLINICAL NEUROSCIENCE
Head of Department: Enrico Smeraldi*
DEPARTMENT AREA COORDINATORS: Barbara Barbini, Francesco Benedetti, Maria Cristina Cavallini, Andrea Fossati*, Ernestina
Politi, Paolo Ronchi
General psychiatry
HEAD OF UNIT: Enrico Smeraldi*
CLINICAL UNIT LEADERS: Roberto Cavallaro, Marco Locatelli
PHYSICIANS: Ilaria Aina, Sara Angelone, Laura Bianchi, Marta Bosia, Federica Cocchi, Michele Cucchi, Daniela Di Molfetta,
Marta Henin, Laura Liperi, Fausto Panigada, Ernestina Politi, Adriana Pontiggia, Paolo Ronchi, Laura Sforzini,
Francesca Siliprandi
RESIDENTS: Giampiero Bottero, Eugenia Fauci, Chiara Ruffini
TECHNICIANS: Margherita Bechi, Vittoria Bottelli, Daniele Cavadini, Francesco Fresi, Alessia Santoro, Tomaso Siccardi
Clinical health psychology
HEAD OF UNIT: Lucio Sarno*
PSYCHOLOGISTS: Valentina Di Mattei, Claudia Finocchiaro, Serena Giuliani, Carola Iris Ferrari, Rita Milesi, Chiara Motta, Liliana
Novella, Valeria Pezzani, Alessandra Pradella, Maria Monica Ratti, Eleonora Sasso, Laura Tirloni
RESIDENT: Stefano Clerici
Clinical psychology and psychotherapy
HEAD OF UNIT: Cesare Maffei*
CLINICAL UNIT LEADERS: Mariagrazia Movalli, Laura Vanzulli
CLINICAL UNIT COORDINATOR: Raffaele Visintini
PHYSICIANS: Marco Battaglia*, Andrea Fossati* Anna Ogliari*
CONSULTANTS: Francesca Biondini, Serena Borroni, Valentina Bregani, Paola Broggi, Elena Campanini, Ilaria Carretta, Paolo
Casati, Elisabetta Cattaneo, Rosaria Devoti, Michela Donini, Cinzia Facchi, Marina Fiore, Sara Gaietta, Nicolò Gaj,
Roberta Gallese, Salvatore La Viola, Gema Moelia Moreno Granados, Alessandro Pieri, Sergio Premoli, Erica Rossi,
Roberto Vanni, Daniele Villa, Annalisa Zanoni
RESIDENTS: Roberta Alesiani, Silvia Boccalon, Naima Coppolino, Maria Chiara Fiorin§, Gianluca Franciosi, Laura Giarolli,
Valeria Parlatini, Paola Pesenti-Gritti§, Chiara Spatola§, Martina Testa
§external residents
Eating disorders
HEAD OF UNIT: Laura Bellodi*
CLINICAL UNIT LEADERS: Stefano Erzegovesi
CLINICAL UNIT COORDINATORS: Giuseppina Diaferia, Maria Cristina Cavallini
PHYSICIANS: Cinzia Arancio, Alessandro Bernasconi, Silvia Cocchi, Angela Gabriele
FELLOWS: Ursula Catenazzi, Emma Fadda, Elisa Galimberti
Mood disorders
HEAD OF UNIT: Cristina Colombo
CLINICAL UNIT LEADERS: Linda Franchini, Adelio Lucca, Raffaella Zanardi
PHYSICIANS: Barbara Barbini, Francesco Benedetti, Euridice Campori, Mara Cigala Fulgosi, Sara Dallaspezia, David Rossini
RESIDENTS: Dario Delmonte, Clara Locatelli, Alessia Malaguti
Neurology
HEAD OF UNIT: Stefano F. Cappa*
CLINICAL UNIT LEADER: Sandro Iannaccone
PHYSICIANS: Luca Bernasconi, Maria Cristina Giusti, Valeria Golzi, Alessandra Marcone, Barbara Sferrazza, Michele Zamboni
RESEARCHERS: Jubin Abutalebi*, Nicola Canessa, Eleonora Catricalà, Pasquale Della Rosa
PSYCHOLOGISTS: Valentina Esposito, Elena Farina, Paola Frasson, Valeria Ginex
Sleep disorders
HEAD OF UNIT: Luigi Ferini-Strambi*
PHYSICIANS: Mauro Manconi, Marco Zucconi
The first and main committment of the Department is to define and to develop
a common guideline for the clinical approach to the different aspects of behavioural disorders, according to the funding principles of our Institution, in order to
overcome the strict meaning of each symptom and to adequately consider the nature and the whole of the individual suffering.
Enrico Smeraldi
The public psychiatric structure is based on the model of Mental Health Department (DSM). Our department, in its psychiatric and psychological component, is based on long term therapeutical assistance, hence resembling DSM and their mode of function,
but it differs from DSM in its objectives.
In DSM, the main aim is to take care of the mental health of a community (differently defined) and it
must be addressed in terms of prevention too. Treating patients in SPDC and CPS is a newly introduced
option which can be considered also as a therapy in social environment (= territory, in the language of social psychiatry), that will be useful and produce mental health.
On the other hand, the activity of our Department is mainly focused on the individual suffering and is
addressed to the patient: the possible interest for the environment in which he lives or for his relationships
is only aimed at improving assistance and therapeutical approach to the patient, who freely chooses our
structure instead of the public one, even if located in his territory.
The relationship between these two types of Psychiatric Departments has not yet been established and
we are trying to find a different model of assistance according to the psychopathological “quality” of each
disease. Another innovative feature is to put together in the same Department cognitive neurology and
psychiatry, since behavioural disorders are frequent and common and the same therapeutical principles
can be applied.
Enrico Smeraldi
DEPARTMENT OF NEUROLOGY
Head of Department: Giancarlo Comi*
CLINICAL UNIT LEADERS: Mauro Comola, Ubaldo Del Carro, Vittorio Martinelli, Fabio Minicucci
DISEASE UNIT COORDINATORS: Bruno Colombo, Raffaella Fazio, Letizia Leocani, Giuseppe Magnani, Paolo Marchettini, Vittorio
Martinelli, Maria Sessa, Giulio Truci, Maria Antonietta Volontè
PHYSICIANS: Stefano Amadio, Giovanna Franca Fanelli, Fabio Formaglio, Roberta Guerriero, Silvia Mammi,
Filippo Martinelli-Boneschi, Stefania Medaglini, Lucia Moiola, Antonella Poggi, Mariaemma Rodegher, Paolo Rossi,
Luisa Roveri, Marina Scarlato
RESIDENTS: Martina Absinta, Valeria Barcella, Mariangela Bianco, Calogera Butera, Francesca Caso, Daniela Ceppi, Raffaella
Chieffo, Elisabetta Coppi, Dacia Dalla Libera, Donatella De Feo, Luisa De Toni Franceschini, Sebastiano Galantucci,
Chiara Ghidinelli, Giacomo Giacalone, Elda Judica, Sara La Gioia, Emanuela Leopizzi, Giuseppe Liberatore, Giulia
Longoni, Ignazio Diego Lopez, Maria Merello, Giulia Pavan, Elisabetta Stefania Perego, Luca Peruzzotti Jametti,
Francesca Spagnolo, Laura Straffi, Habtom Tesfaghebriel, Daniela Ungaro, Chiara Vismara
The Department of Neurology consists of the Neurology Unit
(45 beds), the Neurorehabilitation Unit (42 beds), the laboratory
of Clinical Neurophysiology and the Neuropsychology Service.
The out patient area, day hospital service and the Centres for
Epilepsy, Multiple Sclerosis, Headache, Pain, ALS and Multiple
Sclerosis are the other activity characterising the Department.
Clinical activities are organized in disease units in order to provide
patients an integrated assistance going from the diagnostic aspects
to the advanced therapeutic interventions, including rehabilitaGiancarlo Comi
tion. The Department of Neurology is mostly qualified for advanced treatment strategies in inflammatory diseases of the Central and Peripheral Nervous System, stroke, neurodegenerative disorders, acting in strict interaction with
the Institute of Experimental Neurology. A large number of phase I-IV clinical trials performed in cooperation with pharmaceutical industries and generated by the Department itself make it possible to provide patients with more advanced therapeutic strategies. Points of excellence of the clinical research are
etiologic and symptomatic treatment of multiple sclerosis, epidemiological studies on multiple sclerosis,
and the evaluation of the disease pathogenesis and pathophysiology. Ischemic stroke researches are focused on the risk factors for the occurrence in young adults and on the organisational aspect of the early
intervention. Studies on dementia are conducted in co-operation with Imaging and clinical neurophysiology laboratories and aims to define biomarkers specific for dementia subtypes and to assess the risk for
evolution to Alzheimer Disease in patients with minimal cognitive impairment. In Amyotrophic Lateral
Sclerosis the contribution of instrumental test to the early diagnosis, the characterisation of cognitive dysfunction, the assessment of the value of new treatments are the key research activities.
The recovery medicine is one of the more recent area of research activated in the Department, because
of the possibility to follow neurological dysfunctions due to acute central nervous system lesions, from the
onset to the recovery phase. The impact of various therapeutic strategies to enhance recovery, the functional and molecular bases underlying brain plasticity after acute damage with imaging and neurophysiological examinations are deeply investigated.
Giancarlo Comi
DEPARTMENT OF ONCOLOGY
Head of Department: Federico Caligaris-Cappio*
DEPARTMENT AREA COORDINATORS: Gianni Bordogna, Gianfranco Ciboddo, Consuelo Corti, Andrés Jose Maria Ferreri,
Michele Reni
Internal medicine
HEAD OF UNIT: Federico Caligaris-Cappio*
CLINICAL UNIT LEADERS: Marco Foppoli, Giovanna Petrella
CLINICAL UNIT COORDINATOR: Aurelio Vicari
PHYSICIANS: Gianfranco Ciboddo, Giovanni Citterio, Giovanni Donadoni, Giada Licata, Manuela Pacchioni
RESIDENTS: Chiara Miggiano, Federica Pozzi, Carlo Rossi, Gilda Rossoni, Paolo Strati, Irene Vandoni, Chiara Francesca Verona,
Angela Zanoni
Haematology and bone marrow transplantation
CLINICAL UNIT LEADERS: Massimo Bernardi, Consuelo Corti, Jacopo Peccatori
PHYSICIANS: Andrea Assanelli, Lionello Camba, Matteo Carrabba, Elena Guggiari, Francesca Lunghi, Magda Marcatti, Maria
Teresa Lupo Stanghellini
Medical oncology
HEAD OF UNIT: Eugenio Villa
CLINICAL UNIT LEADERS: Daniela Aldrighetti, Monica Ronzoni
PHYSICIANS: Gianni Bordogna, Stefano Cereda, Andrés Jose Maria Ferreri, Vanesa Gregorc, Elena Mazza, Michele Reni,
Giordano Pietro Vitali, Patrizia Zucchinelli
CONSULTANTS: Carmen Belli, Alessandra Bulotta, Monica Giovannini, Vincenzo Ricci, Alessia Rognone, Luca Tondulli, Maria
Grazia Viganò
Nuclear Medicine
HEAD OF UNIT: Luigi Gianolli
CLINICAL UNIT COORDINATOR: Daniela Perani*
RESEARCHERS: Sara Belloli, Valentino Bettinardi, Assunta Carpinelli, Isabella Castiglioni, Maria Carla Gilardi, Adelmo Grimaldi,
Mario Matarrese, Maria Grazia Minotti, Rosa Maria Moresco, Maria Picchio, Marco Rigamonti, Annarita Savi, Paola
Scifo, Marco Tettamanti, Sergio Todde
PHYSICIANS: Carla Canevari, Flaviano Dosio, Federico Fallanca, Claudio Landoni, Patrizia Magnani, Ursola Pajoro, Andrea
Panzacchi, Gino Pepe, Ana Maria Samanes Gajate, Paola Todeschini, Giovanna Vanoli
CONSULTANTS: Elena Busnardo, Elisabetta Giovannini, Eleonora Manca, Alberto Monello, Pietro Spagnolo
RESIDENTS: Elena Greco, Paola Mapelli, Elena Spinapolice, Ignazio Vilardi
FELLOWS: Emilia Buriova, Elisa Galli, Manuela Giglio, Claudia Francesca Maddé, Claudio Mannu, Valeria Masiello, Eugenio
Rapisarda
PHD STUDENTS: Francesca Gallivanone, Cristina Monterisi, Silvia Valtorta
TECHNICIANS: Luca Brioschi, Patrizia Cerè, Antonia Compierchio, Paola Cordisco, Valeria Crippa, Silvia Debbia, Andrea Fabro,
Davide Gatti, Paola Lanzoni, Stefania Longari, Raffaele Menichini, Giacomo Orlandi, Jacopo Perego, Riccardo Rigamonti,
Silvana Romano, Lucia Rozza, Pasquale Simonelli, Stefano Stucchi, Francesco Sudati, Mauro Vaghi, Raffaele Vannulli
Radiotherapy
HEAD OF UNIT: Nadia Di Muzio
CLINICAL UNIT LEADER: Angelo Bolognesi
PHYSICIANS: Fodor Andrei, Saverio Beatrice, Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Aniko Maria Deli, Italo
Dell’Oca, Micaela Motta, Marcella Pasetti, Paolo Passoni, Najla Slim
RESIDENTS: Filippo Alongi, Brigida Pappalardi
TECHNICIANS: Fabio Baratto, Nietta Barricella, Roberta Bin, Rita Calaciura, Alessandro Capelli, Alberta De Leonardis, Letizia
Erre, Caterina Fiordelisi, Laura Longoni, Marilena Martulano, Lidio Palumbo, Diana Parutto, Vincenzo Sacco,
Giovannella Salvadori, Andrea Sbalchiero, Simone Selli, Antonella Soccio, Marco Spagnuolo, Alessandro Tavilla
The Department of Oncology is transforming everyday
practice into protocol-based clinical activity to achieve optimization of care and acceleration of cure. The specific aims
are: 1) to maintain/reach “state of the art” clinical care for all
types of cancer; 2) to improve logistic and organization ameliorating patient care; 3) to strengthen research with the instruments of Translational Research and an interdisciplinary
approach: this aim foresees the establishment of a Clinical
Trial Unit essentially devoted to Phase I and Phase II clinical
trials; 4) to join efforts with the Division of Molecular Oncology to establish an internationally competitive Integrated
Cancer Center (HSR-ICC).
Clinical activity and Areas of excellence - The Department includes the Divisions of Medicine 1Q and
of Hematology and Bone Marrow Transplantation, the Units of Medical Oncology, Radiotherapy and
Nuclear Medicine. The number of beds is 63, the personnel amounts to over 190 people; there are a management coordinator and a nurse coordinator.
The cultural organization of the Department follows the Disease Unit model and is based upon a fruitful interaction with other Clinical Departments involved in the diagnosis and treatment of cancer and
with several Research Divisions as well. The active Disease Units are Lymphoid, Lung, Pancreas, Breast,
Head and Neck, GastroIntestinal, Melanoma, NeuroOncology, Genito-Urinary and Gynecological Oncology. In 2008 the Department has taken care of about 4500 cancer patients, furthermore a) the Departmental Area of Lymphoid Tumors has been established with 25 ongoing clinical trials (HSR is the coordinating center of 11), b) the Bone Marrow Transplantation Unit has ranked among the firsts in Italy as
for the number of allogeneic transplantations performed and c) 43 clinical trials have been approved by
the Ethical Committee including numerous Phase I and Phase II trials. Blood, thoracic, pancreas and
brain tumors are Areas where the Department is especially active, not to mention the urological cancers
in collaboration with the Department of Urology. The collaboration with the Division of Molecular Oncology is strengthened by the clinical experience in applying new therapies to patients and is favouring
the development of new potential therapeutic tools that are systematically analysed in preclinical settings.
The Department has become member of the European Organization of Cancer Centers (OECI), the
Southern Europe for New Drugs Organization (SENDO), the Swiss Group for Clinical Cancer Research (SAKK), the CLL US/Europe Alliance Organization (driven by the MD Anderson Cancer Center) and is also member of the Network Italiano BioImmunoterapia dei Tumori (NIBIT) and of the Italian Melanoma Intergroup.
Fields of research - Innovative strategies are urgently needed in the areas of diagnosis, patient risk
stratification and treatment. We are building up teams of laboratory-based and clinical investigators
with the aim of defining molecular endpoints in clinical material and use them to develop studies on the
pathobiology of specific tumors and to organize pilot studies and investigator-driven clinical trials. The
currently ongoing projects can be summarized under three main headings: 1) Molecular mechanisms of
disease, one example being the association of infectious agents with the development of specific types of
lymphoid malignancies; 2) New diagnostic and prognostic approaches to define biologically-based prognostic and predictive tools, one example being the validation of a number of new markers with proteomic technologies; 3) New treatment strategies developed by increasing Phase I and I-II studies and by clinically translating the results of preclinical investigations, examples being immunotherapy, anti-angiogenesis-based treatments and the use of tomotherapy in specific types of cancer.
DEPARTMENT OF RADIOLOGY
Head of Department: Alessandro Del Maschio*
DEPARTMENT AREA COORDINATORS: Francesco De Cobelli*, Maurizia Del Maschio, Roberto Nicoletti, Pierluigi Paesano
Radiology HSR
CLINICAL UNIT LEADERS: Francesco De Cobelli*, Maurizia Del Maschio, Roberto Nicoletti, Pierluigi Paesano, Pietro Panizza,
Massimo Venturini
PHYSICIANS: Laura Brasca, Stefano Cappio, Giulia Maria Crespi, Angela De Gaspari, Antonio Esposito, Elda Garuti, Domenico
Ghio, Simone Gusmini, Carlo Martinenghi, Renata Mellone, Maria Grazia Rodighiero, Marco Salvioni, Simona
Irma Tacchini, Roberto Varagona
CONSULTANTS: Marina Benveniste, Roberta Carpanelli, Elena Contrino, Claudio Losio
Radiology HSRT
HEAD OF UNIT: Giuseppe Balconi
CLINICAL UNIT LEADER: Gianpiero Cardone
PHYSICIANS: Elena Capitelli, Francesca Di Sebastiano, Rossana Favia, Cristiana Iabichino, Roberto Lanzi, Massimo Mandelli
TECHNICIANS: Cecilia Bertocchi, Enza Galvano, Caterina Parolo, Alessandra Poggi, Maria Pia Rapallo, Stefano Rovani
The Global Activity of the Clinical Department of radiology includes
more than 165000 diagnostic and interventional procedures (including
emergency) per year.
The Department of Radiology is composed of many inpatienst and outpatients Services covering all the main fields of general Radiology except of
neuroradiology. The Department of Radiology is devided into two groups,
the main at San Raffaele Hospital and the second at Ville Turro buildings.
Moreover, the Department of Radiology works in close interaction with
the Emergency Department, for the evaluation of the main acute diagnostic problems.
The objective of the Department is to integrate clinical activity, research
and education with the aim of helping patients at the best of current medical knowledge and technological expertise.
Clinical activity and Areas of excellence - The Department includes six sections of clinical activity and
areas of excellence:
1. Conventional and Digital Radiology
2. Breast Imaging
3. Ultrasound
4. Computed Tomography
5. Magnetic Resonance Imaging and Spectroscopy
6. Diagnostic and Interventional Radiology/Angiography
Fields of research - The main fields of research are represented by:
• Cardiac magnetic resonance (CMR) Imaging and Spectroscopy and cardiac Computed Tomography
(CT).
• Diffusion-weighted Magnetic Resonance Imaging in cancer patients
• Development of clinical trials with new contrast agents especially in Magnetic Resonance Imaging
• Cellular and molecular imaging with a new 7T magnet dedicated to animal studies
• Pancreatic cancer imaging
• Breast cancer imaging and screening.
Moreover we developed many collaborations with internal and external groups, in particular:
• with the Section of Nutrition/Metabolism and the Faculty of Exercise Sciences, Università degli Studi
di Milano with Prof. Perseghin and Prof. Luzi it has been developed a tight cooperation on Magneticresonance spectroscopy of the heart and of the liver in order to evaluate the functional and metaboliceffects of physical exercise and pathological conditions such as diabetes, obesity or cardiomyopathies;
• with the group of Prof. Manfredi, a non-invasive MR based method for in-vivo cellular tracking has
• been developed and applied to follow the dendritic cells (DCs) in tumor bearing mice, allowing to investigate the critical aspects of DCs migration to establish an immune mediated cancer
therapy;Alessandro Del Maschio
• with the Unit of Radiation Therapy and Medical Physics of Dr. Di Muzio and Dr. Calandrino we
• sought to implement the radiotherapy planning by new imaging-techniques. We have use different
imagingtechnique as MRI and contrast enhanced 4D-CT to improve target volume definition in
prostate cancer and in pancreatic ductal adenocarcinoma;
• with the Transplant Unit of Prof. Secchi and Dr. Maffi we studied the metabolic effects in type 1 diabeticpatients who have undergone kidney or combined kidney-pancreas transplantation or islettransplantation with different imaging or spectroscopic approaches; moreover, with the same group in
the setting of the DRI, a similar approach for cells labelling and imaging was also used to follow the
pancreatic islets fate, after their transplantation in mouse model of type 1 diabetes;
• with the Department of Mechanics, Politecnico di Torino, with the Department of Bioengineering,
Politecnico di Milano, with the Istituto di Bioimmagini e Fisiologia Molecolare, Research National
Council, Milan in order to develop a method for quantifying helical flow in vivo employing time-resolved cine phase contrast magnetic resonance imaging to obtain the complete spatio-temporal description of the three-dimensional pulsatile blood flow patterns in aorta.
DEPARTMENT OF UROLOGY
Head of Department: Patrizio Rigatti*
DEPARTMENT AREA COORDINATORS: Roberto Bertini, Luigi Broglia, Andrea Cestari, Valerio Di Girolamo, Francesco Montorsi*,
Luciano Nava, Vincenzo Scattoni
Urology HSR
HEAD OF UNIT: Patrizio Rigatti*
CLINICAL UNIT COORDINATORS: Roberto Bertini, Renzo Colombo, Francesco Montorsi*, Andrea Salonia
PHYSICIANS: Diego Angiolilli, Alberto Briganti, Lina Bua, Andrea Gallina, Massimo Ghezzi, Caterina Lania, Arianna Lesma,
Marco Raber, Antonino Saccà, Vincenzo Scattoni, Nazareno Suardi, Giuseppe Zanni
RESIDENTS: Firas Abdollah, Marco Bianchi, Tommaso Camerota, Umberto Capitanio, Dario Di Trapani, Matteo Ferrari, Salvatore
Grimaldi, Carmen Maccagnano, Federico Pellucchi, Giovanni Petralia, Lorenzo Rocchini, Francesco Sozzi, Elena Strada,
Manuela Tutolo
Urological endoscopy service and day surgery
HEAD OF UNIT: Valerio Di Girolamo
Strategic Program for uro- andrological research
HEAD OF UNIT: Francesco Montorsi*
Urology HSRT
HEAD OF UNIT: Giorgio Guazzoni*
CLINICAL UNIT LEADERS: Piera Bellinzoni, Luigi Broglia, Luciano Nava
PHYSICIANS: Antonia Centemero, Andrea Cestari, Andrea Losa, Tommaso Maga, Lorenzo Rigatti
CONSULTANTS: Nicolò Maria Buffi, Fabio Fabbri, Mattia Sangalli, Emanuele Scapaticci, Matteo Zanoni
RESIDENT: Giovanni Lughezzani
The Department of Urology at Vita-Salute San Raffaele University, Milan,
chaired by Professor Patrizio Rigatti, is one of the most important institutions
in the field both in terms of clinical and research activity. The Department
was founded in 1985 and it is currently directed by Professor Patrizio Rigatti.
Clinical activity - The surgical activity is based on 25 operating theatre sessions and it is serving 110 beds for ordinary recovery. Every year, about 1000,
500 and 250 surgical procedures are performed for prostate, bladder and kidney cancer, respectively. Specific interest is directed to robotic surgery which is
currently used to perform radical prostatectomy, partial nephrectomy for cancer and reconstructive.
Patrizio Rigatti
Fields of research - The clinical investigations performed in the most recent
years leaded to the publication of 623 scientific contributions for a overall citation index of 6872 (citation index last three years: 3113; h-index: 40) [Source SCOPUS April 2010].
During the last 3 years the Department of Urology ranked first in terms of abstracts presented at the official annual meetings of the European Association of Urology and American Urological Association. The
main clinical research areas consist of prostate cancer, kidney cancer, bladder cancer, infertility and andrology, female sexual medicine, benign prostatic hyperplasia.
Ongoing and new translational researches has been starting after the foundation of the Urological Research Institute (URI), headed by Professors Francesco Montorsi and Petter Hedlund. The main basic research areas consist of prostate and bladder cancer, functional urology, reproductive and erectile dysfunction.
Patrizio Rigatti
CLINICAL SERVICES
Pathology
HEAD OF UNIT: Claudio Doglioni*
CLINICAL UNIT COORDINATORS: Gianluigi Arrigoni, Massimo Freschi, Maurilio Ponzoni, Isabella Sassi, Gianluca Taccagni, Maria
Rosa Terreni
PHYSICIANS: Luca Albarello, Giacomo Dell’Antonio, Nathalie Rizzo
RESEARCHER: Francesca Sanvito
CONSULTANTS: Anna Cremonini, Graziana Famoso
BIOLOGISTS: Maria Giulia Cangi, Lorenza Pecciarini
POST-DOCTORAL FELLOWS: Daniela Clavenna, Greta Grassini, Ilenia Papa
TECHNICIANS: Mara Bertolazzi, Marina Brambilla, Roberta Brambilla, Roberto Cairella, Diana Ciscato, Elena Dal Cin, Stefania
Demasi, Barbara Di Ruvo, Patrizia Ferrari, Marilena Flore, Franco Galli, Stefano Grassi, Laura Labbate, Camilla
Lambiente, Anna Mauri, Martina Rocchi, Graziella Santambrogio, Carlo Silva, Anna Talarico
CYTOTECHNOLOGISTS: Teresa Carbone, Miriam Cosciotti, Grazia Lamonaca, Giulio Legnani, Franca Toffolo
Laboratory medicine
HEAD OF DIVISION: Fernanda Dorigatti
HEADS OF UNIT: Ferruccio Ceriotti, Massimo Clementi*, Maurizio Ferrari*(*), Massimo Locatelli
CLINICAL UNIT LEADERS: Paola Cichero, Stefania Del Rosso, Fulvio Ferrara, Anna Maria Girardi, Cristina Ossi, Marina Pontillo,
Sara Racca, Armando Soldarini, Laura Soldini, Silvana Viganò
PHYSICIANS: Enzo Boeri, Luciano Crippa, Rita Daverio, Annalisa Fattorini, Nicasio Mancini, Andrea Motta, Maria Grazia
Patricelli, Serena Rolla, Loredana Tomassini, Mladen Trbos
BIOLOGISTS: Elena Bazzigaluppi, Sara Benedetti, Silvia Carletti, Anna Carobene, Arianna Crepaldi, Carlo Alberto Ferrero,
Rossella Ieri, Rosanna Latino, Marcello Marinelli, Gabriella Passerini, Elisabetta Pattarini, Flavia Piccini, Barbara Maria
Pirola, Laura Seghezzi, Barbara Sioli, Ivana Spiga, Annunziata Spina, Monica Zanussi
BIOENGINEER: Davide Alessio
CONSULTANTS: Emanuele Bosi*(#), Roberto Burioni*, Armando D’Angelo(#),Silvano Rossini, Orsetta Zuffardi(*)
FELLOWS: Angela Brisci, Francesca Bruno, Filippo Canducci, Maria Rosaria Carbone(*), Emanuela Castiglioni, Vincenza
Causarano, Donata De Marco, Roberta Diotti, Chiara Di Resta, Alessandra Foglio(*), Silvia Galbiati, Nadia Ghidoli,
Carlo Lombardoni(*), Nicola Maganetti, Maria Chiara Marinozzi, Francesca Rigo(*), Monica Sassi, Elena Sommariva(*),
Stefania Stenirri
TECHNICIANS: Rose Mary Carletti, Cinzia Magagnotti(*), Michela Sanpaolo, Francesca Sampietro(#), Nadia Soriani(*)
(*) reporting to the CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS
(#) reporting to the DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Immunohematology and transfusion medicine service
HEAD OF UNIT: Silvano Rossini
CLINICAL UNIT LEADERS: Lorena Barzizza, Laura Bellio
PHYSICIANS: Cinzia Bargiggia, Alketa Bolentini, Katharina Fleischhauer, Salvatore Gattillo, Lucia Malabarba, Lilian Romero,
Paola Ronchi
BIOLOGISTS: Lia Parma, Oriana Perini, Cristina Tresoldi, Elisabetta Zino
CHEMIST: Benedetta Mazzi
TECHNICIANS: Daniela Ceresa, Silvia Corno, Luigi D’Amato, Stefania Dell’Orco, Giuseppe Di Leo, Dina Di Sciacca, Alessandra
Galli, Emanuela Grioni, Maria Antonia Introini, Giuseppina Marabelli, Ilaria Mazzi, Gabriella Salomoni, Massimo
Sacconi, Elisabetta Sironi, Serenesse Tomasi, Gabriele Torriani, Federica Valtorta, Matilde Zambelli, Paola Zappalalio
Emergency medicine
HEAD OF UNIT: Michele Carlucci
DIRECTOR OF EMERGENCY MEDICINE PROGRAM: Marzia Spessot
CLINICAL UNIT COORDINATORS: Pietro Bisagni, Anna Borri, Roberto Faccincani, Maria Vittoria Lavorato, Federica Mariani
PHYSICIANS: Aldo Beneduce, Giuseppe Capasso, Laura Ferrario, Federico Furlan, Giulia Gallotta, Elisa Gatti, Simona Mauri,
Enrico Ortolano, Simona Rocchetti, Maria Vittoria Taglietti, Luca Tomaello, Valentina Tomajer
RESIDENTS: Vanessa Capitanio, Carmen Forestieri, Manuela Fortunato, Shigeki Kusamura, Andrea Laurenzi, Francesco Luparini,
Alessandro Marinosci, Federica Merlini, Federica Milani, Alessio Mocci, Annamaria Pazzi, Elena Peretti, Alessandro
Rossini, Roberta Varale
CLINICAL SERVICES - 217
CLINICAL UNIT COORDINATORS: Gabriele Cornaggia, Paolo Silvani
Anesthesia
CLINICAL UNIT COORDINATORS: Massimo Caldi, Daniela Giudici
PATHOLOGY
The Unit of Anatomy Pathology is a Clinical Service that provides surgical pathology and cytopathology activity, intraoperative consultations, post-mortem examination to the San Raffaele Hospital, performing gross
and microscopic examination and interpretation of tissue specimens that include biopsies and surgical excisions.
Activity
Our Unit evaluated more than 25.000 surgical and 24.000 cytologic specimens in 2009, encompassing most of
the wide variety of pathology scenario. The diversity of the specimen material is reflected in the specialized
medical and surgical practice at San Raffaele Hospital where Pathologists with particular interest and expertise
in different specialty areas (e.g., hematopathology, uropathology, neuropathology, gynecologic pathology, etc.)
interpret and signout these cases. This approach ensures excellent diagnostic interpretations, enhancing collaboration with the specialized clinical services present in San Raffaele Hospital.
A broad, continuously expanding and updated array of specialized techniques is available to complement
routine morphologic examination, including a wide menu of immunohistochemical and immunofluorescence
reagents, molecular pathology analyses, cell cultures, karyotyping of solid tumors and molecular cytogenetic
techniques.
Claudio Doglioni
LABORATORY MEDICINE
Standardization in clinical chemistry.
Two types of activities: 1. a multicenter study for the definition of reference intervals for aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase involving collaboration with Turkey and
China and 2. the development and implementation of reference methods for enzyme catalytic activities to be
applied to set target values to control materials for external quality assessment schemes and to validate and certify other field methods and routine laboratories.
Microbiology and Virology.
1. Microbiology. Resistance and susceptibility to antibiotics and antifungal of bacteria and fungi; molecular
diagnosis of sepsis.
2. Virology. Molecular biology of viral agents of acute respiratory diseases (coronaviruses, respiratory syncytial virus and viruses identified recently in infants with acute respiratory diseases); molecular monitoring of antiviral therapies and of therapies targeting virus fitness; in vitro characterization of anti-HCV neutralizing human monoclonal antibodies; cross-reacting and neutralizing human monoclonal antibody directed against the
HCV\E2 protein; Hepatitis C virus (HCV)-driven stimulation of subfamily-restricted natural IgM antibodies in
mixed cryoglobulinemia; antiviral Response Elicited by Anti-Idiotype Monoclonal Antibodies.
Laboraf collaborates with the research Center for genomics, bioinformatics and biostatistics, with the research Division of metabolic and cardiovascular sciences and with the Department of Internal and specialistic
medicine.
Fernanda Dorigatti
IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE SERVICE
The Hospital San Raffaele (HSR) Immunohematology and Transfusion Medicine Service (ITMS) provides
clinical services to support HSR patients in need of blood component therapy, cellular therapy, therapeutic
apheresis, and specialized laboratory diagnostics. This ISO 9002 Certified unit collects and prepares the blood
components and cellular therapy products used in patient care at the HSR, maintain an accredited Immunohematology Reference Lab and provides education in the field of Transfusion Medicine.
CLINICAL SERVICES - 219
The ITMS is subdivided into three distinct sub-units, each responsible for a particular process:
Blood Donation Center
The blood donation center sub-unit is responsible for the collection and testing of blood to be transfused into patients at the San Raffaele Hospital. It is responsible for handling all aspects of donor recruitment for whole
blood products, apheresis products, the auto-transfusion program and therapeutic phlebotomy.
Therapeutic Apheresis and Cellular Therapy
The Therapeutic Apheresis and Cellular Therapy sub-unit is responsible for collecting and processing
hematopoietic stem cells and performs the necessary diagnostic testing required for bone marrow transplantation procedures. The lab supplies hematopoietic stem cells and relevant cells in support of clinical trials for allogenic bone marrow and peripheral blood transplantation and offers a Stem Cell Cryo Banking service for autologous and allogeneic bone marrow products. Bone Marrow from qualified donors is collected in accordance
and recognition of the Italian Bone Marrow Donor Registry (IBMDR). Therapeutic apheresis procedures to
treat patients with neurologic and blood diseases, including photopheresis, red cell and plasma exchange procedures are also performed routinely.
Clinical Laboratory Diagnostics
The Clinical Laboratory Diagnostics sub-unit includes the following specialized laboratories: Immunohematology, Hematology, Flow Cytometry, Hematological Molecular Biology and an EFI Certified and accredited
HLA tissue typing laboratory. New technologies such as genetic red blood cell typing are being investigated. A
special emphasis is given to onco-hmatologic malignancies. These pathologies are studied using a multi-disciplinary approach.
In 2008, the ITMS distributed over 18,000 RBC Units and 4000 Platelet units, performed over 220 Stem Cell
collections and 660,000 clinical tests.
Silvano Rossini
EMERGENCY MEDICINE
In 2009 the Emergency Department of San Raffaele Hospital provided care for 62.849 patients.
Of the patients triaged 780 were given red code (that is, to be seen immediately in the resuscitation area).
9413 cases were given yellow code (that is, to be seen within 30 minutes of arrival). The largest amount of them
(49634) were given lower priority (green code, that means to be seen within 1 hour of arrival). Only 3022 were
given a white code (that is, patients whose conditions are not true emergencies). In 2009 we have seen 20848
patients with medical problems, 14853 with surgical problems and 11872 with minor trauma.7850 children
have been treated in the pediatric area. In the dedicated area for obstetrics 5187 women received treatment.
9857 patients, after initial evaluation, were admitted to different wards for further investigations and treatments.
In 2009 630 patients received surgery in the Emergency room.
Major trauma (patient with multiple injuries) is treated by a trauma team who has been trained using the principles taught in the internationally recognized Advanced Trauma Life Support course.
Medical emergencies are treated as taught in the Advanced Life Support and Trauma Advanced Life Support
courses.
Some members of the Emergency Room staff are ALS and ATLS instructors and such courses are regularly
held in our Hospital every year.
Staff members receive Emergency Medicine Up-to-date meetings every two weeks.
Medical students from Università Vita e Salute are trained on application of classical emergency medicine
principals in a humanistic and supportive patient environment.
In 2009 physicians attended the following meetings and courses: Il laboratorio d’Urgenza: problematiche organizzative e novità diagnostiche (Cremona, November); Le urgenze neurologiche: dalla diagnosi alla terapia
(Milan, November); International Meeting on Simulation in Healthcare-( Orlando, January); Trauma: Update
and organization (Bologna: February; Rome: October; Parma: September; Milan: December); ESTES Antalya,
May; Congresso SIMEU Lombardia (Milan, June); Medical Response to Major Incidents (Spalato, November).
Michele Carlucci
GENERAL INTENSIVE CARE
In 2008 our General ICU admitted 491 patients. Nearly half of these patients required an intensive treatment,
the others were subjects who needed a postoperative monitoring after major elective surgery.
The occupational rate during last year was around 95%.
Actually we’re changing our strategy to optimize ICU admissions, improving an early postoperative care in recovery room for the postoperative patients, in order to guarantee the care for hospital and territorial emergencies.
In 2008 the principal critical illnesses admitted to our unit included:
• Trauma patients (20% of intensive treatments). As front line of a 2nd level hospital in Milan county, general
ICU accept a significant number of subject involved in traffic and work accident.
• Respiratory failure (40% of intensive treatments). Primary and secondary ARDS (acute respiratory distress
syndrome) are frequent and undesirable evolutions of pneumonia or systemic sepsis, especially in immunecompromised patients like in autoimmune pathology or after transplantation.
• Cardiovascular failure or multiple organ dysfunctions (20% of intensive treatments). Patients rescued from
cardiac arrest or with strong cardiac congestive failure.
• Septic shock (10% of intensive treatments). Severe evolution of sepsis, complication in patients submitted
to major surgery or transplantation.
In our general ICU we can provide a wide range of therapeutic options and protocols for these specific
pathologies, updated to the last international guidelines: the newest strategies in mechanical ventilation including extracorporeal life support, updated antibiotic therapy, hypothermic therapy post cardiac arrest and developments in continuous renal replacement therapy. An important first step has been done in training the staff to
the use of echography in ICU.
The general ICU physicians also provide a medical emergency team (MET) 24 hours a day, which is involved
in hospital emergencies and consulting. This kind of organization allows MET to perform safely a non invasive
ventilation treatment for mild or chronic respiratory failure in non intensive areas. The same ICU staff provides
all the non-cardiosurgery emergency surgical procedures.
Alberto Zangrillo
ANAESTHESIA AND NEUROINTENSIVE CARE UNIT
Neurointensive Care is a 6 beds unit.
300 patients are admitted every year, 50% from the Casualty Department (severe head injury, stroke and subarachnoid haemorrhage) and 50% from the Neurosurgery Unit (tumor, vascular).
20 patients with brain death are treated and 12 of them become organ donors.
The Head and Neck Anaesthesia Staff provides general anaesthesia in neurosurgical, interventional neuroradiology, ENT and ophthalmic surgery for approximately 3000 cases per year and for conscious sedations in
children and adults (1000 cases per year) submitted to diagnostic or therapeutic procedures in Neuroradiology.
The General Anaesthesia Staff provides anaesthesia in the Surgical Department (Gastroenterology, Haepatology, Endocrine, Pancreatic), Orthopaedics, Obstetrics and Gynaecology, Plastic Surgery (approximately 20.000
cases/per year).
Outside the O.R. sedation and anaesthesia are performed for diagnostic and therapeutic interventions in Gastroenterology.
A staff is dedicated to the treatment of the postoperative acute pain and chronical neoplastic pain (“Hospital
without Pain” Committee).
Luigi Beretta
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SAN RAFFAELE IN THE WORLD - 221
AISPO - SAN RAFFAELE IN THE WORLD
HEALTH CARE SUPERVISOR: Gianna Zoppei
GENERAL DIRECTOR: Renato Corrado
PUBLIC RELATIONS: Laura Sincinelli
DESK OFFICERS: Elena Balducci, Giuliano Brumat, Federico Chiodi-Daelli
JUNIOR DESK OFFICERS: Sara Lenzi, Federico Porro
HEALTH ECONOMY ADVISOR: Marco Borgognoni
Gianna Zoppei
CLINICAL AND RESEARCH STAFF:
Ricardo Riberio, Hospital São Rafael, Salvador, Brazil
Milena Soares, Hospital São Rafael, Salvador, Brazil
Paul G. D’Arbela, St. Raphael of St. Francis Hospital Nsambya, Kampala, Uganda
Klaus Reither, Swiss tropical and Public health institute, Bagamyo research and training center, Tanzania
Martin Ogwang, Vice Operational Director, Lacor Hospital, Gulu, Uganda
Daniela Maria Cirillo, Head, Emerging bacterial pathogens Unit
Diego Zallocco, Project manager, Emerging bacterial pathogens Unit
Emanuele Borroni, Biologist, Emerging bacterial pathogens Unit
Gabriella Scarlatti, Head, Viral evolution and transmission Unit
Mariangela Cavarelli, Researcher, Viral evolution and transmission Unit
Stefania Dispinseri, Researcher, Viral evolution and transmission Unit
Adriano Lazzarin, Head, Department of infectious diseases
Massimo Cernuschi, Medical Doctor, Department of infectious diseases
Massimo Clementi, Director, Microbiology Service Laboraf
Flavia Lillo, Researcher, Microbiology Service Laboraf
Fabio Ciceri, Head, Hematology and bone marrow transplant Unit
Consuelo Corti, Consultant, Hematology and bone marrow transplant Unit
Valeria Calbi, Hematologist Cooperant, Hematology and bone marrow transplant Unit
Giacomo Dell’Antonio, Medical Doctor, Pathology Unit
Ottavio Alfieri, Head, Cardiovascular and thoracic surgery department
Antonio Grimaldi, senior cardiologist, Cardiovascular and thoracic surgery department
Francesco Arioli, cardiologist, Cardiovascular and thoracic surgery department
Enrico Ammirati, cardiologist, Cardiovascular and thoracic surgery department
Filippo Figini, fellow cardiologist, Cardiovascular and thoracic surgery department
AISPO - SAN RAFFAELE IN THE WORLD
AISPO is the non-governmental organization born in 1984 under the aegis of the San Raffaele Foundation to respond to its mandate “andate, insegnate, guarite” (go, teach and heal).
ANDATE. One of the first actions was the support and implementation of a reference hospital center in Salvador de Bahia, Brazil. Since, it has operated in cooperation projects mainly in the heath area devoted to the support of public and private institutions. AISPO is now present in 15 countries in South America, Africa, Asia,
Mediterranean area and East Europe. For example in Sri Lanka after the Tsunami AISPO has trained local personnel and is now involved in the reconstruction of a 100-bed large hospital. In Uganda it has almost finalized a new
laboratory with special emphasis on histopathology as to support the project for the diagnosis of human papilloma
virus infection cause of cervical cancer in women, started together with the Department of Pathology of the San
Raffaele. In Vietnam the University of Huè, University Vita-Salute San Raffaele and University of Cagliari have
initiated a center for the control of respiratory diseases.
INSEGNATE. Teaching is key to hand over knowledge. Courses, exchange programs, and ad personam training
were organized to increase clinical, technical or administrative expertise in Africa, Asia and South America also in
collaboration with the academics and other organizations (Ministry of Foreign Affairs, EC, WHO, UNAIDS,
Gates Foundation). In addition clinical, technical, and administrative personnel of the San Raffaele Foundation
travel to these sites in the world for short or long-term interventions.
GUARITE. Research is the basis for understanding the pathogenesis, diagnosis and cure of a disease. Here we
mention only a few examples of the ongoing projects which are representative of the bridging activity between cooperation and research.
Laboratory training in Democratic Republic of Congo.
ONCO – HEMATOLOGY: REDUCTION OF CHILD MORTALITY BY CANCER IN AFRICA
The San Raffaele Hematology and Bone Marrow Transplant Unit is involved in projects of integrated clinical,
epidemiological and basic cancer research in Uganda. Cancer is an increasingly important cause of premature mortality in the developing countries. Approximately 60% of global cancer occurs in developing countries with nearly
10 million new cases per year at present. Unless the increasing incidence rate of cancer can be slowed, it is likely to
double by 2020, mostly in developing countries. Endemic Burkitt lymphoma is confined to areas of the world
where malaria and other infectious diseases are endemic, with the additional involvement of the Epstein-Barr virus
(EBV) as a pathogenic co-factor. In order to cure these increasing diseases more hospitals and specialised centres are
needed. We developed a collaboration with St. Mary’s Hospital - Lacor Gulu (Uganda) with main goals: the reduction of child mortality by cancer, the improvement of diagnostic capacity and the control of non communicable diseases like lymphomas. Essential Partners of the project are AISPO, the NGO “Patologioltrefrontiera” (implementation of a pathology service), and the INCTR (International Network Clinical Trial Research, www.inctr.org). A
multicenter protocol for epidemiology, diagnosis and treatment of Burkitt lymphoma and other aggressive lym-
phoma is running in paediatric and adult patients. INCTR coordinates centres in Tanzania, Kenya, Nigeria and
Uganda joining this protocol, and providing a cancer registry, biological samples for molecular studies and infectious-related investigations, a centralized validation of diagnosis and a database for clinical outcome of treated patients. The San Raffaele hematologist is giving educational training to local staff for improving diagnosis from
blood and bone-marrow smear and for cytofluorimetric analysis of blood cancers.
St. Mary’s Hospital, Lacor Gulu, Uganda.
CARDIOLOGY: ECHOCARDIOGRAPHIC SURVEY FOR PREVENTION AND CURE OF
RHEUMATIC HEART DISEASE
A group of cardiologists from San Raffaele Hospital has established a cooperational programme together with
AISPO and the St. Raphael of St. Francis Hospital Nsambya in Kampala, Uganda.
The main ongoing project is addressed to rheumatic heart disease (RHD), which still accounts for high morbidity
and mortality in developing countries. The cardiologists are carrying out a survey of the prevalence of RHD at the
Hospital in pupils attending a nearby school. Beyond interview and physical examination, enrolled subjects undergo echocardiographic study, useful to detect RHD’s valve lesions. So far, approximately 200 asymptomatic children
have been screened and a high prevalence of subclinical rheumatic lesions has been observed. Careful echocardiographic evaluation, focused on early morphological markers by echo-Doppler standard approach, significantly enhanced the detection of subclinical disease, with high impact on the clinical decision making. Affected children enter a secondary prophylaxis (by penicillin) and follow-up programme. Moreover, every patient examined by the cardiologists is recorded in a detailed Register, thus allowing to collect the epidemiological data on the prevalence of
heart pathology in the local population. Up to now, more than 150 individuals have been evaluated. Major causes
of cardiac morbidity and mortality, such as RHD and hypertensive heart failure, appear preventable both by primary and secondary interventions; a large proportion of patients requires surgical treatment. Since this is not yet
regularly available in Uganda, an international network (currently involving San Raffaele and Ancona Hospital in
Italy, Wolfson Hospital in Israel, The Salam Centre for Cardiac Surgery in Sudan) is under development in order to
allow patients with advanced valve disease – either diagnosed within the screening protocol or during daily clinical
activity - to be operated on. So far, the first two young patients of the project have received heart surgery.
UGANDA AND TANZANIA – EVALUATION OF NEW AND EMERGING DIAGNOSTICS
FOR CHILDHOOD TUBERCULOSIS
AISPO-Uganda (Nsambya Hospital, Kampala) and the San Raffaele Scientific Institute (Emerging Bacterial
Pathogens Unit – IUATLD/WHO Supranational TB Reference Laboratory, Milan) are partners in a multicentre
clinical trial that will be carried out in Uganda and Tanzania from August 2010 to July 2013, funded by the “European and Developing Countries Clinical Trials Partnership” (EDCTP).
The overall objectives of the project “Evaluation of new and emerging diagnostics for childhood tuberculosis in
high burden countries (TB CHILD)” focus on developing sustainable, cross-linked research capacities for the diagnosis of childhood tuberculosis (TB) and on the effective, efficient conduct of clinical evaluation trials on new or
improved diagnostics for paediatric TB. Diagnosis and control of paediatric TB is often a low priority in tuberculosis-endemic regions, as children often develop sputum smear-negative disease and seldom contribute to transmission of TB. However, infants and children carry a large (15-25%) and increasing proportion of the overall burden
of disease. Furthermore, young and HIV-infected children have an increased risk of severe, rapidly progressive
forms of TB, such as disseminated disease and meningitis.
The study, coordinated by the Ifakara Health Institute - Bagamoyo Research and Training Centre, Dar es Salaam,
Tanzania represents a unique opportunity to build new research capacity in the field of diagnosis and management
of paediatric TB in sub-Saharan Africa by exchanging knowledge and expertise between the European and African
partners, improving laboratory and clinical infrastructure, providing short-term training and MSc/PhD scholarships for young scientists.
Nsambya Hospital, Kampala, Uganda
DEMOCRATIC REPUBLIC OF CONGO – SUPPORT TO FIGHT THE LARGE
ENDEMIC DISEASES HIV/AIDS, TB AND MALARIA
Since 2007 AISPO and the San Raffaele Scientific Institute (Viral Evolution and Transmission Unit and
Department of Infectious Diseases) are collaborating with CESVI (NGO with headquarters in Bergamo) and the
Ministry of Health of the Democratic Republic of Congo within a project funded by the Italian Ministry of Foreign
Affairs to implement diagnosis, screening and cure of the major endemic diseases, HIV/AIDS, TB and malaria. The
group operates in the urban area of the capital Kinshasa and in two smaller cities of the region Bas-Congo. Courses
were organized for technician, health care workers, nurses and medical doctors to provide the background and
knowledge on the three large endemics, to support the work of the four newly established health units and the
adjunct laboratories. At the beginning of 2010 more than 10,000 persons were tested for HIV and finally precise
figures of prevalence could be estimated. According to the area the prevalence ranges from 10 to 15% in the adult
population, whereas it shows lower figures (3-5%) in the young aged 15 to 24 years. Approximately 1,000 HIV
infected person are today regularly followed, data collected on informatic support, and given antiretroviral therapy
according to their CD4+ T lymphocyte counts. We have started anonymous blood sampling on filter paper to
respond to two important question for drug treatment and vaccine development: 1) do circulating viruses display
drug resistant mutations, which would urge for changes in the drug regimen used? and 2) which of the more than
30 known subtypes of HIV-1 evolved during these years in the Democratic Republic of Congo?
UGANDA – PREVENTION AND STUDY OF INVASIVE CERVICAL CANCER AND
MANAGEMENT OF GYNECOLOGIC DISORDERS AMONG HIV-POSITIVE WOMEN
Reproductive health care has not been prioritized in care and support. In the setting of HIV infection 30.6% of
Pap smears exhibit cytologic abnormalities and 15.4% have evidence of dysplasia; these rates are 10 times greater
than those observed among HIV-negative women. In Uganda, almost 2/3 of cancers among HIV positives are in
women of child bearing age with an overall incidence rate of Invasive Cervical Cancer increasing from 44 cases per
100,000 in the general population to 70 in HIV positives, with a peak of 200 per 100,000 in the age range of 35-44
years.
The project organized at Nsambya national referral hospital with the Unit of Pathology of the San Raffaele has a
broad and comprehensive approach. The final goal is to integrate an epidemiologic survey as to determine incidence
and prevalence of Human Papilloma Virus (HPV) infection and invasive cancer of the cervix in the general population and among HIV-positive women. Thus, it includes: Community mobilization and increased awareness of cervical cancer in the community. Training of health workers in cervical cancer screening through PAP smears, Visualization in acetic Acid (VIA). Establishment of a referral system between lower health facilities and secondary and
tertiary care for samples and patient referrals.
A laboratory will be established as support for HPV diagnosis, and the activities include:
• Infrastructure renovation and equipment of the Pathology laboratory at Nsambya national referral hospital
• Development and set up of a molecular biology section for the identification and typing of HPV infection
• Set up of a telemedicine program in connection with the Reference Laboratory in Milan for the transfer of images of the cytological and histological slides both for training, quality control and diagnostic second opinion, in
collaboration with Patologi Oltre Frontiera (POF)
• Set up of External Quality Assurance (EQA) programs for cytology, histology and molecular biology
• Carry out outreaches for sample collection and feedback
• Setting up of a data bank
• Analysis of the epidemiological data collected, both on the HPV type circulation in the specific geographical
area and on its distribution by age group and by severity of disease.
Immunohistostaining with CK AE1-3.
BRAZIL – HOSPITAL SÃO RAFAEL, SALVADOR: A SUCCESS STORY FROM
DEVELOPMENT COOPERATION TO RESEARCH
The Hospital São Rafael in Brazil was founded in 1990 and is headquartered in Salvador de Bahia. With 302
beds the hospital is equipped with all the main specialties. In 2009 the Center of Biotechnology and Cell Therapy
(CBTC) was initiated: it is one of the 8 centers selected in Brazil by the Health Ministry for development of cell
therapies of high complexity, and the only one in the northern region of Brazil. It is integrated to the Brazilian
Stem Cell Network. Phase I/II study of bone marrow mesenchymal stem cells for patients with spinal cord injury
as well as Phase III study of bone marrow cell therapy in patients with chronic Chagas disease have been started.
Studies of drug development against the major infectious disease, for example Leishmaniasis, Chagas, and malaria,
are frontline.
Hospital São Rafael, Salvador, Brazil
“Not to strive for changes in the world is humiliating. Our commitment, as God’s children, is to contribute to its improvement. We must offer the best of what we are and the best of what we have.”
D. Luigi Verzè
PUBLICATIONS - 227
PUBLICATIONS
PUBLICATIONS - 229
BEST PAPERS 2009
1. Aiuti, A; Cattaneo, F; Galimberti, S; Benninghoff, U; Cassani, B; Callegaro, L; Scaramuzza, S; Andolfi, G; Mirolo, M; Brigida, I;
Tabucchi, A; Carlucci, F; Eibl, M; Aker, M; Slavin, S; Al-Mousa, H; Ghonaium, AA; Ferster, A; Duppenthaler, A; Notarangelo, L;
Wintergerst, U; Buckley, RH; Bregni, M; Marktel, S; Valsecchi, MG; Rossi, P; Ciceri, F; Miniero, R; Bordignon, C; Roncarolo, MG.
Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med.: 2009; 360(5): 447-458 - Article
IF 2008: 50,017
2. INSIGHT- ESPIRIT Study Group and SILCAAT Scientific Committee; Abrams, D; Lévy, Y; Losso, MH; Babiker, A; Collins, G;
Cooper, DA; Darbyshire, J; Emery, S; Fox, L; Gordin, F; Lane, HC; Lundgren, JD; Mitsuyasu, R; Neaton, JD; Phillips, A; Routy, JP;
Tambussi, G; Wentworth, D. Interleukin-2 therapy in patients with HIV infection. New Engl. J. Med.: 2009; 361(16): 1548-1559 Article
IF 2008: 50,017
3. Vago, L; Perna, SK; Zanussi, M; Mazzi, B; Barlassina, C; Lupo Stanghellini, MT; Perrelli, NF; Cosentino, C; Torri, F; Angius, A;
Forno, B; Casucci, M; Bernardi, M; Peccatori, J; Corti, C; Bondanza, A; Ferrari, M; Rossini, S; Roncarolo, MG; Bordignon, C;
Bonini, C; Ciceri, F; Fleischhauer, K. Loss of mismatched HLA in leukemia after stem-cell transplantation. N. Engl. J. Med.: 2009;
361(5): 478-488 - Article
IF 2008: 50,017
4. Colombo, A; Sharp, AS. The bioabsorbable stent as a virtual prosthesis. Lancet: 2009; 373(9667): 869-870 - Article
IF 2008: 28,409
5. Comi, G; Martinelli, V; Rodegher, M; Moiola, L; Bajenaru, O; Carra, A; Elovaara, I; Fazekas, F; Hartung, HP; Hillert, J; King, J;
Komoly, S; Lubetzki, C; Montalban, X; Myhr, KM; Ravnborg, M; Rieckmann, P; Wynn, D; Young, C; Filippi, M. Effect of glatiramer
acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised,
double-blind, placebo-controlled trial. Lancet: 2009; 374(9700): 1503-1511 - Article
IF 2008: 28,409
6. Ferreri, AJ; Reni, M; Foppoli, M; Martelli, M; Pangalis, GA; Frezzato, M; Cabras, MG; Fabbri, A; Corazzelli, G; Ilariucci, F; Rossi,
G; Soffietti, R; Stelitano, C; Vallisa, D; Zaja, F; Zoppegno, L; Aondio, GM; Avvisati, G; Balzarotti, M; Brandes, AA; Fajardo, J;
Gomez, H; Guarini, A; Pinotti, G; Rigacci, L; Uhlmann, C; Picozzi, P; Vezzulli, P; Ponzoni, M; Zucca, E; Caligaris-Cappio, F; Cavalli, F. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma:
a randomised phase 2 trial. Lancet: 2009; 374(9700): 1512-1520 - Article
IF 2008: 28,409
7. Villablanca, EJ; Raccosta, L; Zhou, D; Fontana, R; Maggioni, D; Negro, A; Sanvito, F; Ponzoni, M; Valentinis, B; Bregni, M;
Prinetti, A; Steffensen, KR; Sonnino, S; Gustafsson, JA; Doglioni, C; Bordignon, C; Traversari, C; Russo, V. Tumor-mediated liver X
receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat. Med.:
2009; 16(1): 98-105 - Article
IF 2008: 27,553
8. Montini, E; Cesana, D; Schmidt, M; Sanvito, F; Bartholomae, CC; Ranzani, M; Benedicenti, F; Sergi Sergi, L; Ambrosi, A; Ponzoni, M; Doglioni, C; Di Serio, C; von Kalle, C; Naldini, L. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy.. J. Clin. Invest.: 2009; 119(4): 964-975 - Article
IF 2008: 16,559
9. Locci, M; Draghici, E; Marangoni, F; Bosticardo, M; Catucci, M; Aiuti, A; Cancrini, C; Marodi, L; Espanol, T; Bredius, RGM;
Thrasher, AJ; Schulz, A; Litzman, J; Roncarolo, MG; Casorati, G; Dellabona, P; Villa, A. The Wiskott-Aldrich syndrome protein is
required for iNKT cell maturation and function. J. Exp. Med.: 2009; 206(4): 735-742 - Article
IF 2008: 15,463
10. Battaglia, M; Pesenti-Gritti, P; Medland, SE; Ogliari, A; Tambs, K; Spatola, CAM. A genetically informed study of the association
between childhood separation anxiety, sensitivity to CO2, panic disorder, and the effect of childhood parental loss. Arch. Gen. Psychiatry: 2009; 66(1): 64-71 - Article
IF 2008: 14,273
11. Gentner, B; Schira, G; Giustacchini, A; Amendola, M; Brown, BD; Ponzoni, M; Naldini, L. Stable knockdown of microRNA in vivo by lentiviral vectors. Nat. Methods: 2009; 6(1): 63-66 - Article
IF 2008: 13,651
12. Ciceri, F; Bonini, C; Lupo Stanghellini, MT; Bondanza, A; Traversari, C; Salomoni, M; Turchetto, L; Colombi, S; Bernardi, M;
Peccatori, J; Pescarollo, A; Servida, P; Magnani, Z; Perna, SK; Valtolina, V; Crippa, F; Callegaro, L; Spoldi, E; Crocchiolo, R; Fleischhauer, K; Ponzoni, M; Vago, L; Santoro, A; Todisco, E; Apperley, J; Olavarria, E; Slavin, S; Weissinger, EM; Hertenstein, B;
Stadler, M; Yannaki, E; Fassas, A; Anagnostopoulos, A; Bregni, M; Gallo Stampino, C; Bruzzi, P; Bordignon, C. Early and effective
immunorecovery after family haploidentical hemopoietic transplantation for leukemia by gene-engineered lymphocytes: the TK007
study. Lancet Oncol.: 2009; 10(5): 489-500 - Article
IF 2008: 13,283
13. Cantarelli, E; Melzi, R; Mercalli, A; Sordi, V; Ferrari, G; Lederer, CW; Mrak, E; Rubinacci, A; Ponzoni, M; Sitia, G; Guidotti,
LG; Bonifacio, E; Piemonti, L. Bone marrow as an alternative site for islet transplantation. Blood: 2009; 114(20): 4566-4574 - Article
IF 2008: 10,432
14. Valle, A; Jofra, T; Stabilini, A; Atkinson, M; Roncarolo, MG; Battaglia, M. Rapamycin prevents and breaks the anti-CD3-induced
tolerance in NOD mice. Diabetes: 2009; 58(4): 875-881 - Article
IF 2008: 8,398
15. Piemonti, L; Calori, G; Lattuada, G: Mercalli, A; Ragogna, F; Garancini, MP; Ruotolo, G; Luzi, L; Perseghin, G. Association between plasma monocyte chemoattractant protein-1 concentration and cardiovascular disease mortality in middle-aged diabetic and nondiabetic individuals. Diabetes Care: 2009; 32(11): 2105-2110 - Article
IF 2008: 7,349
P.1. Abbadessa, G; Accolla, R; Aiuti, F; Albini, A; Aldovini, A; Alfano, M; Antonelli, G; Bartholomew, C; Bentwich, Z; Bertazzoni, U; Berzofsky, JA; Biberfeld, P; Boeri, E; Buonaguro, L;
Buonaguro, FM; Bukrinsky, M; Burny, A; Caruso, A; Cassol, S;
Chandra, P; Ceccherini-Nelli, L; Chieco-Bianchi, L; Clerici, M;
Colombini-Hatch, S; Morghen, CDG; De Maria, A; De Rossi,
A; Dierich, M; Della-Favera, R; Dolei, A; Douek, D; Erfle, V;
Felber, B; Fiorentini, S; Franchini, G; Gershoni, JM; Gotch, F;
Green, P; Greene, WC; Hall, W; Haseltine, W; Jacobson, S;
Kallings, LO; Kalyanaraman, VS; Katinger, H; Khalili, K; Klein,
G; Klein, E; Klotman, M; Klotman, P; Kotler, M; Kurth, R;
Lafeuillade, A; La Placa, M; Lewis, J; Lillo, F; Lisziewicz, J;
Lomonico, A; Lopalco, L; Lori, F; Lusso, P; Macchi, B; Malim,
M; Margolis, L; Markham, PD; Mcclure, M; Miller, N; Mingari,
MC; Moretta, L; Noonan, D; O’Brien, S; Okamoto, T; Pal, R;
Palese, P; Panet, A; Pantaleo, G; Pavlakis, G; Pistello, M;
Plotkin, S; Poli, G; Pomerantz, R; Radaelli, A; Robert-Guroff,
M; Roederer, M; Sarngadharan, MG; Schols, D; Secchiero, P;
Shearer, G; Siccardi, A; Stevenson, M; Svoboda, J; Tartaglia, J;
Torelli, G; Tornesello, ML; Tschachler, E; Vaccarezza, M; Vallbracht, A; Van Lunzen, J; Varnier, O; Vicenzi, E; Von Melchner,
H; Witz, I; Zagury, D; Zagury, JF; Zauli, G; Zipeto, D. Unsung
hero Robert C Gallo. Science: 2009; 323(5911): 206-207 - Letter
P.2. Abrams, D; Lévy, Y; Losso, MH; Babiker, A; Collins, G;
Cooper, DA; Darbyshire, J; Emery, S; Fox, L; Gordin, F; Lane,
HC; Lundgren, JD; Mitsuyasu, R; Neaton, JD; Phillips, A;
Routy, JP; Tambussi, G; Wentworth, D; INSIGHT- ESPIRIT
Study Group and SILCAAT Scientific Committee. Interleukin2 therapy in patients with HIV infection. New Engl. J. Med.:
2009; 361(16): 1548-1559 - Article
IF 2008: 50,017
P.3. Abutalebi, J; Della Rosa, PA; Tettamanti, M; Green, DW;
Cappa, SF. Bilingual aphasia and language control: a follow-up
fMRI and intrinsic connectivity study. Brain Lang. : 2009; 109(23): 141-156 - Article
IF 2008: 2,929
P.4. Abutalebi, J; Tettamanti, M; Perani, D. The bilingual brain:
Linguistic and non-linguistic skills. Brain Lang.: 2009; 109(2-3):
51-54 - Editorial
IF 2008: 2,929
P.5. Achenbach, P; Lampasona, V; Landherr, U; Koczwara, K;
Krause, S; Grallert, H; Winkler, C; Pfluger, M; Illig, T; Bonifacio, E; Ziegler, AG. Autoantibodies to zinc transporter 8 and
SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia:
2009; 52(9): 1881-1888 - Article
IF 2008: 6,418
P.6. Acquaviva, PA; Cerutti, F; Adami, G; Gagliani, M; Ferrari,
M; Gherlone, E; Cerutti, A. Degree of conversion of three composite materials employed in the adhesive cementation of indirect
restorations: A micro-Raman analysis. J. Dent.: 2009; 37(8): 610615 - Article
IF 2008: 2,033
P.7. Agosta, F; Gorno-Tempini, ML; Pagani, E; Sala, S; Caputo,
D; Perini, M; Bartolomei, I; Fruguglietti, ME; Filippi, M. Longitudinal assessment of grey matter contraction in amyotrophic
lateral sclerosis: A tensor based morphometry study. Amyotroph.
Lateral. Scler.: 2009; 10(3): 168-174 - Article
IF 2008: 1,815
P.8. Agosta, F; Rocca, MA; Valsasina, P; Sala, S; Caputo, D; Perini, M; Salvi, F; Prelle, A; Filippi, M. A longitudinal diffusion
tensor MRI study of the cervical cord and brain in amyotrophic
lateral sclerosis patients. J. Neurol. Neurosurg. Psychiatry: 2009;
80(1): 53-55 - Article
IF 2008: 4,622
P.9. Agosta, F; Valsasina, P; Absinta, M; Sala, S; Caputo, D; Filippi, M. Primary progressive multiple sclerosis: tactile-associated
functional MR activity in the cervical spinal cord. Radiology:
2009; 253(1): 209-215 - Article
IF 2008: 9,380
P.10. Agosta, F; Valsasina, P; Caputo, D; Rocca, MA; Filippi, M.
Tactile-associated fMRI recruitment of the cervical cord in healthy
subjects. Hum. Brain Mapp.: 2009; 30(1): 340-345 - Article
IF 2008: 5,996
P.11. Agosta, F; Vossel, KA; Miller, BL; Migliaccio, R; Bonasera,
SJ; Filippi, M; Boxer, AL; Karydas, A; Possin, KL; GornoTempini, ML. Apolipoprotein E ?4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc. Natl. Acad. Sci. U. S. A.: 2009;
106(6): 2018-2022 - Article
IF 2008: 5,395
P.12. Agricola, E; Ielasi, A; Oppizzi, M; Faggiano, P; Ferri, L;
Calabrese, A; Vizzardi, E; Alfieri, O; Margonato, A. Long-term
prognosis of medically treated patients with functional mitral regurgitation and left ventricular dysfunction. Eur. J. Heart Fail.:
2009; 11(6): 581-587 - Article
IF 2008: 3,398
P.13. Aiuti, A; Brigida, I; Ferrua, F; Cappelli, B; Chiesa, R; Marktel, S; Roncarolo, MG. Hematopoietic stem cell gene therapy for
adenosine deaminase deficient-SCID. Immunol. Res.: 2009;
44(1-3): 150-159 - Review
IF 2008: 2,649
P.14. Aiuti, A; Cattaneo, F; Galimberti, S; Benninghoff, U; Cassani, B; Callegaro, L; Scaramuzza, S; Andolfi, G; Mirolo, M;
Brigida, I; Tabucchi, A; Carlucci, F; Eibl, M; Aker, M; Slavin, S;
Al-Mousa, H; Ghonaium, AA; Ferster, A; Duppenthaler, A;
Notarangelo, L; Wintergerst, U; Buckley, RH; Bregni, M;
Marktel, S; Valsecchi, MG; Rossi, P; Ciceri, F; Miniero, R; Bordignon, C; Roncarolo, MG. Gene therapy for immunodeficiency
due to adenosine deaminase deficiency. N. Engl. J. Med.: 2009;
360(5): 447-458 - Article
IF 2008: 50,017
P.15. Akcali, A; Ferini-Strambi, L; Kaynak, H; Karadeniz, D; Akcali, C. Genital restlessness (vulvodynia) events accompanying
restless legs syndrome. Sleep Med.: 2009; 10(3): 395-396 - Letter
IF 2008: 3,163
P.16. Akselrod-Ballin, A; Galun, M; Gomori, JM; Filippi, M; Valsasina, P; Basri, R; Brandt, A. Automatic segmentation and classification of multiple sclerosis in multichannel MRI. IEEE Trans.
Biomed. Eng.: 2009; 56(10): 2461-2469 - Article
IF 2008: 2,496
P.17. Aldrighetti, L; Pulitano, C; Catena, M; Arru, M; Guzzetti,
E; Halliday, J; Ferla, G. Liver Resection with Portal Vein
Thrombectomy for Hepatocellular Carcinoma With Vascular Invasion. Ann. Surg. Oncol.: 2009; 16(5): 1254 - Article
IF 2008: 3,898
P.18. Alfano, M; Mariani, SA; Elia, C; Pardi, R; Blasi, F; Poli, G.
Ligand-engaged urokinase-type plasminogen activator receptor
and activation of the CD11b/CD18 integrin inhibit late events of
HIV expression in monocytic cells. Blood: 2009; 113(8): 16991709 - Article
IF 2008: 10,432
P.19. Alongi, F; Fiorino, C; Cozzarini, C; Broggi, S; Perna, L;
Cattaneo, GM; Calandrino, R; Di Muzio, N. IMRT significantly reduces acute toxicity of whole-pelvis irradiation in patients
treated with post-operative adjuvant or salvage radiotherapy after
radical prostatectomy. Radiother. Oncol.: 2009; 93(2): 207-212 Article
IF 2008: 3,990
P.20. Alpi, E; Landi, E; Barilari, M; Serresi, M; Salvadori, P;
Bachi, A; Dente, L. Channel-interacting PDZ protein, ‘CIPP’, interacts with proteins involved in cytoskeletal dynamics. Biochem.
J.: 2009; 419(2): 289-300 - Article
IF 2008: 4,371
P.21. Altmann, DR; Jasperse, B; Barkhof, F; Beckmann, K; Filippi, M; Kappos, LD; Molyneux, P; Polman, CH; Pozzilli, C;
Thompson, AJ; Wagner, K; Yousry, TA; Miller, DH. Sample
PUBLICATIONS - 231
sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis. Neurology: 2009; 73(7): 595-601 - Article
IF 2008: 7,043
P.22. Altomare, DF; Binda, G; Ganio, E; De Nardi, P; Giamundo,
P; Pescatori, M. Long-term outcome of Altemeiers procedure for
rectal prolapse. Dis. Colon Rectum: 2009; 52(4): 698-703 - Article
IF 2008: 2,615
P.23. Amendola, M; Passerini, L; Pucci, F; Gentner, B; Bacchetta, R; Naldini, L. Regulated and Multiple miRNA and siRNA
Delivery Into Primary Cells by a Lentiviral Platform. Mol. Ther.:
2009; 17(6): 1039-1052 - Article
IF 2008: 5,970
P.24. Andralojc, KM; Mercalli, A; Nowak, KW; Albarello, L;
Calcagno, R; Luzi, L; Bonifacio, E; Doglioni, C; Piemonti, L.
Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia: 2009; 52(3): 486-493 - Article
IF 2008: 6,418
P.25. Angiero, F; Farronato, G; Benedicenti, S; Vinci, R; Farronato, D; Magistro, S; Stefani, M. Mandibular condylar hyperplasia:
Clinical, histopathological, and treatment considerations. CranioJ. Craniomandib. Pract.: 2009; 27(1): 24-32 - Article
IF 2008: 0,556
P.26. Annoni, A; Brown, BD; Cantore, A; Sergi Sergi, L; Naldini,
L; Roncarolo, MG. In vivo delivery of a microRNA-regulated
transgene induces antigen-specific regulatory T cells and promotes
immunologic tolerance. Blood: 2009; 114(25): 5152-5161 - Article
IF 2008: 10,432
P.27. Anselmetti, S; Bechi, M; Bosia, M; Quarticelli, C; Ermoli,
E; Smeraldi, E; Cavallaro, R. ‘Theory’ of mind impairment in
patients affected by schizophrenia and in their parents.. Schizophr. Res.: 2009; 115(2-3): 278-285 - Article
IF 2008: 4,174
P.28. Antinori, A; Ammassari, A; Torti, C; Marconi, P; Andreoni,
M; Angarano, G; Bonora, S; Castagna, A; Cauda, R; Clerici, M;
d’Arminio Monforte, A; De Luca, A; Di Perri, G; Galli, M; Girardi, E; Gori, A; Lazzarin, A; Lo Caputo, S; Mazzotta, F; Montella, F; Mussini, C; Perno, CF; Puoti, M; Rizzardini, G; Rusconi, S; Vullo, V; Carosi, G. Italian Consensus Statement on
Management of HIV-Infected Individuals with Advanced Disease
Naïve to Antiretroviral Therapy. Infection: 2009; 37(3): 270-282
- Article
IF 2008: 1,831
P.29. Antiretroviral Therapy Cohort Collaboration, (ART-CC);
Mocroft, A; Sterne, JA; Egger, M; May, M; Grabar, S; Furrer, H;
Sabin, C; Fatkenheuer, G; Justice, A; Reiss, P; d’Arminio Monforte, A; Gill, J; Hogg, R; Bonnet, F; Kitahata, M; Staszewski, S;
Casabona, J; Harris, R; Saag, M. Variable impact on mortality of
AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal.
Clin. Infect. Dis.: 2009; 48(8): 1138-1151 - Article
IF 2008: 8,266
P.30. Antonelli, M; Acerno, S; Baldoli, C; Terreni, MR; Giangaspero, F. A case of melanotic desmoplastic ganglioglioma: Case
Report. Neuropathology: 2009; 29(5): 597-601 - Article
IF 2008: 1,727
P.31. Antonioli, P; Bachi, A; Fasoli, E; Righetti, PG. Efficient removal of DNA from proteomic samples prior to two-dimensional
map analysis. J. Chromatogr. A: 2009; 1216(17): 3606-3612 Article
IF 2008: 3,756
P.32. Anzalone, N; Gerevini, S; Scotti, R; Vezzulli, P; Picozzi, P.
Detection of cerebral metastases on magnetic resonance imaging:
Intraindividual comparison of gadobutrol with gadopentetate
dimeglumine. Acta Radiol.: 2009; 50(8): 933-940 - Article
IF 2008: 1,091
P.33. Arcidiacono, PG; Calori, G; Carrara, S; McNicol, ED;
Testoni, PA. Celiac plexus block for pancreatic cancer pain in
adults. Cochrane Database Syst Rev.: 2009; -1(CD007519) - Review
IF 2008: 5,182
P.34. Arcidiacono, T; Paloschi, V; Rainone, F; Terranegra, A;
Dogliotti, E; Aloia, A; Soldati, L; Vezzoli, G. Renal osteodystrophy and vascular calcification. J. Endocrinol. Invest. : 2009; 32(4
Suppl): 21-26 - Article
IF 2008: 1,888
P.35. Asperti, C; Astro, V; Totaro, A; Paris, S; de Curtis, I. LiprinÎ±1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins. J. Cell Sci.: 2009;
122(18): 3225-3232 - Article
IF 2008: 6,247
P.36. Baccari, P; Civilini, E; Dordoni, L; Melissano, G; Nicoletti,
R; Chiesa, R. Celiac artery compression syndrome managed by laparoscopy. J. Vasc. Surg.: 2009; 50(1): 134-139 - Article
IF 2008: 3,770
P.37. Baccari, P; Nifosi, J; Ghirardelli, L; Staudacher, C. Laparoscopic incisional and ventral hernia repair without sutures: A single-center experience with 200 cases. J. Laparoendosc. Adv.
Surg. Tech. A: 2009; 19(2): 175-179 - Article
IF 2008: 0,912
P.38. Bacci, M; Capobianco, A; Monno, A; Cottone, L; Di Puppo, F; Camisa, B; Mariani, M; Brignole, C; Ponzoni, M; Ferrari,
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P.44. Barkhof, F; Filippi, M. Multiple sclerosis: MRI-the perfect
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P.68. Berney, T; Secchi, A. Rapamycin in islet transplantation:
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P.77. Bianchi, ME. Editorial: A recipe for inflammation. J. Leukoc.
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P.97. Bosi, E. Metformin - The gold standard in type 2 diabetes:
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P.112. Briganti, A. How to Improve the Ability to Detect Pelvic
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P.113. Briganti, A. Oestrogens and Prostate Cancer: Novel Concepts about an Old Issue. Eur. Urol.: 2009; 55(3): 543-545 - Editorial
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P.114. Briganti, A. Rebuttal from Author re: George N Thalmann
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P.116. Briganti, A; Capitanio, U; Chun, FK; Karakiewicz, PI; Salonia, A; Bianchi, M; Cestari, A; Guazzoni, G; Rigatti, P; Montorsi, F. Prediction of sexual function after radical prostatectomy.
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P.118. Briganti, A; Karakiewicz, PI; Chun, FKH; Suardi, N; Gallina, A; Abdollah, F; Freschi, M; Doglioni, C; Rigatti, P; Montorsi, F. Obesity does not increase the risk of lymph node metastases in patients with clinically localized prostate cancer undergoing radical prostatectomy and extended pelvic lymph node dissection. Int. J. Urol.: 2009; 16(8): 676-681 - Article
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P.119. Briganti, A; Karakiewicz, PI; Joniau, S; Van Poppel, H.
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Patients with Node Positive Prostate Cancer A New Proposal
Based on a Two-Institution Experience on 703 Consecutive N+
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P.121. Brignole, C; Marimpietri, D; Pastorino, F; Di Paolo, D;
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Electrophysiology in chronic inflammatory demyelinating
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P.124. Brini, E; Ruffini, F; Bergami, A; Brambilla, E; Dati, G;
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P.127. Brown, BD; Naldini, L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications.
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P.130. Buffi, N; Mottrie, A; Lughezzani, G; Koliakos, N; Schatteman, P; Carpentier, P; Fonteyne, E. Surgery Illustrated - Surgical
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P.133. Burastero, SE; Paolucci, C; Fabbri, M. Ambient pollutants
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P.134. Burger, JA; Ghia, P; Rosenwald, A; Caligaris-Cappio, F.
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P.135. Burioni, R; Canducci, F; Mancini, N; Clementi, N; Sassi,
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P.139. Cabrini, L; Levati, A. Risk management in anesthesia. Minerva Anestesiol: 2009; 75(11): 638-643 - Note
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P.146. Caligaris-Cappio, F. Chronic lymphocytic leukemia: “Cinderella” is becoming a star. Mol. Med.: 2009; 15(3-4): 67-69 - Article
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P.149. Camaschella, C. Hereditary Sideroblastic Anemias: Pathophysiology, Diagnosis, and Treatment. Semin. Hematol.: 2009;
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Population-based Study of Perioperative Mortality After
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Karakiewicz, PI. Nephrectomy improves survival in patients with
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P.170. Cappelleri, G; Ghisi, D; Fanelli, A; Aldegheri, G; La Colla,
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P.174. Carpi, F; Pappone, C. Magnetic maneuvering of endoscopic
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motor neuron disorders: A multiparametric MRI study. Amyotrophic Lateral Scler.: 2009; 10(5-6): 269-279 - Article
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A; Goldstein, LB; Hennerici, M; Sillesen, H; Rudolph, A;
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P.201. Chen, H; Ko, G; Zatti, A; Di Giacomo, G; Liu, L; Raiteri,
E; Perucco, E; Collesi, C; Min, W; Zeiss, C; De Camilli, P; Cremona, O. Embryonic arrest at midgestation and disruption of
Notch signaling produced by the absence of both epsin 1 and
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P.202. Chiappalone, M; Casagrande, S; Tedesco, M; Valtorta, F;
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P.204. Chiesa, R; Marone, EM; Tshomba, Y; Logaldo, D; Castellano, R; Melissano, G. Aortobifemoral bypass grafting using expanded polytetrafluoroethylene stretch grafts in patients with occlusive atherosclerotic disease. Ann. Vasc. Surg.: 2009; 23(6):
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The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the
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Crews, C; Rafferty, I; Washecka, N; Hernandez, D; Ferrucci, L;
Bandinelli, S; Guralnik, J; Macciardi, F; Torri, F; Lupoli, S;
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Tedeschi, G; Marinou, K; Sabatelli, M; Conte, A; Mandrioli, J;
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RW; Talbot, K; Simmons, Z; Connor, J; Pioro, EP; Dunkley, T;
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F; Huland, H; Karakiewicz, PI. Assessment of Pathological
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P.210. Chung, BH; Roehrborn, CG; Siami, P; Major-Walker, K;
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P.212. Cicchini, GM; Morrone, MC. Shifts in spatial attention affect the perceived duration of events. J. Vision: 2009; 9(1): 1-13 Article
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P.214. Cighetti, G; Fermo, I; Aman, CS; Ferraroni, M; Secchi, A;
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P.216. Ciriaco, P; Casiraghi, M; Negri, G; Gioia, G; Carretta, A;
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Thirty-Day Mortality After Nephrectomy: Clinical Implications
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P.218. Cocucci, E; Racchetti, G; Meldolesi, J. Shedding microvesicles: artefacts no more. Trends Cell Biol.: 2009; 19(2): 43-51 Review
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P.219. Colasante, G; Sessa, A; Crispi, S; Calogero, R; Mansouri,
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P.220. Colombo, A; Bramucci, E; Sacca, S; Violini, R; Lettieri, C;
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P.221. Colombo, A; Latib, A. Surgeons and Interventional Cardiologists in a Collaborative Environment. J. Am. Coll. Cardiol.:
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P.222. Colombo, A; Sharp, AS. The bioabsorbable stent as a virtual
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P.223. Colombo, G; Rusconi, F; Rubino, T; Cattaneo, A; Martegani, E; Parolaro, D; Bachi, A; Zippel, R. Transcriptomic and
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P.224. Colucci, A; Modorati, G; Miserocchi, E; Di Matteo, F; Rama, P. Anterior uveitis complicating zoledronic acid infusion.
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P.225. Combi, R; Ferini-Strambi, L; Tenchini, ML. CHRNA2 mutations are rare in the NFLE population: Evaluation of a large cohort of Italian patients. Sleep Med.: 2009; 10(1): 139-142 - Article
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P.226. Comi, G. Treatment of multiple sclerosis: role of natalizumab. Neurol. Sci.: 2009; (Suppl 2): S155-S158 - Short Survey
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P.227. Comi, G. Shifting the paradigm toward earlier treatment of
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P.229. Compagno, M; Lim, WK; Grunn, A; Nandula, SV; Brahmachary, M; Shen, Q; Bertoni, F; Ponzoni, M; Scandurra, M;
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P.230. Conti, M; Peretti, E; Cazzetta, G; Galimberti, G; Vermigli,
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P.231. Copreni, E; Nicolis, E; Tamanini, A; Bezzerri, V; Castellani, S; Palmieri, L; Giri, MG; Vella, A; Colombatti, M; Rizzotti, P; Conese, M; Cabrini, G. Late generation lentiviral vectors:
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P.232. Corbetta, C; Weber, G; Cortinovis, F; Calebiro, D; Passoni, A; Vigone, MC; Beck-Peccoz, P; Chiumello, G; Persani,
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P.233. Corbetta, S; Gualdoni, S; Ciceri, G; Monari, M; Zuccaro,
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P.235. Corsetti, M; De Nardi, P; Di Pietro, S; Passaretti, S;
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Variome Project Data Collection from Clinics, Data Collection
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P.238. Court, FA; Hewitt, JE; Davies, K; Patton, BL; Uncini, A;
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P.239. Covello, RD; Maj, G; Landoni, G; Maisano, F; Michev, I;
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P.242. Cremasco, V; Mantelli, B; Lazzarin, A; Biswas, P. Improvement of CXCR3 ligand CXCL11/I-TAC measurement in human
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P.243. Crepel, M; Isbarn, H; Capitanio, U; Liberman, D; Jeldres,
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P.247. Crespi, R; Cappare, P; Gherlone, E. Magnesium-enriched
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P.248. Crespi, R; Cappare, P; Gherlone, E. Dental implants placed
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P.251. Crimella, C; Arnoldi, A; Crippa, F; Mostacciuolo, ML;
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P.253. Crivellari, M; Della Valle, P; Landoni, G; Pappalardo, F;
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F; Bacigalupo, A; Fleischhauer, K; for the Gruppo Italiano
Trapianto di Midollo Osseo, Cellule Staminale Ematopoietiche
(CSE) e Terapia Cellulare, and the Italian Bone Marrow Donor
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P.257. Croccolo, F; Quintini, A; Barni, R; Ripamonti, M; Malgaroli, A; Riccardi, C. H-mode inductive coupling plasma for PVC
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P.258. Cunha, C; Angelucci, A; D’Antoni, A; Dobrossy, MD;
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IF 2008: 10,432
P.261. Dagklis, A; Fazi, C; Scarfò, L; Apollonio, B; Ghia, P. Monoclonal B lymphocytosis in the general population. Leuk. Lymphoma: 2009; 50(3): 490-492 - Article
IF 2008: 1,939
P.262. D’Alessandro, R; Klajn, A; Meldolesi, J. Expression of
dense-core vesicles and of their exocytosis are governed by the repressive transcription factor NRSF/REST. Ann.NY Acad.Sci.:
2009; 1152(): 194-200 - Conference Paper
IF 2008: 2,303
P.263. D’Alessio, S; Blasi, F. The urokinase receptor as an entertainer of signal transduction. Front. Biosci.: 2009; 14(): 45754587 - Review
IF 2008: 3,308
P.264. Dall’Asta, C; Vedani, P; Manunta, P; Pizzocri, P; Marchi,
M; Paganelli, M; Folli, F; Pontiroli, AE. Effect of weight loss
through laparoscopic gastric banding on blood pressure, plasma
renin activity and aldosterone levels in morbid obesity. Nutr.
Metab. Carbiovasc. Dis.: 2009; 19(2): 110-114 - Article
IF 2008: 3,565
P.265. D’Amato, A; Bachi, A; Fasoli, E; Boschetti, E; Peltre, G;
Senechal, H; Righetti, PG. In-depth exploration of cow’s whey
proteome via combinatorial peptide ligand libraries. J. Proteome
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IF 2008: 5,684
P.266. D’Angelo, A; Fattorini, A; Crippa, L. Thrombotic microangiopathy in pregnancy. Thromb. Res.: 2009; 123 (Suppl 2): S56S62 - Article
IF 2008: 2,449
P.267. D’Antonio, M; Feltri, ML; Wrabetz, L. Myelin under stress.
J. Neurosci. Res. : 2009; 87(15): 3241-3249 - Article
IF 2008: 3,086
P.268. Dati, E; Baroncelli, GI; Mora, S; Russo, G; Baldinotti, F;
Parrini, D; Erba, P; Simi, P; Bertelloni, S. Body composition and
metabolic profile in women with complete androgen insensitivity
syndrome. Sex. Dev.: 2009; 3(4): 188-193 - Article
IF 2008: 1,000
P.269. De Cobelli, F; Esposito, A; Belloni, E; Pieroni, M;
Perseghin, G; Chimenti, C; Frustaci, A; Del Maschio, A. Delayed-enhanced cardiac MRI for differentiation of fabry’s disease
from symmetric hypertrophic cardiomyopathy. Am. J.
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IF 2008: 2,940
P.270. De Grandi, A; Volpato, CB; Bedin, E; Pattaro, C; Marroni,
F; Pichler, I; Hicks, AA; Casari, G; Pramstaller, PP. ParkScreen:
A Low-Cost Rapid Linkage Marker Panel for Parkinson’s Disease. J. Mol. Neurosci.: 2009; 39(1-2): 235-241 - Article
IF 2008: 2,061
P.271. De Jager, PL; Chibnik, LB; Cui, J; Reischl, J; Lehr, S; Simon, KC; Aubin, C; Bauer, D; Heubach, JF; Sandbrink, R; Tyblova, M; Lelkova, P; Steering committee of the BENEFIT
study; Steering committee of the BEYOND study; Steering
committee of the LTF study; Steering committee of the CCR1
study; Havrdova, E; Pohl; C; Horakova, D; Ascherio, A; Hafler,
DA; Karlson, EW. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol. : 2009; 8(12): 1111-1119 - Article
IF 2008: 14,270
P.272. de Jong, MC; Mayo, SC; Pulitano, C; Lanella, S; Ribero, D;
Strub, J; Hubert, C; Gigot, JF; Schulick, RD; Choti, MA;
Aldrighetti, L; Mentha, G; Capussotti, L; Pawlik, TM. Repeat
Curative Intent Liver Surgery is Safe and Effective for Recurrent
Colorectal Liver Metastasis: Results from an International Multiinstitutional Analysis. J. Gastrointest. Surg.: 2009; 13(12): 21412151 - Article
IF 2008: 2,311
P.273. De Jong, MC; Pulitano, C; Ribero, D; Strub, J; Mentha, G;
Schulick, RD; Choti, MA; Aldrighetti, L; Capussotti, L; Pawlik,
TM. Rates and patterns of recurrence following curative intent
surgery for colorectal liver metastasis: An international multi-institutional analysis of 1669 patients. Ann. Surg.: 2009; 250(3):
440-447 - Article
IF 2008: 8,460
P.274. De Nardi, P; Osman, N; Ferrari, S; Carlucci, M; Persico,
P; Staudacher, C. Laparoscopic treatment of deep pelvic endometriosis with rectal involvement. Dis. Colon Rectum: 2009;
52(3): 419-424 - Article
IF 2008: 2,615
P.275. De Palma, M; Naldini, L. Tie2-expressing monocytes
(TEMs): Novel targets and vehicles of anticancer therapy?.
Biochim. Biophys. Acta-Rev. Cancer: 2009; 1796(1): 5-10 - Review
IF 2008: 10,283
P.276. De Stefano, N; Filippi, M; Confavreux, C; Vermersch, P;
Simu, M; Sindic, C; Hupperts, R; Bajenaru, O; Edan, G;
Grimaldi, L; Marginean, I; Medaer, R; Orefice, G; Pascu, I; Pelletier, J; Sanders, E; Scarpini, E; Mancardi, GL. The results of
two multicenter, open-label studies assessing efficacy, tolerability
and safety of protiramer, a high molecular weight synthetic
copolymeric mixture, in patients with relapsing-remitting multiple sclerosis. Mult. Scler.: 2009; 15(2): 238-243 - Article
IF 2008: 3,312
P.277. Debette, S; Metso, TM; Pezzini, A; Engelter, ST; Leys, D;
Lyrer, P; Metso, AJ; Brandt, T; Kloss, M; Lichy, C; Hausser, I;
Touze, E; Markus, HS; Abboud, S; Caso, V; Bersano, A; Grau,
A; Altintas, A; Amouyel, P; Tatlisumak, T; Dallongeville, J;
Grond-Ginsbach, C; Pandolfo, M; Thijs, V; Metso, T; Metso, A;
Metso, M; Tatlisumak, T; Bodenant, M; Debette, S; Leys, D;
Ossou, P; Louillet, F; Mas, JL; Touze, E; Leder, S; Leger, A;
Deltour, S; Crozier, S; Meresse, I; Samson, Y; Canaple, S; Godefroy, O; Lamy, C; Bejot, Y; Giroud, M; Decavel, P; Medeiros, E;
Montiel, P; Moulin, T; Vuillier, F; Amouyel, P; Dallongeville, J;
Debette, S; Fievet, N; Bellengier, L; Deplanque, D; Libersa, C;
Schilling, S; Montel, S; Remy, C; Grond-Ginsbach, C; Kloss, M;
Lichy, C; Wiest, T; Werner, I; Arnold, ML; Dos Santos, M;
Grau, A; Dichgans, M; Hausser, I; Brandt, T; Thomas-Feles, C;
Weber, R; Del Zotto, E; Giossi, A; Padovani, A; Pezzini, A; Caso, V; Ballabio, E; Bersano, A; Beretta, S; Ferrarese, C; Sessa,
M; Paolucci, S; Engelter, S; Fluri, F; Hatz, F; Gisler, D;
Tiemessen, A; Lyrer, P; Markus, H; Altintas, A; Martin, JJ.
CADISP-genetics: An International project searching for genetic
risk factors of cervical artery dissections. Int. J. Stroke: 2009;
4(3): 224-230 - Article
IF 2008: 2,000
P.278. Dehò, F; Salonia, A; Briganti, A; Zanni, G; Gallina, A;
Rokkas, K; Guazzoni, G; Rigatti, P; Montorsi, F. Anatomical
radical retropubic prostatectomy in patients with a Preexisting
three-piece inflatable prosthesis: A series of case reports. J. Sex.
Med.: 2009; 6(2): 578-583 - Article
IF 2008: 5,393
P.279. Del Rio, D; Valtuena, S; Pellegrini, N; Bianchi, MA; Ardigo, D; Franzini, L; Scazzina, F; Monti, L; Zavaroni, I; Brighenti,
F. Intervention study with a high or low antioxidant capacity diet:
Effects on circulating Î?-carotene. Eur. J. Clin. Nutr.: 2009;
63(10): 1220-1225 - Article
IF 2008: 2,686
P.280. Delaugerre, C; Flandre, P; Chaix, ML; Ghosn, J; Raffi, F;
Dellamonica, P; Jaeger, H; Shurmann, D; Cohen-Codar, I; Van,
PN; Norton, M; Taburet, AM; Delfraissy, JF; Rouzioux, C;
MONARK Study Group. Protease inhibitor resistance analysis
in the MONARK trial comparing first-line lopinavir-ritonavir
monotherapy to lopinavir-ritonavir plus zidovudine and lamivudine triple therapy. Antimicrob. Agents Chemother. : 2009;
53(7): 2934-2939 - Article
IF 2008: 4,716
P.281. Denard, J; Rundwasser, S; Laroudie, N; Gonnet, F; Naldini, L; Radrizzani, M; Galy, A; Merten, OW; Danos, O; Svinartchouk, F. Quantitative proteomic analysis of lentiviral vectors using 2-DE. Proteomics: 2009; 9(14): 3666-3676 - Article
IF 2008: 4,586
P.282. Deponti, D; Buono, R; Catanzaro, G; De Palma, C;
Longhi, R; Meneveri, R; Bresolin, N; Bassi, MT; Cossu, G;
Clementi, E; Brunelli, S. The low-affinity receptor for neurotrophins p75NTR plays a key role for satellite cell function in
muscle repair acting via RhoA. Mol. Biol. Cell: 2009; 20(16):
3620-3627 - Article
IF 2008: 5,558
P.283. Devuyst, O; Meij, I; Jeunemaitre, X; Ronco, P; Antignac, C;
Christensen, EI; Knoers, NV; Levtchenko, EN; Deen, PM;
Müller, D; Wagner, CA; Rampoldi, L; van’t Hoff, WG; EUNEFRON consortium. EUNEFRON, the European Network for
the Study of Orphan Nephropathies. Nephrol. Dial. Transplant.:
2009; 24(7): 2011-2015 - Article
IF 2008: 3,568
P.284. Di Candia, S; Gessi, A; Pepe, G; Sogno Valin, P; Mangano,
E; Chiumello, G; Gianolli, L; Proverbio, MC; Mora, S. Identification of a diffuse form of hyperinsulinemic hypoglycemia by 18fluoro-L-3,4 dihydroxyphenylalanine positron emission tomography/CT in a patient carrying a novel mutation of the HADH
gene. Eur. J. Endocrinol.: 2009; 160(6): 1019-1023 - Case report
IF 2008: 3,791
P.285. Di Caro, S; Franceschi, F; Mariani, A; Thompson, F; Raimondo, D; Masci, E; Testoni, A; La Rocca, E; Gasbarrini, A.
Second-line levofloxacin-based triple schemes for Helicobacter pylori eradication. Dig. Liver Dis.: 2009; 41(7): 480-485 - Article
IF 2008: 2,577
P.286. Di Comite, G; Previtali, P; Rossi, CM; Dell’Antonio, G;
Rovere-Querini, P; Praderio, L; Dagna, L; Corti, A; Doglioni,
C; Maseri, A; Sabbadini, MG; Manfredi, AA. High blood levels
of chromogranin A in giant cell arteritis identify patients refractory to corticosteroid treatment. Ann. Rheum. Dis.: 2009; 68(2):
293-295 - Letter
IF 2008: 7,188
P.287. Di Comite, G; Rossi, CM; Marinosci, A; Lolmede, K;
Baldissera, E; Aiello, P; Mueller, RB; Herrmann, M; Voll, RE;
Rovere-Querini, P; Sabbadini, MG; Corti, A; Manfredi, AA.
Circulating chromogranin a reveals extra-articular involvement in
patients with rheumatoid arthritis and curbs TNF-?-elicited endothelial activation. J. Leukoc. Biol.: 2009; 85(1): 81-87 - Article
IF 2008: 4,605
P.288. Di Giambenedetto, S; Zazzi, M; Corsi, P; Gonnelli, A; Di
Pietro, M; Giacometti, A; Almi, P; Trezzi, M; Boeri, E; Gianotti, N; Menzo, S; Del Gobbo, R; Francisci, D; Nerli, A; Galli, L;
De Luca, A. Evolution and predictors of HIV types-1 drug resistance in patients failing combinatin antiretroviral therapy in Italy.
Antivir. Ther.: 2009; 14(3): 359-369 - Article
IF 2008: 4,105
P.289. Di Girolamo, F; Campanella, L; Samperi, R; Bachi, A.
Mass spectrometric identification of hemoglobin modifications induced by nitrosobenzene. Ecotox. Environ. Safe.: 2009; 72(5):
1601-1608 - Article
IF 2008: 2,590
P.290. Di Lullo, G; Soprana, E; Panigada, M; Palini, A; Erfle, V;
Staib, C; Sutter, G; Siccardi, AG. Marker gene swapping facilitates recombinant Modified Vaccinia Virus Ankara production by
host-range selection. J. Virol. Methods: 2009; 156(01-02): 37-43
- Article
IF 2008: 2,077
P.291. Di Muzio, N; Fiorino, C; Cozzarini, C; Alongi, F; Broggi,
S; Mangili, P; Guazzoni, G; Valdagni, R; Calandrino, R; Fazio,
F. Phase I-II Study of Hypofractionated Simultaneous Integrated
Boost with Tomotherapy for Prostate Cancer. Int. J. Radiat. Oncol. Biol. Phys.: 2009; 74(2): 392-398 - Article
IF 2008: 4,639
P.292. Di Nunzio, S; Cecconi, M; Passerini, L; McMurchy, AN;
Baron, U; Turbachova, I; Vignola, S; Valencic, E; Tommasini,
A; Junker, A; Cazzola, G; Olek, S; Levings, MK; Perroni, L;
Roncarolo, MG; Bacchetta, R. Wild-type FOXP3 is selectively
active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood: 2009; 114(19): 41384141 - Brief Report
IF 2008: 10,432
P.293. Di Paolo, D; Loi, M; Pastorino, F; Brignole, C; Marimpietri, D; Becherini, P; Caffa, I; Zorzoli, A; Longhi, R; Gagliani,
C; Tacchetti, C; Corti, A; Allen, TM; Ponzoni, M; Pagnan, G.
Chapter 12 Liposome-Mediated Therapy of Neuroblastoma.
Methods Enzymol.: 2009; 465(C): 225-249 - Review
IF 2008: 2,312
P.294. Di Stefano, B; Prigione, A; Broccoli, V. Efficient genetic reprogramming of unmodified somatic neural progenitors uncovers
the essential requirement of Oct4 and Klf4. Stem Cells Dev.:
2009; 18(5): 707-715 - Article
IF 2008: 3,273
P.295. Distefano, G; Boca, M; Rowe, I; Wodarczyk, C; Ma, L; Piontek, KB; Germino, GG; Pandolfi, PP; Boletta, A. Polycystin1 regulates extracellular signal-regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its
downstream effectors S6K and 4EBP1. Mol. Cell. Biol.: 2009;
29(9): 2359-2371 - Article
IF 2008: 5,942
P.296. Donati, C; Cencetti, F; De Palma, C; Rapizzi, E; Brunelli,
S; Cossu, G; Clementi, E; Bruni, P. TGF? protects mesoangioblasts from apoptosis via sphingosine kinase-1 regulation. Cell.
Signal.: 2009; 21(2): 228-236 - Article
IF 2008: 4,305
PUBLICATIONS - 243
P.297. Donida, BM; Mrak, E; Gravaghi, C; Villa, I; Cosentino, S;
Zacchi, E; Perego, S; Rubinacci, A; Fiorilli, A; Tettamanti, G;
Ferraretto, A. Case in phosphopeptides promote calcium uptake
and modulate the differentiation pathway in human primary osteoblast-like cells. Peptides: 2009; 30(12): 2233-2241 - Article
IF 2008: 2,565
P.298. Durum, SK; Mazzucchelli, RI. Live from the Liver: Hepatocyte IL-7. Immunity: 2009; 30(3): 320-321 - Short Survey
IF 2008: 20,579
P.299. Eastell, R; Black, DM; Boonen, S; Adami, S; Felsenberg, D;
Lippuner, K; Cummings, SR; Delmas, PD; Palermo, L; Mesenbrink, P; Cauley, JA; HORIZON Pivotal Fracture Trial. Effect
of once-yearly zoledronic acid five milligrams on fracture risk and
change in femoral neck bone mineral density. J. Clin. Endocrinol. Metab.: 2009; 94(9): 3215-3225 - Article
IF 2008: 6,325
P.300. Eichler, F; Grodd, W; Grant, E; Sessa, M; Biffi, A; Bley, A;
Kohlschuetter, A; Loes, DJ; Kraegeloh-Mann, I. Metachromatic
leukodystrophy: A scoring system for brain MR imaging observations. Am. J. Neuroradiol.: 2009; 30(10): 1893-1897 - Article
IF 2008: 2,745
P.301. Elsheikh, A; Ross, S; Alhasso, D; Rama, P. Numerical study
of the effect of corneal layered structure on ocular biomechanics.
Curr. Eye Res.: 2009; 34(1): 26-35 - Article
IF 2008: 1,519
P.302. Ensoli, B; Fiorelli, V; Ensoli, F; Lazzarin, A; Visintini, R;
Narciso, P; Di Carlo, A; Tripiciano, A; Longo, O; Bellino, S;
Francavilla, V; Paniccia, G; Arancio, A; Scoglio, A; Collacchi,
B; Ruiz Alvarez, MJ; Tambussi, G; Tassan Din, C; Palamara, G;
Latini, A; Antinori, A; D’Offizi, G; Giuliani, M; Giulianelli, M;
Carta, M; Monini, P; Magnani, M; Garaci, E. The preventive
phase I trial with the HIV-1 Tat-based vaccine. Vaccine: 2009;
28(2): 371-378 - Article
IF 2008: 3,298
P.303. Esposito, A; De Cobelli, F; Perseghin, G; Pieroni, M; Belloni, E; Mellone, R; Canu, T; Gentinetta, F; Scifo, P; Chimenti,
C; Frustaci, A; Luzi, L; Maseri, A; Del Maschio, A. Impaired
left ventricular energy metabolism in patients with hypertrophic
cardiomyopathy is related to the extension of fibrosis at delayed
gadolinium-enhanced magnetic resonance imaging. Heart: 2009;
95(3): 228-233 - Article
IF 2008: 4,964
P.304. Fallanca, F; Giovacchini, G; Picchio, M; Bettinardi, V;
Messa, C; Fazio, F. Incidental detection by [11C]choline
PET/CT of meningiomas in prostate cancer patients. Q. J. Nucl.
Med. Mol. Imag.: 2009; 53(4): 417-421 - Article
IF 2008: 2,640
P.305. Famoso, G; Ponzoni, M; Terreni, MR; Assanelli, A; Mortini, P; Doglioni, C; Ferreri, AJM. Primary intracranial
meningeal marginal zone B cell lymphoma of malt type (PMML)
with osseous infiltration. Ann. Hematol.: 2009; 88(6): 599-601 Letter
IF 2008: 2,454
P.306. Fanos, V; Scarcella, A; Puddu, M; Gallini, F; Tuminelli, F;
Bragetti, P; Gallina, MR; Quartulli, L; Benincori, N; Citro, G;
Dalla Via, L; Barera, G; Di Luzio Paparatti, U; Merolla, R; Romano, GV; Guida, G; Silvestri, M; Rossi, GA. Respiratory disorders and hospitalization rates during the second RSV season in
preterm infants who received palivizumab prophylaxis during
their first RSV season. J. Chemother.: 2009; 21(3): 302-310 - Article
IF 2008: 0,843
P.307. Fanti, L; Agostoni, M; Gemma, M; Gambino, G; Facciorusso, A; Guslandi, M; Torri, G; Testoni, PA. Remifentanil
vs Meperidine for Patient-Controlled Analgesia During
Colonoscopy: A Randomized Double-Blind Trial. Am. J. Gastroenterol.: 2009; 104(5): 1119-1124 - Article
IF 2008: 6,444
P.308. Farinazzo, A; Restuccia, U; Bachi, A; Guerrier, L; Fortis, F;
Boschetti, E; Fasoli, E; Citterio, A; Righetti, PG. Chicken egg
yolk cytoplasmic proteome, mined via combinatorial peptide ligand libraries. J. Chromatogr. A: 2009; 1216(8): 1241-1252 - Article
IF 2008: 3,756
P.309. Fazio, R; Malosio, ML; Lampasona, V; De Feo, D; Privitera, D; Marnetto, F; Centonze, D; Ghezzi, A; Comi, G; Furlan,
R; Martino, G. Antiacquaporin 4 antibodies detection by different techniques in neuromyelitis optica patients. Mult. Scler.:
2009; 15(10): 1153-1163 - Article
IF 2008: 3,312
P.310. Fedeli, M; Napolitano, A; Wong, MP; Marcais, A; de Lalla,
C; Colucci, F; Merkenschlager, M; Dellabona, P; Casorati, G.
Dicer-dependent microRNA pathway controls invariant NKT cell
development. J. Immunol.: 2009; 183(4): 2506-2512 - Article
IF 2008: 6,000
P.311. Felice, B; Cattoglio, C; Cittaro, D; Testa, A; Miccios, A;
Ferrari, G; Luzi, L; Recchia, A; Mavilio, F. Transcription factor
binding sites are genetic determinants of retroviral integration in
the human genome. PLoS ONE: 2009; 4(2): e4571 - Article
P.312. Fellay, J; Ge, D; Shianna, KV; Colombo, S; Ledergerber, B;
Cirulli, ET; Urban, TJ; Zhang, K; Gumbs, CE; Smith, JP;
Castagna, A; Cozzi-Lepri, A; De Luca, A; Easterbrook, P; Gunthard, HF; Mallal, S; Mussini, C; Dalmau, J; Martinez-Picado,
J; Miro, JM; Obel, N; Wolinsky, SM; Martinson, JJ; Detels, R;
Margolick, JB; Jacobson, LP; Descombes, P; Antonarakis, SE;
Beckmann, JS; O’Brien, SJ; Letvin, NL; McMichael, AJ;
Haynes, BF; Carrington, M; Feng, S; Telenti, A; Goldstein, DB;
NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI).
Common genetic variation and the control of HIV-1 in humans.
PLoS Genet.: 2009; 5(12): e1000791 - Article
IF 2008: 8,883
P.313. Fellin, G; Fiorino, C; Rancati, T; Vavassori, V; Baccolini,
M; Bianchi, C; Cagna, E; Gabriele, P; Mauro, F; Menegotti, L;
Monti, AF; Stasi, M; Valdagni, R. Clinical and dosimetric predictors of late rectal toxicity after conformal radiation for localized
prostate cancer: Results of a large multicenter observational
study. Radiother. Oncol.: 2009; 93(2): 197-202 - Article
IF 2008: 3,990
P.314. Fellstroem, BC; Jardine, AG; Schmieder, RE; Holdaas, H;
Bannister, K; Beutler, J; Chae, DW; Chevaile, A; Cobbe, SM;
Granhagen-Riska, C; De Lima, JJ; Lins,R; Mayer, G; McMahon, AW; Parving, HH; Remuzzi, G; Samuelsson, O; Sonkodi,
S; Sci, D; Saleymanlar, G; Tsakiris, D; Tesar, V; Todorov, V;
Wiecek, A; Wuthrich, RP; Gottlow, M; Johnsson, E; Zannad, F;
AURORA Study Group. Rosuvastatin and cardiovascular events
in patients undergoing hemodialysis.. N. Engl. J. Med.: 2009;
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IF 2008: 50,017
P.315. Fenoglio, D; Poggi, A; Catellani, S; Battaglia, F; Ferrera, A;
Setti, M; Murdaca, G; Zocchi, MR. Vdelta1 T lymphocytes producing IFN-gamma and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans. Blood: 2009; 113(26):
6611-6618 - Article
IF 2008: 10,432
P.316. Fenyo, EM; Heath, A; Dispinseri, S; Holmes, H; Lusso, P;
Zolla-Pazner, S; Donners, H; Heyndrickx, L; Alcami, J;
Bongertz, V; Jassoy, C; Malnati, M; Montefiori, D; Moog, C;
Morris, L; Osmanov, S; Polonis, V; Sattentau, Q; Schuitemaker,
H; Sutthent, R; Wrin, T; Scarlatti, G . International network for
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P.317. Ferguson, S; Raimondi, A; Paradise, S; Shen, H; Mesaki, K;
Ferguson, A; Destaing, O; Ko, G; Takasaki, J; Cremona, O; O
Toole, E; De Camilli, P. Coordinated Actions of Actin and BAR
Proteins Upstream of Dynamin at Endocytic Clathrin-Coated
Pits. Dev. Cell: 2009; 17(6): 811-822 - Article
IF 2008: 12,882
P.318. Fernandez, MI; Shariat, SF; Margulis, V; Bolenz, C; Montorsi, F; Suardi, N; Remzi, M; Wood, CG; Roscigno, M;
Kikuchi, E; Oya, M; Zigeuner, R; Langner, C; Weizer, A; Lotan,
Y; Koppie, TM; Raman, JD; Karakiewizc, P; Bensalah, K;
Schultz, M; Bernier, P. Evidence-based Sex-related Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: Results of Large Multicenter Study. Urology: 2009; 73(1):
142-146 - Article
IF 2008: 2,242
P.319. Ferrai, C; Naum-Ongania, G; Longobardi, E; Palazzolo,
M; Disanza, A; Diaz, VM; Crippa, MP; Scita, G; Blasi, F. Induction of HoxB transcription by retinoic acid requires actin polymerization. Mol. Biol. Cell: 2009; 20(15): 3543-3551 - Article
IF 2008: 5,558
P.320. Ferrario, F; Barone, MT; Landoni, G; Genderini, A; Heidemperger, M; Trezzi, M; Piccaluga, E; Danna, P; Scorza, D.
Acetylcysteine and non-ionic isosmolar contrast-induced
nephropathy - A randomized controlled study. Nephrol. Dial.
Transplant.: 2009; 24(10): 3103-3107 - Article
IF 2008: 3,568
P.321. Ferreri, AJ; Reni, M; Foppoli, M; Martelli, M; Pangalis,
GA; Frezzato, M; Cabras, MG; Fabbri, A; Corazzelli, G; Ilariucci, F; Rossi, G; Soffietti, R; Stelitano, C; Vallisa, D; Zaja, F;
Zoppegno, L; Aondio, GM; Avvisati, G; Balzarotti, M; Brandes,
AA; Fajardo, J; Gomez, H; Guarini, A; Pinotti, G; Rigacci, L;
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Graefen, M; Karakiewicz, PI. A Population Based Assessment of
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P.398. Ito, K; Bernardi, R; Pandolfi, PP. A novel signaling network
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of a Highly Accurate Nomogram for the Prediction of Perioperative Mortality After Transurethral Resection of the Prostate for
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P.401. Jonikaitis, D; Deubel, H; de’Sperati, C. Time gaps in mental
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P.402. Kahlberg, A; Marrocco-Trischitta, MM; Marone, EM; Amato, ACM; Melissano, G; Chiesa, R. An unusual case of dysphagia after endovascular exclusion of thoracoabdominal aortic
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P.409. Karl, A; Carroll, PR; Gschwend, JE; Knuchel, R; Montorsi,
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L; Mirel, D; Parkin, M; Burtt, N; Gabriel, SB; Samani, NJ;
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Linsel-Nitschke, P; Lieb, W; Ziegler, A; Konig, IR; Hengstenberg, C; Fischer, M; Stark, K; Grosshennig, A; Preuss, M;
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Thorsteinsdottir, U; Stefansson, K; Engert, JC; Do, R; Xie, C;
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P.412. Kato, M; Zanardi, R; Rossini, D; De Ronchi, D; Okugawa,
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PUBLICATIONS - 249
JA. Left ventricular geometry and endogenous ouabain in a Flemish population. J. Hypertens.: 2009; 27(9): 1884-1891 - Article
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P.421. La Colla, L; Albertin, A; La Colla, G. Pharmacokinetic
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P.427. Landoni, G; Fochi, O; Tritapepe, L; Guarracino, F; Belloni, I; Bignami, E; Zangrillo, A. Cardiac protection by volatile
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P.438. Levi, S; Rovida, E. The role of iron in mitochondrial function. Biochim. Biophys. Acta-Gen. Subj.: 2009; 1790(7): 629636 - Review
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P.440. Lira Luce, F; Sarandria, D; Pozzobon, G; Chiumello, G;
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P.516. Messina, G; Sirabella, D; Monteverde, S; Gonzalez
Galvez, B; Tonlorenzi, R; Schnapp, E; De Angelis, L; Brunelli,
S; Relaix, F; Buckingham, M; Cossu, G. Skeletal muscle differentiation of embryonic mesoangioblasts requires Pax3 activity.
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IF 2008: 7,741
P.517. Messina, M; Boroli, F; Landoni, G; Bignami, E; Dedola,
E; Batonga, JN; Magrin, S; Zangrillo, A. A comparison of
epidural vs paravertebral blockade in thoracic surgery. Minerva
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P.518. Messina, M; Magrin, S; Bignami, E; Maj, G; Carozzo, A;
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blind comparison of ropivacaine and levobupivacaine for superficial plexus anesthesia in carotid endoarterectomy. Minerva
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P.519. Mezzi, G; Arcidiacono, PG; Carrara, S; Perri, F; Petrone,
MC; De Cobelli, F; Gusmini, S; Staudacher, C; Del Maschio,
A; Testoni, PA. Endoscopic ultrasound and magnetic resonance
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P.520. Micali, N; Ferrai, C; Fernandez-Diaz, LC; Blasi, F; Crippa,
MP. Prep1 directly regulates the intrinsic apoptotic pathway by
controlling Bcl-XL levels. Mol. Cell. Biol.: 2009; 29(5): 11431151 - Article
IF 2008: 5,942
P.521. Migliaccio, R; Agosta, F; Rascovsky, K; Karydas, A;
Bonasera, S; Rabinovici, GD; Miller, BL; Gorno-Tempini, ML.
Clinical syndromes associated with posterior atrophy: Early age at
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P.522. Migliori, GB; Sotgiu, G; Richardson, MD; Centis, R; Guenther, G; Hoffmann, H; Cirillo, DM; Toungossova, O; Kliiman,
K; De Lorenzo, S; Spanevello, A; Lange, C. Consensus not yet
reached on key drugs for extensively drug-resistant tuberculosis
treatment. Clin. Infect. Dis.: 2009; 49(2): 315-316 - Letter
IF 2008: 8,266
P.523. Mikulak, J; Gianolini, M; Versmisse, P; Pancino, G; Lusso,
P; Verani, A. Biological and physical characterization of the X4
HIV-1 suppressive factor secreted by LPS-stimulated human
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P.524. Miluzio, A; Beugnet, A; Volta, V; Biffo, S. Eukaryotic initiation factor 6 mediates a continuum between 60S ribosome biogenesis and translation. EMBO Rep.: 2009; 10(5): 459-465 - Review
IF 2008: 7,099
P.525. Miotto, P; Saleri, N; Dembele, M; Ouedraogo, M;
Badoum, G; Pinsi, G; Migliori, GB; Matteelli, A; Cirillo, DM.
Molecular detection of rifampin and isoniazid resistance to guide
chronic TB patient management in Burkina Faso. BMC Infect.
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IF 2008: 2,536
P.526. Mirone, V; Fusco, F; Rossi, A; Sicuteri, R; Montorsi, F.
Tadalafil and vardenafil vs sildenafil: A review of patient-preference studies. BJU Int.: 2009; 103(9): 1212-1217 - Review
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P.527. Miserocchi, E; Modorati, G; Rama, P. Atypical toxoplasmosis masquerading late occurrence of typical findings. Eur. J. Ophthalmol. : 2009; 19(6): 1091-1093 - Article
IF 2008: 1,010
P.528. Miyazawa, M; Lopalco, L; Mazzotta, F; Caputo, SL; Veas,
F; Clerici, M. The?immunologic advantage? of HIV-exposed
seronegative individuals. AIDS: 2009; 23(2): 161-175 - Editorial
IF 2008: 5,460
P.529. Moch, H; Artibani, W; Delahunt, B; Ficarra, V; Knuechel,
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P.530. Modorati, G; Miserocchi, E; Galli, L; Picozzi, P; Rama, P.
Gamma knife radiosurgery for uveal melanoma: 12 years of experience. Br. J. Ophthalmol.: 2009; 93(1): 40-44 - Article
IF 2008: 2,859
P.531. Molteni, R; Lage Crespo, C; Feigelson, S; Moser, C; Fabbri, M; Grabovsky, V; Krombach, F; Laudanna, C; Alon, R;
Pardi, R. ?-Arrestin 2 is required for the induction and strength-
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IF 2008: 10,432
P.532. Monforte, AD; Cozzi-Lepri, A; Castagna, A; Antinori, A;
De Luca, A; Mussini, C; Caputo, SL; Arlotti, M; Magnani, G;
Pellizzer, G; Maggiolo, F; Puoti, M; Icona Foundation Study
Group. Risk of developing specific aids-defining illnesses in patients coinfected with HIV and hepatitis c virus with or without
liver cirrhosis. Clin. Infect. Dis.: 2009; 49(4): 612-622 - Article
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P.533. Montalban, X; Sastre-Garriga, J; Filippi, M; Khaleeli, Z;
Téllez, N; Vellinga, M; Tur, C; Brochet, B; Barkhof, F; Rovaris,
M; Miller, DH; Polman, CH; Rovira, A; Thompson, AJ. Primary progressive multiple sclerosis diagnostic criteria: A reappraisal.
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IF 2008: 3,312
P.534. Monti, L; Cinquetti, R; Guffanti, A; Nicassio, F; Cremona,
M; Lavorgna, G; Bianchi, F; Vignati, F; Cittaro, D; Taramelli,
R; Acquati, F. In silico prediction and experimental validation of
natural antisense transcripts in two cancer-associated regions of
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P.535. Monti, P; Brigatti, C; Heninger, AK; Scirpoli, M; Bonifacio, E. Disengaging the IL-2 receptor with daclizumab enhances
IL-7-mediated proliferation of CD4+ and CD8+ T Cells. Am. J.
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P.536. Montini, E; Cesana, D; Schmidt, M; Sanvito, F; Bartholomae, CC; Ranzani, M; Benedicenti, F; Sergi Sergi, L; Ambrosi,
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L. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse
model of HSC gene therapy. J. Clin. Invest.: 2009; 119(4): 964975 - Article
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P.537. Montironi, R; Cheng, L; Lopez-Beltran, A; Mazzucchelli,
R; Scarpelli, M; Kirkali, Z; Montorsi, F. Joint Appraisal of the
Radical Prostatectomy Specimen by the Urologist and the
Uropathologist: Together, We Can Do It Better. Eur. Urol.: 2009;
56(6): 951-955 - Editorial
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P.538. Montironi, R; Cheng, L; Lopez-Beltran, A; Scarpelli, M;
Mazzucchelli, R; Mikuz, G; Kirkali, Z; Montorsi, F. Stage pT0
in Radical Prostatectomy with No Residual Carcinoma and with
a Previous Positive Biopsy Conveys a Wrong Message to Clinicians and Patients: Why Is Cancer Not Present in the Radical
Prostatectomy Specimen?. Eur. Urol.: 2009; 56(2): 272-274 - Editorial
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P.539. Montironi, R; Cheng, L; Mazzucchelli, R; Scarpelli, M;
Kirkali, Z; Montorsi, F; Lopez-Beltran, A. Critical Evaluation of
the Prostate from Cystoprostatectomies for Bladder Cancer: Insights from a Complete Sampling with the Whole Mount Technique. Eur. Urol.: 2009; 55(6): 1305-1309 - Editorial
IF 2008: 6,512
P.540. Montorsi, P; Ravagnani, PM; Galli, S; Ali, SG; Briganti, A;
Salonia, A; Montorsi, F. The Triad of Endothelial Dysfunction,
Cardiovascular Disease, and Erectile Dysfunction: Clinical Implications. Eur. Urol. Suppl.: 2009; 8(2): 58-66 - Review
IF 2008: 1,711
P.541. Mora, S; Cafarelli, L; Erba, P; Puzzovio, M; Zamproni, I;
Giacomet, V; Vigano, A. Differential effect of age, gender and
puberty on bone formation rate assessed by measurement of bonespecific alkaline phosphatase in healthy Italian children and adolescents. J. Bone Miner. Metab.: 2009; 27(6): 721-726 - Article
IF 2008: 2,100
P.542. Mora, S; Vigano, A; Cafarelli, L; Pattarino, G; Giacomet,
V; Gabiano, C; Mignone, F; Zuccotti, G. Applicability of quantitative ultrasonography of the radius and tibia in HIV-infected
children and adolescents. J. Acquir. Immune Defic. Syndr. :
2009; 51(5): 588-592 - Article
IF 2008: 4,570
P.543. Morbiducci, U; Ponzini, R; Rizzo, G; Cadioli, M; Esposito,
A; De Cobelli, F; Del Maschio, A; Montevecchi, FM; Redaelli,
A. In vivo quantification of helical blood flow in human aorta by
time-Resolved three-dimensional cine phase contrast magnetic
resonance imaging. Ann. Biomed. Eng.: 2009; 37(3): 516-531 Article
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P.544. Morichetti, D; Mazzucchelli, R; Lopez-Beltran, A; Cheng,
L; Scarpelli, M; Kirkali, Z; Montorsi, F; Montironi, R. Secondary neoplasms of the urinary system and male genital organs.
BJU Int.: 2009; 104(6): 770-776 - Short Survey
IF 2008: 2,704
P.545. Morsica, G; Ancarani, F; Bagaglio, S; Maracci, M; Cicconi,
P; Cozzi Lepri, A; Antonucci, G; Bruno, R; Santantonio, T; Tacconi, L; Baldelli, F; Piscopo, R; Santoro, D; Lazzarin, A;
D’Arminio Monforte, A HepaICONA and the ICONA Study
Groups. Occult Hepatitis B Virus Infection in a Cohort of HIVPositive Patients: Correlation with Hepatitis C Virus Coinfection,
Virological and Immunological Features. Infection: 2009; 37(5):
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P.546. Morsica, G; Bagaglio, S; Cicconi, P; Capobianchi, MR;
Pellizzer, G; Caramello, P; Orani, A; Moioli, C; Rizzardini, G;
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infections in HIV-positive patients. J. Acquir. Immune Defic.
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P.547. Morsica, G; Bagaglio, S; Uberti-Foppa, C; Galli, L; Lazzarin, A. Detection of hepatitis c mutants with natural resistance
to ns3/4a protease inhibitors in hiv/hcv-coinfected individuals
treated with antiretroviral therapy. J. Acquir. Immune Defic.
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P.548. Motta, M; Alongi, F; De martin, E; Fiorno, C; Maggiulli,
E; Rigoni, L; Landoni, C; Broggi, S; Deli, AM; Calandrino, R;
Di Muzio, N. Helical tomotherapy for scalp recurrence of primary eccrine mucinous adenocarcinoma. Tumori: 2009; 95: 832835 - Article
IF 2008: 0,791
P.549. Mottrie, A; Buffi, N; Lughezzani, G; Denaeyer, G; Schatteman, P; Carpentier, P; Fonteyne, E. Surgery Illustrated - Surgical
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P.550. Mottrie, A; Cestari, A; Buffi, N; Guazzoni, G; Irwin, BH;
Aron, M; Gill, IS. The Motion: A Robot is Necessary for Laparoscopic Enucleation of Renal Masses. Eur. Urol.: 2009; 55(5):
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P.551. Murphy, RL; Autran, B; Katlama, C; Brucker, G; Debre, P;
Calvez, V; Clotet, B; Clumeck, N; Costagliola, D; Deeks, SG;
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P.552. Mussini, C; Touloumi, G; Bakoyannis, G; Sabin, C;
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treatment interruption. J. Acquir. Immune Defic. Syndr.: 2009;
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IF 2008: 4,570
PUBLICATIONS - 255
P.553. Muzio, M; Bertilaccio, MTS; Simonetti, G; Frenquelli, M;
Caligaris-Cappio, F. The role of Toll-like receptors in chronic B
cell malignancies. Leuk. Lymphoma: 2009; 50(10): 1573-1580 Review
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P.554. Muzio, M; Scielzo, C; Bertilaccio, MTS; Frenquelli, M;
Ghia, P; Caligaris-Cappio, F. Expression and function of toll like
receptors in chronic lymphocytic leukaemia cells. Br. J. Haematol.: 2009; 144(4): 507-516 - Article
IF 2008: 4,478
P.555. Nagpal, AD; Torracca, L; Fumero, A; Denti, P; Cioni, M;
Alfieri, O. Concurrent prophylactic left atrial appendage exclusion: results from a randomized controlled trial pilot study. Eur. J.
Cardio-Thorac. Surg.: 2009; 36(3): 553-557 - Article
IF 2008: 2,181
P.556. Naldini, L. A comeback for gene therapy. Science: 2009;
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IF 2008: 28,103
P.557. Naspro, R; Bachmann, A; Gilling, P; Kuntz, R; Madersbacher, S; Montorsi, F; Reich, O; Stief, C; Vavassori, I. A Review of the Recent Evidence (2006-2008) for 532-nm Photoselective Laser Vaporisation and Holmium Laser Enucleation of the
Prostate. Eur. Urol.: 2009; 55(6): 1345-1357 - Review
IF 2008: 6,512
P.558. Nativ, O; Witjes, JA; Hendricksen, K; Cohen, M; Kedar, D;
Sidi, A; Colombo, R; Leibovitch, I. Combined ThermoChemotherapy for Recurrent Bladder Cancer After Bacillus Calmette-Guerin. J. Urol.: 2009; 182(4 SUPPL.): 1313-1317 - Article
IF 2008: 3,952
P.559. Nebuloni, M; Cinque, P; Sidenius, N; Ferri, A; Lauri, E;
Omodeo-Zorini, E; Zerbi, P; Vago, L. Expression of the urokinase plasminogen activator receptor (uPAR) and its ligand (uPA)
in brain tissues of human immunodeficiency virus patients with
opportunistic cerebral diseases. J. Neurovirol.: 2009; 15(1): 99107 - Article
IF 2008: 1,858
P.560. Nigro, EA; Brini, AT; Soprana, E; Ambrosi, A; Dombrowicz, D; Siccardi, AG; Vangelista, L. Antitumor IgE adjuvanticity: key role of Fc epsilon RI. J. Immunol.: 2009; 183: 4530-4536 Article
IF 2008: 6,000
P.561. Nobile, M; Rusconi, M; Bellina, M; Marino, C; Giorda, R;
Carlet, O; Vanzin, L; Molteni, M; Battaglia, M. The influence of
family structure, the TPH2 G-703T and the 5-HTTLPR serotonergic genes upon affective problems in children aged 10-14 years.
J. Child Psychol. Psychiatry : 2009; 50(3): 317-325 - Article
IF 2008: 4,854
P.562. Nocerino, V; Colombo, C; Bonfanti, R; Iafusco, D; Barbetti, F. Mutations in IAPP and NEUROG3 genes are not a common cause of permanent neonatal/infancy/childhood-onset diabetes. Diabetic Med.: 2009; 26(6): 660-661 - Letter
IF 2008: 3,172
P.563. O’Connor, P; Filippi, M; Arnason, B; Comi, G; Cook, S;
Goodin, D; Hartung, HP; Jeffery, D; Kappos, L; Boateng, F;
Filippov, V; Groth, M; Knappertz, V; Kraus, C; Sandbrink, R;
Pohl, C; Bogumil, T. 250 ?g or 500 ?g interferon beta-1b versus
20 mg glatiramer acetate in relapsing-remitting multiple sclerosis:
a prospective, randomised, multicentre study. Lancet Neurol.:
2009; 8(10): 889-897 - Article
IF 2008: 14,270
P.564. Olgiati, P; Mandelli, L; Lorenzi, C; Marino, E; Adele, P;
Ferrari, B; De Ronchi, D; Serretti, A. Schizophrenia: Genetics,
prevention and rehabilitation: Review article. Acta Neuropsychiatr.: 2009; 21(3): 109-120 - Review
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P.565. Origoni, M; Cavoretto, P; Conti, E; Ferrari, A. Isolated
tubal torsion in pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol.: 2009; 146(2): 116-120 - Review
IF 2008: 1,565
P.566. Orru, V; Tsai, SJ; Rueda, B; Fiorillo, E; Stanford, SM; Dasgupta, J; Hartiala, J; Zhao, L; Ortego-Centeno, N; D’Alfonso,
S; Arnett, FC; Wu, H; Gonzalez - Gay, MA; Tsao, BP; Pons Estel, B; Alarcon - Riquelme, ME; He, Y; Zhang, ZY; Allayee,
H; Chen, XS; Martin, J; Bottini, N; Danieli, G; Galeazzi, M;
Sabbadini, MG; Migliaresi, S; Domenico, G. A loss-of-function
variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum. Mol. Genet.: 2009; 18(3): 569-579 Article
IF 2008: 7,249
P.567. Paciaroni, M; Agnelli, G; Caso, V; Corea, F; Ageno, W; Alberti, A; Lanari, A; Micheli, S; Bertolani, L; Venti, M; Palmerini, F; Billeci, AM; Comi, G; Previdi, P; Silvestrelli, G. Acute hyperglycemia and early hemorrhagic transformation in ischemic
stroke.. Cerebrovasc. Dis.: 2009; 28(2): 119-123 - Article
IF 2008: 3,041
P.568. Padeletti, L; Pappone, C; Curnis, A; Zanotto, G; Calo, L;
Ricciardi, G; Pieragnoli, P; Dondina, C; Raciti, G; Michelucci,
A. Product-experience reporting on endocardial defibrillation
leads: A 4-year national perspective. Expert Rev. Med. Devices:
2009; 6(4): 383-388 - Article
IF 2008: 2,071
P.569. Padua, L; Briani, C; Jann, S; Nobile-Orazio, E; Pazzaglia,
C; Morini, A; Mondelli, M; Ciaramitaro, P; Cavaletti, G; Cocito, D; Fazio, R; Santoro, L; Galeotti, F; Carpo, M; Plasmati, R;
Benedetti, L; Schenone, A; Marchettini, P; Cruccu, G. Validation of the Italian version of the Neuropathic Pain Symptom Inventory in peripheral nervous system diseases. Neurol. Sci.: 2009;
30(2): 99-106 - Article
IF 2008: 1,435
P.570. Pagano, L; Valentini, CG; Posteraro, B; Girmenia, C; Ossi,
C; Pan, A; Candoni, A; Nosari, A; Riva, M; Cattaneo, C; Rossini, F; Fianchi, L; Caira, M; Sanguinetti, M; Gesu, GP; Lombardi, G; Vianelli, N; Stanzani, M; Mirone, E; Pinsi, G; Facchetti,
F; Manca, N; Savi, L; Mettimano, M; Selva, V; Caserta, I;
Scarpellini, P; Morace, G; D’Arminio Monforte, A; Grossi, P;
Giudici, D; Tortorano, AM; Bonini, A; Ricci, L; Picardi, M;
Rossano, F; Fanci, R; Pecile, P; Fumagalli, L; Ferrari, L; Capecchi, PL; Romano, C; Busca, A; Barbui, A; Garzia, M; Minniti,
RR; Farina, G; Montagna, MT; Bruno, F; Morelli, O; Chierichini, A; Placanica, PM; Castagnola, E; Bandettini, R; Giordano,
S; Monastero, R; Tosti, ME; Rossi, MR; Spedini, P; Piane, R;
Nucci, M; Pallavicini, F; Bassetti, M; Cristini, F; La Sorda, M;
Viviani, M. Zygomycosis in Italy: A survey of FIMUA-ECMM
(Federazione Italiana di Micopatologia Umana ed Animale and
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2009; 21(3): 322-329 - Article
IF 2008: 0,843
P.571. Palacios, S; Castano, R; Graziottin, A. Epidemiology of female sexual dysfunction. Maturitas: 2009; 63(2): 119-123 - Review
IF 2008: 2,032
P.572. Palacios, S; Graziottin, A. Patient scenario: A 53-year-old
woman with hypoactive sexual desire disorder. Maturitas: 2009;
63(2): 164-168 - Review
IF 2008: 2,032
P.573. Palumbo, R; De Marchis, F; Pusterla, T; Conti, A; Alessio,
M; Bianchi, ME. Src family kinases are necessary for cell migration induced by extracellular HMGB1. J. Leukoc. Biol.: 2009;
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IF 2008: 4,605
P.574. Panaroni, C; Gioia, R; Lupi, A; Besio, R; Goldstein, SA;
Kreider, J; Leikin, S; Vera, JC; Mertz, EL; Perilli, E; Baruffaldi,
F; Villa, I; Farina, A; Casasco, M; Cetta, G; Rossi, A; Frattini,
A; Marini, JC; Vezzoni, P; Forlino, A. In utero transplantation of
adult bone marrow decreases perinatal lethality and rescues the
bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta. Blood: 2009; 114(2): 459-468 - Article
IF 2008: 10,432
P.575. Panfoli, I; Calzia, D; Bianchini, P; Ravera, S; Diaspro, A;
Candiano, G; Bachi, A; Monticone, M; Aluigi, MG; Barabino,
S; Calabria, G; Rolando, M; Tacchetti, C; Morelli, A; Pepe, IM.
Evidence for aerobic metabolism in retinal rod outer segment
disks. Int. J. Biochem. Cell Biol.: 2009; 41(12): 2555-2565 - Article
IF 2008: 4,178
P.576. Papa, M; Gaspardone, A; Fragasso, G; Ajello, S; Gioffre,
G; Iamele, M; Iani, C; Margonato, A. Usefulness of Transcatheter Patent Foramen Ovale Closure in Migraineurs With
Moderate to Large Right-to-Left Shunt and Instrumental Evidence of Cerebrovascular Damage. Am. J. Cardiol.: 2009; 104(3):
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IF 2008: 3,905
P.577. Papagno, C; Fogliata, A; Catricala, E; Miniussi, C. The lexical processing of abstract and concrete nouns. Brain Res.: 2009;
1263(C): 78-86 - Article
IF 2008: 2,494
P.578. Papale, A; Cerovic, M; Brambilla, R. Viral vector approaches to modify gene expression in the brain. J. Neurosci. Methods:
2009; 185(1): 1-14 - Review
IF 2008: 2,092
P.579. Papaleo, E; Unfer, V; Baillargeon, JP; Chiu, TT. Contribution of myo-inositol to reproduction. Eur. J. Obstet. Gynecol.
Reprod. Biol.: 2009; 147(2): 120-123 - Review
IF 2008: 1,565
P.580. Papaleo, E; Unfer, V; Baillargeon, JP; Fusi, F; Occhi, F; De
Santis, L. Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles A prospective, controlled, randomized trial. Fertil. Steril.: 2009; 91(5): 1750-1754 - Article
IF 2008: 4,167
P.581. Pappalardo, F; Maj, G; Scandroglio, A; Sampietro, F; Zangrillo, A; Koster, A. Bioline® heparin-coated ECMO with bivalirudin anticoagulation in a patient with acute heparin-induced
thrombocytopenia: The immune reaction appeared to continue
unabated. PERFUSION-UK: 2009; 24(2): 135-137 - Article
IF 2008: 0,667
P.582. Pappone, C; Radinovic, A; Manguso, F; Vicedomini, G;
Sala, S; Sacco, FM; Ciconte, G; Saviano, M; Ferrari, M; Sommariva, E; Sacchi, S; Ciaccio, C; Kallergis, EM; Santinelli, V.
New-onset atrial fibrillation as first clinical manifestation of latent Brugada syndrome: Prevalence and clinical significance. Eur.
Heart J.: 2009; 30(24): 2985-2992 - Article
IF 2008: 8,917
P.583. Pappone, C; Santinelli, V. Where are we with atrial fibrillation ablation?. Rev. Esp. Cardiol.: 2009; 62(10): 1087-1091 Editorial
IF 2008: 2,880
P.584. Paradiso, A; Mangia, A; Orlando, C; Verderio, P; Belfiglio,
M; Marchetti, A; Bertario, L; Chiappetta, G; Gion, M; Tonini,
GP; Podo, F; Vocaturo, A; Silvestrini, R; Romani, M; Belloni,
E; Cavallo, D; Ulivi, P; Tommasi, S; Steffan, A; Russo, A;
Alessio, M; Calistri, D; Zancan, M; Parrela, P; Broggini, M;
Giuseppe, A; Buttitta, F; Finocchiaro, G; Mazzocco, K;
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F; Venuti, A; Giannelli, G; Quaranta, M; Trojano, V. The Integrated Oncology Program of the Italian Ministry of Health. Analytical and clinical validation of new biomarkers for early diagnosis: network, resources, methodology, quality control, and data
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IF 2008: 6,488
P.782. Zini, L; Patard, JJ; Capitanio, U; Crepel, M; De La Taille,
A; Tostain, J; Ficarra, V; Bernhard, JC; Ferriere, JM; Pfister, C;
Villers, A; Montorsi, F; Karakiewicz, PI. Cancer-specific and
non-cancer-related mortality rates in European patients with T1a
and T1b renal cell carcinoma. BJU Int.: 2009; 103(7): 894-898 Article
IF 2008: 2,704
P.783. Zini, L; Patard, JJ; Capitanio, U; Mejean, A; Villers, A; de
La Taille, A; Ficarra, V; Crepel, M; Bertini, R; Salomon, L; Verhoest, G; Perrotte, P; Bensalah, K; Arjane, P; Biserte, J; Montorsi, F; Karakiewicz, P. The use of partial nephrectomy in European tertiary care centers. Eur J Surg Oncol: 2009; 35(6): 636642 - Article
IF 2008: 2,491
P.784. Zini, L; Perrotte, P; Capitanio, U; Jeldres, C; Duclos, A;
Arjane, P; Villers, A; Montorsi, F; Patard, JJ; Karakiewicz, PI.
Race affects access to nephrectomy but not survival in renal cell
carcinoma. BJU Int.: 2009; 103(7): 889-893 - Article
IF 2008: 2,704
P.785. Zini, L; Perrotte, P; Capitanio, U; Jeldres, C; Shariat, SF;
Antebi, E; Saad, F; Patard, JJ; Montorsi, F; Karakiewicz, PI.
Radical versus partial nephrectomy: Effect on overall and noncancer mortality. Cancer: 2009; 115(7): 1465-1471 - Article
IF 2008: 5,238
P.786. Zini, L; Perrotte, P; Jeldres, C; Capitanio, U; Duclos, A; Jolivet-Tremblay, M; Arjane, P; Peloquin, F; Pharand, D; Villers,
A; Montorsi, F; Patard, JJ; Karakiewicz, PI. A population-based
comparison of survival after nephrectomy vs nonsurgical management for small renal masses. BJU Int.: 2009; 103(7): 899-904 Article
IF 2008: 2,704
AUTHOR INDEX - 267
AUTHOR INDEX
A
Abdollah, Firas
4, 215
P118, P355, P660, P661, P705
Absinta, Martina
31, 210
P9, P635, P636, P638
Abutalebi, Jubin
28, 208
P3, P4
Accarino, Gianfranco 193
Acerno, Stefania
28, 199
P30, P499
Agosta, Federica
31
P7, P8, P9, P10, P11, P141, P199,
P327, P328, P416, P466, P521, P637,
P647
Agostoni, Massimo
28, 196
P307
Agresti, Alessandra
149, 156
P707
Agricola, Eustachio 65, 193
P12
Aiello, Patrizia
113, 206
P287
Aina, Ilaria
29, 208
Airaghi, Barbara
196
Aiuti, Alessandro
86, 87, 88, 103, 105, 204
P13, P14, P99, P178, P350, P357,
P442, P476, P667, P668
Alagna, Laura
202
Albarello, Luca
216
P24, P423, P497
Albieri, Ilaria
27
Alcalà-Franco, Beatriz 87
Aldovrandi, Valeria
194
Aldrighetti, Daniela 4, 211
Aldrighetti, Luca
114, 132, 196
P17, P272, P273, P404, P664
Alemanno, Federica 28
Alesiani, Roberta
29, 208
Alessio, Davide
216
Alessio, Massimo
167, 172
P157, P573, P584
Alfano, Massimo
112
P1, P18, P179, P740
Alfieri, Beatrice
112
Alfieri, Ottavio
65, 78, 193, 195, 221
P12, P65, P239, P246, P420, P450,
P460, P461, P555, P620, P710
Al-Lamee, Rasha
64, 193
Almirante, Giada
Alongi, Filippo
204
211
P19, P126, P240, P291, P331, P548
Alto, Giorgio
65, 199
Amadio, Stefano
31, 210
P605
Amato, Ninfa
30
Amendola, Mario
86
P23, P86, P173, P361
Ammirati, Enrico
64, 221
P325
Amodio, Giada
87
Anand, Santosh
149
P410
Andolfi, Grazia
87
P14
Andolfo, Annapaola 167
P722
Andrei, Fodor
211
Andreolli, Elena Maria 29
Anelli, Tiziana
149
Angelone, Sara
29, 208
P612
Angiolilli, Diego
215
Angiolini, Adriana
199
Annoni, Andrea
87
P26
Antonelli, Antonella 149
Antonini, Stefania
85
Antonino, Felicia
196
Adalgisa
Antonio, Massimo
29
Anzalone, Nicoletta 28, 199
P32
Anzani, Alfredo
X
Apollonio, Benedetta 1
P261
Apollonio, Stefano
XII
Arancio, Cinzia
29, 208
Arcidiacono, Paolo
3, 16, 196
Giorgio
P33, P175, P480, P519, P630, P716
Arcidiacono, Teresa 151, 206
P34
Ardu, Veronica
177
Arendar, Irina
193
Arioli, Francesco
64, 192, 193, 221
P337, P701
Arrigoni, Gianluigi
216
P121
Ascagni, Miriam
Asperti, Claudia
Assanelli, Andrea
Astore, Domenico
Astro, Veronica
Augello, Giuseppe
Avitabile, Maria
Aydin, Didem
Azzoni, Emanuele
185
27
P35
86, 211
P255, P305, P322, P721
65, 194
27
P35
65, 192
192
87
85
B
Baccari, Paolo Aldo
Raul
Baccelli, Nicola
Baccellieri, Domenico
Bacchetta, Rosa
3, 196
P36, P37
65, 199
65, 194
86, 87, 102, 204
P23, P292, P679
Bacchi, Fabrizio
XII
Bachi, Angela
149, 157
P20, P31, P71, P91, P223, P265,
P289, P308, P500, P575, P724
Bacigaluppi, Marco 30
P39
Badaloni, Aurora
27
P211
Bagaglio, Sabrina
113, 202
P545, P546, P547
Balconi, Giuseppe
213
Baldini, Mattia
113, 206
P501, P502
Baldissera, Elena
113, 206
P287
Baldoli, Cristina
28, 199
P30, P85, P359, P747
Balducci, Elena
221
Ballarotto, Carlo
193
Ballis, Rosa
151
Balzano, Gianpaolo 3, 196
P629, P630
Bandello, Francesco 65, 80, 199
Bandiera, Alessandro 3, 194
P42, P176, P177, P512
Banfi, Arianna
196
Banfi, Michela
65
Baratto, Fabio
211
P339
Barbini, Barbara
29, 208
Barcella, Valeria
210
Barchi, Roberto
XII
Barera, Graziano
64, 73, 204
P306, P497
Bargiggia, Cinzia
216
Barile, Luigi
Barili, Valeria
Barricella, Nietta
Barzaghi, Federica
Barzaghi, Lina
Raffaella
Barzizza, Lorena
Bassanelli, Giorgio
Basso, Veronica
Batonga, Jaques
N’zepa
Battaglia Parodi,
Maurizio
Battaglia, Manuela
Battaglia, Marco
Battaglino, Roseila
Bazzigaluppi, Elena
Beatrice, Saverio
Beccaria, Paolo
Federico
Bechi, Margherita
65
27
211
88
28, 199
P448
216
193
112
194
P517
65, 199
114, 135
P49, P50, P351, P587, P746
29, 208
P48, P504, P561
115
216
211
197
29, 208
P27, P185
Belfiore, Marcello
27
Bellanca, Raimondo 193
Bellani, Serena
27
P698
Belli, Carmen
211
P55
Bellini, Chiara
3, 199
P713, P715, P731
Bellinzoni, Piera
215
Bellio, Laura
86, 216
Bellodi, Laura
29, 208
P417, P657, P680
Belloli, Sara
177, 211
P56, P145, P433, P761
Bellomo, Daniela
XII
Bellone, Matteo
112, 124
P56, P172
Belloni, Daniela
1
Benasciutti, Elisa
149
P250
Benedetti, Francesco 29, 44, 208
P58, P59, P60, P61, P62, P349, P481
Benedetti, Sara
167, 216
P251
Benedetti, Sara
85
Benedicenti, Fabrizio 87
P536
Benedini, Stefano
63
P51, P63
Beneduce, Aldo
216
Benussi, Stefano
65, 193
P65
Benveniste, Marina
213
AUTHOR INDEX - 269
Benzoni, Ivana
Berardi, Genoveffa
Beretta, Edoardo
Beretta, Luigi
185
177, 211
196
28, 40, 196, 199, 217, 220
P359, P360
Bergamante, Valentina 88
Bergamaschi, Andrea 30
P192
Bergamaschi, Luca
4
Bergami, Alessandra 30
P124, P192
Bergonzi, Pier Carlo 197
P138
Bernardi, Giovanna XII
Bernardi, Massimo
3, 211
P110, P213, P741, P750
Bernardi, Rosa
1, 10
P348, P398
Bernascone, Ilenia
150
P472
Bernasconi,
29, 208
Alessandro
P58, P59, P61
Bernasconi, Fabio
199
Bernasconi, Luca
208
P715
Berno, Roberta
XII
Bertilaccio, Maria
1
Teresa Sabrina
P503, P553, P554
Bertini, Diego Maria XII
Bertini, Roberto
4, 215
P70, P259, P408, P642, P643, P783
Bertocchi, Cecilia
213
Bertoglio, Luca
65, 194
P508
Bertolazzi, Mara
216
Bertolotti, Milena
149
Bestetti, Arabella
113, 202
Bettegazzi, Barbara
27
Bettin, Paolo
65, 199
Bettinardi, Valentino 177, 211
P72, P304, P368, P468, P505
Beugnet, Anne
2
P524
Biagetti, Raffaella
XII
Bianchi Marzoli,
65, 199
Stefania
P67
Bianchi, Laura
29, 208
Bianchi, Marco
4, 215
P116, P117, P120, P259, P279
Bianchi, Marco E.
149, 155, 185, 187
P77, P78, P79, P152, P179, P443,
P471, P573, P619, P707, P709, P733,
P768
Bianchi, Veronica
28
P80
Bianco, Mariangela
30, 210
Bianconi, Eleonora
Bianconi, Irene
Biasco, Luca
64
111
87
P350
Biffi, Alessandra
87, 88, 100, 204
P91, P171, P198, P300, P495, P604,
P761
Biffi, Valentina
115, 204
Biffo, Stefano
XXVIII, 2, 13
P524, P626
Bignami, Elena
65, 194
P83, P244, P245, P253, P427, P517,
P518, P772, P773, P774, P775
Bin, Roberta
211
Biondini, Francesca 208
Bione, Silvia
150
P234, P644, P728
Bisagni, Pietro
216
Bissolati, Massimiliano 196
Biswas, Priscilla
112
P242
Biziato, Daniela
86
P618
Bizzozero, Daniele
29
Bizzozero, Laura
86
Blasi, Francesco
150, 159
P18, P263, P319, P500, P520, P722,
P760
Blasi, Valeria
28, 185
P85, P359
Blasio, Andrea
193
P461
Boari, Nicola
28, 199
Boccalatte, Francesco 86
Boccalon, Silvia
29, 208
Boemo, Cinzia
3, 196
Boeri, Enzo
216
P1, P155, P288, P585, P776
Bogni, Silvia
150
Bolamperti, Simona 63
Bolentini, Alketa
216
Boletta, Alessandra
150, 159
P295, P765
Bolino, Alessandra
31, 52
P91
Bolis, Annalisa
31
P91
Bolognesi, Angelo
211
P240, P259, P342
Bolognesi, Gianluigi 65, 199
Bombelli, Ferdinando 204
Bombelli, Giovanna XII
Bonavida, Giovanna 151
Bondanza, Attilio
86
P213, P404, P741
Bondi, Stefano
3, 199
Bonetti, Fabrizio
193
Bonfanti, Chiara
Bonfanti, Riccardo
85
115, 139, 204
P92, P562, P621
Boni, Andrea
150
Bonini, Chiara
86, 95
P93, P213, P404, P496, P741
Bonisolli, Loredana 65
Bordogna, Gianni
211
Borgognoni, Marco
221
Bornaghi, Viviana
167
Borri, Anna
216
P42
Borroni, Emanuele
112, 221
Borroni, Serena
208
P334, P335, P336
Bortolanza, Sergia
85
Bosi, Emanuele
64, 71, 114, 115, 134, 138, 206, 207,
216
P97, P98, P230, P341, P450, P659,
P673, P681, P728
Bosia, Marta
29, 208
P27, P58, P612
Bossolasco, Simona
113, 202
Bosticardo, Marita
87
P99, P442, P476
Bosurgi, Lidia
85
P152, P443
Bottelli, Vittoria
29, 208
Bottero, Giampiero 29, 208
Botti, Francesca
27
Botti, Renato
XXXI, XXXIII
Botticelli, Irene
151, 206
Bove, Maddalena
204
Bove, Tiziana
65, 194
Bozzolo, Enrica P.
113, 206
Braga, Marco
3, 196
P104, P711
Bragonzi, Alessandra 111, 120
P105
Brambilla, Elena
30
P39, P124, P605, P606
Brambilla, Marina
216
Brambilla, Riccardo 30, 48
P258, P578
Brambilla, Roberta
216
Brasca, Laura
213
Breda, Daniela
111
P132
Bregani, Valentina
208
Brendolan, Andrea
1, 10
Brigante, Claudio
204
Briganti, Alberto
4, 215
P112, P113, P114, P115, P116, P117,
P118, P119, P120, P162, P163, P164,
P259, P278, P355, P540, P656, P659,
P660, P661, P662, P705
Brigatti, Cristina
115
P464, P535
Brigida, Immacolata 87
P13, P14
Brina, Daniela
2
Brioni, Elena
151
Brioschi, Chiara
65, 194
Brioschi, Luca
211
Brisci, Angela
167, 216
P462
Broccoli, Vania
28, 39
P219, P294
Broggi, Paola
208
Broggi, Sara
177
P19, P126, P291, P331, P548, P593
Broglia, Luigi
215
Brumat, Giuliano
221
Brunati, Martina
149, 150
Brunelli, Silvia
85, 92
P282, P296, P370, P424, P443, P516
Bruno Ventre, Marta 3
Bruno, Francesca
167, 216
P128, P479
Bruschi, Elena
65, 199
Bua, Lina
215
Buetti, Ivan
150
P728
Buffi, Nicolò Maria
4, 215
P130, P549, P550
Bulotta, Alessandra
4, 211
Buono, Roberta
86
P282
Burastero, Samuele E. 111, 119
P41, P131, P132, P133
Buratti, Luca
65
Burioni, Roberto
216
P135, P136, P154, P467
Buriova, Emilia
211
Busnardo, Elena
177, 211
Bussi, Mario
3, 17, 29, 44, 199
P360, P440, P713, P714, P715, P731
Butera, Calogera
31, 210
Butti, Erica
XXVI, 30
P192
Buzzetti, Fabio
65, 193
Buzzotta, Alessio
65, 199
C
Cabianca, Daphne
Cabinio, Monia
Cabrini, Luca
Caiolfa, Valeria R.
Cairella, Roberto
85
28, 185
65, 197
P138, P139, P140
1, 9
216
AUTHOR INDEX - 271
Calabrese, Alice
Calabrese, Donato
Calabrese, Maria
Chiara
Calabrò, Maria Grazia
Calaciura, Rita
Calamita, Piera
Calandrino, Riccardo
Calbi, Valeria
Caldana, Elena
Caldara, Rossana
Caldi, Massimo
Caligaris-Cappio,
Federico
Calissano, Carlo
Callegaro, Luciano
Calori, Giliola
Calvi, Maria Rosa
Cama, Francesco
Camaschella, Clara
Camba, Lionello
Cambiaghi, Marco
Cambiaghi, Valeria
Camerota, Tommaso
Camesasca, Chiara
Camisa, Barbara
Cammarata, Bruna
Cammarata, Gabriella
Cammino, Stefania
Camnasio, Francesco
Campana, Lara
Campanella,
Alessandro
Campanini, Elena
Campori, Euridice
Canali, Paola
Canciani, Cristina
Candiani, Massimo
Candotti, Guido
Canducci, Filippo
Canessa, Nicola
Canevali, Paolo
Canevari, Carla
Cangi, Maria Giulia
193
P12, P325
112
193
P461
194
211
28
177, 180
P19, P126, P144, P145, P291, P331,
P548, P593
86, 221
P76
87
113, 206
196, 217
1, 3, 7, 211, 212
P134, P146, P147, P148, P260, P321,
P375, P553, P554
1
88, 204
P14, P213
X, XII
P33, P337, P487, P488, P508, P601
28, 199
P359
194
150, 161
P149, P150, P151, P690, P728
211
30
2
215
193
86
P38
204
65, 199
29
196
85
P152, P443
27
P153
208
208
29
193
4, 64, 114, 204
204
216
P135, P136, P154, P155
28, 208
P156, P184, P485
111
177, 211
216
Cannalire, Giuseppe
Cannavale, Salvatore
Cannistraci, Carlo
Vittorio
Canonico, Emanuele
Cantarelli, Elisa
204
193
167
P157
185
115
P158
Cantoni, Anna
XII
Cantore, Alessio
86
P26
Canu, Elisa
31
Canu, Tamara
177
P303, P464, P595, P596
Capasso, Giuseppe
216
Capelletti, Alberto
65
Capelli, Alessandro
211
Capitanio, Umberto 4, 215
P73, P74, P116, P117, P159, P160,
P161, P162, P163, P164, P165, P166,
P167, P168, P169, P209, P217, P243,
P394, P395, P396, P399, P400, P407,
P408, P451, P478, P643, P659, P682,
P684, P779, P780, P781, P782, P783,
P784, P785, P786
Capitanio, Vanessa
114, 196, 216
Capitelli, Elena
213
Capobianco, Annalisa 85
P38, P471, P503, P606
Capocasa, Tania
196
Capossela, Simona
150
Capotondo, Alessia
87
P198, P604
Cappa, Stefano F.
28, 41, 208
P3, P156, P184, P354, P622, P719,
P752, P757, P758, P762
Capparé, Paolo
151
P247, P248, P669
Cappellari, Ornella
85
Cappelletti, Alberto 193
Cappelletti, Chiara
64, 206
Cappelli, Barbara
86, 204
P13, P171
Cappio, Stefano
213
Capretti, Giovanni
114, 196
Caputo, Alessandra 115
Caputo, Luigi
114, 204
P771
Carbone, Maria
216
Rosaria
Carbone, Teresa
216
Cardani, Anna
204
Cardone, Gianpiero 213
Carletti, Rose Mary
167, 216
Carletti, Silvia
216
P467
Carlino, Mauro
64, 193
P122, P203, P337, P363, P369
Carlucci, Michele
216, 219
P274
Carlucci, Silvia
63
Carminati, Guia
114
Carobene, Anna
216
Carozzo, Andrea
194
P518
Carpanelli, Roberta
213
Carpinelli, Assunta
177, 211
Carrabba, Matteo
3, 211
P750
Carrabino, Salvatore 150
Carrara, Silvia
3, 196
P33, P175, P519, P716
Carrera, Paola
167
P237, P341, P364, P406, P751
Carretta, Angelo
3, 194
P42, P176, P177, P216, P512
Carretta, Ilaria
X, 208
Carrieri, Domenica
194
Carvello, Michele
3, 196
Casà, Valentina
85
Casamassima, Nunzia 151
P419, P677, P678
Casari, Giorgio
167, 169
P270, P410, P465, P472, P491, P671
Casati, Paolo
208
Cascavilla, Maria
65, 199
Lucia
Casiraghi, Giuseppina 65, 194
Maria
Casiraghi, Miriam
88, 204
P668
Casiraghi, Tiziana
196
Caso, Francesca
31, 210
Casorati, Giulia
112
P310, P442, P723
Cassella, Patrizia
31
Cassetta, Luca
112
P179, P740
Cassina, Giulia
111
P125
Cassina, Laura
167
Castagna, Antonella 113, 128, 202
P28, P155, P236, P312, P532, P552,
P700, P749
Castagnaro, Laura
1
Castellano, Antonella 28, 185
Castellano, Marina
XII
Castellano, Renata
65, 193, 194
Clotilde
P204, P486
Castellazzi, Paola
28, 199
Castelli, Alfredo
64, 193
P122
Castelli, Maddalena 150
Castiello, Maria
87
Carmina
Castiglioni, Alessandra 3, 85
Castiglioni, Alessandro 193
P450
Castiglioni, Emanuela 167, 216
Castiglioni, Isabella
177, 211
P144, P182
Castiglioni, Maria
64, 74, 204
Teresa
P183
Castoldi, Carlo
196
Castoldi, Renato
3, 196
Castronovo, Vincenza 29
P184, P463
Casucci, Monica
86
P741
Catalano, Marco
29
Catena, Marco
114, 196
P17
Catenaccio, Barbara 65, 194
Catenazzi, Ursula
29, 208
Catricalà, Eleonora
28, 208
P577
Cattaneo, Angela
149
P223
Cattaneo, Elisabetta 208
Cattaneo, Federica
XII
Cattaneo, Giovanni
177
Mauro
P19, P126, P144, P331, P593
Cattoglio, Claudia
150
P311, P350, P496
Catucci, Alessandro 149
Catucci, Marco
87
P442
Caumo, Andrea
63
P595
Causarano, Vincenza 167, 216
P128
Cavadini, Daniele
29, 208
Cavallaro, Roberto
29, 208
P27, P58, P185, P385, P612
Cavallini, Maria
29, 208
Cristina
Cavarelli, Mariangela 112, 221
P186
Cavazzin, Chiara
87
P494
Cavenago, Francesca 194
Caviezel, Francesco X
Cavoretto, Paolo
64, 204
P187, P356, P565
Cazzato, Denise
86
Cecconi, Virginia
112
Celona, Barbara
149
Cenci, Simone
149, 153
P76, P250
Centemero, Antonia 215
Ceppi, Daniela
210
AUTHOR INDEX - 273
Cera, Michela
Cerè, Patrizia
Cereda, Stefano
Ceresa, Daniela
Ceriotti, Ferruccio
Cernuschi, Massimo
Cerri, Federica
Cerri, Marco
Cesana, Daniela
Cesani, Martina
Cestari, Andrea
Chiara, Anna
Chiaravalli, Marco
Chieffo, Alaide
Chieffo, Raffaella
Chiesa, Roberto
Chignola, Francesca
65
P338
211
4, 211
P629, P630
216
216
P193, P194, P195, P196
202, 221
30
P197, P465, P491
199
87
P350, P536
88
P198
4, 215
P116, P162, P163, P164, P326, P355,
P550, P705, P706
177, 211
150
P765
64, 193
P136, P203, P363, P430, P434, P507,
P687
30, 210
65, 78, 194
P13, P36, P171, P204, P205, P402,
P457, P483, P486, P487, P488, P508,
P509, P510, P511
167
P206
X
221
Chiodi, Maurizio
Chiodi-Daelli,
Federico
Chiumello, Giuseppe 63, 64, 115, 204, 205
P69, P85, P92, P232, P252, P284,
P440, P663
Ciaccio, Cristiano
192
P582
Ciampi, Carlo
65, 199
Ciampi, Pietro
196
Cianflone, Domenico 64, 76, 193
P136, P325, P429, P457, P503
Ciasca, Paola
65, 199
Ciboddo, Gianfranco 211
Cicenia, Gabriella
113, 206
Ciceri, Fabio
3, 18, 85, 86, 96, 211, 221
P14, P110, P171, P213, P254, P255,
P256, P322, P333, P404, P741
Cichero, Paola
216
P40, P467
Ciconte, Giuseppe
65, 192
P582, P665
Cigala Fulgosi, Mara 29, 208
Cigana, Cristina
111
Cino, Ilaria
64
Cinque, Paola
113, 128, 202
P215, P559
Cioni, Micaela
193
P555
Cipriani, Antonella
199
Cipriani, Federica
114, 196
Ciriaco, Paola
3, 194
P42, P176, P177, P216, P512
Cirillo, Daniela Maria 112, 124, 221
P40, P455, P522, P525, P697
Cirillo, Sara
185
Ciscato, Diana
216
Citro, Antonio
115
Citterio, Giovanni
4, 211
P375
Citterio, Lorena
151
P484, P677, P678, P732
Civilini, Efrem
65, 194
P36, P508
Clavenna, Daniela
216
Clementi, Emilio
86, 95
P81, P282, P296, P443
Clementi, Francesco X
Clementi, Massimo
216, 221
P135, P136, P154, P155, P236, P467
Clerici, Daniela
86
Clerici, Stefano
208
Clissi, Barbara
111
P753
Cocca, Massimiliano 150
Cocchi, Federica
29, 208
P185
Cocchi, Silvia
208
Codazzi, Franca
27
Codella, Roberto
63
Codenotti, Marco
65, 199
Colasante, Gaia
28
P219
Colciago, Giorgia
28
Collu, Egidio
193
Colnaghi, Eleonora
196
Colombelli, Cristina 150
Colombo, Antonio
64, 75, 193
P122, P136, P203, P220, P221, P222,
P239, P363, P369, P403, P418, P430,
P431, P432, P434, P460, P490, P506,
P507, P685, P687, P689
Colombo, Barbara
2
Colombo, Bruno
31, 210
P715
Colombo, Cristina
29, 208
P59, P60, P61, P412, P470, P481
Colombo, Elena
28
P498
Colombo, Gabriella 204
Colombo, Giselda
113, 206
Colombo, Ilaria
204
Colombo, Renzo
Colombo, Sergio
Coltella, Nadia
Colucci, Annalisa
Comi, Giancarlo
Comola, Mauro
Comotti, Laura
Compierchio, Antonia
Comuzzi, Barbara
Consalez, Gian
Giacomo
Consogno, Giuseppe
Consonni, Alessandra
Consonni, Monica
Conti, Antonio
Conti, Enrico
Conti, Valentina
Contrino, Elena
Conversano, Andrea
Coppi, Elisabetta
Coppi, Giovanni
Coppolino, Naima
Coradin, Tiziana
Corbetta, Sara
Cordisco, Paola
Corea, Francesco
Corna, Gianfranca
Cornaggia, Gabriele
Cornero, Guglielmo
Corno, Daniela
Corno, Laura
Corno, Silvia
Corrado, Renato
Corre, Tanguy
Corsetti, Maura
Corsin, Patrizia
Cortella, Carlo Alberto
Corti, Angelo
4, 215
P70, P558, P660, P661, P706
65, 197
P138, P140
1
65, 199
P224
XXVII, 30, 46, 210
P39, P57, P124, P190, P191, P192,
P197, P198, P199, P226, P227, P228,
P309, P365, P415, P492, P493, P514,
P563, P567, P605, P606, P614, P635,
P637, P638, P695, P712, P715, P734,
P735
210
196
177, 211
167
27, 37
P211, P472
112
27
28
P184
167
P573
204
P565
85
213
193
31, 210
65, 194
P486, P508
29, 208
113
27
P233
211
31
P567
85
217
193, 194
85
65
216
221
150
P234
196
P235
64
151
2, 14
P286, P287, P293
Corti, Consuelo
3, 211, 221
P741
Corti, Laura
167
Corti, Valeria
167
Cortini, Margherita
149
Cortinovis, Francesca 204
P232
Cosciotti, Miriam
216
Cossarini, Francesca 113, 202
P236
Cossetti, Chiara
30
P605, P606
Cossu, Giulio
85, 91
P282, P296, P370, P443, P515, P516,
P672, P739
Costa, Sabrina
63
Cottonaro, Sara
167
Cottone, Lucia
85
P38
Covarello, Diego
85
P370
Covello, Remo Daniel 65, 194
P239, P772
Coviello, Silvia
31
P91
Covino, Cesare
185
P503
Cozzarini, Cesare
177, 211
P19, P120, P126, P240, P259, P291,
P331, P593, P743
Cozzi, Anna
27
P153
Cozzi, Silvano
199
Cremona, Ottavio
2, 13
P201, P317, P767
Cremonesi, Laura
167
P128, P462, P479, P744
Cremonini, Anna
216
Crepaldi, Arianna
216
Crescenti, Antonella 194
Crespi, Giulia Maria 213
Crespi, Marco
XII
Crespi, Roberto
151
P247, P248, P249, P250, P640
Crippa, Ambra
150
Crippa, Luca
2
Crippa, Luciano
63, 216
P266
Crippa, Massimo
150, 160
P319, P520
Crippa, Valentina
64, 206
Crippa, Valeria
211
Crisà, Simonetta
192
Cristallo, Marco
196
Cristell, Nicole
64, 193
Crivello, Pietro
85
AUTHOR INDEX - 275
Croci, Laura
Crotta, Alessandro
Cucchi, Michele
Cuko, Amarild
Cuppari, Irene
Curci, Francesco
Curnis, Flavio
Cursi, Marco
Curti, Cesarina
Cusimano, Melania
27
P211, P472
3
29, 208
192
P701
86
XII
2
30
X
30
P686
D
D’Adamo, Patrizia
28, 38
P80
D’Alessandro, Rosalba 27
P262, P415, P713
D’Alessio, Silvia
150
P263
D’Aliberti, Teresa
206
D’Amato, Alfonsina 149
P265, P501
D’Amato, Luigi
216
D’Ambrosio, Rosa 167
Lucia
D’Angelo, Armando 63, 69, 216
P253, P266, P330, P454, P590, P728
D’Annibale, Sara
167
D’Antonio, Maurizio 149
P267, P767
D’Isa, Raffaele
30
Dacci, Patrizia
31
Dadda, Alice
113
Dagklis, Antonis
1
P260, P261
Dagna, Lorenzo
113, 206
P286
Dal Cin, Elena
216
Dall’Occhio, Luca
31
Dalla Libera, Dacia
210
Dallabà, Elisa
29
Dallalibera, Dacia
30
Dallaspezia, Sara
29, 208
P58, P59, P61
Daneri, Riccarda
XII
Daniele, Tiziana
167
Danise, Anna
202
D’Arbela, Paul G.
221
Davalli, Alberto
64, 206
P378
Daverio, Rita
216
De Benedetto,
65, 199
Umberto
De Bonis, Michele
De Cobelli, Francesco
De Curtis, Ivan
De Feo, Donatella
De Fusco, Maurizio
De Gaspari, Angela
De Lalla, Claudia
De Leonardis, Alberta
De Luca, Monica
De Marchis, Francesco
De Marco, Donata
De Martino, Emanuela
De Marzi, Patrizia
De Monte, Lucia
De Nardi, Paola
De Palma, Clara
De Palma, Michele
De Pellegrin, Maurizio
De Ponti, Alessandro
De Santis, Giuseppe
De Santis, Lucia
65, 193
P420, P710
177, 213
P269, P303, P464, P477, P508, P519,
P543, P593, P595, P596
27, 35
P35, P233
210
P309
167
213
112
P310
211
194
P245
149
P573, P619
216
P135, P136
111
4, 204
112
3, 196
P22, P235, P274
86
P282, P296
XXVIII, 86, 96
P275, P618
196
196
30
64
P580, P631
31, 210
De Toni Franceschini,
Luisa
De Vitis, Assunta
28, 199
P359
Debbia, Silvia
211
Decembrino, Mariela 196
Defidio, Giuseppe
XII
Degano, Massimo
112, 123
P154
Deidda Vigoriti, Vivian 85
Del Carro, Ubaldo
31, 55, 210
P605, P662
Del Maschio,
115, 177, 179, 213, 214
Alessandro
P63, P144, P269, P303, P381, P464,
P477, P508, P519, P543, P595, P596
Del Maschio, Maurizia 213
Del Monte, Dario
29
Del Rosso, Stefania
216
Del Vecchio, Antonella 177
P145
Delai, Stefania
87
Deli, Aniko Maria
177, 211
P548
Dell’Acqua, Antonio
Dell’Antonio,
Giacomo
Dell’Oca, Italo
Dell’Orco, Stefania
Della Chiara, Giulia
Della Rosa, Pasquale
199
216, 221
P286
177, 211
216
112
28, 208
P3
Della Torre, Emmanuel113, 206
Della Torre, Liviana 113
Della Valle, Patrizia 63
P253
Dellabona, Paolo
112, 125
P310, P442, P723
Dellavalle, Arianna
85
P370
Delli Carpini, Simona 151
Delmonte, Dario
208
Delogu, Marta
112
Demarchi, Barbara
193
Demasi, Stefania
216
Deni, Francesco
196
Dentali, Sara
27
Denti, Paolo
193
P461, P555
Deponti, Daniela
151, 196
Deriu, Maria Grazia 31
Devoti, Rosaria
208
Di Candia, Stefania
64, 204
P284
Di Carlo, Valerio
3, 19, 114, 132, 196
P346, P629, P630, P711, P745
Di Girolamo, Valerio 215
P117
Di Leo, Giuseppe
216
Di Leo, Milena
3, 196
Di Lucia, Pietro
112
Di Lullo, Giulia
112
P290
Di Marco, Andrea
193
Di Mattei, Valentina 208
Di Matteo, Federico 65, 199
P224, P623
Di Molfetta, Daniela 208
Di Muzio, Nadia
177, 180, 211
P19, P126, P240, P291, P331, P368,
P548, P593
Di Nunzio, Sara
87
P292
Di Palo, Saverio
3, 196
P756
Di Piazza, Lara
204
Di Pietro, Caterina
115
Di Puppo, Francesca 204
P38
Di Resta, Chiara
167, 216
Di Ruvo, Barbara
216
Di Sciacca, Dina
Di Sebastiano,
Francesca
Di Stefano, Bruno
216
213
XXVII, 28
P294
Di Tomaso, Tiziano 2
Di Trapani, Dario
4, 215
Diaferia, Giuseppina 208
Dina, Giorgia
30
Dindelli, Moreno
204
P771
Diomede, Lorenzo
111
P737
Diotti, Roberta
216
P135
Dipinto, Angelica
28
Dispinseri, Stefania
112, 221
P316
Distefano, Gianfranco 150
P295
Dodero, Francesca
XII
Doglioni, Claudio
19, 185, 216, 218
P24, P70, P118, P120, P286, P305,
P323, P333, P339, P390, P423, P476,
P489, P497, P536, P606, P611, P721,
P753, P759
Donadoni, Giovanni 3, 211
Dondossola, Eleonora 2
Donghi, Valentina
204
Donini, Annalisa
63
Donini, Michela
208
Dordoni, Laura
65, 194
P36
Doria, Valentina
64, 206
Dorigatti, Fernanda 216, 218
Dorigo, Enrica
193
P65
Dosio, Flaviano
211
Draghici, Elena
87
P442, P476
Dugani, Erica
115
Durante, Alessandro 65
E
Ekkirala, Chaitanya
Ramesh
Erre, Letizia
Erzegovesi, Stefano
Esposito, Antonio
Esposito, Federica
Esposito, Gloria
Esposito, Valentina
Evangelio, Costanza
112
211
29, 208
177, 213
P269, P303, P464, P543, P595, P596
31
65, 194
208
204
P171
AUTHOR INDEX - 277
F
Fabbri, Fabio
Fabbri, Monica
Fabiano, Beatrice
Fabro, Andrea
Facchi, Cinzia
Faccincani, Roberto
Faccio, Lucia
Fadda, Emma
Fagioli, Claudio
Falcone, Marika
Falcone, Sestina
Falini, Andrea
Fallanca, Federico
Falqui, Luca
Famoso, Graziana
Fanelli, Giovanna
Franca
Fano, Greta
Fanti, Lorella
215
111
P133, P531
3, 199
P714
177, 211
208
216
XII
29, 208
149
115, 136
P750
86
28, 42, 199
P58, P59, P184, P190, P191, P199,
P493, P638, P761
177, 211
P255, P304, P367
115, 206
216
P305
31, 210
194
3, 196
P307
Fanto, Manolis
28, 38
Farina, Elena
208
Fasano, Stefania
30
Fasce, Francesco
65, 199
Fatone, Tiziana
85
Fattorini, Annalisa
63, 216
P266
Fauci, Eugenia
208
Favia, Rossana
204, 213
Fazi, Claudia
1
P260, P261
Fazio, Raffaella
31, 56, 210
P251, P309, P569
Fedeli, Maya
112
P310
Feltri, Maria Laura
150, 160
P103, P238, P267, P441, P754, P766
Ferini-Strambi, Luigi 29, 45, 209
P15, P184, P225, P463, P472, P622
Ferla, Gianfranco
3, 18, 114, 196
P17, P664
Fermo, Isabella
167
P214, P422, P589
Ferrara, David
193
Ferrara, Fulvio
216
Ferrari Da Passano, 28, 199
Camillo
Ferrari, Angela
64
Ferrari, Carola Iris
Ferrari, Davide
Ferrari, Giuliana
208
114, 204
87, 101
P158, P311, P699
Ferrari, Karin
2
Ferrari, Matteo
4, 215
P479
Ferrari, Maurizio
167, 171, 216
P128, P364, P582, P741
Ferrari, Patrizia
216
Ferrari, Stefano
204
P38, P274
Ferrarini, Marina
1, 8
Ferrario, Fabrizio
29, 199
Ferrario, Federica
28, 199
Ferrario, Laura
216
Ferrario, Matilde
204
Ferraro, Alessandra 114
P351
Ferreri, Andrés Jose 3, 20, 211
Maria
P255, P305, P321, P322, P323, P324,
P383, P611, P721
Ferrero, Carlo Alberto 216
Ferrero, Elisabetta
1, 11
Ferretti, Francesca
113
Ferri, Cinzia
149
Ferro, Mattia
27
Ferron, Simona
2
Ferrua, Francesca
88, 204
P13, P171
Fesce, Riccardo
167, 170
Fiacco, Enrico
196
Figini, Filippo
64, 193, 221
Filippi, Massimo
31, 51
P7, P8, P9, P10, P11, P16, P21, P44,
P57, P141, P142, P143, P189, P190,
P191, P199, P228, P276, P327, P328,
P329, P387, P415, P416, P466, P493,
P514, P533, P563, P635, P636, P637,
P638, P647, P648, P649, P695
Filippis, Susanna
204
P771
Finazzi, Renato
114, 196
Finizio, Valentina
204
P171
Finocchiaro, Claudia 208
Fiordelisi, Caterina
211
Fiore, Marina
208
Fiori, Marina
65, 199
Fiori, Rossana
194
Fiorin, Maria Chiara 29, 208
Fiorina, Paolo
113
P214, P753
Fiorino, Claudio
177
P19, P54, P126, P240, P291, P313,
P331, P332, P593, P625, P743
Fleischhauer,
Katharina
85, 93, 216
P213, P254, P256, P340, P404, P679,
P741
Flore, Marilena
216
Florea, Ioana
177
Florio, Francesca
149
Florita, Marcello
29
Fodor, Andrei
177
Foglieni, Chiara
112
P203
Foglio, Alessandra
167, 216
Fontana, Barbara
63
Fontana, Francesca
149
P76
Fontana, Raffaella
2
P333, P759
Foppoli, Marco
3, 211
P321
Forcina, Alessandra 86
Forestieri, Carmen
196, 216
Formaglio, Fabio
31, 210
Formenti, Ilaria
64, 206
Fornasiero, Eugenio 27
Forti, Maddalena
65, 199
P731
Fortis, Claudio
111, 202
Fortunato, Manuela 64, 206, 216
Fossati, Andrea
29, 208
P46, P334, P335, P336
Fossati, Marco
204
P171
Fotios, Economou
64, 193
Fousteri, Georgia
87
Fracassetti, Dario
196
Fragasso, Enrico
31
Fragasso, Gabriele
65, 193
P337, P338, P339, P576, P701
Franchini, Linda
29, 208
Franchini, Stefano
113, 206
P89
Franciosi, Gianluca
29, 208
P334
Franco, Annalisa
194
Franco, Margherita
204
François, Stephanie 85
Franzin, Alberto
28, 199
P342
Franzoni, Irene
65
Fraschini, Gianfranco 151, 196
P675
Frascoli, Cristina
199
Frasson, Paola
208
Frati, Elena
65
Fratta, Pietro
149
Frau, Giovanna
194
P245
Freschi, Massimo
216
P42, P56, P70, P118, P120, P172,
P240, P641, P659, P706
Fresi, Francesco
29, 208
Frigoli, Enrico
192
Frittoli, Marta
88
Frontino, Giulio
115, 204
Fucci, Rita Nunzia
149
Fumagalli, Francesca 88
P198
Fumagalli, Luca
202
P347, P570
Fumero, Andrea
193
P65, P555
Furci, Lucinda
112
Furlan, Federico
216
Furlan, Roberto
30, 50
P81, P124, P192, P309, P646, P720
Fusi, Francesco
204
P580, P631
Fusi, Maria Grazia
X
G
Gabellini, Daniela
Gabellini, Davide
Gabriele, Angela
Gaetani, Massimiliano
63
85, 92
208
167
P206
Gagliani, Nicola
114
P351
Gagliardi, Filippo
28
Gagliardi, Marco
65, 199
Gaiera, Giovanni
202
Gaietta, Sara
208
Gaj, Nicolò
208
Galanti, Andrea
193
P65
Galantucci, Sebastiano 31, 210
Galbiati, Silvia
167, 216
P128, P479
Galimberti, Elisa
29, 208
Galimberti, Gabriella 64, 206
P230
Gallese, Roberta
208
Galli, Alessandra
216
Galli, Andrea
113, 202
P155
Galli, Elisa
211
Galli, Franco
216
Galli, Laura
113, 202
P236, P530, P547, P694, P700
Galli, Rossella
85, 94
P494
Galliani, Alberto
XXXI
AUTHOR INDEX - 279
Gallina, Andrea
4, 215
P117, P118, P120, P162, P164, P259,
P278, P355, P659, P660, P661, P705
Gallivanone, Francesca 177, 211
Gallotta, Giulia
202, 216
P154
Galluccio, Elena
63
P681
Galvano, Enza
213
Gambaro, Margherita XXXI
Gandini, Luca
204
Gangemi, Fabrizio
112
Garavaglia, Claudio 112
Garavaglia, Elisabetta 4, 204
P356
Garbetta, Gisella
204
Garcia-Manteiga, Jose 149
P482
Garuti, Elda
213
Garzetti, Livia
30
Gasparri, Anna
2
Gatti, Davide
211
Gatti, Elisa
216
Gatti, Roberto
29, 46
P637
Gattillo, Salvatore
216
Gavinelli, Chiara
29
Gazzetta, Paolo
3
Gelera, Emma
192
Gemma, Marco
28, 199
P307, P359, P360
Generoso, Luca
112
Genovese, Pietro
86
Genovese, Silvia
63
Gentile, Cinzia
4, 204
P356
Gentilomo, Andrea
X
Gentner, Bernhard
86
P23, P361, P362
Gerasi, Laura
150
Gerevini, Simonetta 177, 199
P32, P215
Gerli, Chiara
194
P253, P773
Gerosa, Stefano
193
P337
Gherlone, Enrico
151, 162
P6, P247, P248, P249, P250, P617,
P696, P717
Gherner, Daniela
3, 199
Ghezzi, Massimo
215
Ghezzi, Silvia
113
Ghia, Paolo
1, 8
P134, P260, P261, P382, P426, P554,
P736
Ghidinelli, Chiara
31, 210
Ghidinelli, Monica
150
Ghidoli, Nadia
216
P467
Ghidoni, Matteo
65, 199
Ghio, Domenico
213
Ghirardelli, Luca
3
P37, P756
Ghitti, Michela
167
Giacalone, Giacomo 210
Giacomini, Andrea
193
Giannandrea, Maila 28
P698
Giannelli, Serena
28
Giannese, Francesca 112
Gianolli, Luigi
177, 181, 211
P255, P284, P337, P367, P368, P599
Gianotti, Nicola
113, 202
P102, P155, P236, P288, P666, P694,
P700
Giardelli, Alessandra 204
Giardina, Paolo
204
Giarolli, Laura
29, 208
P334
Giatsidis, Silvia
65, 199
Giglio, Fabio
3
Giglio, Manuela
177, 211
Gilardi, Maria Carla 177, 211
P72, P182, P368, P468, P505
Gilardini, Cristina
196
Ginex, Valeria
208
Gioia, Giuseppe
196
P216
Gioia, Lorenzo
28, 199
Gioia, Luigi
199
P360
Giordano Resti,
65, 199
Antonio
P731
Giordano, Leone
3, 199
Giorgi, Emiliano
196
Giovanardi, Michele 3, 194
P42, P177
Giovannini, Elisabetta 211
Giovannini, Monica 4, 211
P55
Girardi, Anna Maria 216
Gismano, Elena
64
Giudici, Daniela
196, 217
P570
Giuliani, Serena
208
Giussani, Antonella 3, 196
P175, P480
Giustacchini, Alice
86
P361
Giusti, Maria Cristina 28, 208
Giusto, Elena
30
Gobbo, Livia
112
Godino, Cosmo
64, 193
P369
Godio, Cristina
Golzi, Valeria
Gomarasca, Silvia
Gonzalez-Rosa, Javier
Goudy, Kevin
Govi, Silvia
Grandi, Elisabetta
Granetto, Michele
Granieri, Camilla
Grassi, Stefano
Grassini, Greta
Greco, Elena
Greco, Raffaella
Gregorc, Vanesa
85
208
65
30
87
3
199
XII
113
216
3, 216
211
86
4, 22, 211
P375
Gregori, Silvia
87, 103
P376, P587
Gremizzi, Chiara
113, 206
Gremmo, Annamaria 3, 194
Grimaldi, Adelmo
211
P474
Grimaldi, Antonio
193, 221
P420, P710
Grimaldi, Salvatore
215
Grioni, Emanuela
216
Grioni, Matteo
112
P172
Grispigni, Crispino
196
Gritti, Angela
87, 100
P377, P494, P495, P605, P761
Grogan, Pauline
64, 115
Grohovaz, Fabio
27, 36, 185, 186
Grosso, Stefano
2
P626
Guarisco, Lauretta
65, 199
Guarneri, Maria Pia 204
Guarnerio, Ylenia
1
Guarnieri, Fabrizia
27
Guazzoni, Giorgio
215
P53, P70, P116, P117, P162, P163,
P164, P240, P278, P291, P326, P355,
P550, P660, P661, P662, P705, P706
Guerriero, Roberta
31, 210
Guffanti, Monica
202
Guggiari, Elena
3, 211
Guglielmi, Barbara
113, 206
Guidotti, Andrea
65, 193
P460, P461
Guidotti, Luca G.
112, 114, 125, 134
P158
Gulletta, Simone
192
P665
Guslandi, Mario
114, 133, 196
P307
Gusmini, Simone
213
P381, P519
Guzzoni, Samantha 30
H
Hasson, Hamid
Ibrahim
Hedlund, Petter
Hegde, Nagabhooshan
Hellriegel, Christian
Heltai, Silvia
Henin, Marta
Hess-Michelini,
Rodrigo
Hidetoshi, Hoshia
Huichalaf, Claudia
113, 202
P236
4
112
1
111
29, 208
112
P56
85
85
I
Iabichino, Cristiana
Iaci, Giuseppe
Iadanza, Antonella
213
193
28, 185
P184, P359
Iannaccone, Sandro 28, 208
P622
Iannacone, Matteo
112
Ianniello, Margherita XII
Ielasi, Alfonso
64, 193
P12, P363
Ierardi, Rossella
87
Ieri, Rossella
216
P467
Indrigo, Marzia
30
Innocenzi, Anna
85
Insacco, Chiara
28, 199
Introini, Maria Antonia 216
Introini, Ugo
65, 199
Inuggi, Alberto
30
Isotti, Luca
XII
J
Jachetti, Elena
112
P56
Jankaricova, Marie
151
Janus, Agnieszka
1
Jofra Hernandez, Raisa 87
P668
Jofra, Tatiana
114
P746
Judica, Elda
31, 210
K
Kahlberg, Andrea
Kajaste-Rudnitski,
Anna
65, 194
P402, P487, P488
113
AUTHOR INDEX - 281
Kara, Sinem
Kusamura, Shigeki
30
3, 216
Lazzarin, Adriano
L
La Canna, Giovanni
193
P246, P420, P450, P710
La Gioia, Sara
31, 210
La Marca, Rosa
31
La Viola, Salvatore
208
Labbate, Laura
216
Lacerenza, Marco
28
Lage Crespo, Carolina 111
P531
Laino, Giovanni
193
Lambiente, Camilla 216
Lamonaca, Grazia
216
Lampasona, Vito
167
P5, P92, P309
Landoni, Claudio
177, 211
P367, P368, P548, P588
Landoni, Giovanni
65, 194
P83, P138, P239, P244, P245, P246,
P253, P320, P427, P428, P517, P518,
P772, P773, P774, P775
Lania, Caterina
215
P706
Lanterna, Claudia
2
Lanzani, Chiara
151, 206
P732
Lanzi, Roberto
213
Lanzi, Roberto
64, 206
Lanzoni, Paola
177, 211
Lapenna, Elisabetta 193
P710
Lapio, Barbara
XII
Larato, Daniela
196
Laterza, Cecilia
30
Latib, Azeem
64, 193
Mohamed
P203, P220, P363, P430, P431, P432,
P434
Latino, Rosanna
216
Lattanzi, Annalisa
87
P495
Lattanzio, Rosangela 65, 199
Lattuada, Guido
63
P595, P596, P597, P601
Laurenzi, Andrea
64, 206, 216
Lavazza, Fanny
193
Lavorato, Maria
216
Vittoria
Lavorgna, Giovanni 167
P534
Lazzari, Chiara
4
Leggieri, Carlo
Legnani, Giulio
Legorini, Francesca
Leiva, Andrea
Lenti, Elisa
Lenzi, Sara
Leo, Loredana
Leocani, Letizia
Leopizzi, Emanuela
Leporati, Ennio
Lepore, Marco
Lesma, Arianna
Levi, Sonia
Liberatore, Giuseppe
Licata, Giada
Lidonnici, Maria Rosa
Lillo, Flavia
Limardo, Pietro
Liperi, Laura
Lira Luce, Francesca
Liu, Jaron
Locatelli, Clara
Locatelli, Marco
Locatelli, Massimo
Locatelli, Simona
Locci, Michela
Logaldo, Davide
Lombardo, Angelo
Lombardoni, Carlo
Longaretti, Roberta
Longari, Stefania
Longo, Alessandro
Longobardi, Barbara
Longoni, Giulia
Longoni, Laura
Longoni, Matteo
Longoni, Simona
Lopalco, Lucia
Lopalco, Sara
Loperfido, Francesco
Lopez, Ignazio Diego
Lorè, Nicola Ivan
Lorenzetti, Isabella
111, 113, 202, 203, 221
P28, P63, P155, P236, P242, P302,
P347, P411, P436, P445, P545, P547,
P551, P552, P586, P694, P700, P725,
P769
197
P138
216
65, 199
2
1
221
167
30, 48, 210
210
63
112
215
27, 38
P153, P438, P693
210
3, 211
87
221
P1, P586
3, 199
29, 208
3, 199
P440
149
29, 208
29, 208
216
XII
87
P442, P476
65, 194
P204, P205
86
167, 216
185
P85
211
XXXI
177
31, 210
177, 211
193
4
111, 122, 202
P1, P131, P528, P737
28
65, 199
30, 210
P197
111
30
Lorenzi, Cristina
29
P564
Lorenzi, Mara
63
Lorioli, Laura
88
Lorusso, Anna
27
Losa, Andrea
215
Losa, Marco
28, 199
P448, P670
Losio, Claudio
177, 213
Lucarelli, Barbarella 87
Lucca, Adelio
29, 208
Luchini, Stefania
204
Lucotti, Pietro
64
P450, P681
Lughezzani, Giovanni 4, 215
P130, P395, P399, P451, P452, P549,
P779
Lukacs, Anna
111
Lunghi, Francesca
3, 211
P333
Luparini, Francesco 3, 196, 216
Lupo Stanghellini, Maria Teresa
86, 211
P213, P741
Luzi, Livio
63, 67
P24, P51, P63, P303, P311, P595,
P596, P597, P601
M
Maccagnano, Carmen 4, 215
Maccagni, Davide
193
Maccalli, Cristina
2
P454
Macchi, Andrea
65, 193
Macco, Romina
27
Madaschi, Sara
64, 206
Maddé, Claudia
211
Francesca
Maderna, Claudio
87
Maestranzi, Gisella
65, 199
Maestroni, Anna
63
Maestroni, Silvia
63
Maffei, Cesare
29, 45, 208
P334, P335, P336
Maffi, Paola
115, 138, 206
P51, P341, P464
Maga, Tommaso
215
Magagnotti, Cinzia
167, 216
Maganetti, Nicola
216
Maggioni, Daniela
2
P333, P759
Magistretti, Paola
115
Magnani, Chiara
87
P376
Magnani, Giuseppe 31, 54, 210
Magnani, Patrizia
177, 211
Magnani, Zulma
86
P213
Magri, Laura
85
Magrin, Silvio
193, 194
P517, P518
Maida, Giorgio
65, 192
Mailhac, Alessandra 193
Maillard, Myriam
202
Mainetti, Eliseo
196
Mainetti, Lara
112
Mainetti, Marta
112
Maiorino, Chiara
30
Maisano, Francesco 65, 193
P239, P370, P420, P459, P460, P461
Maj, Giulia
65
P239, P518, P581
Malabarba, Lucia
216
Malaguti, Alessia
29, 208
Malato, Simona
3
Malegori, Angela
65, 199
Malgaroli, Antonio
27, 37
P257
Malnati, Mauro S.
111, 119
P125, P316
Malosio, Maria Luisa 115, 137
P309, P464
Maltecca, Francesca 167
P465
Mammi, Silvia
31, 210
Mamo, Daniela
197
Manca, Eleonora
211
Manca, Mario
193
Mancini, Nicasio
216
P135, P136, P467
Mancini, Niky
196
Mancino, Marilena
2
Manclossi, Chiara
199
Manconi, Mauro
29, 209
P622
Mandelli, Carlo
28, 199
P469
Mandelli, Davide
196
Mandelli, Giacomo
87
Mandelli, Maria Rosa XII
Mandelli, Massimo
213
Manenti, Rosa
28
Manfredi, Angelo A. 85, 94
P38, P79, P136, P152, P286, P287,
P325, P443, P471, P501, P502, P503,
P606
Mangiavini, Laura
151, 196
P675
Mangili, Giorgia
4, 20, 204
P356, P474, P688
Mangili, Paola
177
P291, P593
Manitto, Maria Pia
65, 199
AUTHOR INDEX - 283
Mannella, Valeria
Mannu, Claudio
Mantegani, Paola
Mantovani, Elena
Manunta, Paolo
Manzo, Teresa
Manzoni, Marco
Federico
Mapelli, Paola
Mappa, Silvia
Marabelli, Giuseppina
Maranta, Francesco
Marassi, Alberto
Marcatti, Magda
Marchettini, Paolo
Marchi, Monica
Marchisio, Pier Carlo
Marcone, Alessandra
Marelli, Guido
Marelli, Sara
Marenzi, Karen
Marescotti, Diego
Margittai, Eva
Margonato, Alberto
Mari, Gilberto
Mari, Silvia
Mariani, Alberto
Mariani, Elisabetta
Mariani, Federica
Mariani, Samanta
Marinaro, Cinzia
Marinelli, Marcello
Marinelli, Matteo
Marino, Giovanni
Marinosci, Alessandro
Marinozzi, Maria
Chiara
Marktel, Sarah
Maroli, Giovanni
Marone, Enrico Maria
Marrocco-Trischitta,
Massimiliano
167
P206
211
112
65, 199
151, 163, 206
P75, P264, P419, P475, P677, P678,
P732
112
64, 206
P341
211
3
216
65
196
3, 211
31, 210
P569
64, 206
P264, P344
2
28, 208
P354, P622, P752, P757, P758
204
29
P184
64, 204
112
149
65, 77, 193
P12, P337, P338, P339, P576, P701
196
167
3, 196
P285, P480, P497, P716
149
P250
216
112
P18
30
216
150
65, 193, 194
P244, P253, P774
206, 216
P287
216
P154, P155
86, 204
P13, P14, P171, P679
85
65, 193, 194
P204, P402, P483
65, 194
P402, P457, P486, P487, P488
Marsiglio, Elena
Martani, Carla
Martina, Elisabetta
Martinelli, Chiara
Martinelli, Cristina
Martinelli, Vittorio
Martinelli-Boneschi,
Filippo
Martinenghi, Carlo
Martinenghi, Sabina
Martino, Gianvito
Martoglio, Alberto
Martulano, Marilena
Marturano,
Emerenziana
Marzi, Alessandra
Marzorati, Patrizia
Mascia, Daniele
Masciullo, Corrado
204
196
65, 199
63
29
31, 53, 210
P57, P228, P365, P492, P493
31, 210
P493, P757
213
P381
115, 206
P339
27, 30, 49
P39, P124, P192, P309, P605, P606,
P607, P646, P686
XII
211
3
192
150
65, 194
150
P728
Masiello, Valeria
177, 211
Masperi, Carla
XXXI
Massani, Simona
65
Massimino, Luca
27
Mastaglio, Sara
86
P404
Matafora, Vittoria
149
P500
Matarrese, Mario
177, 211
P761
Mattarucchi, Roberta 3, 86
Mattioli, Cristina
199
Matuska, Stanislav
28, 199
P623
Mauceri, Paolo
65, 199
Maugeri, Norma
65
P325, P501, P502, P503
Mauri, Anna
216
Mauri, Simona
216
Mauro, Fabio
204
Mavilio, Fulvio
150, 158
P178, P311, P350, P496, P591
Mazza, Elena
4, 211
P629, P630
Mazzeo, Lucio Aniello 28
Mazzi, Benedetta
216
P154, P741
Mazzi, Ilaria
216
Mazzieri, Roberta
86
Mazzoleni, Stefania
85
Mazzone, Patrizio
192
P665
Mazzucchelli, Renata
Ilde
Mazzuconi, Roberts
Meani, Alessandro
Meani, Renato
Medaglini, Stefania
Medone, Marzia
Melandri, Marco
Meldolesi, Jacopo
87
P298
X, XXXI
31
196
31, 210
28, 199
206
27, 35
P218, P262, P414, P698, P703
Meli, Annalisa
29, 199
Melissano, Germano 65, 193, 194
P36, P204, P205, P402, P486, P487,
P488, P508, P509, P510, P511
Melisurgo, Giulio
194
P457
Mellone, Renata
213
P303
Melloni, Giulio
3, 194
P42, P176, P177, P216, P512
Meloni, Carlo
193
Melzi, Lisa
65, 199
Melzi, Raffaella
115
P158, P464
Memoli, Massimo
113, 206
Menegon, Andrea
185
Menichini, Raffaele
211
Mennella, Roberta
194
P518
Meoni, Massimiliano XII
Merati, Valentina
111
Mercalli, Alessia
115, 196
P24, P158
Merello, Maria
210
Merlini, Federica
114, 196, 216
Merlino, Lino
206
Meroni, Titti
XII
Meschi, Franco
64, 73, 204
P92, P447
Messa, Maria Cristina 177
P304, P367, P456, P474, P588
Messa, Massimo
193
Angelo
Messaggio, Elisabetta 151
P419, P732
Messina, Graziella
85
P424, P515, P516
Messina, Melissa
65, 194
P517, P518, P772
Mezzadri, Umberto 196
Mezzi, Gianni
3, 196
P519
Micali, Nicola
150
P520
Micheletti, Luisa
27
Miggiano, Chiara
211
Mignogna, Giovanna 63
P728
Mignogna, Maria Lidia 28
Mikulak, Joanna
27
P523
Milan, Enrico
149
Milani, Davide
28
Milani, Federica
3, 196, 216
Milazzo, Rita
87
Milesi, Jacopo
65, 199
Milesi, Rita
208
Miluzio, Annarita
2
P524
Minici, Claudia
112
Minicucci, Fabio
31, 56, 210
Minotti, Maria Grazia 177, 211
Miotto, Paolo
112
P525
Miracoli, Giuseppe
XII
Misci, Paolo
31
Miserocchi, Elisabetta 65, 199
P224, P527, P530
Mizzi, Anna Maria
65
P773, P774
Mocci, Alessio
3, 196, 216
Modorati, Giulio
65, 199
P224, P527, P530
Mogliani, Patrizia
XII
Moi, Davide
86
P618
Moiola, Lucia
31, 210
P228, P365, P614, P635
Moizo, Elena
197
Molgora, Michela
64, 204
Mollica, Luca
167
P131, P206
Molteni, Laura
115, 206
Molteni, Raffaella
111
P531
Monaco, Fabrizio
194
P245, P775
Mondino, Anna
112, 126
P404
Monello, Alberto
211
Monno, Antonella
85
P38
Montanaro, Claudia 65
P338
Monterisi, Cristina
177, 211
Montesano, Anna
63
Monteverde, Stefania 85
P516
Monti, Giacomo
65
P138, P140, P772
Monti, Lucilla D.
63, 70
P279, P450, P534, P681
AUTHOR INDEX - 285
Montini, Eugenio
Montoli, Serena
Montorfano, Matteo
Montorsi, Francesco
Monzani, Elena
Mora, Stefano
87, 101
P178, P350, P536
4, 204
64, 193
P122, P203, P363
4, 22, 215
P43, P45, P47, P52, P53, P70, P73,
P74, P90, P109, P115, P116, P117,
P118, P120, P159, P160, P161, P162,
P163, P164, P165, P166, P167, P168,
P209, P210, P217, P240, P243, P259,
P278, P318, P326, P355, P380, P386,
P388, P393, P395, P396, P397, P399,
P400, P408, P409, P451, P452, P478,
P526, P529, P537, P538, P539, P540,
P544, P557, P613, P624, P628, P639,
P641, P642, P643, P659, P660, P661,
P662, P683, P684, P705, P706, P770,
P779, P780, P781, P782, P783, P784,
P785, P786
27
63, 70, 204
P208, P268, P284, P541, P542
208
Moreno Granados,
Gema Moelia
Morero, Silvia
197
Marolina
Mores, Federica
199
Moresco, Rosa Maria 177, 211
P56, P433, P761
Mori, Silvia
150
P500
Moriggia, Stefano
193
Moro, Andrea
28
P719
Moro, Gianluigi
63, 196
Morosini, Sara
85
Morsica, Giulia
113, 202
P545, P546, P547
Mortini, Pietro
28, 42, 199
P129, P305, P342, P448, P632
Motta, Andrea
216
Motta, Chiara
208
Motta, Francesca
113, 206
Motta, Micaela
177, 211
P548
Movalli, Mariagrazia 29, 208
Mrak, Emanuela
63
P158, P297, P668
Mucci, Milena
197
Mukenge, Mvunde
3, 196
Mulas, Ines
196
Mungo, Maurizio
199
Muraro, Ornella
XII
Muriana, Piergiorgio 3, 194
Murino, Marcello
193
Musco, Giovanna
Musner, Nicolò
Mussardo, Marco
Musso, Alessandra
Muzio, Luca
Muzio, Marta
Muzza, Andrea
167, 172
P206
149
64, 193
111
P609
30
P192, P646
1, 9
P553, P554
199
N
Nai, Antonella
150
P690
Naio, Rita
192
Naldini, Luigi
85, 86, 98, 99
P23, P26, P86, P127, P173, P178,
P198, P275, P281, P350, P361, P476,
P536, P556, P604, P618, P761
Nano, Rita
115, 140
P71, P464
Napoletano, Anna
112
Napoletano, Francesco 28
Napolitano, Sara
86, 204
P171
Nascimbene, Simona 193
P65
Natali Sora, Maria
31
Grazia
Nava, Luciano
4, 215
Negri, Giampiero
3, 194
P216
Negri, Giulio
XII
Negrini, Sara
27
Negro, Aurora
2
P759
Neguembor,
85
Marie Victoire
Neri, Margherita
87
Nicoletti, Roberto
213
P36, P381, P630
Nifosi, Jacopo
3
P37
Nigro, Annamaria
30
Nigro, Elisa
149
P560
Nisoli, Ilaria
28
Nitti, Cinzia
193
Noè, Anna
204
P171
Notaristefano, Chiara 3, 196
P716
Novati, Roberto
202
Novella, Liliana
208
Noviello, Maddalena
Nozza, Silvia
Ntoufa, Stavroula
Nuzzaco, Grazia
Nuzzi, Massimiliano
86
113, 202
1
31
194
O
Occhi, Francesca
Occhi, Simona
Odazio, Veronica
Ogliari, Anna
Ogwang, Martin
Oldani, Alessandro
Oliva, Laura
Olivieri, Stefano
Oppizzi, Michele
Orellana, Daniel
Orfanelli, Ugo
Origoni, Massimo
Orlandi, Giacomo
Ornaghi, Francesca
Orombelli, Lisa
Orsenigo, Elena
Ortolano, Enrico
Osnago, Ombretta
Ossi, Cristina
Ottolina, Jessica
Ozino, Stefania
114, 204
P580
28
65, 199
29, 208
P48
221
29
149
P76
167
65, 193
P12
30
149
114, 131, 204
P565
211
149
XII
3, 196
P756
216
192
216
P467, P570, P726
4
29
P
Pacchioni, Manuela
Paesano, Pierluigi
Paganelli, Michele
Pagani, Alessia
Pagani, Antonella
Pagani, Elisabetta
Paganoni, Giorgio
Paglino, Gabriele
Pajoro, Ursola
Pala, Maria Grazia
211
213
114, 196
P264, P344, P358, P610
150
P690
63
P690
31
P7, P190, P191, P514, P638, P647
28, 199
P623
192
P665
211
193
P450
Pala, Mauro
Palini, Alessio
Palmigiano, Angela
Palmisano, Ilaria
85
185, 187
167
167
P692
Palmisano, Marilena 150
Palmisano, Michela
111
Palonta, Francesca
199
P713
Paloschi, Vera
113, 206
P34
Palumbo, Lidio
211
Palumbo, Roberta
149
P573, P619
Panacci, Nicoletta
64, 204
Panattoni, Martina
111
Pancaldi, Alessandra 193
Panigada, Fausto
29, 208
Panizza, Pietro
177, 213
Pannese, Maria
150
Panzacchi, Andrea
177, 211
Panzeri, Maria Carla 185
Papa, Ilenia
216
Papa, Marco
193
P576
Papale, Alessandro
30
P578
Papaleo, Enrico
64, 74, 204
P579, P580
Pappalardi, Brigida
177, 211
Pappalardo, Federico 65, 194
P253, P581, P774
Pappone, Alessia
65, 192
Pappone, Carlo
65, 192
P174, P568, P582, P583, P665
Pardi, Ruggero
111, 118
P18, P531, P753
Pardini, Celia
167
Paredi, Giulia
29
Parezanovic, Vanda XII
Parlatini, Valeria
29, 208
Parma, Barbara
204
P497
Parma, Lia
216
Parmiani, Giorgio
1, 2, 11
P389, P454, P711
Parolini, Danilo
196
Parolo, Caterina
213
Paroni, Moira
111
P105
Parutto, Diana
211
Pasetti, Marcella
177, 211
Pasi, Federica
64, 204
P183
Pasi, Massimo
151
P617
AUTHOR INDEX - 287
Pasqualetto, Elena
149
P76
Passaretti, Sandro
114, 196
P235
Passerini, Gabriella
216
Passerini, Laura
87
P23, P292
Passoni, Arianna
204
P232
Passoni, Paolo
177, 211
P629, P630, P745
Pastore, Matteo Rocco 115, 206
Pastori, Claudia
111, 202
Paterra, Rosina
27
Patricelli, Maria
216
Grazia
Pattarini, Elisabetta 63, 216
Pavan, Giulia
31, 210
Pavani, Giulia
63
Pavoni, Ernesto
150
Pazzi, Annamaria
202, 216
Peccatori, Jacopo
86, 211
P110, P213, P741
Pecciarini, Lorenza
216
P721
Pedrazzi, Maria Rosa XII
Pedretti, Elisa
111
Pedrigi, Cristina
193
Pelizzoni, Ilaria
27
Pella, Francesca
4, 204
Pellegatta, Marta
150
Pellucchi, Federico
4, 215
Pema, Monika
150
P765
Pengo, Niccolò
149
P76
Pennucci, Roberta
27
Pepe, Gino
211
P284
Perani, Daniela
28, 43, 211
P4, P94, P95, P156, P182, P590,
P622, P655, P719
Perani, Laura
85
Perduca, Alessandra 204
Perego, Elisabetta
31, 210
Stefania
Perego, Jacopo
211
Perego, Marco
1
Peretti, Elena
64, 206, 216
P230
Peretti, Giuseppe M. 151, 164, 196
P675, P763
Peretti, Umberto
4
Perini, Oriana
86, 216
Perna, Lucia
177
P19, P331, P593
Perotti, Valeria
196
Perrotta, Cristiana
86
P81
Perseghin, Gianluca 63, 68
P63, P269, P303, P594, P595, P596,
P597, P601
Persichini, Luisa
151, 206
Persico, Paola
204
P274
Perticone, Francesca 64, 206
Perucca, Simone
150
P671
Peruzzotti Jametti,
30, 210
Luca
P39
Pesce, Elisa
2
Pesenti-Gritti, Paola 29, 208
P48
Pessina, Patrizia
85
Petralia, Giovanni
4, 215
P70
Petrella, Giovanna
211
Petrelli, Alessandra
113
Petrolini, Melissa
31
Petrone, Maria Chiara 3, 196
P519
Petrone, Micaela
4, 204
Pezzani, Valeria
208
Piani, Cecilia
64, 206
Piantoni, Lara
31
Piatti, Piermarco
64, 72, 206
P450, P681
Picariello, Marco
XII
Picchio, Maria
177, 211
P56, P304, P367, P368, P474, P588,
P599, P688
Piccini, Flavia
216
Piccioni, Lucia Oriella 29, 199
P360, P713
Piccoli, Susanna
199
Picozzi, Piero
28, 199
P32, P321, P342, P367, P530, P600
Piemonti, Lorenzo
115, 136, 196
P24, P158, P464, P601
Pieralli, Sandra
199
Pieri, Alessandro
208
Pierro, Luisa
65, 199
Pievani, Michela
31
P602
Pilla, Lorenzo
2
Pintonello,
185
Maria Luisa
Piraino, Daniela
64, 193
Pirola, Barbara Maria 216
Pirola, Serena
204
Pirovano, Adele
29
P60, P470, P481
Pisa, Viviana
86
Piscopo, Maria
Antonietta
Pistis, Giorgio
204
150
P728
Pistocchi, Anna
85
P672
Pistoni, Mariaelena
85
Pitea, Marco
204
Pizzamiglio, Carlo
177
Pizzetti, Giuseppe
193
Pizzi, Sara
177
Pizzo, Riccardo
XXXI
Pizzocolo, Cecilia
202
Plati, Tiziana
87
P198, P604
Pluchino, Stefano
30, 50
P39, P605, P606, P607, P686
Podini, Paola
27
P197, P414
Poggi, Alessandra
213
Poggi, Antonella
31, 210
Poggiali, Erika
150
P151
Pogliaghi, Manuela
113, 202
Poitelon, Yannick
150
Poletti, Sara
29
P58, P185
Poletti, Valentina
150
Poli, Davide
28, 199
Poli, Guido
112, 122
P1, P18, P179
Politi, Ernestina
29, 208
Politi, Letterio
177, 181, 199
Salvatore
P761
Poloniato, Antonella 64, 204
Polverigiani, Silvia
185
Pontesilli, Silvia
28, 199
P85, P747
Pontiggia, Adriana
29, 208
Pontillo, Marina
216
Pontiroli, Barbara
65
Ponzi, Elena
XII
Ponzoni, Maurilio
216
P158, P213, P229, P255, P305, P321,
P323, P361, P390, P404, P476, P536,
P606, P721, P759
Porrello, Emanuela
XXVI, 30
Porrino, Lucy
113, 202
Porro, Federico
221
Potenza, Maria Teresa 204
Pozza, Guido
X
Pozzi, Alessandro
151, 196
P675
Pozzi, Benedetta
1
Pozzi, Federica
211
Pozzi, Paola
XII
Pozzobon, Gabriella
64, 204
P440
Prada, Ilaria
27
P414
Pradella, Alessandra 208
Praderio, Luisa
113, 206
P286
Prati, Matteo
65, 199
Premoli, Sergio
208
Presti, Francesca
196
Previtali, Stefano
30, 49
Carlo
P91, P197, P435
Preziosa, Paolo
31
Privitera, Daniela
31
P309
Privitera, Ylenia
65, 193
Protti, Maria Pia
112, 126
P711
Provasi, Elena
86
P404
Psacharopulo, Daniele 65, 194
Puccetti, Patrizia
193
Pucci, Ferdinando
86
P23, P618
Puglisi, Armando
3, 194
P176, P177
Pulitanò, Carlo
196
P17, P272, P273, P664
Pultrone, Cinzia
85, 113
Pusterla, Tobias
149
P573, P619
Putignano, Antonella 3
Puzzovio, Maria
63, 204
P541
Q
Quario, Lorenzo
Quartagno, Rita
Quattrini, Angelo
196
206
30, 47
P91, P111, P197, P465, P491
194
Quattrocchi, Tiziana
Giuseppa
Querques, Marialuisa 151, 206
Quilici, Giacomo
167
R
Rabaiotti, Emanuela
Raber, Marco
Racanicchi, Leda
Racca, Sara
Racchetti, Gabriella
4, 204
215
P662
115
216
27
P218, P703
AUTHOR INDEX - 289
Raccosta, Laura
2
P333, P759
Radaelli, Daniele
29
P58, P59, P61
Radaelli, Maria Grazia 64, 206
Radaelli, Marta
31
P492
Radinovic, Andrea
65, 192
P582, P665
Ragogna, Francesca 63
P595, P596, P597, P601
Rainone, Francesco
151, 206
P34
Rama, Paolo
28, 41, 199
P224, P301, P425, P527, P530, P591,
P623
Ramella, Barbara
3, 199
Ramoni, Andrea
65, 199
Rampoldi, Luca
150, 161
P64, P283, P472, P671
Ranghetti, Anna
86
Ranzani, Marco
87
P536
Ranzato, Elia
2
P626
Rapallo, Maria Pia
213
Rapisarda, Eugenio
177, 211
P72
Raschi, Alessandra
193
Ratti, Deborah
202
Ratti, Francesca
3, 196
Ratti, Maria Monica 208
Raucci, Angela
149
Ravanetti, Lara
112
Ravizza, Alfredo
199
Rebagliati, Paola
XII
Recanati, Paola
3, 199
P714
Recchia, Alessandra 150
P311, P350, P496
Redaelli, Anna
204
Redaelli, Chiara
167
Regali, Laura
65, 199
Reichlin, Massimo
X
Reineke, Raffaella
196
Reiss, Laura
XII
Reither, Klaus
221
Reni, Michele
4, 21, 211
P107, P108, P321, P629, P630, P745
Resnati, Massimo
150
Restuccia, Umberto 149
P308
Riba, Michela
167
Ribecca, Antonella
199
Riberio, Ricardo
221
Riccaboni, Roberta
29
P58
Ricci, Vincenzo
Ricciardi, Sara
Riccitelli, Gianna
211
28
31
P514, P638
Ricupito, Alessia
112
Ridolfi, Cristina
3, 196
Rigamonti, Andrea
115, 204
Rigamonti, Elena
85
Rigamonti, Marco
177, 211
Rigamonti, Nicolò
112
P172
Rigamonti, Riccardo 211
Rigatti, Lorenzo
215
Rigatti, Patrizio
215
P70, P116, P117, P118, P120, P163,
P240, P259, P278, P355, P659, P660,
P661, P662, P705, P706
Righi, Claudio
177, 199
Rigo, Francesca
167, 216
Rinaldi, Rosanna
185
Ripamonti, Anna
87
Ripamonti, Maddalena 27
P257
Riva, Elisabetta
XII
Riva, Nilo
30
Rivoltini, Paola
196
Rizzato, Elisa
204
Rizzi, Chiara
112
P179
Rizzo, Nathalie
216
Rocca, Alda
28
Rocca, Maria Assunta 31, 52
P8, P10, P57, P143, P189, P190,
P191, P329, P416, P466, P493, P514,
P635, P636, P637, P638, P648
Rocchetti, Simona
216
Rocchi, Martina
185, 216
Rocchini, Lorenzo
4, 215
P660, P661, P662
Rodegher, Mariaemma 31, 210
P191, P228, P492, P493
Rodighiero, Maria
213
Grazia
Rofena, Simone
64, 204
Rognone, Alessia
4, 211
P629, P630
Rojo, Carmen
65, 199
Rolandi-Maciotta,
85
Simona
Rolla, Serena
216
Roma, Andrea
XXXI
Romano, Maria
XXXI
Romano, Michele
112
Cosmo
Romano, Silvana
211
Romano, Vittorio
193
Romero, Lilian
216
Roncarolo, Maria
Grazia
Ronchetti, Clara
Ronchi, Paola
Ronchi, Paolo
Rondinelli, Beatrice
Ronfani, Lorenza
Ronzoni, Monica
Ronzoni, Riccardo
Rosa, Isabella
Rosa, Susanna
Roselli, Emanuela
Anna
Rossetti, Maura
Rossi, Carlo
X, XII, XXI, 86, 87, 88, 97, 102, 104,
204
P13, P14, P26, P49, P50, P99, P171,
P178, P198, P292, P351, P376, P442,
P476, P668, P679, P741, P746
113, 202
216
208
2
185
P709, P768
4, 211
149
65
64, 204
P183
87
87
211
P286, P287, P645
Rossi, Claudia
87
Rossi, Erica
208
Rossi, Gemma
3
Rossi, Giuliana
85
Rossi, Michela
65, 199
Rossi, Paolo
31, 210
P637, P734, P735
Rossini, Alessandro
64, 206, 216
Rossini, David
208
P412
Rossini, Silvano
86, 97, 216, 219
P741
Rossodivita,
193
Alessandra
P450
Rossoni, Gilda
4, 211
Rovani, Stefano
213
Rovelli, Elisabetta
27
P153
Rovelli, Rosanna
64, 204
Rovere-Querini,
85, 94
Patrizia
P38, P87, P88, P152, P179, P183,
P286, P287, P325, P443, P444, P471,
P501, P502, P503, P606
Roveri, Luisa
31, 210
Rowe, Isaline
150
P295, P765
Rozza, Lucia
211
Rubinacci, Alessandro 63, 69
P158, P297, P651, P668, P669, P728
Ruffini, Chiara
29, 208
Rugarli, Claudio
X
Ruggeri, Annalisa
86
Ruggeri, Laura
65
Rusconi, Vega
113, 202
Russo, Alberto
XXXI
Russo, Gianni
Russo, Vincenzo
64, 204
P69, P268
2, 12
P93, P333, P404, P759
S
Sabbadini, Maria
Grazia
Saccà, Antonino
Sacchi, Angelina
Sacchi, Luisa
Sacchi, Stefania
Sacco, Vincenzo
Sacconi, Massimo
Saccucci, Stefania
Saccuman, Cristina
Saibene, Alessandro
Sala, Cinzia
Sala, Simone
Sala, Stefania
Salandini, Maria
Chiara
Salani, Giuliana
113, 130, 206
P183, P286, P287, P501, P502, P566,
P750
4, 215
P355, P660, P661, P662
2
199
192
P582, P665
211
216
150
28
P85
64, 206
150
P260, P631, P728
65, 192
P582, P665
31
P7, P8, P9
3
30
P39, P606
Salaris, Davide
65, 197
P138
Salerno, Anna
65
P338, P701
Salmaggi, Chiara
206
Salmaso, Flavia
202
Salomoni, Gabriella 216
Salonia, Andrea
4, 215
P116, P117, P162, P163, P164, P259,
P278, P355, P540, P658, P659, P660,
P661, P662, P705, P706
Salpietro, Stefania
202
P236, P700
Salvadori, Giovannella 177, 211
Salvioni, Marco
213
Salvo, Fulvio
113, 206
Samanes Gajate,
177, 211
Ana Maria
Samarati, Maria
XII
Sammartino,
XXXI
Piergiorgio
Sampietro, Francesca 63, 216
P330, P581, P589
Sana, Maria Elena
167
AUTHOR INDEX - 291
Sangalli, Mattia
Sanna, Alberto
Sanpaolo, Michela
Santagostino,
Andreina
Santagostino, Ilaria
Santambrogio,
Graziella
Santambrogio, Paolo
215
XXXI
216
192
3
216
27
P153, P464, P634, P652
Santambrogio, Sara
87
P671
Santarella, Roberto
XII
Santinelli, Vincenzo 65, 79, 192
P582, P583, P665
Santoro, Alessia
208
Sanvito, Francesca
185, 188, 216
P339, P404, P476, P536, P753, P759
Saporiti, Nicoletta
206
Sarandria, Daniela
199
P440
Sarno, Lucio
208
Sarro, Lidia
31
Sartirana, Claudia
87
Sartori, Serenella
150
Sassi, Isabella
216
Sassi, Monica
216
P135
Sasso, Eleonora
208
Sauer, Aisha Vanessa 87
P667, P668
Saveri, Paola
149
Savi, Annarita
211
P145
Savi, Maurizio
XII, XXIV
Savia, Veronica
XII
Saviano, Massimo
65, 192
P582
Savio, Michol
111
Sbalchiero, Andrea
211
Scandola, Elena
199
Scandroglio,
194
Anna Mara
P581
Scapaticci, Emanuele 215
Scaramuzza, Samantha 87
P14, P454, P476
Scarfò, Lydia
1
Scarioni, Monica
196
Scarlato, Marina
210
P111, P197
Scarlatti, Gabriella
112, 127, 221
P186, P316
Scarpellini, Paolo
202
P40, P570
Scattoni, Vincenzo
4, 215
P240
Scavini, Marina
Schaeffer, Céline
Schena, Elisa
Schiaffino, Maria
Vittoria
Schiavi, Davide
Schira, Giulia
Sciarrone Alibrandi,
Maria Teresa
Scielzo, Cristina
115, 139
P183
150
P671
112
167, 170
P392, P692
65, 193
86
P361
151, 206
1
P260, P554
Scifo, Paola
177, 185, 211
P63, P156, P303, P595, P596, P654
Sciorati, Clara
86
Scola, Elisa
28, 185
P359
Scolari, Chiara
XII
Scomazzoni, Francesco 177, 199
Scotti, Celeste
151, 196
P675
Scotti, Fabrizio
65, 199
Scotti, Giuseppe
177, 185, 188, 199, 201
P58, P59, P85, P199, P359, P638,
P719, P761
Scotti, Patrizia
XII
Scotti, Raffaella
206
Scotti, Roberta
28, 199
P32, P493, P747
Secchi, Antonio
113, 115, 131, 206
P51, P68, P214, P464
Secchi, Cristiana
XII
Secchi, Massimiliano 111
P676
Seghezzi, Laura
216
Selli, Simone
177, 211
Senesi, Pamela
63
Sensi, Cristina
167
Serafini, Audrey
64, 204
P187, P373, P374
Sergi Sergi, Lucia
86
P26, P198, P536
Serra, Carlo
28
P342
Sessa, Alessandro
28
P219
Sessa, Luca
149
Sessa, Maria
31, 54, 88, 105, 210
P198, P277, P300
Sestini, Stefano
3, 194
Setaccioli, Marco
65, 199
Setola, Emanuela
64
P450, P681
Sferrazza, Barbara
208
Sforzini, Laura
29, 208
Sgaramella, Paola
Sibilia, Mauro
Siccardi, Antonio
204
31
149, 154
P1, P290, P560
Siccardi, Tomaso
29, 208
Sigismondi, Cristina 4
Signorotto, Patrizia
177
Silipigni, Carmen
193
Siliprandi, Francesca 208
Silva, Carlo
216
Silvani, Paolo
65, 217
Silvestri, Laura
150
P690
Simionato, Franco
177, 199
Simonelli, Pasquale
177, 211
Simonetti, Giorgia
1
P553
Simonini, Marco
151, 206
Sincinelli, Laura
221
Sioli, Barbara
216
Sironi, Elisabetta
216
Sironi, Francesca
111
Sirtori, Marcella
63
P728
Sirtori, Paolo
196
Sitia, Giovanni
112
P158
Sitia, Roberto
149, 153
P76, P650
Sizzano, Federico
85
Slavich, Massimo
65
Slaviero, Giorgio
206
Slim, Najla
177, 211
Smeraldi, Enrico
29, 208, 209
P27, P58, P59, P60, P61, P62, P185,
P481, P612
Smid, Maddalena
64, 204
P747
Snider, Silvia
28, 199
P342
Soares, Milena
221
Socci, Carlo
114, 133, 196
Soccio, Antonella
211
Sogno Valin, Paola
204
P284
Soldarini, Armando 216
Soldini, Laura
216
P586
Soliman, Clara
204
P171
Sommariva, Elena
167, 216
P582
Soprana, Elisa
149
P290, P560
Sora, Nicoleta
65, 192
Sordi, Valeria
115, 196
P158
Soriani, Nadia
Sorlini, Cristina
Sosio, Corrado
Sottocorna, Ornella
Sovena, Gloria
Sozzi, Francesco
167, 216
4
151, 196
194
2
4, 215
P70
Spada, Danilo
29
Spagnolo, Daniele
204
P356, P747
Spagnolo, Francesca 30, 210
Spagnolo, Pietro
177, 211
Spagnuolo, Marco
211
Spagnuolo, Vincenzo 113, 202
P155, P700
Spatola, Chiara
29, 208
P48
Spelta, Sara
65, 194
Spessot, Marzia
216
Spiga, Ivana
216
Spiliotoupulos,
167
Dmitrios
Spina, Annunziata
216
Spinapolice, Elena
211
Spinelli, Alessandra 65, 199
P96, P623
Spinelli, Antonello
177
Spinelli, Maria
31
Carmela
Spitaleri, Andrea
167
P206
Spoladore, Roberto
192, 193
P338, P701
Spotti, Donatella
151, 206
Spreafico, Anna
4
Squadrito, Mario
86
Leonardo
Squilla, Mario
193
Stabilini, Angela
114
P746
Staudacher, Carlo
3, 16, 114, 196, 198
P37, P235, P274, P519, P756
Stefani, Chiara
114, 204
Stella, Marco
114, 196
Stella, Paola
206
Stenirri, Stefania
167, 216
P364
Stoppani, Monica
65, 199
Storti, Maurizio
206
Strada, Elena
4, 215
P70, P706
Straffi, Laura
30, 210
P492
Strati, Paolo
4, 211
Stratta, Gregorio
196
Stucchi, Stefano
211
Stuccillo, Michela
64
AUTHOR INDEX - 293
Suardi, Nazareno
Sudati, Francesco
Sussani, Lara
4, 215
P73, P74, P117, P118, P120, P162,
P164, P165, P167, P169, P209, P259,
P318, P355, P407, P408, P628, P641,
P642, P660, P661, P705, P706
177, 211
65
T
Taccagni, Gianluca
Tacchetti, Carlo
Tacchini, Simona Irma
Tadini, Patrizia
Taffi, Ilaria
Taglietti, Maria
Vittoria
Takagi, Kensuke
Talarico, Anna
Talarico, Daniela
Tamburini, Andrea
Marco
Tambussi, Giuseppe
216
177
213
X
31
216
64, 193
216
150
P691
3, 196
113, 130, 202
P2, P302, P445
Taramasso, Maurizio 193
P461, P710
Tarlasco, Camilla
65
Tassan Din, Chiara
202
P40, P302, P445
Tassara, Michela
3
Taveggia, Carla
31, 53
P91
Taverna, Rosaria
199
Tavilla, Alessandro
211
Tavola, Alessandra
65
Tedesco, Saverio
85
Teggi, Roberto
29, 199
P713, P714, P715
Tei, Laura
XII
ten Hacken, Elisa
1
Terreni, Maria Rosa 216
P30, P305, P367
Terruzzi, Ileana
63
P63
Tesfaghebriel, Habtom 31, 210
Testa, Manuela
113
Testa, Martina
29, 208
Testoni, Pier Alberto 3, 15, 114, 196
P33, P175, P235, P285, P307, P480,
P497, P498, P519, P716
Testoni, Sabrina
3
Tettamanti, Andrea
29
Tettamanti, Marco
28, 211
P3, P4, P719
Teuta, Domi
30
Tezza, Sara
Tiberi, Simon
Tiboni, Francesca
Tinelli, Elisa
Tiraboschi, Mirta
Tirloni, Laura
Todde, Sergio
Todeschini, Paola
Toffalori, Cristina
Toffolo, Franca
Togni, Miriam
Tolazzi, Monica
Tomaello, Luca
Tomajer, Valentina
Tomasi, Serenesse
Tomasoni, Daniela
Tomasoni, Romana
Tomassini, Loredana
Tondulli, Luca
Toniolo, Daniela
Tonlorenzi, Rossana
Tonoli, Diletta
Tonon, Giovanni
Tornaghi, Paola
Torriani, Gabriele
Torta, Federico
Totaro, Antonio
Touvier, Thierry
Traglia, Michela
Travi, Giovanna
Trbos, Mladen
Tremolada, Gemma
Tresoldi, Cristina
Tresoldi, Eleonora
Tresoldi, Moreno
Triberti, Cesare
Trimarchi, Matteo
Trimarco, Amelia
Trisciuoglio, Lisa
Truci, Giulio
Trudu, Matteo
Tshiombo,
Gianbattista
2
202
P586
87
149
113, 206
208
177, 211
P145
177, 211
85
216
XII
112
216
196, 216
216
87
112
216
211
150, 158
P80, P234, P260, P631, P644, P728
85
P370, P443, P516
27
2, 12
P708, P748, P777
112
216
149
P724
27
P35
85
150
P728
202
P730
216
63, 199
216
P382
87
113, 206
P750
X
3, 199
P731
31
149
P733
210
150
65, 194
Tshomba, Yamume
Tuoro, Antonio
Turi, Stefano
Tuscano, Antonella
Tutolo, Manuela
65, 194
P204, P205
3, 194
65
P772, P775
112
4, 215
P117
U
Uberti-Foppa,
Caterina
Uccellatore,
Annachiara
Ugarte, Gonzalo
Ungari, Silvia
Ungaro, Daniela
Ungaro, Federica
Usuelli, Vera
113, 129, 202
P546, P547
64, 206
85
87
31, 210
P761
28
115
V
Vaccari, Ilaria
Vaghi, Mauro
Vago, Luca
Vago, Riccardo
Vailati, Cristian
Valentini, Giovanna
Valeri, Roberto
Valle, Andrea
Valle, Micol
Valsasina, Paola
Valsecchi, Luca
Valtorta, Federica
Valtorta, Flavia
Valtorta, Silvia
Vandoni, Irene
Vanelli, Irene
Vangelista, Luca
Vanni, Roberto
Vannulli, Raffaele
Vanoli, Giovanna
Vanzulli, Laura
Varagona, Roberto
Varale, Roberta
31
177, 211
86
P213, P256, P340, P741
167
P699, P742
3, 196
196
196
114
P746
28, 199
31
P8, P9, P10, P16, P189, P191, P387,
P636, P638
64, 204
P187, P356, P747
216
27, 34
P202, P698
211
P56
211
29
111, 121
P560, P676
208
211
211
29, 208
213
196, 216
Vassena, Lia
Vavassori, Stefano
Vecellio, Magda
Velikova, Svetla
Venereau, Emilie
Venturini, Massimo
Vergani, Andrea
Vergara, Pasquale
Vermi, Anna Chiara
Verona, Chiara
Francesca
Verzini, Alessandro
Veschini, Lorenzo
Vezzoli, Giuseppe
Vezzoli, Michela
Vezzulli, Paolo
Viale, Edi
Vicari, Aurelio
Vicedomini, Gabriele
Vicenzi, Elisa
Viganò, Fiammetta
Viganò, Giorgio
Viganò, Maria Grazia
Viganò, Maurizia
Viganò, Riccardo
Viganò, Silvana
Vignali, Andrea
Vigone, Maria Cristina
Vilardi, Ignazio
Villa, Anna
Villa, Chiara
Villa, Daniele
Villa, Eugenio
Villa, Isabella
Villa, Liliana
Villa, Valentina
Vinci, Raffaele
Vinciguerra, Federico
Vino, Arianna
111
112
206
P80
30
149
177, 213
113, 206
P753
65, 192
65
3, 211
P255
193
P710
1
151, 206
P34, P488, P727, P755
85
P443
28, 185, 199
P32, P321
3, 196
211
192
P582, P665
113, 127
P1, P653
150
193
P461
4, 211
28, 199
4, 204
P474
63, 216
3, 196
P756
64, 204
P85, P232
211
87, 104
P99, P442, P476, P668
185
208
4, 211
P629, P630
63
P297, P574
X
64
P341
151
P25, P717, P718
197
3
AUTHOR INDEX - 295
Viscardi, Matteo
64, 204
P92
Visciano, Maria Luisa 111
Visigalli, Ilaria
87
P91, P495, P604, P761
Visintini, Raffaele
29, 208
P302, P445
Vismara, Chiara
31, 210
Vismara, Elena
28
Carlotta
Vitali, Giordano Pietro 4, 211
Vitali, Matteo
196
Vizzuso, Domenica
149
Voci, Carlopietro
3, 193, 194
Volontè, Maria
31, 210
Antonietta
Volta, Viviana
2
P524
Vorobjova, Tamara
115
Vuotto, Roberto
31
W
Weber, Giovanna
Wozinska, Monika
Wrabetz, Lawrence
Wysocka, Ewa
64, 72, 204
P85, P232
150
149, 156
P238, P267, P371, P754, P766
X
X
Xynos, Alexandros
85
Y
Yacoub, Mona-Rita
111, 206
Z
Zacchetti, Daniele
Zagato, Laura
Zaghetto, Ambra
Zallocco, Diego
Zamai, Moreno
Zambelli, Matilde
Zambon, Massimo
Zamboni, Michele
27
151
P732
149
112, 221
1
216
194
P428
28, 208
P622
Zambroni, Desirée
Zamproni, Ilaria
Zanardelli, Maria
Elisabetta
Zanardi, Raffaella
Zandonella Necca,
Stefano
Zangrillo, Alberto
150
63, 204
P541
X
29, 208
P412, P470
151
65, 77, 194, 197, 217, 220
P83, P239, P244, P245, P246, P253,
P427, P428, P517, P518, P581, P772,
P773, P774, P775
Zanni, Giuseppe
215
P278, P355, P659, P662, P705
Zannini, Piero
3, 18, 194
P42, P176, P177, P216, P512
Zanoni, Angela
211
Zanoni, Annalisa
208
Zanoni, Matteo
215
Zanotti, Lucia
30
P606, P607
Zanussi, Monica
216
P741
Zappalalio, Paola
216
Zatti, Alessandra
2
P201
Zeni, Daniele
167
Zerbi, Alessandro
114
P346, P629, P630
Zerbini, Gianpaolo
63, 68
Zimarino, Vincenzo 27
Zino, Elisabetta
216
P256
Zito, Laura
85
Zocchi, Maria Raffaella 111, 121
P315, P608, P609
Zonari, Erika
86
Zoppei, Gianna
X, XXXI, 221
Zordan, Paola
85
Zuber, Veronica
196
Zucchelli, Chiara
167
P206
Zucchiatti, Ilaria
65, 199
Zucchinelli, Patrizia 4, 211
Zucconi, Marco
29, 209
P622
Zuccotti, GianvincenzoX
Zuffada, Francesca
192
Zuffardi, Orsetta
216
P631
Zuliani, Walter
3, 196
Zuppelli, Paola
65
San Raffaele Scientific Institute
Via Olgettina, 60
20132 Milano
Tel. 02 26431
www.sanraffaele.org

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