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Scientific Report
2010
San Raffaele
Scientific Institute
Scientific Report
2010
San Raffaele
Scientific Institute
Cover image: unpublished image by Francesco Bandello
(see Vision first Unit, pages 92-93):
The new OCT instruments allow histologic exam of the retina in vivo;
in this case the vitreomacular traction is perfectly detected.
Some of the images in this book has been published in scientific papers:
Figure 2, p. 16: Seminars in Cancer Biology
Figure 10, p. 60: PLoS ONE
Figure 11, p. 61: Radiology
Figure 12, p. 63: Neurology
Figure 19, p. 108: Cancer Cell
Figure 22, p. 117: Human Molecular Genetics
Figure 25, p. 140: International Archives of Allergy and Immunology
Figure 30, p. 147: Cancer Research
Figure 31, p. 148: Nature
Figure 34, p. 161: Journal of Autoimmunity
Figure 35, p. 162: Advances in Experimental Medicine and Biology
Figure 36, p. 182: Seminars in Cell and Developmental Biology
Figure 37, p. 183: Journal of Biological Chemistry
Figure 38, p. 184: Current Opinion in Cell Biology
Figure 43, p. 191: Molecular and Cellular Biology
Figure 45, p. 193: Cell
Figure 47, p. 196: Science Translational Medicine
Figure 49, p. 207: Journal of Neuroscience
Figure 52, p. 218: PNAS
Figure 53, p. 221: Radiology
Edited by the San Raffaele Library
Layout project by Rolando Cassinari
Printed by Grafiche Parole Nuove, Brugherio
INDEX
INTRODUCTIONS
VII
Introduction by the President
IX
Introduction by the Scientific Director XVI
Introduction by the Chief
Operating Officer
XXVI
San Raffaele Scientific Retreat 2010 XXVIII
Introduction by the General Director
Clinical Area
XXXVI
2010 Seminars and lectures
XXXVIII
Medical oncology Unit - Clinical trials
Medical oncology Unit - Phase I and lung
cancer clinical trials
URI, Urological Research Institute
26
Selected publications
28
DIVISION OF
NEUROSCIENCE
Introduction by the Directors
26
27
35
42
Research Units
DIVISION OF MOLECULAR
ONCOLOGY
5
10
Research Units
Lymphoid malignancies Unit
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
B-cell neoplasia Unit
Functional genomics of cancer Unit
Molecular histology and cell growth Unit
Tumor biology and vascular targeting Unit
11
11
12
13
13
14
14
15
15
16
17
17
19
Clinical Research Units
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
20
20
21
21
22
22
23
23
24
25
25
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
43
43
44
44
45
46
46
47
47
47
Acute brain protection, Acute post-operative
pain, Drugs and central nervous
system Unit
Cognitive neuroscience Unit
Experimental neurosurgery Unit
Eye repair Unit
Functional neuroradiology Unit
In vivo Human molecular and structural
neuroimaging Unit
Neuroothology Unit
Psychiatry and clinical psychobiology
Sleep medicine
Clinical psychology
Motor function rehabilitation
52
53
53
53
54
55
Institute of Experimental
Neurology (INSPE)
56
Introduction by the Director
56
49
49
50
50
50
Research Units
Experimental neuropathology
Experimental neurophysiology
Molecular genetics of behaviour
Neuromuscular repair
Neuroimmunology Unit
Clinical neuroimmunology
57
57
58
58
59
60
III
INDEX
CNS repair
Neuroimaging research Unit
Neuroimaging of CNS white matter
Human inherited neuropathies Unit
Axo-glia interactions Unit
60
61
62
63
64
DIVISION OF REGENERATIVE
MEDICINE, STEM CELLS
AND GENE THERAPY
99
Inflammatory CNS disorders Unit
Cerebrovascular disorders
Memory disorders
Movement disorders
Neuromuscular disorders
Paroxysmal events
65
65
66
66
67
67
68
Skeletal muscle development
and therapy Unit
Functional genetics of muscle regeneration
Neural stem cell biology
Angiogenesis and tumor targeting Unit
Autoimmunity & vascular inflammation Unit
Innate immunity and tissue remodelling
Cellular pharmacology Unit
Experimental hematology Unit
Gene expression and muscular
dystrophy Unit
Molecular and functional
immunogenetics Unit
DIVISION OF METABOLIC
AND CARDIOVASCULAR
SCIENCES
75
Research Units
Introduction
Research Units
79
Amino acid and stable isotopes Unit
Complications of diabetes
Obesity and metabolic related diseases
Bone metabolism Unit
Coagulation service & thrombosis
research Unit
Cardiodiabetes & core Lab
Pediatric endocrinology research
80
80
81
82
Hematology and hematopoietic stem cell
transplantation Unit
Immunohematology and transfusion
medicine Unit
PSIEP - Strategic Program of Pediatric
Immunohematology
104
105
106
106
107
108
109
110
111
111
112
113
113
114
82
83
83
The San Raffaele-Telethon Institute
for Gene Therapy (HSR-TIGET)
Research Units
85
85
86
86
87
Gene transfer technologies and new gene
therapy strategies Unit
116
Gene/Neural stem cell therapy for lysosomal
storage diseases
116
Hematopoietic stem cell based gene
therapy for the treatment of lysosomal
storage disorders
117
Safety of gene therapy and insertional
mutagenesis
118
Gene transfer into stem cells Unit
118
Immunological tolerance Unit
119
From FOXP3 mutation to IPEX syndrome
119
Tolerogenic dendritic cells
120
Pathogenesis and therapy of ADA-SCID
Unit
120
Gene therapy for WASP/Omenn
121
Diabetes and endocrinology Unit
Cardio-metabolic and clinical trials
Gynecology and infertility Unit
Fetal-maternal medicine
Clinical pediatric endocrinology
Diabetes and metabolic diseases in children
and adolescents
Neonatology
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
Vision first Unit
91
91
92
92
94
88
88
89
89
90
115
115
PCRU - Gene therapy for Wiskott-Aldrich
Syndrome
122
INDEX
PCRU - ADA gene transfer into hematopoietic
stem cells for the treatment of ADA-SCID 122
PCRU - Clinical trial of gene therapy in
metachromatic leukodystrophy
123
Experimental diabetes
β cell biology
Cell imaging
Immune tolerance Unit
124
DIVISION OF IMMUNOLOGY,
TRANSPLANTATION, AND
INFECTIOUS DISEASES
131
Research Units
138
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
Dynamics of immune responses Unit
Emerging bacterial pathogens Unit
Experimental immunology Unit
Immunopathology Unit
Lymphocyte activation Unit
Tumor immunology Unit
Viral evolution and transmission Unit
Viral pathogens and biosafety Unit
139
140
141
141
142
143
144
145
145
146
147
148
149
149
150
151
151
152
Management and antiretroviral treatment
of HIV infection
Neurovirology
Study and treatment of hepatotropic viruses
related diseases
Vaccine and immunotherapy
Clinical immunopathology and advanced
medical therapeutics Unit
Clinical transplant Unit
Pancreatic tumors Unit: immunotherapy
and β cell function substitution
Gynecological cancers immunology
Immunology in liver neoplasms
Clinical hepato-gastroenterology
Digestive pathophysiology
Diabetes Research Institute (DRI)
Research Units
153
153
161
161
162
163
Islet transplantation
Prevention in Type 1 diabetes
Epidemiology & data management
Childhood diabetes
Islet processing activity
164
164
165
165
166
167
DIVISION OF GENETICS
AND CELL BIOLOGY
177
Research Units
181
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
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
182
183
184
185
186
187
188
188
189
189
190
191
191
192
193
Dento-facial histopathology Unit
Genomics of renal diseases
and hypertension Unit
Tissue engineering and biomaterials
196
197
155
155
198
156
156
157
158
159
CENTER FOR
TRANSLATIONAL GENOMICS
AND BIOINFORMATICS 205
154
154
160
160
195
Research Units
206
Neurogenomics Unit
Biomolecular NMR Laboratory
207
208
V
INDEX
Genomic Unit for the diagnosis of human
pathologies
Organelle biogenesis and motility Unit
Proteome biochemistry Unit
209
209
210
211
IMAGING
EXPERIMENTAL CENTER
215
Research Units
217
Mouse functional genetics Unit
218
Clinical and experimental radiology Unit
High technology in radiation therapy Unit
Medical physics Unit
Molecular imaging Unit
Neuroradiology research group
219
219
220
220
221
Service Units
ALEMBIC, Advanced Light and Electron
Microscopy BioImaging Center
Intravital microscopy
Preclinical MRI
223
224
224
226
FRACTAL, Flow cytometry Resource,
Advanced Cytometry Technical
Applications Laboratory
CERMAC, Centre of Excellence of High
Field Magnetic Resonance
ProMiFa, PROtein MIcrosequencing FAcility
Mouse histopathology
THE CLINICAL
DEPARTMENTS
RESEARCH
PROGRAMMES
231
Brain Regeneration usIng medical
Devices, Gene vectors and stEm
cells (BRIDGE)
231
Program in Immunology and
Bio-immunotherapy of Cancer (PIBIC)
233
Islet Trasplantation Program (ITP)
235
Human Brain Invivo Mapping with
neuroimaging (BRAINMAP)
237
Bone Physiopathology Program
(BoNetwork)
239
Correlates of HIV-Associated Immune
Response Modulation program (CHARM) 242
Microenvironment and Genes in Cancers of the
Blood (MAGIC)
245
FACILITIES
249
CFCM, San Raffaele-Telethon Core Facility for
Conditional Mutagenesis
250
251
251
252
257
Cardio-thoracic-vascular Department
Department of general and specialistic
surgery
Head and neck Department
Department of infectious diseases
Maternal and child health Department
Department of internal and specialistic
medicine
Department of clinical neuroscience
Department of neurology
Department of oncology
Department of radiology
Department of urology
CLINICAL SERVICES
250
259
263
266
269
271
274
276
278
280
283
285
287
Pathology
Laboratory medicine
Immunohematology and transfusion service
Emergency medicine
General intensive care
Anaesthesia and neurointensive care Unit
289
289
290
290
291
291
AISPO - San Raffaele
in the world
293
PUBLICATIONS
301
Best papers 2010
List of 2010 publications
303
304
INTRODUCTIONS
VII
INTRODUCTIONS
Introduction by the President
Introduzione del Presidente
I am particularly delighted to present this Annual Sono particolarmente felice di presentare anche
Report of the scientific research work carried on by quest’anno il lavoro dei nostri eccellenti ricercatori.
the numerous researchers operating in our Univer- Sono convinto da sempre che non ci sia cura
sity and Research Centers.
senza ricerca. È perciò che mi sento soddisfatto di
I personally believe that it is impossible to choose vedere una piattaforma scientifica del San Raffaele
a path of research while not following at the same di così vaste proporzioni.
time different others: a research is made out of dif- Una piattaforma che comprende in una unità stretferent paths interweaved together. Thus, I cannot tamente organizzata e integrata la ricerca di base,
help but notice my satisfaction in
la ricerca traslazionale, la riobserving such an important and
cerca clinica e applicata.
great scientific platform as San
Carissimi Raffaeliani Medici, RiRaffaele is.
cercatori di base e Clinici, PerSuch platform includes the basic
sonale tutto,
research, the translational reche costituite in Italia e nei nostri
search and the clinic and apSan Raffaele all’estero un vero
plied researches into a joined
esercito per battere la malattia e
unity.
la morte mai volute da Dio.
Dear Raffaelians, Physicians, ReLui, infatti, ha creato l’uomo in
searchers, and all Personnel
condizione eucrasica, atto a viYou all, who here in Italy and in our
vere in longevità perfettamente
San Raffaele centres abroad form
sano.
a true Army to fight illness and
Tocca a Voi ricercare le condideath, which were never sought
zioni biologiche, ambientali, ed
after by God. (God, that is, who
etico-equilibranti adeguate a far
created man in a condition of full
tornare l’uomo al suo stato perstrength, apt for a perfectly healthy life.)
fetto originale, quale re-padrone dell’Universo
You are in charge of searching for the adequate bi- Creatore con l’ordine di dominarlo “possidete
ological, environmental, and ethical conditions to eam”.
carry man back to his original state of perfection, as Non arrendeteVi alle difficoltà.
a king-owner of the Generating Universe, with the La consapevolezza del Vostro “io”, cioè del valore
duty of ruling it and mastering it [possidete eam].
uomo che sta in ciascuno di noi, ci induce alla reDo not surrender to difficulties.
sponsabilità, alla prudenza e, insieme, alla tenacia
Your self-awareness - which is to say, your aware- e all’audacia necessarie.
ness of the human value which resides in each one Sappiate che “Tutto è possibile a chi crede”.
of us leads us to responsibility, prudence, and, at Anch’io, pover-uomo e squattrinato, Ve ne ho dato
the same time, to the requisite resilience and au- l’esempio tirando fuori da una marcita la Vostra
daciousness.
“Città dell’uomo S. Raffaele”.
You shall know that “Everything is possible to him Cercate e troverete “pregate e vi sarà dato”.
who has faith”.
Vi penso e Vi amo tutti.
Even I, poor man and penniless, have shown this Vostro
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
(Fondatore, Presidente, Rettore)
(Founder, President, Provost)
IX
INTRODUCTIONS
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 (till September 2010), Alessandro Bartucci (from
October 2010)
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
The San Raffaele Scientific Institute is a teaching hospital affiliated to the Università Vita-Salute San
Raffaele (DGR 3 dicembre 1999, n. 6/46798)
Organization chart
Board of Directors
General Secretary
of the Presidency
President
Employer
Vice President
Healt
& Safety
SAB
Supervisory Body
Legisl. Decree
231/2001
Human Resources
Corporate Department
Agreement with
Vita-Salute
SR University
Technical
Department
Administration & Finance
Communications
Public Relations
Department
Legal & General Affairs
Chief Operating Officer
Clinical Area
Internal
Supervisory
Committee
Internal
Audit
Department
Scientific Director
Research Area
Staff
CLINICAL
DEPARTMENTS
Hospital
Director
Staff
RESEARCH
DIVISIONS AND CENTERS
INTRODUCTIONS
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.
XI
INTRODUCTIONS
Scientific Advisory Board, SAB
Professor Paul Herrling, Head of Novartis Institutes for Developing World Medical Research, Novartis Institutes for Biomedical Research, Novartis International AG (former Head of Global Research Novartis
Pharma), chair of the SAB
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 Jacques Banchereau, Sr. Vice President – DTA Inflammation & Virology and Chief Science Officer, Hoffmann-La Roche Inc., Nutley, NJ, 2009 Award in Human Immunology Research - American Association of Immunologists - Dana Foundation (former Director of the Baylor Institute for Immunology
Research in Dallas, Texas);
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)
INTRODUCTIONS
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XIII
SCIENTIFIC DIRECTORATE
Scientific Director:
Maria Grazia Roncarolo
Chief Operating Officer:
Maurizio Savi
SECRETARY: Sonia Fedeli, Titti Meroni
ASSISTANT TO THE SCIENTIFIC DIRECTOR: Laura Reiss
PROGRAM MANAGER TO THE SCIENTIFIC DIRECTOR: Marina Castellano
STUDIES, DEVELOPMENT & QUALITY OFFICE MANAGER: Vanda Parezanovic
HEAD OF SCIENTIFIC SECRETARIAT: Giulio Negri
GRANT OFFICE: Stefano Apollonio, Riccarda Daneri, Michele Granetto, Paola Rebagliati
GRANT OFFICE SCIENTIFIC SUPPORT: Maria Guttinger
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, Federica Violante
HEAD OF OFFICE OF BIOTECHNOLOGY TRANSFER: Lucia Faccio
OFFICE OF BIOTECHNOLOGY TRANSFER: Elisabetta Greco, Simona Locatelli, Paola Pozzi,
Roberto Santarella
HEAD OF LIBRARY: Laura Tei
LIBRARY: Angelo Angarano, Diego Maria Bertini, Francesco Curci, Elena Ponzi, Maria Samarati,
Mirella Verza*
HEAD OF RESEARCH ADMINISTRATIVE OFFICE: Maria Rosa Pedrazzi
RESEARCH ADMINISTRATIVE OFFICE: Roberto Barchi*, Giovanna Bernardi, Francesca Dodero,
Barbara Lapio, Massimiliano Meoni, Ornella Muraro, Marco Picariello, Patrizia Scotti, Miriam Togni
HEADS OF MARKETING & FUNDRAISING OFFICE: Luca Isotti, Lisa Orombelli
MARKETING & FUNDRAISING OFFICE: Federica Cattaneo, Patrizia Mogliani, Chiara Scolari,
Cristiana Secchi
HEAD OF HUMAN RESOURCES OFFICE: Giuseppe Defidio
HUMAN RESOURCES OFFICE: Roberta Berno, Alberto Martoglio
LOGISTICS & IT SERVICES: Marco Crespi, Giuseppe Miracoli
* Università Vita-Salute San Raffaele
XV
INTRODUCTIONS
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 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 these goals, we want to perform cutting-edge science and to advance the knowledge of
human diseases resulting in the identification of novel therapies. Translational research, the bench-tobedside-to-bench transfer of information and results, is our vision and the future for SRSI. In five years
from now we want to be a consolidated leading national and international Health Care Center where
translational medicine is smoothly and regularly applied to patients in order to provide to each and every
one of them the best, most appropriate and most advanced treatment available.
The Scientific Institute
Established in 1971, the SRSI is part of the San Raffaele Biomedical Science Park and it is composed
by the Research Hospital and by two Research Departments, Di.Bi.T.1 and Di.Bi.T.2, where clinical and
research activities are conducted. The Biomedical Science Park also includes the Vita-Salute San Raffaele University, 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 addition, the San Raffaele Biomedical Science Park hosts several
biotechnology companies, including MolMed, Telbios and Axxam, which interact with the SRSI.
In 1972 SRSI 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. Today the Hospital counts more than 1400 beds. In
1992, a research building (about 40,000 sq m or 431,000 sq ft) was opened to accommodate the Department 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 Ministry of Health.
In 2009 three new buildings (Di.Bi.T.2) were built on campus. This allowed the much needed growth of
the University and created 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.
Since 2008 the San Raffaele Scientific Institute is structured in Clinical Departments and Research Divisions in a classical matrix model. Research Divisions include both laboratory and clinical research with
Basic Research Units and Clinical Research Groups. In addition, 2 Research Centers focused on technology-oriented research have been established. This research structure is based on the concept that
Research is the backbone of the SRSI, intersecting and connecting with both the clinical and the
teaching programs. The objective of this research organization is to further integrate research, teaching
and clinical activities by aligning preclinical, translational and clinical research with our clinical strengths.
In addition to the research divisions and centers, SRSI comprises 3 Research Institutes and 7 Institutional
Facilities. This research structure was designed in 2007 and approved by the Board of the Foundation
in June 2008. The mandate to implement the new research structure was conferred to the Scientific Director and to the Chief Operating Officer for Research in March 2008. The reorganization was completed in 2009.
Research Divisions and Centers
The 6 Research Divisions and 2 Research Centers represent existing areas of expertise and excellence,
as well as new strategic areas of research in which we want to invest for the future. They are led by directors, associate and co-directors who are prominent scientists in the organization with international
reputation and excellent expertise in basic or clinical research.
INTRODUCTIONS
RESEARCH DIVISIONS
Director
Associate Director
Molecular Oncology
Federico Caligaris-Cappio Giorgio Parmiani
Neuroscience
Gianvito Martino
Flavia Valtorta
Regenerative Medicine, Stem Cells
Giulio Cossu
Fabio Ciceri, Luigi Naldini
Ruggero Pardi
Adriano Lazzarin
Genetics and Cell Biology
Roberto Sitia
Marco Bianchi
Metabolic and Cardiovascular Sciences
TBA
TBA
RESEARCH CENTERS
Director
Co-Director
Experimental Imaging
Carlo Tacchetti
Alessandro Del Maschio
Translational Genomics and Bioinformatics
Giorgio Casari
TBA
and Gene Therapy
Immunology, Transplantation and Infectious
Diseases
At present (June 2011), approximately 1.482 people are working in the 6 Research Divisions (including
those working in the Research Institutes), the 2 Research Centers and the Institutional Facilities:
• 767 people, including scientists, technicians, as well as postdoctoral fellows, PhD students and undergraduate students, working on preclinical and translational research in the laboratories of Di.Bi.T 1
and Di.Bi.T 2;
• 688 people, including physicians, research nurses, residents and clinical fellows, working on clinical research projects in the hospital;
• 27 people, including heads of facility, lab managers, research associates and technicians working in institutional facilities.
Research Institutes
SRSI hosts 3 major research Institutes (see table below) which are integrated within the Divisional organization but have a high degree of scientific and administrative independence, based on specific agreement 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. In 2010 HSRTIGET has secured an important industrial agreement with Glaxo-Smith-Kline and the Telethon Foundation. Under this trilateral agreement Glaxo-Smith-Kline obtained an exclusive license on the ADA-SCID
program, and an option for an exclusive license on other 6 gene therapy programs (metachromatic
leukodystrophy, Wiskott Aldrich syndrome, globoid leukodystrophy, mucopolysaccharidosis type I,
chronic granulomatosis and beta-thalassemia).
• The Institute for Experimental Neurology (INSPE), which is based on an agreement with Merck-Serono,
investigates the biological and molecular mechanisms underlying diseases of the nervous system with
a strong focus on multiple sclerosis and clinical translation. In 2010 INSPE has secured the renewal of
the industrial agreement with Merck-Serono. This strategic alliance was established in 2004 and it is
instrumental for INSPE clinical, training and research programs.
In addition, in 2010 INSPE established a Weizmann-San Raffaele Joint Lab focused on neuroimmune,
neurodegenerative and mental disorders.
• The Diabetes Research Institute (HSR-DRI), which is part of the DRI Federation, whose main objective
is to identify and apply novel treatments to prevent islet beta cell destruction and to restore sufficient insulin production in type 1 diabetes.
XVII
INTRODUCTIONS
RESEARCH INSTITUTE
Director
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET)
Luigi Naldini
Institute for Experimental Neurology (INSPE)
Giancarlo Comi
Diabetes Research Institute (HSR-DRI)
Luca Guidotti
Emanuele Bosi (Co-Director)
Research Programs
Interdivisional and interdepartmental Research Programs are strategic projects created with the aim of integrating basic and clinical research to reach a defined scientific goal. They represent a major tool in organizing research activities that are transversal both to Research Divisions and to Clinical Departments.
At present seven Research Programs have been approved and are running.
Research Programs
Head
Brain Regeneration usIng medical Devices, Gene vectors
Head:
and stEm cells (BRIDGE)
G. Martino (ad interim)
Deputy Head
L. Naldini (ad interim)
Program in Immunology and Bio-immunotherapy of Cancer (PIBIC)
Co-Heads:
P. Dellabona
G. Parmiani
Pancreatic Islet Trasplantation
Co-Heads:
L. Piemonti
P. Maffi
Human Brain In vivo Mapping with neuroimaging (BRAINMAP)
Head:
M. Filippi
Deputy Head:
A. Falini
Bone Physiopathology Program (BoNetwork)
Co-Heads:
R. Sitia
E. Gherlone
Correlates of HIV-Associated Immune Response Modulation (CHARM)
Co-Heads:
P. Cinque
G. Poli
Microenvironment and Genes in Cancers of the Blood (MAGIC)
Co-Heads:
P. Ghia
G. Tonon
INTRODUCTIONS
Scientific activities in 2010
The Scientific Advisory Board
2010 was an important year for Research at SRSI. The Advisory Board has been appointed by the Board
of Directors of the San Raffaele Foundation with 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.
The Board is composed of four internationally renowned scientific leaders:
• Professor Paul Herrling, Head of Novartis Institutes for Developing World Medical Research, Novartis Institutes for Biomedical Research, Novartis International AG (former Head of Global Research Novartis
Pharma), chair of the SAB;
• 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 Jacques Banchereau, Sr. Vice President – DTA Inflammation & Virology and Chief Science
Officer, Hoffmann-La Roche Inc., Nutley, NJ, 2009 Award in Human Immunology Research - American
Association of Immunologists - Dana Foundation, (former Director of the Baylor Institute for Immunology Research in Dallas, Texas);
• 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 first Scientific Advisory Board meeting took place on July 8 and 9, 2010 and consisted a very intensive
two-day meeting, with presentations both by the Division Directors and by selected Pis (see page XIII).
The outcome of the meeting was a Report containing a series of recommendations with the aim of ensuring the future success and growth of hSR to achieve its mission.
Professor Paul Herrling, Chair of the SAB, presented the SAB Report to the Foundation’s and the University’s Boards of Directors joint meeting on November 15, 2010.
The hSR Cancer Center
A new, important initiative developed in 2010: the planning of the hSR Cancer Center, with the goal of
curing cancer by creating an internationally competitive structure with a network organization, multidisciplinary teams and defined programs for different tumors, in order to integrate cancer research, treatment
and education.
The mission of the hSR Cancer Center is twofold:
• State-of-the-art clinical care for all cancers
• “Second to none” in selected areas of excellence
An Operating Committee was established in February 2010. It was composed by Maria Grazia Roncarolo, Maurizio Savi, Gianna Zoppei, Renato Botti (until Dec. 31, 2010), Gianluca Santoro, Federico Caligaris-Cappio (representatives of Fondazione), and by Alessandro Del Maschio (representative of
Vita-Salute University). The committee was coordinated by Prof. Riccardo Dalla Favera (Director of the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA) as external consultant and advisor to the scientific director.
The Division of Metabolic and Cardiovascular Sciences
In 2010 further steps have been taken in the construction of the Division of Metabolic and Cardiovascular Sciences.
The Executive Committee of the Research Division in Metabolic and Cardiovascular Sciences was appointed in February 2010; it was coordinated by Maria Grazia Roncarolo, Scientific Director, and it was
composed by Ottavio Alfieri, Emanuele Bosi, Paolo Camici, Roberto Chiesa, Gianluca Perseghin, Alberto
Zangrillo, and since July 2010 by Francesco Bandello and Antonio Colombo. The Committee was supported by Zaverio Ruggeri (Head, Division of Experimental Haemostasis and Thrombosis, Director, Roon
Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, CA, USA) as external consultant and advisor to the scientific director.
XIX
INTRODUCTIONS
The Committee gave new impulse to the process of establishing the Division and in the past year achieved
several important goals including:
• Identify strategic areas of research;
• Elaborate a first draft of the Strategic Plan for the Division;
• Plan and identify the lab spaces for the Division;
• Define the governance of the Division;
• Organize a very successful Divisional Retreat.
The Center for Translational Genomics and Bioinformatics
The Center for Translational Genomics and Bioinformatics (formerly known as Center for Genomics, Bioinformatics and Biostatistics) made significant progress in 2010 with the start up of new fully equipped labs
in the Basilica/San Raffaele building, the installation of main instrumentation (circular dichroism, analytical
ultracentrifuge, microarray scanner iScan Illumina, Real Time PCR ABI, Hamilton robot), the purchase of
Illumina HiSeq 2000 next generation sequencing machine and the transfer of existing staff to the new
venue. In addition, the co-director of the Center was selected.
Imaging Experimental Center
The Imaging Experimental Center’s 2010 achievements include the start up of a new department of Ultrastructural and Molecular Imaging at the European Center for Nanomedicine (CEN), the installation and
validation of main instrumentation (Bruker 7T MRI), the acquisition of new technology within ALEMBIC for
quantitative/morphologic flow cytometry analysis and the activation of one new research unit: ‘Mouse
functional genetics’ (HU: Ottavio Cremona). In 2010 the Pre-Clinical MRI Facility Manager was promoted
to a tenure-track and a radiology technician was transferred from the Clinical Area to the Research Area
in support to the Imaging Experimental Center.
Other scientific activities
The impressive critical mass and quality of our scientific community was highlighted during our yearly Scientific Retreat, which in 2010 was again organized in Stresa with three full days of scientific presentations
given by basic and clinical scientists (see pages XXVIII-XXXIII). A total of 550 scientists participated to the
San Raffaele Research Retreat and 295 abstracts were submitted. During the event, the top publications
of 2009 in three different areas of research (Basic, Translational and Clinical research) were awarded with
the SRSI innovation prize:
Basic
Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Eduardo J Villablanca, et al., Nature Medicine.
Translational (ex-aequo)
Loss of mismatched HLA in leukemia after stem-cell transplantation. Luca Vago, et al., The New England
Journal of Medicine
Gene therapy for immunodeficiency due to adenosine deaminase deficiency. Alessandro Aiuti et al., The
New England Journal of Medicine
Clinical (ex-aequo)
High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with
primary CNS lymphoma: a randomized phase-2 trial. Andrés J M Ferreri, et al., The Lancet
Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically
isolated syndrome (PreCISe study): a randomized, double blind, placebo-controlled trial. Giancarlo Comi,
et al., The Lancet.
Finally, in 2010 a number of important educational initiatives, scientific events and prestigious international
meetings were organized and hosted by our basic and clinical scientists. In the past year SRSI hosted
more than 50 seminars and lectures with external speakers (see pages XXXVIII-XLI).
INTRODUCTIONS
Scientific productivity in 2010
2010 was a very productive year for the SRSI in terms of scientific publications and clinical trials.
The total number of scientific publications was 832, with a total Impact Factor of 4625 (Figures 1 and 2).
Almost 8% of all SRSI publications are in top-level scientific journals (Impact Factor over 10). Based on
these results, our Institution is once more the most highly ranked Italian IRCCS (among the 45 Italian Research Hospitals) in terms of scientific quality and scientific productivity.
Figure 1.
Publications and total Impact Factor of SRSI
in the past 3 years
4624,629
4.153,262
3.870,073
740
2008
(average IF: 5,230)
832
773
2009
(average IF: 5,373)
Total IF 2008-2010
2010
(average IF: 5,558)
Publications 2008-2010
Figure 2.
% of SRSI publications sorted according to Impact Factor ranges
Percentage of publications
100,0%
80,0%
65,1%
62,2% 63,4%
60,0%
40,0%
30,0%
26,0% 27,3%
20,0%
7,8%
10,6%
7,6%
0,0%
< 5,000
5,000-9,999
Impact Factor ranges
2008
2009
ш 10,000
2010
XXI
INTRODUCTIONS
The excellence of the SRSI in the area of clinical research is demonstrated by the SRSI ability to design
and conduct clinical trials, some of which are enabled through support from pharmaceutical and biotechnology companies.
In 2010, the Ethics Committee examined 270 protocols, 136 (50 %) of which were sponsored by Pharmaceutical Companies. Submission of these 270 clinical trial protocols was supported and guided by the
Clinical Research Office (Figures 3 and 4).
Figure 3. Clinical trials evaluated by the HSR Ethics Committee in 2010
TYPE OF PROTOCOLS EXAMINED BY EC, YEAR 2010
PHARMACOLOGICAL PROTOCOLS
OBSERVATIONAL PROTOCOLS
BASIC RESEARCH PROTOCOLS
MEDICAL DEVICE PROTOCOLS
18%
28%
5%
49%
INTRODUCTIONS
Figure 4. Clinical trials run by Clinical Departments and approved in 2010
The Office of Biotechnology Transfer (OBT), which is in charge of the management of intellectual property, patents and know–how, and of the creation of spin–off companies, is under the direct responsibility of the Scientific Directorate as of 2008. Lucia Faccio has become Head of the Office as of January
2010.
As of December 2010 the OBT managed 311 sponsored research and industrial collaboration contracts,
with around 114 biotech and pharma companies. In the last 10 years 110 patent families (patented technologies) have been filed of which, 45 patent families (corresponding to around 250 patents and patent
applications in portfolio) are still alive, while 53 license/option and evaluation agreements have been finalized with industrial partners.
In 2010 the OBT was heavily involved in finalizing a) the strategic alliance between Glaxo Smith Kline, Fondazione San Raffaele, and Fondazione Telethon in the field of gene therapy for genetic diseases; b) the
strategic alliance between Merck Serono and Fondazione San Raffaele in the field of Neuroscience. This
strategic alliance was established in 2004 and renewed in 2007, and it was instrumental to the establishment of the Institute of Experimental Neurology (INSPE). The second renewal of this agreement, signed
in November 2010, aims at supporting INSPE research for the next three years.
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INTRODUCTIONS
New initiatives in 2010
International Postdoctoral Programme
In 2010 SRSI implemented a competitive International Postdoctoral Programme to recruit highly skilled
experienced researchers who will bring new ideas and increase the international dimension of our institution. Cofunding for the Programme by the European Union Seventh Framework Programme, Marie
Curie Co-funding of Regional, National and International Programmes (COFUND) is provided.
The Institute is planning to open 20 positions for Postdocs in the next 48 months.
Physician Scientist
In 2010 we defined and approved, together with the Human Resources Head and the General Director
of the Clinical Area a dedicated career path for Physician Scientists: highly qualified professionals who
have both the competence and the responsibility to carry out clinical practice as well as research activities.
The Institute believes this is a major achievement in the process of integration between clinical activities,
teaching and research, as these professionals will be the bridge that will allow swift communication between the three areas. The Physician Scientist is a key figure to achieve our vision as a leading center
for translational medicine.
New Career Paths
In 2010 new career paths for young and senior researchers were defined.
The goals of this project are:
• To establish well defined and common standards for the salary scales, the development and the promotion paths of research staff;
• To define, with transparent and meritocratic criteria, professional progression and the achievement of
scientific and financial independence.
Conclusions and future perspectives
In the past year we continued to make significant progress towards the initial goal to establish research
as the backbone of our Institution with constant efforts to integrate preclinical and clinical research exemplified by:
• the establishment of Research Programs, which, as indicated above, are strategic projects with the
aim of integrating basic and clinical research to reach a defined scientific goal. These Programs will be
strengthened and expanded in 2011;
• the definition of a specific career path for Physician Scientists, which will be fully implemented in 2011.
Relevant steps forward have been made in 2010 to unify the Foundation’s and the University’s research
activities under one vision and one strategy while respecting the single identities and missions. To
strengthen this collaboration and to share a strategic plan for the new recruitments are the objective for
2011.
An important shift in paradigm and a cultural change in the perception of research from an intangible to
a tangible asset were major achievements in 2010. The exploitation of patents and licenses, the successful alliances with industry, and the valorization of the grant portfolio secured our research funding for
the coming years.
A concerted action to align our organization with major international institutions started in 2010 with new
initiatives such as the International Postdoc Programme, and will continue in 2011 with the implementation of international calls for recruitments of staff scientists and directors.
All the above was achieved despite a year of severe financial crisis for the Institution, which significantly
slowed down the implementation of our strategic plan for new recruitments and investments.
INTRODUCTIONS
In the future we foresee that the SRSI will continue to be a multidisciplinary Institute focused on translational medicine with an international reputation and high capability to attract top international scientists and
competitive external funding. It is important to note that prerequisites to these goals are:
• the unity of research, with a shared vision between the Foundation and the University and a structure
which unifies research under the same governance, while respecting the single identities;
• the integration between clinical, translational and preclinical research with a common strategic research
plan;
• the necessary investments to support the new research structure and to strengthen the technological
platforms.
Many thanks to the Research Directors, Associate and Co-Directors for their dedication in designing and
implementing the new organizational and strategic research plan in the past three years. Thanks to their
hard teamwork, SRSI further strengthen its leading position in Italy and its international reputation as a leading institute in biomedical science.
I also would like to express my gratitude to the project and group leaders and to all members of the scientific community for their continuous support and sense of responsibility in this difficult year. I believe that
despite many hurdles the young investigators who joined SRSI in 2010 will find an environment where they
can growth both personally and professionally.
A special thank you goes also 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
2010 Scientific Report.
Finally, the vision of our President, which can be summarized in three key elements: “there is no cure
without research”, “research is the backbone of the San Raffaele” and “basic research is the foundation of our knowledge and culture” will continue to guide and inspire us in the future. To him go our
deepest thanks for believing in and promoting research during each and every step towards the build up
of the SRSI; an incredible adventure and challenge.
Finally, I would like to remind to all of us that “In the middle of difficulty lies opportunity” (Albert Einstein)
I hope you will find our report interesting and informative.
Scientific Director
XXV
INTRODUCTIONS
Introduction by the Chief Operating Officer
The San Raffaele Scientific Institute is one of the leading health care and biomedical research centers in
Italy. Its ability and potential to attract grants both at the national and at the international level and its high
scientific productivity, measured by number and quality of publications, technology transfer activities and
clinical trials, are the best indicators of the excellence of its research.
The aim of the Chief Operating Officer of Research and of the Research Staff is to continue to support
the core business: basic, translational and clinical research, as described in the 5-year Research Strategic Plan. To achieve this important and strategic goal, the Chief Operating Officer has established an efficient and streamlined management and control system that focuses on four components: finances,
organizational development, human resources and infrastructure, and marketing and fundraising.
The 2010 activities are briefly summarized:
Planning and management control
In 2010 a 4-year development plan for the Research Area was put in place based on the contents of the
Strategic Plans for each Division and Center, the economic sustainability, and the goal to optimize resources and create synergy. The objective of this 4-year plan is to guarantee the steady development of
the Institute’s research lines, applying efficient and effective management strategies.
Research Data Warehouse
A Data Warehouse for Research was planned to manage, update and monitor administrative-managerial information (organization, personnel, funding, etc.) as well as information related to scientific production (publications, clinical trials, patents, etc) in a regular and rapid way. The program is structured in
“modules” and as a web-based platform that interacts with, and is fed by, information from other institutional databases. This structure is designed to ensure that data are constantly aligned and updated (e.g.
personnel database, funds database, publications database, etc). The first two modules were set up in
2010: one regards organization, the other personnel. Subsequently, the system ran the first census on
the Institute’s basic and/or clinical researchers, whose main aim was to ensure the integration, traceability and sharing of information, regarding both the San Raffaele Foundation and the University, within a single database. This information already exists to a large extent, but it was not configured to manage and
integrate data automatically. This first census is the prerequisite for future censuses of research activities
and “products”, as well as for the allocation of present and future space and any other resources.
Divisional Regulatory Framework
The launch and implementation of the new Research Area organization in the past three years led to the
need to define a Regulatory Framework able to meet the operational and managerial needs of the various Research Divisions and Centers.
Accordingly, in 2010 a purpose-specific Steering Committee and workgroup were nominated by the Research Directorate. The Regulatory Framework will provide guidance for each Research Division/Center
and will thus enable the development of a coherent and homogenous divisional model, at the same time
as heeding the specific and differing characteristics of each Division.
New Data Processing Center
The need for a new Data Processing Center (DPC), one that has greater capacity and is better suited and
more specific to the Research Area, was accelerated by the implementation plan for the Translational
Genomics and Bioinformatics Center, the Imaging Experimental Center, and the Division of Molecular
Oncology in 2010.
The research area will benefit from upgraded and secure services such as:
Standardized backup procedures
Increased File Sharing areas (sharing files within a common network)
Improvement and strengthening of electrical continuity through the implementation of suitable rack solution (collection and optimization of the local servers).
The aim of the new Data Processing Center for Research is to create an independent area in order to
maximize access flexibility by different groups while maintaining a high level of security.
INTRODUCTIONS
Communication and marketing
The role of the Marketing and Fundraising Office in 2010 was increasingly oriented towards defining a coherent and incisive development plan for fundraising and communication activities, based on the exploitation of research results and excellence. Such activities are in line with and support the implementation
of the Scientific Strategic Plan.
Communication plays a key role: that of emphatically enhancing awareness of San Raffaele’s competitive position, as a nationally and internationally recognized leading research institute delivering a complete Teaching-Research-Care service to mankind.
Objective for 2011 will be a thorough re-development of the Foundation’s website and hence of the three
core areas. More generally, all internal and external communication channels will be reviewed on the
basis of a meticulous and effective media-planning strategy.
Fundraising actions will seek new opportunities, by re-launching existing campaigns (patients, bequests,
5x1000*), by generating new events of a local or national nature, and by establishing co-marketing agreements with industrial and commercial organizations.
Focus on some numbers
Research
Total revenues year 2010
Other revenues;
6,82%
Research revenues;
93,18%
Research revenues
year 2010
Other revenues
year 2010
Sponsored research;
6,82%
Clinical trials;
7,25%
External grants;
49,68%
Public funds;
36,25%
External services;
24,80%
Other income;
5,91%
Internal services;
12,76%
Donations;
56,52%
All in all we can conclude that, despite the financial crisis, 2010 has been a year in which the Research
Area continued to secure funding, to create value and to be the characterizing element of the San Raffaele
brand.
Maurizio Savi
Chief Operating Officer
*[5 x 1000 is an arrangement whereby the taxpayer can allocate five thousandths of his/her income tax
payment to support voluntary organizations, or medical or scientific research]
XXVII
INTRODUCTIONS
San Raffaele Scientific Retreat 2010
The Scientific Committee
INTRODUCTIONS
XXIX
INTRODUCTIONS
INTRODUCTIONS
Best poster award
1st - Federica Cerri
Regenerating peripheral nervous system: gene expressione analysis
2nd - Marco Ranzani
Insertional mutagenesis by genotoxic lentiviral vectors identifies new cancer genes involved in the process
of hepatocarcinogenesis
3rd - Claudia Montanaro
Detrimental effects of acute non-esterified fatty acids deprivation on cardiac metabolism and function in
patients with heart failure
XXXI
INTRODUCTIONS
Best paper award
The winners of the Best paper 2009 award session
Basic research
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-α activation inhibits CC
chemokine receptor-7 expression on dendritic cells
and dampens antitumor responses. Nat. Med.
published online 27 Dec 2009
Translational research (ex-aequo)
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
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 stemcell transplantation. N. Engl. J. Med.: 2009; 361(5):
478-488
INTRODUCTIONS
Clinical research (ex-aequo)
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
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
XXXIII
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 & LOGISTICS DIRECTOR: Alberto Russo
HEALTH AREA PROJECT DEVELOPMENT DIRECTOR: Maria Romano
CUSTOMER SERVICE DIRECTOR: Riccardo Pizzo
TECHNICAL SERVICE DIRECTOR: Andrea Roma (till September 2010),
Alessandro Bartucci (from October 2010)
E-SERVICES FOR LIFE AND HEALTH DIRECTOR: Alberto Sanna
PROMOTION & DEVELOPMENT MANAGER: Alberto Galliani
ORGANIZATION & DEVELOPMENT MANAGER: Margherita Gambaro
LEGAL OFFICE MANAGER: Piergiorgio Sammartino
XXXV
INTRODUCTIONS
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 2010 the
hSR activity counts 55.390 in-patients, 65.135 patients admitted to the Emergency Room, more than
8.000.000 out-patients and diagnostic tests (the latter is a 2009 outcome, the 2010 data of the out-patients and diagnostic tests are currently being processed). 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-Thoracic-Vascular 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 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.
INTRODUCTIONS
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 and of Director of the Università Vita-Salute 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
XXXVII
INTRODUCTIONS
2010 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 translational genomics and bioinformatics
■
Imaging experimental Center
■ January 11, 2010
Dorsal signaling factors regulate
oligodendrocyte maturation during
development and disease
Judy Grinspan, Department of Neurology
Children’s Hospital of Philadelphia and
University of Pennsylvania
Guest: Lawrence Wrabetz
■ January 13, 2010
Oxytocin autocrine-paracrine tuner of bone
cell activity: mechanism ofaction and
intracellular signalling
Alberta Zallone, Department of Human
Anatomy and Histology, University of Bari
Guest: Simone Cenci
■ January 14, 2010
Targeting the skeleton to treat breast cancer
Katherine Weilbaecher, Department of
Medicine & Cell Biology, Washington
University School of Medicine, St. Louis
Guest: Simone Cenci
■ February 15, 2010
“Primo Levi Lectures” nel giorno della
memoria
Le radici teologiche dell’antisemitismo
Vito Mancuso, Università Vita-Salute San
Raffaele
■ March 3, 2010
The p38 MAPK/CREB pathway regulates
mesoderm patterning during early Xenopus
laevis development
Aviad Keren, The Ruth and Bruce Faculty of
Medicine, Israel Institute of Technology
Guest: Giulio Cossu
■ March 8, 2010
IL-7 in the Life and Death of T Cells
Scott K. Durum, National Cancer Institute &
National Institute of Health, Frederick, MD,
USA
Guest: Anna Villa
■ January 18, 2010
Genetic pathways controlling cardiac function
Gianluigi Condorelli, National Research
Council and IRCCS Multimedica, Roma
Guest: Stefano Biffo
■ March 15, 2010
CSPG4-specific monoclonal antibody-based
immunotherapy of malignant diseases
Soldano Ferrone, University of Pittsburgh
Cancer Institute
Guests: Giorgio Parmiani, Cristina Maccalli
■ January 22, 2010
Structural studies on the E6 oncoprotein
produced by high-risk papillomaviruses
responsible for cervical cancers
Gilles Travè, Centre National de la
Recherche Scientifique, Université de
Strasbourg
Guest: Giovanna Musco
■ March 22, 2010
Molecular Characterization of the Lymphoma
Genome: from Integrative Data Analysis to
Targeted Therapy
Stefano Monti, Broad Institute of MIT &
Harvard Cancer Program Cambridge, MA
Guest: Giovanni Tonon
INTRODUCTIONS
■ March 29, 2010
Targeting cell cycle and signal transduction in
cancer cells
Francesco Colotta, Direttore Ricerca e
Sviluppo, Nerviano Medical Sciences
Guest: Claudio Bordignon
■ April 12, 2010
Polyglutamine disease: post-translational
modifications as therapeutic targets
Maria Pennuto, Department of
Neuroscience, Italian Institute of Technology,
Genova
Guest: Lawrence Wrabetz
■ April 13, 2010
Regulatory mechanisms in iron homeostasis
Martina Muckenthaler, Department of
Pediatric Oncology, Hematology and
Immunology, University of Heidelberg
Guest: Sonia Levi
■ April 27, 2010
The B-cell receptor signaling pathway in CLL:
Implications for pathogenesis and treatment.
Dimitar Efremov, Molecular Hematology
International Centre for Genetic Engineering &
Biotechnology, (ICGEB), Rome
Guest: Marta Muzio
■ April 28, 2010
Bringing genetically modified T cell therapies
into mainstream medicine
Gianpietro Dotti, Center for Cell & Gene
Therapy, Baylor College Houston (TX)
Guest: Attilio Bondanza
■ April 29, 2010
Succesful Immunotherapy of established
lesions induced by high risk HPV
Cornelis J.M. Melief, Departments of
Immunohematology and Blood Transfusion,
Leiden, University Medical Center, and ISA
Pharmaceuticals, Leiden, the Netherlands
Guest: Giorgio Parmiani
■ May 14, 2010
Molecular basis of protein disulfide bond
formation in the cell
Kenji Inaba, Medical Institute of Bioregulation,
Kyushu University
Guest: Roberto Sitia
■ May 17, 2010
The Next Generation of Gene Fusion
Discovery in Cancer
Arul M. Chinnaiyan, Michigan Center for
Transaltional Pathology, University of Michigan
Guest: Marta Muzio
■ May 21, 2010
Diseases of iron homeostasis: molecular
understanding leads to new therapies
Tomas Ganz, Departments of Medicine and
Pathology, School of Medicine, University of
California, Los Angeles
Guest: Clara Camaschella
■ May 24, 2010
Myosin VI a crossroad between endocytosis
and cancer
Claudia Puri, TIGEM, Napoli
Guest: Massimo Crippa
■ May 25, 2010
Following transcription factors one molecule at
a time.
Davide Mazza, Laboratory for receptor
biology and gene expression (LRBGE)
NCI/NIH, Bethesda (MD), USA
Guest: Carlo Tacchetti
■ May 28, 2010
Regulation of developmentally-programmed
DNA methylation
Irina Stancheva, Wellcome Trust Centre for
Cell Biology, University of Edinburgh
Guest: Davide Gabellini
■ May 31, 2010
mTOR, a “master regulator” of cell functions
Christopher Proud, School of Biological
Sciences, University of Southampton,
Southampton General Hospital
Guest: Stefano Biffo
■ June 14, 2010
Notch and Calcineurin signaling in integrated
control of skin homeostasis and carcinogenesis
G. Paolo Dotto, Department of Biochemistry,
Lausanne University
Guest: Silvia D’Alessio
■ June 21, 2010
Signalling from the Met receptor: Molecular
aspects and medical implications
Livio Trusolino, Institute for Cancer Research
and Treatment IRCC, Torino
Guest: Michele De Palma
XXXIX
INTRODUCTIONS
2010 Seminars and Lectures
■ June 28, 2010
Histone deacetylases in developmental
myelination and demyelinating disorders
Patrizia Casaccia, Mount Sinai School of
Medicine, New York
Guest: Carla Taveggia
■ September 24, 2010
Thymic microenvironments that shape T cell
repertoire
Yousuke Takahama, Institute for Genome
Research, The University of Tokushima
Guest: Andrea Brendolan
■ July 12, 2010
From Filopodia to Synapses: the Cell Biology
of Neuronal Wiring
Michela Matteoli, Dept of Pharmacology and
CNR Institute of Neuroscience, Milano
Guest: Romana Tomasoni
Homeostatic plasticity: from synapses to the
axon initial segment
Juan Burrone, MRC Centre for
Developmental Neurobiology, King’s College
London
Guests: Eugenio Fornasiero, Flavia
Valtorta
■ July 16, 2010
From Inorganic nanoparticles towards their
assembly in mesoscale structures designed
for biological applications
Teresa Pellegrino, National Nanotechnology
Laboratory of CNR-INFM, Lecce & Italian
Institute of Technology, Genova
Guest: Carlo Tacchetti
Use of the iron hormone hepcidin prevents
iron overload and ameliorates erythropoiesis in
ß-thalassemia
Stefano Rivella, Department of Pediatric
Hematology-Oncology, Weill Cornell Medical
College, New York
Guest: Giuliana Ferrari
On interpreting experimental data on
biomolecular systems using molecular
simulation
Wilfred F. van Gunsteren, Laboratory of
Physical Chemistry, IGC Group, ETH
Hönggerberg, HCI, Zurich
Molecular Mechanisms of Muscle Wasting
and Cancer Cachexia
Alfred Goldberg, Department of Cell Biology,
Harvard Medical School, Boston
Guest: Roberto Sitia
Macrophage Receptors and Innate Immunity
Siamon Gordon, University of Oxford, Sir
William Dunn School of Pathology, Oxford
Guest: Michele De Palma
Identification of serum RNA biomarkers of viral
or cellular origin that are predictive of disease
progression and liver cancer in chronic
Hepatitis C Virus infection
Raffaele de Francesco, Istituto Nazionale di
Genetica Molecolare, INGM, Milano
Guest: Marco E. Bianchi
■ October 11, 2010
Engineered extracellular materials for
engineering of bone,cartilage and tendon (and
muscle?)
Jons Hilborn, Department of Materials
Chemistry, Uppsala University
Guest: Giulio Cossu
■ October 20, 2010
Theta network oscillations: focus on
GABAergic interneurons of amygdala and
hippocampus
Marco Campogna, Department of
Pharmacology,MRC Anatomical
Neuropharmacology Unit, Oxford, UK
Guest: Flavia Valtorta
■ October 22, 2010
The Use of Biochemical Profiling for Biomarker
Discovery
John Ryals, President and CEO, Metabolon
Inc., Durham, U.S.A.
Guest: Jose M. García Manteiga
■ October 25, 2010
The role of BACE1 in peripheral myelination by
processing of neuregulin-1
Michael Willem, Deutsches Zentrum für
Neurodegenerative Erkrankungen, LudwigMaximilians-Universität München
Guests: Daniele Zacchetti, Carla Taveggia
INTRODUCTIONS
■ November 8, 2010
NETs - from infection to autoimmunity
Arturo Zychlinsky, Max Planck Institute for
Infection Biology, Berlin
Guest: Marco E. Bianchi
PI3K as enzymes and scaffold proteins in
health and disease
Emilio Hirsch,Molecular Biotechnology
Center, University of Torino
Guest: Alessandra Boletta
The roles of the mammalian Hippo Signaling
Pathway in epithelial tissue development, adult
stem cells and tumorigenesis.
Dae-Sik Lim, National Creative Research
Initiative Center, Department of Biological
Sciences, KAIST
Guest: Vania Broccoli
Macrophage Diversity Promotes Tumor
Progression and Metastasis
Jeffrey W. Pollard, Dept Developmental and
Molecular Biology, Albert Einstein College of
Medicine, New York
Guest: PhD Invited Lecture Committee
Super Experiments and the Application of
System-wide Proteomic Analyses in Cell
Biology
Angus Lamond, Wellcome Trust Centre for
Gene Regulation and Expression, University
of Dundee
Guest: Francesco Blasi
■ December 20, 2010
Probing molecular recognition using fragmentbased approaches: from enzyme active sites
to protein-protein interfaces
Alessio Ciulli, Department of Chemistry,
University of Cambridge
Fifty ways to leave your blood vessels: new
insights on endothelial exit signals for immune
cells
Ronen Alon, Dept. of Immunology, The
Weizmann Institute of Science, Rehovot, Israel
Guest: Ruggero Pardi
XLI
SCIENTIFIC REPORTS
La “Squadra”
The Scientific Director, the Chief Operating Officer, the Directors and Associated Directors of the Research
Divisions and Centers, the Directors of the Institutes, and the Scientific and Technical Committee
1
Divisions, Centers, Institutes and Research programmes
Microenvironment
and Genes in Cancers
of the Blood
(MAGIC)
DIVISION OF
MOLECULAR
ONCOLOGY
DIVISION OF
NEUROSCIENCE
INSPE
INSTITUTE OF EXPERIMENTAL
NEUROLOGY
Human Brain Invivo
Mapping with
neuroimaging
(BRAINMAP)
DIVISION OF
METABOLIC AND
CARDIOVASCULAR
SCIENCES
Brain Regeneration
usIng medical
Devices, Gene vectors
and stEm cells
(BRIDGE)
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
DIVISION OF
Program in
Immunology and
Bio-immunotherapy
of Cancer (PIBIC)
DRI
DIABETES RESEARCH
INSTITUTE
Islet Trasplantation
Program (ITP)
GENETICS AND
CELL BIOLOGY
CENTER FOR
TRANSLATIONAL
GENOMICS AND
BIOINFORMATICS
IMAGING
EXPERIMENTAL CENTER
Correlates of
HIV-Associated
Immune Response
Modulation
Program (CHARM)
Bone Physiopathology
Program (BoNetwork)
3
DIVISION
OF
MOLECULAR ONCOLOGY
Director:
Federico Caligaris-Cappio*
Associate Director:
Giorgio Parmiani
Research Units
Lymphoid malignancies Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 11
HEAD OF UNIT: Federico Caligaris-Cappio*,
POST-DOCTORAL FELLOWS: Maria Teresa Sabrina Bertilaccio, Carlo Calissano, Cristina Scielzo
PHD STUDENT: Benedetta Apollonio**
FELLOWS: Elisa ten Hacken, Stefano Vergani
TECHNICIAN: Pamela Ranghetti
Biology of multiple myeloma–––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 11
GROUP LEADER: Marina Ferrarini
POST-DOCTORAL FELLOW: Daniela Belloni
Cell activation and signalling ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 12
GROUP LEADER: Marta Muzio
FELLOWS: Eleonora Fonte, Marta Tocchetti
TECHNICIAN: Tania Veliz Rodriguez
Dynamic fluorescence spectroscopy in biomedicine –––––––––––––––––––––––––––– 13
GROUP LEADER: Valeria R. Caiolfa
POST DOCTORAL FELLOWS: Valeria Corti, Christian Hellriegel, Giulia Ossato, Antonio Trullo
FELLOW: Moreno Zamai
Lymphoid organ development ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 13
GROUP LEADER: Andrea Brendolan
MASTER STUDENTS: Sara Maruzzelli
PHD STUDENTS: Laura Castagnaro, Elisa Lenti
5
DIVISION OF MOLECULAR ONCOLOGY
Research Units
Preclinical models of cancer ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 14
GROUP LEADER: Rosa Bernardi
POST-DOCTORAL FELLOWS: Nadia Coltella, Benedetta Pozzi
PHD STUDENT: Ylenia Guarnerio**
FELLOW: ROBERTO Cuttano
Tumor microenvironment –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 14
GROUP LEADER: Elisabetta Ferrero
PHD STUDENT: Lorenzo Veschini
Immuno-biotherapy of melanoma and solid tumors Unit –––––––––––––––––––––––––––––– 15
HEAD OF UNIT: Giorgio Parmiani
RESEARCHER: Cristina Maccalli
PHYSICIAN: Lorenzo Pilla
POST-DOCTORAL FELLOW: Tonia Mazzarella
PHD STUDENTS: Valeria Cambiaghi, Amir Jamil, Michela Spinelli
TECHNICIAN: Gloria Sovena
Cancer gene therapy ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 15
GROUP LEADER: Vincenzo Russo
PHD STUDENTS: Raffaella Fontana**, Aida Paniccia, Laura Raccosta
FELLOWS: Claudia Lanterna, Andrea Leiva
TECHNICIAN: Daniela Maggioni
B-cell neoplasia Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 16
HEAD OF UNIT: Paolo Ghia*
POST-DOCTORAL FELLOWS: Antonis Dagklis**, Claudia Fazi**, Agnieszka Janus**
PHD STUDENTS: Maria Gounari, Giorgia Simonetti
FELLOW: Lydia Scarfò
Functional genomics of cancer Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 17
HEAD OF UNIT: Giovanni Tonon
POST-DOCTORAL STUDENTS: Michela Frenquelli, Manuela Occhionorelli, Simona Segalla
PHD STUDENTS: Aurora Negro**, Beatrice Rondinelli**
Molecular histology and cell growth Unit ––––––––––––––––––––––––––––––––––––––––––––––––– 17
HEAD OF UNIT: Stefano Biffo
POST-DOCTORAL FELLOWS: Daniela Brina, Piera Calamita (from March 2010), Stefano Grosso,
Elia Ranzato
PHD STUDENTS: Simone Gallo**, Elisa Pesce
FELLOWS: Anne Beugnet, Marilena Mancino, Maria Veronica Russo
TECHNICIAN: Annarita Miluzio
Tumor biology and vascular targeting Unit ––––––––––––––––––––––––––––––––––––––––––––––– 19
HEAD OF UNIT: Angelo Corti
RESEARCHER: Flavio Curnis
PHD STUDENT: Eleonora Dondossola**
FELLOW: Luca Crippa
TECHNICIANS: Barbara Colombo, Anna Gasparri, Angelina Sacchi
Digestive and pancreatico-biliary endoscopy Unit –––––––––––––––––––––––––––––––––––––– 20
HEAD OF UNIT: Pier Alberto Testoni*
PHYSICIANS: Giulia Martina Cavestro, Lorella Fanti, Antonella Giussani, Alberto Mariani, Edi Viale
RESIDENTS: Milena Di Leo, Chiara Notaristefano, Cristian Vailati
FELLOWS: Elisabetta Goni, Antonella Putignano, Gemma Rossi, Sabrina Testoni
Endosonography: diagnostic and therapeutic endoscopic ultrasound –––––– 20
CLINICAL GROUP LEADER: Paolo Giorgio Arcidiacono
PHYSICIANS: Silvia Carrara, Gianni Mezzi, Maria Chiara Petrone
RESIDENT: Cinzia Boemo
Gastrointestinal surgical oncology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––– 21
HEAD OF UNIT: Carlo Staudacher*
PHYSICIANS: Paola De Nardi, Saverio Di Palo, Elena Orsenigo, Andrea Marco Tamburini, Andrea
Vignali
RESIDENTS: Damiano Chiari, Serena Pozzi
FELLOWS: Massimiliano Bissolati, Michele Carvello, Paolo Gazzetta, Cristina Gilardini,
Gregorio Stratta
Head and neck oncology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 21
HEAD OF UNIT: Mario Bussi*
PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Matteo Trimarchi
CONSULTANTS: Chiara Bellini, Beatrice Fabiano
RESIDENTS: Pietro Limardo, Paola Recanati, Daniela Sarandria, Salvatore Toma
TECHNICIANS: Daniela Gherner, Barbara Ramella
Multidisciplinary group for thoracic surgical oncology –––––––––––––––––––––––––––––––– 22
HEAD OF UNIT: Piero Zannini*
PHYSICIANS: Alessandro Bandiera, Angelo Carretta, Paola Ciriaco, Giulio Melloni, Giampiero Negri*,
Armando Puglisi, Carlopietro Voci*
RESIDENTS: Annamaria Gremmo, Piergiorgio Muriana, Stefano Sestini, Silvia Raimondi Cominesi
Oncogenesis in liver neoplasms Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––– 22
HEAD OF UNIT: Gianfranco Ferla*
PHYSICIAN: Mvunde Mukenge
RESIDENT: Francesca Ratti
Onco-hematology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 23
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
STUDY COORDINATOR: Stefania Trinca
RESEARCH NURSE: Marzia Pedrocchi
DATA MANAGER: Anna Sparano
TECHNICIAN: Roberta Mattarucchi
7
Pancreatic cancer Unit: biology and new therapeutic approaches ––––––––––––––––– 23
HEAD OF UNIT: Valerio Di Carlo*
PHYSICIANS: Gianpaolo Balzano, Walter Zuliani
RESIDENT: Giovanni Capretti
FELLOW: Cristina Ridolfi
Pathology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 24
HEAD OF UNIT: Claudio Doglioni*
PHYSICIANS: Massimo Freschi, Maurilio Ponzoni, Nathalie Rizzo, Francesca Sanvito, Isabella Sassi
BIOOGISTS: Maria Giulia Cangi, Lorenza Pecciarini
PHD STUDENTS: Daniela Clavenna, Greta Grassini, Ilenia Papa
FELLOWS: Emanuela Brunetto, Lorenzo Spagnuolo, Caterina Vicentini
TECHNICIANS: Elena Dal Cin, Stefano Grassi, Martina Rocchi, Graziella Santambrogio,
Anna Talarico
Clinical lymphoid malignancies –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 25
HEAD OF UNIT: Federico Caligaris-Cappio*
CLINICAL GROUP LEADER: Andrés Jose Maria Ferreri
PHYSICIANS: Marta Bruno Ventre, Giovanni Donadoni, Marco Foppoli, Silvia Govi, Silvia Mappa,
Angela Zanoni
RESIDENT: Emerenziana Marturano
TECHNICIAN: Arianna Vino
Gynecologic oncology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 25
HEAD OF UNIT: Massimo Candiani*
CLINICAL GROUP LEADER: Giorgia Mangili
PHYSICIANS: Patrizia De Marzi, Davide Ferrari, Serena Montoli, Emanuela Rabaiotti,
Riccardo Viganò
RESIDENTS: Cinzia Gentile, Jessica Ottolina, Francesca Pella
PHD STUDENTS: Alice Bergamini, Cristina Sigismondi
Medical oncology Unit
HEAD OF UNIT: Eugenio Villa
Clinical trials –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 26
CLINICAL GROUP LEADER: Michele Reni
PHYSICIANS: Daniela Aldrighetti, Gianni Bordogna, Stefano Cereda, Elena Mazza,
Monica Ronzoni, Giordano Pietro Vitali, Patrizia Zucchinelli
CONSULTANTS: Carmen Belli, Vincenzo Ricci, Alessia Rognone
RESEARCH NURSES: Domenica Ceraulo, Simona Longoni
Phase I and lung cancer clinical trials ––––––––––––––––––––––––––––––––––––––––––––– 26
CLINICAL GROUP LEADER: Vanesa Gregorc
PHYSICIANS: Giovanni Citterio, Maria Grazia Viganò
RESIDENTS: Luca Bergamaschi, Chiara Lazzari, Cristina Sorlini, Gabriele Todisco
PHD STUDENT: Anna Spreafico
FELLOWS: Alessandra Bulotta, Teresa Fabozzi, Gilda Rossoni
URI, Urological Research Institute –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 27
HEAD OF UNIT: Francesco Montorsi*
PRE-CLINICAL RESEARCH COORDINATOR: Petter Hedlund
PHYSICIANS: Roberto Bertini, Alberto Briganti, Nicolò Maria Buffi, Andrea Cestari,
Renzo Colombo, Andrea Gallina, Luciano Nava, Donata Rigatti, Antonino Saccà,
Andrea Salonia,Vincenzo Scattoni, Nazareno Suardi
RESIDENTS: Firas Abdollah, Marco Bianchi, Tommaso Camerota, Umberto Capitanio, Fabio
Castiglione, Dario Di Trapani, Ettore Di Trapani, Matteo Ferrari, Giulio Maria Gadda, Giovanni
Lughezzani, Carmen Maccagnano, Rayan Matloob, Federico Pellucchi, Lorenzo Rocchini,
Francesco Sozzi, Manuela Tutolo, Luca Villa
CONSULTANTS: Fabio Benigni, Federico Sobrero
POST-DOCTORAL FELLOWS: Roberta Buono, Ilaria Cavarretta
TECHNICIANS: Arianna Bettiga, Giorgia Colciago
DATA MANAGERS: Ibrahim Buthaina, Cristina Carenzi, Elena Farina, Nadia Finocchio, Amy
Sussmann
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
9
Mission and Vision - The Division’s aim starts from the notion 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. We plan
to develop translational and clinical research programmes devoted to the treatment of cancer by fostering extensive collaborations between basic scientists and clinicians and improving international connections.
Organization - The Division of Research of Molecular Oncology entails 14 Basic Research Units (URB)
and 15 groups of Clinical Research (GRC) that are organizing themselves into Research Programs. The
Personnel is close to 190 people. The Lab space allocated to the Division is about m2 2500. Through
fruitful collaborations with both Clinical Departments and other Research Divisions we are developing infrastructure facilities that favour a more mature organization. These include an annotated data base of patients with lymphoid tumors linked to a bio-bank (in collaboration also with the Department of Pathology),
mouse and cell line registers as well.
Goals - The main goal is to join efforts with the Clinical Department of Oncology to create an internationally competitive Cancer Center (HSR-ICC) which integrates cancer research, treatment and education with
the aim of curing cancer and the purpose of becoming “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 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 and involve Lymphoid Malignancies, Pancreatic Cancer, Thoracic Cancers, Urinary Cancers,
Neuro Oncology, Breast Cancer, 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 is obtaining interesting basic/pre-clinical results and plans to translate these results into novel, proof of principle clinical trials.
MAGIC has been developed through the expertise, network organization and multidisciplinarity of different Units which bridge the Division of Molecular Oncology with the Clinical Department of Oncology.
Magic investigations also entail the participation of numerous Research Divisions. The program spans
from genomic, epigenomic and proteomic studies to the characterization of the microenvironment in the
development and progression of blood cancers. It combines and compares the genetic and microenvironment analysis into a fully integrated genotype-phenotype and tumor-microenvironment scientific approach utilizing a whole range of mouse models, many already established by different members of the
Division. 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, offers numerous post-doc opportunities and is well
prepared to host, train and mentor Physician Scientists.
Research Units
The aim of our Unit is to elucidate the cross-talk
between the leukemic clone and its microenviroment. In Chronic Lymphocytic Leukemia (CLL) the
relationships between cell accumulation within lymphoid organs and proliferation are not cleared, and
the mechanisms regulating CLL cell migration and
re-circulation between peripheral blood and the
lymphoid tissues are poorly characterized. Our previous studies demonstrated that Hematopoietic cell
specific Lyn substrate 1 (HS1), a pivotal molecule
in the signal transduction pathway triggered by the
B-cell receptor, is a potential prognostic marker in
CLL and interacts with several cytoskeletal components.
Given the role played by the cytoskeleton in controlling cellular shape, mobility and homing, we hypothesized that HS1 could be relevant in the
regulation of CLL cells infiltration into lymphoid tissues and re-circulation between peripheral blood
and tissues. To study HS1 function, we silenced its
expression in a CLL cell line (MEC1) and we utilized
B lymphocytes from HS1 knock-out (KO) mice.
Both cell types were then studied for their migration, adhesion, actin-polymerization and aggregation capacity through in vitro and in vivo assays.
In both cellular systems HS1-deficient B cells were
severely impaired in their migration and adhesion
capacity. A decrease in F-actin polymerization and
an increased homotypic aggregation ability were
also evident in cells lacking HS1.
To test in vivo HS1 function, we injected MEC1
cells silenced for HS1 in Rag2-/-γc-/- mice and
observed that cells lacking HS1 spread and localize preferentially in the bone marrow (BM) and in
the lymph nodes as compared to control cells. To
further investigate HS1 role in the onset and progression of CLL, we crossed HS1 KO mice with
Emu-TCL1 transgenic animals (CLL mouse
model). The HS1 KO/TCL-1 transgenic mice
showed an earlier disease onset and a preferential
accumulation of leukemic cells in the BM where
they are usually observed only at low frequencies
in the Emu-TCL1 mouse.
These findings suggest that HS1 has an important
role in controlling cell migration and tissue invasion
by leukemic B cells. This points at HS1 as a potential target for development of novel cancer treatments aimed at interfering with tissue infiltration and
invasion.
Federico Caligaris-Cappio
Biology of multiple myeloma
Angiopoietins and multiple myeloma-associated angiogenesis
Main focus of our research is to dissect the role of
bone marrow (BM) microenvironment in Multiple
Myeloma (MM) pathogenesis. In particular, BM angiogenesis deeply contributes to MM development
and progression; the identification of the pathophysiological mechanisms involved is therefore expected to lead to the identification of biomarkers of
ongoing angiogenesis, and possibly of new therapeutic targets for the disease, which remains ultimately incurable.
Angiopoietins (Angs) represent important regulators of angiogenesis and vascular stability via the
competitive binding to the common tyrosine kinase
receptor Tie2, which is mostly expressed by Endothelial Cells (EC). Ang-1 ensures vascular stability, while Ang-2 destabilizes neo-forming vessels.
The balance between Ang-1 and Ang-2 is critical
in developing angiogenesis in solid tumours. More
recently, high levels of circulating Ang-2 were found
to be prognostic in haematological malignancies,
including MM.
In collaboration with Dr. Elisabetta Ferrero, HSR, we
investigated the expression and pro-angiogenic
functions of Angs in BM sera from MM patients.
Our results indicate that BM levels of Ang-1 and
Ang-2, and particularly the Ang-1/Ang-2 ratio, discriminate between patients with advanced MM and
those with smouldering MM or MGUS, while levels
of VEGF, SDF-1, CXCL8/IL-8 and CCL2/MCP-1,
all involved in angiogenesis, were not significantly
different among groups. Moreover, we found that
MM plasma cells, in addition to BM macrophages
and EC from patients with MM, may be sources of
Ang-2. At variance with EC, exposure to hypoxia
did not affect Ang-2 production by MM cells. Finally,
differential contents of Angs in the BM sera of MM
patients determined their pro-angiogenic potential,
as assessed by specific in vitro assays. Altogether,
our results indicate that Angiopoietins can be further exploited as biomarkers of angiogenesis and
as molecular targets in MM.
Marina Ferrarini
11
Research Units
Toll-like receptors in chronic lymphocytic leukemia
Our main research interest is to dissect the molecular events which regulate B-cell receptor (BCR)
and Toll-like receptors (TLR) signaling pathways in
normal and malignant B lymphocytes. TLR are key
players in host defence from infection. Several reports recently demonstrated the involvement of
TLR stimulation in the transformation/progression
of solid tumors. Emerging evidence suggest that
TLR may play a similar role also in chronic B-cell
malignancies including chronic lymphocytic
leukemia (CLL).
During 2010, we investigated the role of TLR in
leukemic cell proliferation; in details, we analyzed
functional relationships between TLR, microRNA
221/222 (miR-221/222) and p27, a key regulator
of cell cycle. When CLL cells were induced in vitro
to enter cell cycle with TLR ligands (i.e. CpG
oligonucleotides) a significant increase of miR221/222 expression and a marked down-regulation of p27 protein were evident. This data
suggests that miR-221/222 and p27 represent a
regulatory loop that may be regulated by TLR.
The available data on TLR expression in CLL are
limited and derive from a small series of patients.
We therefore set up an international collaboration
to perform a systematic gene expression profiling of the TLR signaling pathway in a larger series of patients with CLL. The analysis extended
from all TLR known to be functional in normal B
cells to adaptors, effectors, inhibitors and members of the NFKB, JNK and p38 signaling pathways downstream of TLR. In conclusion, the
TLR gene expression profile of CLL is consistent
with derivation from antigen-experienced B cells.
In addition, significant variations were identified in
different subgroups of cases defined by BCR
molecular features, indicating distinctive activation patterns of the TLR signaling pathway, with
potential implications about the nature of the
antigenic stimulation.
Overall these findings further 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 novel
approaches for treatment of these tumors.
Figure 1. Schematic representation of BCR and TLR signaling pathways
Marta Muzio
Dynamic fluorescence spectroscopy in biomedicine
Assembly and signaling of cell membrane receptors by single molecule
and FLIM live imaging
A number of cell membrane receptors are involved
in distinct signaling pathway, which are triggered
by interaction with co-receptors, various extracellular ligands and intercellular cross-talk. Often the
regulation and the molecular determinants of receptors’ signaling are inferred from batch analyses
that lack spatio-temporal resolution. Alternatively,
the “where, when and how” question can be approached in real time and in live samples by combining optical microscopy and fluorescence
spectroscopy.
We take advantage of a number of innovative approaches in phasor-FLIM and brightness analysis,
which overcome the spatial resolution limit of visible light, for deciphering receptor signaling mechanisms with unprecedented detail.
We have demonstrated that tetraspanins relocated
at the immune synapse within minutes, forming
tight and specific complexes also with CAM re-
ceptors. The interactions are dynamic and evolve
differently in the developing synapse (cSMAC,
pSMAC) as followed by phasor-FLIM imaging.
Other membrane proteins, such as growth factor
receptors have non-canonical extracellular ligands
that elicit a cellular response different than that of
growth factor molecules. In the case of FGFR,
NCAM initiates cell migration through the activation
of Src. At the membrane level, the binding kinetics
and the NCAM-induced reorganization of FGRF
are clearly different than that of FGF2 as demonstrated by N&B imaging. FGF2 induced a sustained dimerization of the receptors, before
internalization and degradation. In contrast, in the
presence of NCAM, FGFR undergoes fast assembly and disassembly cycles that might represent
internalization and recycling of naïve receptors at
the cell membrane.
Valeria R. Caiolfa
Lymphoid organ development
The research in our laboratory is focused on the
identification of 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
functional artificial lymphoid-like structures 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 role of the oncogenic transcription factor Tlx1 in lymphoid organ development.
By DNA-microarray analysis and chromatin immunoprecipitation coupled to deep sequencing
we are identifying the transcriptional networks
controlled by Tlx1 in proliferation and differentiation of progenitor cells during organogenesis.
Using these approaches, we uncovered several
developmental pathways deregulated in the absence of Tlx1 during organ expansion. We are
currently testing whether these pathways are also
deregulated during Tlx1-induced leukemogensis.
2. Uncovering the function of stromal cells in normal lymphoid and leukemia/lymphoma development. We have exploited a genetic approach in
mice to label stromal progenitors within developing lymphoid organs. We are currently identifying
the contribution of lineage-specific mesenchymal
progenitors to the adult stromal cell pool, and analyzing the stromal cell signals implicated in lymphoid cell proliferation/differentiation and survival.
3. Generating functional artificial lymphoid organs
(aLOs). By exploiting primary mesenchymal cells
as a source of stromal progenitors, we have developed aLOs with features resembling secondary lymphoid organs, including presence of Tand B-cell compartments as well as stromal-cell
networks. We are currently testing the ability of
transplantable aLOs to enhance anti-tumor immunity and control tumor growth.
Andrea Brendolan
13
Research Units
Role of HIF factors in hematological malignancies
The main objective of this unit is to understand the
role of pro-angiogenic factors in leukemogenesis
and the efficacy of their targeting as a novel therapeutic approach for hematological malignancies.
Emerging data shows that numerous hematological tumors express high levels of pro-angiogenic
factors such as VEGF and have increased angiogenesis. We hypothesized that activation of the
transcription factor HIF-1α, the main positive regulator of VEGF expression in solid tumors, may
cause high VEGF expression, increased angiogenesis and increased resistance to therapy in some
types of leukemias. Therefore, inhibiting HIF-1α activity in combination with current therapies may be
a useful approach to restrain leukemogenesis.
In the past year we have:
1. Studied the role of HIF-1α in mouse models of
acute promyelocytic leukemia (APL). In particular,
we have created a xenograft model of APL by injecting human APL cells into immunocompromized mice. In this model we have established
that inhibition of HIF-1α by shRNA strategies and
use of inhibitors prolongs survival and impacts
on neo-angiogenesis. To extend these results to
a more physiological context, we have generated
de novo murine APL by lentiviral transduction of
mouse bone marrow cells with the leukemogenic
fusion protein PML-RARα, followed by transplantation into recipient mice. This protocol led
to the occurrence of transplantable mouse APL,
which we are currently characterizing for its dependence on HIF-1α.
2. We have analyzed a number of established cell
lines representative of human hematopoietic
neoplasms and found that the expression of
HIF-1α is high in B cell malignancies. For this
reason, as part of the Institutional AIRC 5x1000
effort, we have extended our studies on the role
of HIF factors from myeloid leukemia to B cell
malignancies. In detail, we have generated stable human cell lines of B cell malignancies with
HIF-1α down regulation and have begun charactering the effects of HIF-1α silencing both in
vitro and in vivo.
3. Preliminary experiments show that the effect of
HIF-1α on leukemogenesis may be contextspecific and therefore its inhibition by novel therapeutic agents might reveal useful for specific
hematological tumors.
Rosa Bernardi
Tumour microenvironment
MM 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 anti-myeloma
drugs, including the proteasome inhibitor Bortezomib and the immunomodulatory drugs (IMiD)
could also depend on the 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 the Unit of M. Ferrarini, HSR,
we assessed the functional, pro-angiogenic potential of BM sera from MM patients, and found
that those containing Angiopoietin-2 indeed induce endothelial cells (EC) permeability, migration
in a wound healing assay and incomplete vessels
formation on Matrigel, strongly suggesting a role
for the molecule in promoting MM associated
aberrant angiogenesis. The technology of 3-D
culture model in bioreactor has been validated by
us (in collaboration with prof G. Mazzoleni) with
skin biopsies and murine tibia and found to be
able to preserve architecture, viability and functions of MM samples. Moreover, the 3D culture
system allows the assessment of response to anti-myeloma drugs both in term of plasma cells
apoptosis and of anti-angiogenic effects.
Elisabetta Ferrero
Immuno-biotherapy of melanoma and solid tumors Unit
During the year 2010, our Unit focused its activity
on both pre-clinical and clinical work.
A. Preclinical work
1. New mutated antigens of colorectal cancer
(CRC)
We have tested the in vitro immunogenicity of somatically mutated new CRC antigens, previously
identified by sequence analysis of the mutations of
CRC cells and of their cancer stem cells CSC).
Some of the mutated epitopes were shown to be
more immunogenic than the cognate non-mutated
peptide. This work involves the collaboration with
the Unit of Experimental Immunology (P. Dellabona)
within the framework of the PIBIC interdivisional research program.
2. CSC. CSC have been isolated in vitro from CRC
and their immune profile defined
We have previously shown that CSC of human
glioblastoma may be immune-suppressive; last
year we found that this may occur by the CSC-mediated activation of the indolamine 2,3-dioxigenase, an enzyme that may deprive T cells from
essential Amino Acids.
3. Molecular mechanisms of poor prognosis in ulcerated melanoma
We have analyzed by Immuno-histochemistry (IHC)
the presence of immunological markers and of
HMGB1 protein in the melanoma tissues. In vitro
studies have been performed to assess the potential inhibitory activity of HMGB1 on the antimelanoma immune responses.
4. Adoptive immunotherapy of melanoma
New studies allowed to identify the best procedure
for in vitro expansion for patient anti-tumor T cells.
It was shown that the in vitro stimulation of T cells
with autologous tumor cells in the presence of IL2 and IL-15 followed by the rapid expansion
(based on the usage of allogeneic irradiated feeder
plus OKT3) will favour such expansion. We are currently applying this protocol to GMP preparation of
T cells for their exploitation to the clinics.
B. Clinical work.
Over 120 patients affected by melanoma were
seen at out Unit; a portion has been treated and/or
enrolled in clinical trials. The new protocol based
on the combination of NGR-hTNF and peptide
vaccine in metastatic melanoma has been approved and initiated; 2 patients have been enrolled.
Another spontaneous trial combining the antibody
Ipilimumab and Fotemustine was approved for
metastatic melanoma; the patient accrual has
started in December 2010. As of March 2011, 12
patients have been enrolled and treated.
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 well-established intrinsic oncogenic
factors to fully explain tumor formation/establishment and metastasis. In recent years, several mol-
ecules 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 of identifying new strategies to improve antitumor immune responses.
Particularly, 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 es15
Research Units
cape, which dampens the spontaneous immune-mediated control of tumor growth by impairing the functional expression of the lymphoidorgan homing receptor CCR7 on maturing dendritic cells. Notably, the use of drugs interfering
with this pathway, restores the spontaneous antitumor immune response and the control of tumor
growth in mouse tumor models (Villablanca et al.
Nat Med, 2010).
Vincenzo Russo
Our research aims at investigating the field of malignant B cell development with particular interest
in indolent lymphomas. In the recent past we have
directed our work to define the biological relationship between MBL, an asymptomatic preclinical
condition characterized by the presence of small
B cell clones in the peripheral blood of otherwise
healthy subjects, and the most frequent adult
leukemia in the Western World, i.e chronic lymphocytic leukemia (CLL). MBL is detectable in >3%
of the general population and seems to be a melting-pot containing several entities, identical in terms
of phenotype but with extremely different risks of
leukemia development.
During 2010 we obtained further insight into the
genetic and environmental factors potentially involved in the transformation from MBL to CLL.
On the one side, we proceeded from recent data
suggesting that, at least in a portion of cases, MBL
might represent a progenitor lesion for chronic lym-
Figure 2. Hypothetical pathogenetic model of MBL. Infectious or self-antigens trigger a polyclonal B-cell activation
where few cells acquire a CLL-like phenotype. The persistent antigenic stimulation selects a single clone, that
might evolve into clinical MBL and possibly progress to clinically overt CLL. The role of genetic predisposition and
the presence of additional genetic hits need to be defined.
phocytic leukemia (CLL) and a surrogate for inherited predisposition. We analyzed 10 common single
nucleotide polymorphisms (SNPs), that have been
shown to confer a small but sizeable increase in CLL
risk, in 3 case-control series totalling 419 cases and
1753 controls. An association between genotype
and MBL risk was seen for 9 SNPs, reaching statistical significance in 6 cases (rs17483466,
rs13397985, rs757978, rs872071, rs2456449,
and rs735665). Collectively, these data provide support for genetic variation influencing CLL risk through
predisposition to MBL (Blood. 2010;116:5957-60).
On the other side, it has been proposed that MBL
could arise following chronic and persistent antigenic stimulation. The (rare) possibility to evolve
into a frank leukemia might then depend on biological and molecular factors insofar unknown that
may modify the modality of cell reaction as well as
the potential to acquire further genetic abnormalities. Using five-colour flow cytometry, we analyzed
123 HCV positive subjects affected by chronic
hepatitis (94) or cirrhosis (29) (in 16 cases associated with hepatocellular carcinoma) and identified
35 (28.5%) MBL, at significantly higher frequency
than in the general population. All three MBL types
have been identified in HCV-infected individuals
and were more frequent in subjects with an advanced disease stage. In particular, the frequency
of CLL-like MBL was almost double as compared
to the general population, suggesting that chronic
exposition to infectious agents may be a potentially
driving force for MBL onset (Cytometry B Clin
Cytom. 2010;78 Suppl 1:S61-8).
These studies helped to define the biologic features of MBL and represent a major step to understand the biological roots of leukemia, by,
potentially leading to the identification, at individual
level, of those cases that are at risk of developing
a clinically overt disease.
Paolo Ghia
Our laboratory is currently pursuing the following
lines of research:
2. Receptor tyrosine kinase receptors in the development of Multiple Myeloma.
1. Role of histone methylation and demethylation
in cancer development.
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 this deadly disease.
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 highthroughput 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.
Giovanni Tonon
Translational control in cancer cells
Translation is the decoding of an mRNA into a
protein through an accurate process. Translation
is inherently slower than transcription and this fact
poses a limitation to gene expression, meaning
that (many) mRNAs compete for (less) ribosomes.
Initiation is the rate-limiting process of translation
17
Research Units
and requires Initiation Factors (IF) acting downstream of signaling pathways, and performing
mechanistic steps. Recent work has shown that
targeting Initiation Factors in cancer cells is an important therapeutic avenue. For instance the remarkable development of the eIF4F field in biology, from basic mechanisms to a prognostic factor
and therapeutic target in cancer, has become
proof-of-principle that translational control of cancer cells may be targeted (Silvera, D. et al.,
(2010). Translational control in cancer. Nat Rev
Cancer 10, 254-266).
Our laboratory has focused on the analysis of
eIF6, an Initiation Factor that keeps free ribosomes ready for translation. We discovered that
50% eIF6 depletion does not create tissues ab-
normalities or pathogenic diseases. However, upon growth factor stimulation eIF6 heterozygous fibroblasts have a delay in G1/S phase and are not
efficiently transformed by oncogenes, such as
Ras, Myc or mutant p53. Furthermore, in recent
work, we observed that eIF6 depletion reduces
tumorigenesis and tumor growth also in a lymphomagenesis model, without adverse effects.
These data are a step toward the validation of
eIF6 as a target for therapy. Our lab is combining
genetic, biochemical and cell biology approaches
to further dissect molecular mechanisms of translation relevant in cancer, and to identify antagonists of eIF6 action.
Stefano Biffo
Figure 3. eIF6 localization in FG2 cancer cells (red, eIF6; green, actin cytoskeleton; cyan, GABP transcription
factor).
Tumor vascular targeting and anti-angiogenic agents
Our research activities focus on studies on tumor
vascular biology and on the development of new
strategies for cancer therapy based on drugs that
affect the tumor vasculature and microenvironment. 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 observed that circulating CgA, an RGD-containing protein secreted by many neuroendocrine
cells and granulocytes, is elevated in patients with
cancer and other inflammatory diseases. We have
also discovered that 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 (asparagine-glycine-arginine) this sequence
is present in many molecules of the extracellular
matrix. We have demonstrated that it can undergo
rapid deamidation reactions generating the isoAspGly-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 shown that the NGR-to-isoDGR
switch in fibronectin and in other proteins of the
ECM can work as a “molecular switch” for the timedependent generation of new binding sites for integrins. Finally, we have shown that peptides
containing the isoDGR motif can be exploited for
the delivery of cytokines, drugs and nanoparticles
to tumors.
Angelo Corti
19
Digestive and pancreatico-biliary endoscopy Unit
The Unit is involved in the development and clinical
application of advanced endoscopic imaging, endoluminal therapy and biomarkers 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 advanced imaging techniques
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
pancreatico-biliary ductal system by ERCP. Using
this technique, we were able to characterize the intraductal tissue structure and differentiate between
neoplastic and inflammatory strictures. At present,
surface and contrast enhanced endoscopic imaging is used to investigate mucosal preneoplastic
and neoplastic lesions; the technique appears particularly useful in Barrett’s esophagus, gastric dysplasia, and colonic flat adenomas. Confocal
endomicroscopy is used since the beginning of
2010. The technique enables in vivo microscopy
with subcellular resolution during ongoing endoscopy and is very effective in detecting neoplastic lesions at a very early stage, and gives
information about living cells in human beings. Confocal endoscopy can be performed also in the pancreatico-biliary ductal during ERCP procedures.
Endoluminal therapy
Endoscopy is commonly used for treatment of
neoplastic lesions of the G.I. tract confined within
the submucosa, because the technique allows to
remove tissue by mucosal resection, submucosal
dissection, and radiofrequency ablation. Radiofrequency can also be delivered into the pancreaticobiliary ductal system to treat neoplastic strictures.
The Unit is involved in the development of new devices for tissue removal and radiofrequency delivering for both G.I. tract and pancreatico-biliary
system. By using these devices, dysplastic epithelium and early cancers can be completely removed, and neoplastic ductal strictures can be
treated.
Circulating biomarkers
Clinical surveillance in digestive diseases is an important target in prevention of malignancy and
recognition and endoscopic treatment of cancers
at early stage. An ideal biomarker should be useful to these purposes. Cancer cells release many
proteins and other macromolecules into the extracellular fluid through secretion that can serve as
biomarkers. Circulating levels dosage of apoptosis
inhibitory proteins and mRNA will be analyzed. In
particular, QSOX-1, survivin, XAF-1 and bcl-2 will
be tested in Barretts esophagous /esophageal
adeno- and squamocellular carcinoma, gastric
cancer, colon cancer, IPMN, pancreatic adenocarcinoma.
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 screen-
ing 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 pan-
creatic 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 evaluated the efficacy of this new hybrid
cryotherm probe (CTP) in destroying neoplastic tissue of explanted pancreas of patients with pancreatic adenocarcinoma, and now we are
performing 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 main research objective is to understand the
role of molecular patterns in gastrointestinal neoplasm and the efficacy of their targeting as a novel
therapeutic approach. Our second objective is to
evaluate innovative surgical approaches and treatments in oncological patients.
Over the past year we have pursued the following
research projects:
1. Role of the induction of innate antitumor immunity in nonmetastatic rectal cancer patients
treated with neoadjuvant CT-RT and its relationship with pCR and survival. The aim was to verify whether innate factors influence the outcome
of antineoplastic treatment, and whether they
may predict the clinical response and survival.
2. Evaluation of the clinical significance of circulating Tumor Cells (CTCs) in patients with gastrointestinal cancers. The aim was 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 was to test prognostic value regarding OS and DFS.
3. Evaluation of parameters for tumor response to
neoadjuvant chemotherapy in advanced gas-
trointestinal cancers in an attempt to coin a new
tumor regression grade system.
4. Evaluation of surrogate biomarkers of oncological
outcome in gastric cancer which includes the
assessment of Cox-2 and VEGF expression.
5. HIPEC in the treatment of locally advanced gastric cancer following preoperative chemotherapy
and curative surgery. The purpose was to evaluate feasibility, morbidity, toxicity, mortality and
oncological outcome 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.
7. Sentinel node mapping during laparoscopic
gastrectomy for gastric cancer. Laparoscopic
modified surgery based on SNL status would be
the goal of a minimally invasive approach for
pathologically node negative early gastric cancer. The aim was to evaluate the feasibility in patients who underwent laparoscopic.
Carlo Staudacher
Head and neck oncology Unit
In 2010 our scientific activity concentrated both on
clinic and research; in details, four clinical and one
experimental projects, based on HPV related pharyngeal tumour, have been successfully planned
and carried out.
The first one evaluates the satisfaction and the
quality of life in laryngectomies after vocal rehabilitation using voice prostheses. We conclude that
voice prosthesis implantation after laryngectomy
show positive effects on patients’ quality of life.
The second work studies the accessory nerve
damage after radical and superselective neck dis-
section in terms of quality of life and shoulder motility. The nerve conduction was tested before and
after surgery both with electroneurography/electromiography and Neck Dissection Quality of Life
questionnaire. The preliminary results show an axonotmesis of the accessory nerve due to surgery
but no impairment of life quality.The third project indicates new cosmetic solution in reconstructive
surgery. The technique of harvest radial forearm
free flap is standardized while reconstruction of the
forearm donor site defect is somewhat controversial. We describe a modified closure technique (V21
Y advancement flap with a new shape like arrow)
developed to reduce skin tension and subsequent
cosmetic impairment of the forearm donor site. The
fourth project finally analyzes functional outcome
after partial laringectomies in terms of timing for oral
feeding restoration, decannulation and days of
hospitalization in a cohort of 41 pz. Just one subtotal procedure (CHEP) shows a very good functional
recovery in few days. The last experimental work
regards the development of head and neck squamous cell carcinoma, (independent of tobacco and
alcohol use) and concomitant high risk human pa-
pilloma virus (HPV) infections. This research is carried out in collaboration with the Laboratory of
Tumor Immunology with the aim of showing the
presence of viral genoma (HPV 16) in tumour cells.
At the same time, we are investigating a specific
immune response in patients’ blood: the target is
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 reaach final conclusions.
Mario Bussi
Multidisciplinary group for thoracic surgical oncology
Mutldisciplinary approach for patients affected by non-small cell lung
cancer (NSCLC) or colorectal (CRC) and renal cancer (RC) lung
metastases (LM)
Surgery remains the best treatment for patients affected by NSCLC although advanced age, cardiorespiratory co-morbidities and pathological
mediastinal lymph nodes (LN) present contraindications to surgical resection. Moreover, a more effective prognostic evaluation of patients with CRC
and RC LM is needed to predict recurrences. Our
aim is to enhance the results of surgical treatment
(ST) by means of the following lines of research.
Assessment of a new technique (vibration response imaging-deep breeze) for the prediction of
the postoperative respiratory function (PFR) of patients undergoing lung resection for lung cancer.
We intend to evaluate the effectiveness of this
technique, which is able to capture lung sounds
generated by the flow of air through the lungs, in
predicting PFR after lung resection. We then compare this technique with present-day methods that
calculate post-operative PFR on the basis of resected anatomical lung segments, CT scan and
perfusion scan.
Endobronchial ultrasound-guided transbronchial
needle aspiration (EBUS-TBNA) has emerged as
an alternative to mediastinoscopy to confirm or exclude LN metastases. Preliminary studies have
demonstrated that it may lead to improvement in
the results of N-staging by decreasing the morbidity related to mediastinoscopy. The aim of the study
is to assess the effectiveness and safety of EBUSTBNA in staging NSCLC patients.
A further study aims to assess the results of new
treatment-strategies such as percutaneous radiofrequency thermoablation and tomotherapy, a
recently-developed radiotherapy technique, in
managing patients with early-stage NSCLC that
have a contraindication to ST.
The aim of another study is to evaluate the use of
immunohistochemical analysis to assess the prognostic value of such tumor markers as microsatellite instability and S100a4 protein in the
management of LM from CRC and RC. ST for LM
from both CRC and RC is currently a well-established treatment. However, the identification of new
tumor markers to supplement clinical and pathological staging may allow to identify those patients
with LM from CRC and RC at highest risk for recurrence following surgery. Finally, we plan to evaluate the results of ST of lung cancer in patients
with lymphoproliferative disorders.
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 compe-
tences 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 focused on 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, lymphomas 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, REL). Clinical research is
organized in Diseases Unit: Leukemia Unit and
Myeloma Unit and we contribute also to the Lymphoma Unit.
During 2010, we continued to enroll patients with
newly diagnosed AML and ALL in the two NILG
master trials: AML 02/06 and ALL 10/07
(www.nilg.it). A new project has started within the
AML study to determine the prognostic significance of early disease clearance in the peripheral
blood, by means of flow cytometry. In 2010 we
also took part in other cooperative studies including GIMEMA studies for multiple myeloma treatment (first-line or relapsed/refractory) with
lenalidomide and for polycythemia vera, CytoPV,
(www.gimema.org). We also actively partecipated
to several cooperative studies within the regional
hematologic network (Rete Ematologica Lombarda
- REL), for diagnosis and treatment of acute
leukemias, MDS, CML and MM.
Main internal projects started in 2010 and still ongoing include: WT1 levels monitoring in bone marrow and peripheral blood of AML patients to establish the predictive significante of disease
persistence or relapse (MRD) to tailor adoptive immunotherapy strategies post allogeneic bone marrow transplantation; metabolomic and angiopoiesis
of MGUS and multiple myeloma; implementation of
a biological bank for standardized sampling and
cryopreservation of cell/nucleic acids from hematologic neoplasias, for ongoing and future biological studies. Additional specific trials testing new
drugs (plerixaphor, eltrombopag, clofarabine, treosulfan, BI6727 plk-1 inhibitor) are ongoing for
leukemia, myeloma and MDS.
Fabio Ciceri
Pancreatic cancer Unit: biology and new therapeutic
approaches
The Unit of Pancreatic Surgery performed 146 resections in 2010, a surgical volume among the
highest in Europe. These cases are a source of
data and material for clinical and basic science.
Pancreatic cancer was the main indication for resection: it is the fourth leading cause of cancer
mortality and it has the worst prognosis among
malignancies, with a discouraging 5-years survival
23
lower than 5%. New therapeutic strategies are
under evaluation: our Institute is the coordinating
centre of a multicentre randomised study (involving more than 25 hospitals in Italy) that was
planned to investigate the role of new chemotherapeutic schemes and strategies in the treatment
of resectable pancreatic cancer. One of the study
arms will test the efficacy of preoperative
chemotherapy (PCHT); to assess the safety of
PCHT in candidates to pancreatic resection, we
revised, in a case-match comparison, 40 patients
treated with gemcitabine-based PCHT between
2003 and 2010: we found that PCHT did not adversely affect operative outcome and was associated with a higher rate of N0.
Another study was aimed to assess the presence and the prognostic role of circulating tu-
mour cells (CTCs) in blood samples of patients
with resectable pancreatic cancer. CTCs were
identified in 9 out of 20 patient (45%), but we
found no correlations between the presence or
the number of CTCs and disease-free survival/overall survival.
Finally we analysed the data collected in a
prospective observational study on patients undergoing pancreatic resection, to evaluate the role
of uncontrolled glucose metabolism, insulin resistance and insulinemia in tumor progression and
prognosis. We found that insulinemia and insulin
resistance (evaluated as homeostatic model assessment HOMA2IR) appeared independent risk
factors for tumor progression in a multivariate Cox
regression analysis.
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 lympho-
cytes subclasses, monocyte-macrophages cells,
dendritic and stromal cells-, in these heterogeneous malignancies. Regarding T lymphocytes we
are characterizing their immunomodulatory role in
follicular lymphomas. 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 and xenografts 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. In collaboration with the
group headed by M.P. Protti, we are also characterizing the immunologic microenvironment conditioning the ineffective immune response in
pancreatic adenocarcinoma patients.
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
A phase II study to investigate the prevalence of infectious agents in
ocular adnexae marginal zone lymphoma (OAMZL) and the efficacy of
first-line antibiotic therapy (IELSG#27 TRIAL)
Ocular adnexal marginal zone lymphoma (OAMZL)
is associated with Chlamydophila psittaci (Cp) infection with important geographic variation. Previously reported studies were retrospective, with a
single prospective trial mostly including pts with relapsed disease, and confirmed that Cp eradication
is followed by lymphoma regression in ~50% of
pts.
Study endpoints were the prevalence of chlamydiae infections, the bacterial eradication rate and
anti-lymphoma activity of doxycycline (DOX) in
OAMZL.
We conducted the first prospective multicentric
phase II trial to address Cp prevalence and DOX
activity in pts with newly diagnosed OAMZL
(IELSG#27 trial). The trial was composed by two
parts. Patients with stage-IEA OAMZL and measurable disease were enrolled in part A, and received DOX 100 mg bid for 21 days. Patients with
other lymphomas, benign lesions or MZL not eligible for part A entered the part B and were treated
following local practice. Chlamydiae infections
were evaluated on diagnostic biopsies by three
PCR. The same PCRs were performed on conjunctival swabs and peripheral blood mononuclear
cells (PBMC) collected before and after (at 3 & 12
months) DOX to monitor bacterial eradication.
From 2006 to 2010, 54 pts were enrolled. Among
44 available cases, Cp was detected in biopsies of
32/37 (86%) assessed OAMZL and in 4/7 nonMZL.
Twenty-eight of the 34 patients enrolled in part A
were assessable for Cp eradication (positive PCR
on pre-DOX swabs in 8, PBMC in one or both in
19). All pts completed DOX treatment. Thirteen patients(46%) achieved Cp eradication (negative PCR
in post-DOX samples); Cp was detected again at
one year in two of them.
Complete response was observed in 6 pts, partial
in 15 (ORR= 62%, 95%CI: 46-78%); 12 had stable
disease and one progressive disease (PD). At a
median follow-up of 24 months (range 3-51), 15
responders are relapse-free, while 6 responders
and 6 no-responders experienced PD, with 2-year
progression free survival (PFS) of 54±10%. A trend
to a higher response rate (82% vs. 53%; p=0.12)
and PFS (2-yr: 74% vs. 52%; p=0.18) in eradicated patients was observed.
In conclusion, we observed that Cp infection is
common in OAMZL at diagnosis. First-line DOX
was associated with lymphoma regression in 62%
of patients but failed to eradicate Cp infection in
half of the patients, with a negative impact on outcome. Studies aimed to improve antibiotic efficacy
are warranted.
Andrés Jose Maria Ferreri
Gynecologic oncology
Recent therapeutic advances in oncology have led
to better survival rates in women with malignancies.
However current cancer therapies, including both
radiation and chemotherapy, can lead to premature infertility in women, which is attributed to decreased ovarian reserve. Infertility can be a
consequence of many of more aggressive chemoradiation therapy that prolong and save life. Clinicians must be aware of current research in the
area of fertility preservation but different studies
suggest that many oncologists do not discuss the
possibility of treatment-related infertility with their
patients.
The aim of the project is to translate into clinical application emerging options for the preservation of
fertility in patients with cancer and providing a conceptual framework for managing concerns about
fertility at the time of diagnosis. The goal is to pro-
vide and develop methods of fertility preservation
that permit a range of options for patients that are
linked to a multidisciplinary treatment plan until cancer treatments can be specifically targeted to cancer cells.
Fertility preservation options vary by age and potential effects of cancer therapy that can result in
subfertility or sterility due to gonad removal or permanent damage to germ cells from adjuvant therapy. Although several malignant conditions affect
young women, including melanoma, cervical cancer, leukemia, lymphoma, and ovarian cancer, the
cancer with the highest incidence in this population is breast cancer At diagnosis, plans for fertility
preservation must take into consideration the individual patient’s priorities in conjunction with the recommended treatment strategy.
Giorgia Mangili
25
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 gastro-intestinal, central nervous system (CNS), and genitourinary cancer. Scientific activity regards also translational
research. 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 response biomarkers b) a pharmacogenetic trial to assess the impact on the outcome of the SNPs involved in the metabolism of
antiblastic drugs c) a phase II-III trial randomizing
patients with resectable disease to receive peri-operative or post-operative chemotherapy d) a phase
II randomized trial exploring the role of metformin in
the therapeutic management of metastatic pancreatic cancer and biomarkers for activity e) a
phase II trial assessing the role of trabectidin as salvage therapy in metastatic pancreatic cancer. We
have explored a new chemotherapy combination in
advanced biliary tract cancer. In the topic of CNS
tumors, ongoing trials are aimed to: a) individuate
a proteomic profile able to predict the outcome of
newly diagnosed glioblastoma (GBM) treated with
standard chemo-radiation (RT); b) assess the role
of temozolomide (TMZ) associated to RT in newly
diagnosed GBM in elderly patients; c) assess the
role of TMZ concurrent to RT and adjuvant in non1p/19q deleted anaplastic glioma; e) analyze the
role of primary chemotherapy with TMZ versus RT
after stratification for 1p loss in low grade glioma; f)
explore the role of salvage therapy with hydroxyurea alone or in combination with imatinib in
meningiomas.
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. In advanced colorectal cancer patients we have explored the role of circulating endothelial cells and endothelial progenitors as
predictive markers of clinical response to bevacizumab-based first-line treatment.
Michele Reni
Medical oncology Unit - Phase I and lung cancer clinical trials
The research activity of our Unit is divided into three
main areas: pathogenesis of NSLCL, translational
research trials and phase I/II studies.
In the first area, we are focusing on molecular
mechanisms related to new and standard therapies, specific toxicities and pathways of drug resistance for defining personalized therapies. We
have 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 and
select those patients who do not benefit from EGFR
TKIs highlighting that the molecular species generating VeriStratTM classifier may identify a primary resistance mechanism. 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 α1antichimotrypsin, suggesting that inflammation may
play a role in the EGFR-TKIs resistance. Currently,
we are evaluating if SAA has a direct role in cancer
pathogenesis and progression. Moreover, a phase
III trial has been designed and is currently ongoing
to prospectively evaluate the application of VeriStratTM algorithm for selection of 2nd line therapy
between chemotherapy and EGFR-TKis.
Our experience with regards to phase I studies
started in 2003, with an antivascular targeting
agent (VTA), NGR-hTNF which has been discovered and fully characterized at DIBIT Laboratory
and subsequently tested in first-in human trials at
the Department of Oncology of our institution. In
2010, 3 phase II studies with NGR-hTNF in combination with chemotherapy have been conducted:
2 in combination with doxorubicin in small cell carcinoma (SCLC) and in ovarian carcinoma (OC), 1
in combination with a cisplatin-based regimen in
non small cell lung cancer (NSCLC) in 1st line. In
addition, a phase III study started in malignant pleural mesothelioma (MPM). NGR-hTNF has shown a
good toxicity profile, with evidence of transient
grade 1-2 constitutional symptoms (especially
chills) during infusion. The objectives of phase II
studies (PFS) have been reached, with promising
results on antitumor activity.
Vanesa Gregorc
URI, Urological Research Institute
The Urological Research Institute during 2010, beside an ongoing clinical research program, has implemented translational research modalities in
clinically relevant topics of functional urology and
uroncology. Aims are to identify novel therapeutic
opportunities for the overactive bladder, prostatic
and ureter disorders and to improve functional recovery after urological cancer surgery. We have
acquired genetic and molecular biological techniques, functional organbath methods and validated an animal protocol of cavernous nerve injury
simulating erectile dysfunction after radical prostatectomy. We have developed a female rat model
mimicking the pelvic nerve damages of nerve-sparing hysterectomy. Using these models we are investigation various pathogenetic mechanisms and
pharmacological targets for neuroprotection. Attention is given to the endocannabinoid system,
glucocorticoid and GnRH receptors, stemcell-related signals, and new drug-delivery systems. We
have also developed a new animal model to study
in vivo function of the obstructed ureter in which
we are evaluating new pharmacological principles
to facilitate passage of ureter stones.
To support translational research activities, our
datamanagers continuously retrieve clinical information in databases and a dedicated uropathologist has been hired to ensure perioperative
collection of normal, diseased and cancer tissues,
and blood and urine samples from patient to secure a wide biorepository of primary cells and tissues for urological malignancies and dysfunctions.
We are evaluating vitamin D3 binding protein in
plasma as a prognostic biomarker in prostate cancer and are also analyzing correlations of plasma
sex hormones, prostatic expression of estrogen receptors, and tumor aggressiveness in urological
cancer.
Mesenchymal stem cells (MSCs) has an inherent
ability to migrate to tumor lesions. We are exploring
safety and efficacy of MSCs that express prodrug
converting enzymes as cellular vehicles in targeted
prostate cancer therapy.
We are evaluating a novel clinical protocol of neoadjuvant intravesical chemotherapy in bladder cancer, currently on trial at the department of Urology
of the HSR, and we are investigating in vitro differentiated drug exposures in order to overcome
chemoresistance.
Francesco Montorsi
27
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Stilgenbauer, S. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic
lymphocytic leukaemia: A randomised, open-label, phase 3 trial. Lancet: 2010; 376(9747): 11641174 - Article
IF 2009: 30,758
Scarfò, L; Dagklis, A; Scielzo, C; Fazi, C; Ghia, P. CLL-like monoclonal B-cell lymphocytosis: Are
we all bound to have it? Semin. Cancer Biol.: 2010; 20(6): 384 - 390 - Review
IF 2009: 6,918
Scielzo, C and Bertilaccio, MTS; Simonetti, G; Dagklis, A; Ten Hacken, E; Fazi, C; Muzio, M;
Caiolfa, V; Kitamura, D; Restuccia, U; Bachi, A; Rocchi, M; Ponzoni, M; Ghia, P and CaligarisCappio, F. HS1 has a central role in the trafficking and homing of leukemic B cells. Blood: 2010;
116(18): 3537-3546 - Article
IF 2009: 10,555
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-α activation
inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses.
Nat. Med.: 2010; 16(1): 98 - 105 - Article
IF 2009: 27,136
29
Dynamic fluorescence spectroscopy in biomedicine
Immuno-biotherapy of melanoma and solid tumors Unit
31
33
DIVISION
OF
NEUROSCIENCE
Director:
Gianvito Martino
Associate Director:
Flavia Valtorta*
Research Units
Neuropsychopharmacology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 43
HEAD OF UNIT: Flavia Valtorta*
POST-DOCTORAL FELLOWs: Francesca Botti, Davide Pozzi
PHD STUDENTS: Serena Bellani**, Eugenio Fornasiero**, Fabrizia Guarnieri **
FELLOW: Stefania Russo
TECHNICIAN: Elena Monzani
Cell adhesion Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 43
HEAD OF UNIT: Ivan de Curtis*
POST-DOCTORAL FELLOW: Roberta Pennucci
PHD STUDENTS: Claudia Asperti**, Veronica Astro**, Antonio Totaro**
FELLOWS: Luisa Micheletti, Valentina Montinaro
TECHNICIAN: Diletta Tonoli
Cellular and molecular neurobiology Unit –––––––––––––––––––––––––––––––––––––––––––––––– 44
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
Cellular neurophysiology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 44
HEAD OF UNIT: Fabio Grohovaz*
RESEARCHER: Daniele Zacchetti
PHD STUDENTS: Barbara Bettegazzi**, Alessandra Consonni, Romina Macco**, Ilaria Pelizzoni**
TECHNICIAN: Franca Codazzi
35
DIVISION OF NEUROSCIENCE
Research Units / Clinical Research Units
Developmental neurogenetics Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 45
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 ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 46
HEAD OF UNIT: Antonio Malgaroli*
RESEARCHER: Vincenzo Zimarino
POST-DOCTORAL FELLOW: Maddalena Ripamonti**
PHD STUDENTS: Alessandro Arena, Marcello Belfiore **, Mattia Ferro, Jacopo Lamanna
Proteomics of iron metabolism Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 46
HEAD OF UNIT: Sonia Levi*
RESEARCHERS: Anna Cozzi, Paolo Santambrogio
PHD STUDENT: Alessandro Campanella** (till August 2010)
FELLOW: Elisabetta Rovelli
Molecular genetics of mental retardation Unit (Dulbecco Telethon Institute) –––– 47
GROUP LEADER: Patrizia D’Adamo
POST-DOCTORAL FELLOW: Maila Giannandrea
PHD STUDENTS: Veronica Bianchi, Maria Lidia Mignogna
FELLOW: Elena Carlotta Vismara
Neural degeneration Unit (Dulbecco Telethon Institute) –––––––––––––––––––––––––––––– 47
GROUP LEADER: Manolis Fanto
PHD STUDENT: Piera Calamita** (till February 2010)
Stem cells and neurogenesis –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 47
GROUP LEADER: Vania Broccoli
PHD STUDENTS: Gaia Colasante**, Serena Giannelli**, Sara Ricciardi**, Alessandro Sessa**,
Federica Ungaro**
FELLOWS: Massimiliano Caiazzo, Giorgia Colciago, Maria Teresa Dell’Anno, Bruno Di Stefano,
Sara Loponte
Acute brain protection, Acute post-operative pain, ––––––––––––––––––––––––––––––––––– 49
Drugs and central nervous system Unit
HEAD OF UNIT: Luigi Beretta*
PHYSICIANS: Massimo Agostoni, Maria Rosa Calvi, Assunta De Vitis, Marco Gemma
FELLOWS: Massimiliano Greco, Elisa Nicelli
Cognitive neuroscience Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 49
HEAD OF UNIT: Stefano F. Cappa*
RESEARCHERS: Jubin Abutalebi*, Nicola Canessa*
PHYSICIANS: Maria Cristina Giusti, Sandro Iannaccone, Alessandra Marcone, Michele Zamboni
POST-DOCTORAL FELLOW: Eleonora Catricalà
PHD STUDENT: Federica Alemanno**
Experimental neurosurgery Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 50
HEAD OF UNIT: Pietro Mortini*
PHYSICIANS: Stefania Acerno, Lina Raffaella Barzaghi, Nicola Boari, Paola Castellazzi, Camillo Ferrari
da Passano, Alberto Franzin, Lorenzo Gioia, Marco Losa, Carlo Mandelli, Piero Picozzi, Micol Valle
PHD STUDENT: Silvia Snider**
RESIDENTS: Jody Capitanio, Elena Colombo, Filippo Gagliardi, Lucio Aniello Mazzeo, Marzia Medone,
Davide Milani, Vittoria Orlandi, Giorgio Spatola, Alfio Spina
Eye repair Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 50
HEAD OF UNIT: Paolo Rama
CONSULTANTS: Giulio Ferrari, Federica Ferrario, Chiara Insacco, Stanislav Matuska, Giorgio
Paganoni, Elena Scandola, Maurizia Viganò
Functional neuroradiology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 50
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 ––––––––––––––––––––––––– 52
HEAD OF UNIT: Daniela Perani*
RESEARCHER: Marco Tettamanti
PHD STUDENTS: Riccardo Cafiero, Laura Verga
POST-DOCTORAL FELLOWS: Chiara Cerami**, Monica Consonni**, Pasquale Della Rosa**, Giuliana
Gelsomino
FELLOWS: Elena Maria Andreolli, Danilo Spada
Neuroothology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 53
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 –––––––––––––––––––––––––––––––––––––––––––– 53
HEAD OF UNIT: Francesco Benedetti
PHYSICIANS: 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: Paola Canali, Elisa Galimberti, Sara Poletti, Roberta Riccaboni
POST-DOCTORAL FELLOW: Daniele Radaelli
FELLOWS: Margherita Bechi, Vittoria Bottelli, Chiara Brambilla, Maria Chiara Buonocore,
Valentina Capelli, Ursula Catenazzi, Daniele Cavadini, Emma Fadda, Marcello Florita,
Francesco Fresi, Chiara Gavinelli, Chiara Giacosa, Irene Gorni, Stefania Ozino, Giulia Paredi,
Adele Pirovano**, Elena Pozzi, Liana Ricci, Tomaso Siccardi
37
RESIDENTS IN PSYCHIATRY: Giampiero Bottero, Dario Delmonte, Clara Locatelli, Alessia
Malaguti, Chiara Ruffini, Irene Vanelli
TECHNICIAN: Cristina Lorenzi
Sleep medicine ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 53
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 –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 54
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 ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 55
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 –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 57
GROUP LEADER: Angelo Quattrini
PHD STUDENTS: Federica Cerri, Nilo Riva**
TECHNICIAN: Giorgia Dina
Experimental neurophysiology –––––––––––––––––––––––––––––––––––––––––––––––––––––– 57
GROUP LEADER: Letizia Leocani
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
Molecular genetics of behaviour ––––––––––––––––––––––––––––––––––––––––––––––––––––– 58
GROUP LEADER: Riccardo Brambilla*
PHD STUDENTS: Raffaele d’Isa**, Ilaria Morella, Daniel Orellana**, Alessandro Papale**,
Nicola Solari**
FELLOW: Stefania Fasano
TECHNICIANS: Maura Figini, Marzia Indrigo
Neuromuscular repair ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 58
GROUP LEADER: Stefano Carlo Previtali
PHYSICIAN: Marina Scarlato
POST-DOCTORAL FELLOW: Domi Teuta
PHD STUDENT: Emanuela Porrello**
FELLOW: Daniela Triolo (till June 2010)
RESIDENT: Ignazio Diego Lopez
TECHNICIAN: Isabella Lorenzetti
39
Research Units/Clinical Research Units, INSPE
Neuroimmunology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 59
HEAD OF UNIT: Gianvito Martino
RESEARCHER: Luca Muzio
POST-DOCTORAL FELLOWS: Erica Butti, Melania Cusimano
PHD STUDENTS: Benedetta Arnò**, Marco Bacigaluppi**, Roberta De Ceglia, Francesca
Grassivaro**, Cecilia Laterza**, Cinzia Marinaro**, Annamaria Nigro**
RESIDENTS: Donatella De Feo, Luca Peruzzotti Jametti
TECHNICIANS: Andrea Bergamaschi, Elena Brambilla, Francesca Ruffini
Clinical neuroimmunology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 60
GROUP LEADER: Roberto Furlan
PHD STUDENTS: Giuseppe De Santis, Livia Garzetti, Chiara Maiorino
RESIDENT: Dacia Dalla Libera
TECHNICIANS: Alessandra Bergami, Annamaria Finardi
CNS repair ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 60
GROUP LEADER: Stefano Pluchino
POST-DOCTORAL FELLOWS: Denise Drago
Neuroimaging research Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 61
HEAD OF UNIT: Massimo Filippi*
BIOENGINEERS: Elisabetta Pagani, Paola Valsasina
PHD STUDENTS: Federica Agosta**, Elisa Canu**, Laura Parisi,** Michela Pievani**
RESIDENTS: Martina Absinta**, Sebastiano Galantucci**, Giulia Longoni**, Maria Josè Messina**
FELLOWS: Paolo Preziosa, Lidia Sarro, Antonio Scarale
TECHNICIANS: Luca Dall’Occhio, Alessandro Meani, Melissa Petrolini, Stefania Sala,
Roberto Vuotto
Neuroimaging of CNS white matter –––––––––––––––––––––––––––––––––––––––––––––––– 62
GROUP LEADER: Maria Assunta Rocca
PHD STUDENT: Gianna Riccitelli**
TECHNICIANS: Paolo Misci, Mauro Sibilia
Human inherited neuropathies Unit (Dulbecco Telethon Institute) –––––––––––––––––– 63
HEAD OF UNIT: Alessandra Bolino
PHD STUDENTS: Roberta Noseda**, Ilaria Vaccari
FELLOWS: Sophie Belin, Andrea Gorzanelli, Daniela Triolo (from July 2010)
Axo-glia interactions Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 64
GROUP LEADER: Carla Taveggia, FISM
POST-DOCTORAL FELLOW: Amelia Trimarco
FELLOW: Evelien Fredrickx
TECHNICIAN: Rosa La Marca
Inflammatory CNS disorders Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 65
HEAD OF UNIT: Vittorio Martinelli
RESEARCHERS: Filippo Martinelli-Boneschi, Lucia Moiola, Mariaemma Rodegher
PHYSICIAN: Paolo Rossi
Clinical Research Units, INSPE
PHD STUDENTS: Federica Esposito**, Marta Radaelli**
RESIDENTS: Valeria Barcella **, Elda Judica**, Giuseppe Liberatore**, Giulia Pavan**,
Elisabetta Stefania Perego**, Marzia Romeo**, Francesca Sangalli**
Cerebrovascular disorders ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 65
CLINICAL GROUP LEADER: Maria Sessa
PHYSICIANS: Silvia Mammi, Antonella Poggi, Luisa Roveri
PHD STUDENTS: Grazia Maria Nuzzaco**, Maria Carmela Spinelli**
RESIDENTS: Clara Guaschino, Sara La Gioia
Memory disorders –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 66
CLINICAL GROUP LEADER: Giuseppe Magnani,
RESIDENTS: Francesca Caso, Elisabetta Coppi, Laura Ferrari
PSYCHOLOGISTS: Claudia Arcari, Alessandra Barbieri, Rosalinda Cardamone, Monica
Falautano, Agnese Fiorino, Francesca Onofrio
Movements disorders ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 66
CLINICAL GROUP LEADER: Ubaldo Del Carro
PHYSICIANS: Stefano Amadio, Roberta Guerriero, Maria Grazia Natali Sora, Maria Antonietta
Volontè
RESIDENTS: Francesca Bianchi, Calogera Butera, Habtom Tesfaghebriel, Daniela Ungaro
Neuromuscular disorders ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 67
CLINICAL GROUP LEADER: Raffaella Fazio
PHYSICIAN: Patrizia Dacci
PHD STUDENT: Daniela Privitera**
Paroxysmal events ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 67
CLINICAL GROUP LEADER: Fabio Minicucci
PHYSICIANS: Bruno Colombo, Giovanna Franca Fanelli, Paolo Marchettini
RESIDENT: Maria Grazia Deriu
41
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 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 neurodegeneration 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 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 these ambitious aims we are systematically assessing the progress of the existing staff and the
achievement of the proposed milestones. Furthermore, we are recruiting excellent investigators in selected key fields and continuously implementing technological platforms and facilities.
Research Units
The main focus of research in the laboratory has
been on the protein family of the synapsins and
their link to neurological and psychiatric disorders.
The synapsins are a family of brain phosphoproteins involved in the regulation of neuronal development and of neurotransmitter release. Synapsin
KO mice develop an epileptic phenotype, and mutations in the human synapsin I gene have been
associated with epilepsy. We have now found that
mutations in the synapsin I gene can also underlie
cases of X-linked autistic disorder and/or mental
retardation. Indeed, cognitive impairment is also a
feature of synapsin KO mice.
When expressed in neurons in culture, mutant
synapsins exhibit distinct features. All the mutant
synapsins tested fail to rescue the deficit in neurotransmitter release exhibited by KO neurons, and
the molecules which lack the C-terminal tail impair
axonal growth. In addition, most of the mutant
synapsins fail to concentrate at synaptic sites. The
study of the biological properties of synapsins carrying mutations identified in the various kinds of
human pathologies may shed light on the physiological role of the synapsins as well as provide insights into the pathophysiology of such disorders.
We have also completed the study on the role
of cAMP-dependent phosphorylation of the
synapsins in synapse formation and stability. The
data available so far indicate that the phosphorylation of Synapsins by PKA plays a key role in the
regulation of neurite outgrowth, synaptic vesicle
dynamics in the growth cone and formation of excitatory and inhibitory synapsses.These results
further confirm the central role in neural development of the activation of cAMP-dependent protein
kinase and the integration between the cAMPand Ca2+/calmodulin-linked signal transduction
pathways occurring through site-1 phosphorylation of the synapsins.
Flavia Valtorta
Figure 4. Axonal growth cones of hippocampal neurons in culture prepared form either wild type mice or from
mice knocked out for the various isoforms of the synapsins (red, actin; green, synaptic vesicles). Modified from
Fornasiero et al., 2010
Cell adhesion Unit
Molecular networks 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 defects in
specific neuronal populations of double and single
KO mice. The GABAergic interneuronal network is
strongly decreased in the cortex and hippocampus of double KO mice, and still significantly affected in Rac1N and Rac3KO animals. These
phenotypes correlate with an epileptic phenotype
observed in young double KO animals and adult
Rac1N mice. Electrophysiological analysis on sections from double KO animals confirmed their
higher sensitivity to induction of seizures by 4aminopyridine.
The GIT complexes are involved in the regulation
of neuronal development and cell migration.
We have analyzed the function of the GIT/PIX complexes in the early neuronal development and
found specific effects on neurite branching by GIT2
and αPIX, an exchange factor for Rac mutated in
43
Research Units
patients with mental retardation. Biochemical analysis has led to the identification of new isoforms of
αPIX that interact with both GIT proteins and the
PAK3 kinase, another gene mutated in mental retardation.
Liprin-α1 is a scaffold protein involved in the assembly of neuronal synapses and in the organization of adhesions.
Liprin-α1 positively regulates motility, while its
downregulation prevents spreading and adhesions
turnover. 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. Time-lapse video-imaging has shown specific
effects of liprin-α1 on the dynamics of both lamellipodia and invadopodia in human breast cancer
cells. The effects observed in the cells depleted of
endogenous liprin indicate a defect in directional
migration that may explain the positive effects of
liprin in migration and invasion.
Ivan De Curtis
Cellular and molecular neurobiology Unit
Phenotype of nerve cells and astrocytes in physiology and pathology. Role
of the REST/NRSF transcription repressor
In previous work we discovered that the transcription repressor REST/NRSF orchestrates the expression of the nerve cell phenotype not only
during development but also upon maturation. We
found that expression and regulated exocytosis of
the organelles filled with neurotransmitters, the
clear and dense-core vesicles, is repressed in
nerve cells by increases of REST levels and re-activated upon its decreases; and that a new form of
neurite outgrowth occurs (in appropriately stimulated nerve cells including growing neurons), sustained by the exocytosis of a new cytoplasmic
organelle that we named enlargeosome. In 2010
this work was extended to astrocytes, a non-excitable cell type which however shares with nerve
cells the release of neurotransmitters and thus participates in synaptic transmission. In astrocytes expression and discharge of clear vesicles was found
to occur independently of REST, whereas densecore vesicles appear, and are discharged by regulated exocytosis, only when the repressor is
decreased. Interestingly, in the human brain cortex
the astrocyte levels of REST are not fixed, as in
other cells, but variable from low to high as in neurons and microglia, respectively. REST, therefore,
accounts for a structural and functional heterogeneity of brain astrocytes. In parallel we have
studied the role of REST in the proliferation of PC12
nerve cells. Together with the Mondino’s group we
found the process to be governed by a newly discovered feed-forward loop composed by REST,
the GAP TSC2 and the transcription co-factor βcatenin which participates in the expression of
REST itself. This new signaling paradigm, which
demonstrates the role of REST to extend to general
functions of nerve cells, opens new opportunities
to the understanding and therapy of nerve cells tumors. Finally, we have started the study of REST in
the expression of an adhesion protein, L1-CAM,
whose mutations sustain a group of brain diseases
defined together by the acronym CRASH. Our interest is focused on the cell biology of L1-CAM
and on the changes in nerve cell function depending on the various mutations: decreased levels of the protein due to defective expression
and/or turnover, altered intracellular traffic, modified
adhesion and surface signaling etc.
Jacopo Meldolesi
Physiopathological mechanisms in neuroprotection and
neurodegeneration
With the aim to understand the molecular mechanisms underlying neurodegeneration and neuroprotection, our unit focused on: a) Alzheimer’s disease (AD), the most frequent form of dementia, b)
iron-mediated oxidative stress, a condition reported
in several diseases of the central nervous system,
including stroke and Parkinson, and c) glia activation and its role in neuropathological conditions.
We continued to investigate the translational control of BACE1, the neuronal β-secretase responsible for the production of the neurotoxic amyloid-β
peptides that accumulate in AD brain. We demonstrated the existence of mechanisms that allow
BACE1 translation in neurons but not in astrocytes,
where BACE1 transcript is kept silent and β-secretase activity is due to BACE2.
Concerning the mechanisms of iron handling in
hippocampal neurons, we demonstrated that both
voltage operated calcium channels and NMDA receptors represent physiopathological routes for
iron entry. In parallel, we investigated another putative pathway for iron entry, the Divalent Metal
Transporter 1 (DMT1), i.e. the main transporter involved in systemic and cellular iron intake. We
characterized the expression of DMT1 in terms of
isoforms, subcellular distribution and modulation
by cellular iron levels. We demonstrated that our
neuronal cultures express the DMT1-1B/IRE(+)
isoform that is mainly found in lysosomal com-
partments and that, even after overexpression,
does not play a significant role in non-transferrin
bound iron uptake. The control of intracellular iron
homeostasis is also being addressed by employing a transgenic mouse expressing a mutated ferritin light chain, as an animal model for hereditary
neuroferritinopathy (in collaboration with S. Levi
and O. Cremona).
As for the role of glia, we setup in vitro assays to reproduce pathological conditions such as oxidative
stress, amyloid-β challenge and neuroinflammation. By these approaches, we started an analysis
of the molecular mechanisms responsible for glia
activation processes, as well as an evaluation of
treatments able to induce protective phenotypes.
The relative contribution of astrocytes and microglia
is investigated by controlled co-culture conditions
and by a comprehensive analysis of gene expression profiling.
Fabio Grohovaz
Developmental neurogenetics Unit
Regulation of neurogenesis in the developing cerebellum. Implications for
malformative and degenerative disorders of the cerebellum
In 2010, the Developmental Neurogenetics unit
has analyzed the genetic regulation of cerebellar
neurogenesis making use of 3 different mouse
models. These studies have furthered our understanding of basic neurogenetic mechanisms occurring during normal ontogeny, and may have
farther reaching implications for the study and management of malformative and degenerative disorders of the CNS.
In the first project, we have analyzed the molecular mechanisms underlying neonatal Purkinje cell
death in mice carrying a null mutation for the HLH
TF EBF2. In this model, we showed that Igf1 is
sharply downregulated right before the onset of PC
death. In vitro, EBF2 binds a conserved Igf1 promoter region. The pro-survival PI3K signaling pathway is inhibited in mutant cerebella. Ebf2 null
organotypic cultures respond to IGF1 treatment by
inhibiting PC apoptosis. Consistently, wild type
slices treated with an IGF1 competitor feature a
sharp increase in PC death. Our findings identify a
new mechanism regulating the local production of
Igf1 in the CNS, with potential implications for our
understanding of mechanisms regulating neuronal
survival in physiology and neurodegenerative dis-
ease (Croci, Barili et al., 2011).
In the second project, we have further clarified the
role of a gene, Zfp423, as a regulator of cerebellar
neurogenesis. ZFP423 encodes a 30 Zn-finger
transcription factor involved in cerebellar and olfactory development. ZFP423 is a known interactor of SMAD1-SMAD4 and of Collier/Olf-1/EBF
proteins, and acts as a modifier of retinoic acid-induced differentiation. In this project, we have
shown that ZFP423 interacts with the Notch1 intracellular domain in vitro and in vivo, to activate the
expression of the Notch1 target Hes5/ESR1. This
effect is antagonized by EBF transcription factors
and enhanced by BMP4, suggesting that ZFP423
acts to integrate BMP and Notch signaling, selectively promoting their convergence onto the Hes5
gene (Masserdotti et al, 2010). By extending our
analysis to primary cultures of neuroepithelial progenitors, we have shown that the same variants of
Zfp423 affect the maintenance of the neural progenitor pool in different ways. A mutant carrying
one of these mutations features the classic appearance of Dandy Walker malformation.
Gian Giacomo Consalez
45
Research Units
Neurobiology of learning Unit
A novel family of indicators to monitor synaptic activity in vivo
Nowadays, although many functional techniques
can be used to monitor neuronal activity in vivo,
none of the available methods do provide reliable
activity signals from individual neurons and/or small
neuronal circuits. Undeniably, the greatest limitation of these approaches, is their poor spatial and
temporal resolution. We have recently designed a
series of innovative synaptic activity sensors that
permit the visualization of active synapses. This
family of recombinant molecules is based on a pair
of binders, one mounted on the synaptic vesicle
membrane, the other freely diffusible in the extracellular space. When synaptic transmission occurs, synaptic vesicle undergo exocytosis and the
bait sequence is exposed to the extracellular environment: when this happens the small fluorescent
cognate molecule is bound and captured inside
the endocytosed vesicle. The signal to noise ratio
of this technique and the diffusive properties of the
fluorescent tracer are such that synaptic activity in
dissociated cultures and in brain slices can be precisely quantified. To characterize the feasibility of
this novel methodology for in vivo brain analysis we
studied the light induced activation of the visual
pathway. Our tool was expressed in retinal ganglion
cells and the activation pattern of lateral geniculate
nucleus (LGN) synapses was investigated with different light illumination protocols. These experiments were run in freely behaving animals, and the
resolution which was attained was enough to resolve the light induced activation of individual
synapses. To express our tool in all brain tissues
and at any time point in development we have recently begun a collaboration with the Developmental neurogenetics Unit directed by Gian
Giacomo Consalez. The idea is to insert our sensor into the Rosa26 genomic locus through homologous recombination. Once the knock-in
animal will be available, probe expression in specific brain areas will be achieved by crossing the
Rosa26-bait line with Cre-recombinase lines (constitutive or tamoxifen-inducible) under control of
brain area specific promoters.
Antonio Malgaroli
Iron and ferritin in neurodegeneration
Iron and mitochondrial dysfunction are important in
many neurodegenerative diseases. Iron plays a
crucial role in the nervous system, involved in
events such as the production of myelin and the
synthesis of catecholamine neurotransmitters.
However, mainly in mitochondria, uncontrolled increases in iron promote the generation of reactive
oxygen species. The main proteins responsible for
protecting cells from iron induced oxidative stress
are cytosolic and mitochondrial ferritins. We are investigating the physiological roles of these two proteins and their involvement in neurodegenerative
processes. Nucleotide insertions that modify the C
terminus of cytosolic ferritin light chain cause neurodegenerative movement disorders, named neuroferritinopathies. The disorders are dominantly inherited and characterized by abnormal brain iron
accumulation. By biochemical and crystallographic
studies we demonstrated that a few mutated Lchains are sufficient to modify ferritin capacity to incorporate iron, thus the dominant negative action of
the mutations explains the dominant transmission
of the disorder. We also described the effects produced by the over-expression of two of the patho-
genic L-ferritin variants in cellular models. These
cells showed an increase in cell death, decrease in
proteasomal activity and formation of iron-ferritin aggregates. The addition of iron chelators or antioxidants restored proteasomal activity and reduced
the formation of aggregates. The data indicated that
cellular iron imbalance and oxidative damage are
primary causes of cell death, while aggregate formation is a secondary effect.
Given the importance and relationship between
iron and mitochondrial activity, we started analyzing
the cellular distribution of mitochondrial ferritin in
multiple regions of the mouse brain. Mitochondrial
ferritin was found in all regions of the brain, although staining intensity varied between regions.
The cell type that stains most prominently for mitochondrial ferritin is neuronal, but oligodendrocytes
also stain strongly in both gray and white matter
tracts. Mice deficient in H-ferritin do not differ in the
mitochondrial ferritin staining pattern or intensity
compared with control mice, suggesting that there
is no compensatory expression of these proteins.
Sonia Levi
Human Mental Retardation (MR) is a common human disorder that may be the only symptom, as in
non -specific/ non-syndromic MR, or one of the
clinical signs of a syndrome (as in Down syndrome), or it may be associated with metabolic,
mitochondrial or developmental disorders. Symptoms appear early in post-natal life and affect approximately 2-3% of the human population with
devastating effects on the life of patients and
caregivers. The social costs for the treatments of
these patients is particularly financially challenging
for the community. Family studies have demonstrated a relatively large number of X-linked forms
(XLMR) with a prevalence of about 0,9-1,4/1000
males. In recent years more than 90 different
genes were identified, which encode for proteins
with a variety of functions: chromatin remodelling,
synaptic function, intracellular trafficking, etc.
Thus, XLMR represents the ultimate result of
many different types of abnormal cellular processes leading to pre- and/or post-synaptic neuronal
terminals dysfunction.
Our research is focused on the understanding on
the mechanisms and pathways leading to development of the cognitive functions altered in XLMR.
The first pathway we discover, by mutation study,
is GDI1-RAB39B; two functional related proteins
involved in vesicular traffic. We showed that mutations in GDI1, one of the protein controlling the recycling of small RAB GTPases, are responsible for
XLMR and that lack of GDI1 in animal models alters
cognitive functions and the biogenesis and recycling of synaptic vesicles (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. The lab has analysed cellular degeneration
in Drosophila models for DRPLA, reporting
through cutting edge techniques (V.Volpi,
D.Mackay and M.Fanto 2011) that Atrophins
block digestion of the autophagic organells after
fusion with the lysosomes (I.Nisoli et al., 2010;
B.Charroux and M.Fanto, 2010).
The lab has also finalised its investigations on the
role of Fat/Hippo in mediating neurodegeneration
by polyglutamine Atrophin (F. Napoletano et al.,
2011; P. Calamita and M. Fanto, 2011 in press).
This work has revealed a surprising neuroprotective
role for a tumour suppressor pathway, though control of autophagy.
Manolis Fanto
Revealing the function of the microcephaly gene Tbr2 during cerebral
cortex development
During development, cerebral cortex growth is
promoted by the expansion of two major types of
precursors: radial glia cells which constitute the
ventricular zone and basal progenitors (BPs) in the
sub-ventricular zone that give rise to a large variety of cortical neurons in a number of well-orchestrated steps which referred to as cortical neuroge-
nesis. The T-brain gene-2 (Tbr2) is specifically expressed in BPs and its inactivation causes microcephaly and cognitive defects in humans. Despite
this relevance, its function in the developing cortex has so far been overlooked due to the early
lethality of Tbr2 mutant embryos. We conditional
ablated Tbr2 in the developing forebrain and re47
Research Units
vealed how its inactivation results in the specific
loss of BPs and their differentiated progeny in mutant cortex. Intriguingly, early loss of BPs led to a
decrease in cortical surface expansion and thickness with a neuronal reduction observed in all
cortical layers. This is reminiscent of the defects
present in the human patients indicating the conditional mutant mice as good animal model of the
Tbr2-dependent microcephaly. Intriguingly, we
demonstrated that misexpression of Tbr2 is sufficient to induce BPs identity in radial glial cells. Together, these findings identify Tbr2 as a critical
factor for the specification of BPs. During its formidable expansion, the cerebral cortex is able to
maintain the correct balance between excitatory
and inhibitory neurons. In fact, while the former
are born within the cortical primordium, the latter
originate outward in the ventral pallium. Therefore,
it is unclear how these two neuronal populations
coordinate their relative amounts in order to build
a functional cortical network. We showed that
Tbr2-positive BPs dictate the migratory route and
control the amount of subpallial GABAergic interneurons through a non-cell-autonomous
mechanism. In fact, Tbr2 interneuron attractive
activity is moderated by Cxcl12 chemokine signaling, whose forced expression in the Tbr2 mutants can rescue, to some extent, SVZ cell migration. We thus propose that INPs are able to control simultaneously the increase of glutamatergic
and GABAergic neuronal pools, thereby creating
a simple way to intrinsically balance their relative
accumulation.
Vania Broccoli
Figure 5. BRAINBOW: triple immunofluorescence of developing cerebral cortex highlighting the three different
compartments of ventricular area (green), sub-ventricular zone (red) and cortical plate (violet).
Acute brain protection, Acute post-operative pain, Drugs
and central nervous system Unit
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 hyperventilation 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).
• Pain and hemodynamic control during
transsphoenoidal surgery by spheonopalatine
block(randomized controlled study).
• Pain control during and after major ENT surgery
with lidocaine i.v. continuous infusion (randomized controlled study).
• Study of complications in children sedated for
neuroradiologic procedures (prospective observational study).
Luigi Beretta
Cognitive neuroscience Unit
The Unit research focus is the multi-disciplinary
study of the neural mechanisms of cognitive function. The experimental approaches include behavioural studies in normal subjects and in neurological
patients andfunctional and structural brain imaging.
A substantial effort of the Unit is devoted to the implementation and development of state-of-the-art
methods for multimodal neuroimaging data analysis. This involves in particular integrated approaches combining Magnetic Resonance Imaging
data of different modalities (structural, functional,
and diffusion data) for the analysis of brain connectivity. One major long-term goal is to develop
standardized databases integrating neuropsychological, neuroimaging and neurophysiological data
in the form of normative parameters of the healthy
population for specific cognitive functions, allowing
for a quantitative diagnosis of neuro-cognitive disorders in brain damaged patients. The main lines of
research, based on behavioral and neuroimaging
studies in both healthy and pathological populations, are: the neurobiological mechanisms of syntactic processing, i.e. the elucidation of the role of
cortical and subcortical brain regions in the computation of hierarchical structural relations in human
language and other cognitive domains; the neural
basis of knowledge representation (semantic
memory), with a special emphasis on the mechanisms underlying the acquisition and processing of
abstract concepts; the representation of multiple
languages in the polyglot brain and their impact on
other cognitive functions; social cognitive neuroscience, i.e. the neural mechanisms of decisionmaking in condition of uncertainty and risk, in
particular from the point of view of the impact of
social context and of the role of individual differences.
Stefano F. Cappa
49
Experimental neurosurgery Unit
Clinical and basic research in neurosurgery:
• Results of Gamma Knife Radiosurgery in the
treatment of pituitary adenomas
• Results of Gamma Knife Radiosurgery in the
treatment of vestibular schwannomas
• 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).
• 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
Eye repair Unit
Clinical and basic research in the treatment of corneal and ocular surface
diseases
Clinical research
Basic research
• Cultivated corneal limbal epithelial stem cells
transplantation. It is a procedure performed since
1998, recognized by SSN and reimbursed with
a specific DRG. This technique is indicated for
the reconstruction of the corneal surface due to
deficiency of the limbal stem cells (particularly
burns). The results of the long term survival have
been published in The New England Journal of
Medicine (2010).
• Retrospective study on the treatment of Acanthamoeba keratitis in collaboration with the Moorfields Eye Hospital, London.
• Genic Therapy of corneal hereditary dystrophies
• Project in collaboration with the University of
Modena, Center of Regenerative Medicine and
the Department of Biomedical Sciences (Dr. De
Luca and Dr. Pellegrini).
• In collaboration with Dr. Marco Bianchi : Expression of HMGB-1 on the ocular surface (normal
and pathological) for a possible therapeutic application.
• Biophysical study of cornea and sclera to analyze the normal and pathological response and
to create a model of engineered cornea; study in
collaboration with Dr. A.Elsheikh of the Division of
Civil Engineering University of Dundee.
Future projects
Transplant of oral mucous stem cells for the treatment of the limbal bilateral deficiency, in collaboration with the University of Modena, Center of
Regenerative Medicine and the Department of Biomedical Sciences (Dr. De Luca e Dr. Pellegrini).
Paolo Rama
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, dur-
ing 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-tempo-
ral 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
m
m
m
m
Figure 6. Functional Diffusion Maps: serial evaluation of a diffusion parameter (isotropy) in patients with brain
tumors treated with chemoterapy, in order to see tissue modification undetectable with conventional MRI
51
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.
We applied in vivo PET molecular imaging to study
brain mechanisms of neurodegeneration in dementias associated pathology. In particular we explored the mechanisms of neuroinflammation the
alteration of neurotransmission systems, the role of
amyloid burden in Alzheimer’s disease.
By using 11C-PK-PET we evaluated patients with
Parkinson’s Disease and Dementia with Lewy Bodies (DLB) in early disease phase the presence of
activated microglia and its correlation with proteomic analysis in the CSF.
We used 11C-MP4 and PET to evaluate acethylcolinesterasis activity in patients with probable AD
and in amnesic MCI subjects as well as in DLB
cases. The consistent reduction of cholinergic activity was significantly associated with change in
long term memory capacity in AD and MCI. We validated a new Bayesian parametric method of
analysis for quantification of the enzymatic activity
as measured by MP4 and PET.
MRI structural studies were also used to address
functional changes and morphometric changes
(voxel-based-morphometry (VBM) and diffusion
tensor imaging (DTI) techniques) in developmental
disorders (dyslexia with a genetic association).
Using fMRI we also addressed functional and morphometric studies in newborns addressing the
study of language neural substrates.
Daniela Perani
Figure 7. Activated microglia, marker of neuroinflammation, as detected by 11C PK and PET in individual patients
with Parkinson Disease (PD) and Dementia with Lewy Bodies (DLB)
Figure 8. The altered white matter tracts in genetic dyslexia overimposed on brain templates of Fractional
Anisotropy.
Neuroothology Unit
During 2010, our scientific collaboration with neurologists and psychiatrists produced 3 works, concerning vertigo and migraine; genetics of Menière
Disease and migrainous vertigo (in collaboration
with Division of Nephrology) was also investigated.
We studied above all the vestibular signs during
crisis-free periods in patients with recurrent migrainous vertigo; moreover, we demonstrated a
higher prevalence of Adducin 1 mutation in
Menière’s Disease patients above all with comorbidity for migraine.
In order to increase our sample, studies concerning genetics of Menière’s Disease and migrainous
vertigo are continuing.
Another collaboration with the University of
Granada has been approved by our Ethics Committee in order to establish genetic mutations in patients with definite Menière’s Disease.
In collaboration with the Division of Psychiatry,
mechanisms related with equilibrium in patients with
Panic Disorders and agoraphobia have been studied and we demonstrated a higher sensitivity to
non-foveal visual stimuli in these subjects (results
have been published on Psychiatry Research).
In another collaboration with Neurophysiology Unit,
we demonstrated EEG abnormal brain activity in
limbic areas of patients with chronic tinnitus without
hearing loss; results have been presented in a recent congress and they will be soon published. We
obtained the approval of our Ethics Committee in
order to assess the efficacy of repetitive Transcranial Magnetic Stimulation in subjects with disabling
chronic tinnitus.
In collaboration with psychologists we are studying the “emotional features” of patients with chronic
disabling tinnitus.
Two more works have been published about
“residual dizziness” after successful repositioning
maneuvers for BPPV (Benign Paroxysmal Positional
Vertigo); in elderly we demonstrated a correlation
between residual dizziness and anxiety they developed.
Finally, we studied cerebral network activation during verbal communication in total laryngectomees
using functional Magnetic Resonance Imaging
(fMRI); an activation of prefrontal gyrus, cerebellar
lobulus VI and VIII and 42 Broadmann area have
been demonstrated during the phonatory motor
tasks.
Mario Bussi
Psychiatry and clinical psychobiology
During the year 2010 we continued our research
activities with a traslational approach, and published results in many research areas in the broad
field of Psychiatry and Clinical Psychobiology.
With an innovative imaging-genetics approach, we
identified genetics variants of the biological clockAkt/GSK pathways which play a protective role
against grey matter loss in schizophrenia. In the
field of psychiatric genetics, we discovered new influences of gene variants in monoaminergic signaling pathways on core features of illness and of
response to treatments. We published the first reports on the effects of COMT variants on psychosis in mood disorders and on antidepressant
response to drugs and chronotherapeutics, and
on 5-HTTLPR on cognition in schizophrenia. We
gained new insights on the biological underpinnings of obsessive-compulsive disorder by studying abnormalities in brain white matter structure,
and executive dysfunctions. We studied the brain
correlates of panic attacks with quantitative electroencephalography. We improved knowledge
about language distortions in schizophrenia, and
about the clinical usefulness of computer-aided
cognitive remediation techniques.
Francesco Benedetti
Sleep medicine
The main objective of our research program was
the evaluation of patients affected by Restless legs
syndrome (RLS) and periodic leg movements during sleep (PLMS). We have conducted epidemiological studies for evaluating RLS prevalence in
patients affected by multiple sclerosis, or cancer.
High prevalence of RLS in multiple sclerosis and a
significant correlation between RLS and cervical
spinal cord damage have been found. The prevalence of RLS in cancer patients undergoing
chemotherapy resulted 18.3%, about double of
that expected in the general population: the oc53
currence of RLS was much more frequent in female patients and with longer-term chemotherapy.
In our study, cancer patients afflicted by RLS had
significantly higher levels of anxiety and depression,
and poorer quality of life especially in the physical
well-being dimension.
By neurophysiological studies, we found that
PLMS are usually embedded in a general oscillatory mechanism in which central, peripheral and
autonomous nervous system changes can be
seen. The time distribution of PLMS shows in the
majority of RLS patients a progressively decreasing
course during the night while. This is different in
various diseases as i.e. sleep apnea syndrome
(OSA) compared to RLS or narcolepsy and may
increase diagnostic certainty when used in clinical
settings. We also evaluated the change in PLMS
by dopamine agonists in RLS patients. The reduction in PLMS index was accompanied by no
change in sleep microstructure.
It is well known that OSA is commonly associated
with neurocognitive impairments that, however,
have not been consistently related to specific brain
structure abnormalities. We investigate the cognitive deficits and the corresponding brain morphology changes in OSA, and the modifications after
treatment, using combined neuropsychological
testing and Voxel-Based-Morphometry. Pre-treatment impairments were associated with focal reductions of grey-matter volume in the left
hippocampus (enthorinal cortex), left posterior parietal cortex and right superior frontal gyrus. After 3month treatment with Continuous Positive Air
Pressure (CPAP), we observed significant improvements in memory and executive-functioning
that paralleled grey-matter volume increases in hippocampal and frontal structures.
Luigi Ferini-Strambi
Clinical psychology
Clinical psychology and psychotherapy
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: a series
of studies on emotion dysregulation in adolescence and adulthood, with particular reference
to its relationships with self-destructive behaviors, personality dysfunction, and poor dispositional mindfulness, as well on mentalization have
been started (A. Fossati). A retrospective study
on childhood history of ADHD symptoms, current conduct problems and the mediating role
of sensation-seeking, impulsivity and aggressive
personality traits in adolescence was also carried out. Finally, the Unit started a research program on the continuities and differences
between narcissistic personalities and psychopathic trait. 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.
2. The Development and Psychopathology SubUnit (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.
3. 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 our Unit.
Cesare Maffei
Motor function rehabilitation
Analysis and rehabilitation of motor function
The research activities of 2010 focused on the following aspects of human movement: 1) biomechanical analysis of coupled movements coordination and anticipatory postural adjustments (APA),
2) measure of cortical activations during the execution of motor tasks performed with cognitive facilitations (action observation, motor imagery,
acoustic feedback) by fMRI and EEG, and 3) the interaction between language and movement.
The common denominator of the above studies is
the connection between cognitive aspects and
motor task execution in both the agonist and postural components of movement.
The purpose of the study about APA was to observe whether differences can be found in APA timing and duration when a subject is asked to perform the same action using different verbal orders.
A collaboration with the Experimental Neurophysiology Group, was about cortical rhythms during
motor task learning using cognitive facilitation (CF).
The observation of a gesture is an effective cognitive tool for motor learning. A previous study suggests action observation as a possibly more effective facilitation than motor imagery in learning a
complex four limb coordination. The aim of the
study was to compare these two CF in learning the
abovementioned action through quantitative EEG
and kinematic analysis.
Another collaboration with the Neuroimaging Research Unit, allowed to study, by functional magnetic resonance imaging, the changes induced by
a motor manual dexterity training carried out with
and without acoustic feedback on functional brain
plasticity and on short-term structural changes.
Motor training is associated with significant brain
activity changes. Moreover the different feedback
mechanisms are associated with different patterns
of activation during motor learning. Structural
changes seem to occur more rapidly in the feedback group.
With the In Vivo Human Molecular and Structural
Neuroimaging Unit we studied the interaction between language and movement. Listening to action
related sentences activates a brain network that is
mostly the same of the mirror neuron system. The
aim of the study was to investigate the effects of linguistic negation on a grasping movement.
Roberto Gatti
55
INSPE
Institute of Experimental Neurology
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 research 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, INSPE
Experimental neuropathology
Optimal micro-patterning of a collagen scaffold coordinates the induction
of morphogenetic pathways in adult nerve regeneration
Nerve injury is a frequent event especially after traumatic injury, affecting mainly young people. Various
therapeutic approaches have been proposed for
patients suffering from peripheral nerve injuries. Results have been, so far, inconsistent, in terms of
both quality as well as extent of nerve regeneration
and re-innervation.
We have previously developed a micro-patterned
collagen scaffold (MPCS) with a peculiar radially
aligned porosity of the tube wall, and predicted that
its microstructure might play a significant role in the
regulation of cellular and molecular mechanisms
sustaining cell behaviour inside the scaffold and, in
turn, improving distal induced regeneration. In the
present investigation, we tested in vivo the clinicopathological impact of this MPCS over a 10-mm
critical size defects in the adult rat sciatic nerve.
Rats with transection of the sciatic nerve and implanted with either commercial collagen or silicon
conduits were used as controls. MPCS-implanted
rats showed significantly improved nerve regeneration at both neurophysiological and neuropatho-
logical levels, as compared to control rats. Our
data demonstrate that this specific, sharply controlled tubular scaffold micro-patterning orchestrates physiological regeneration in the adult rat
sciatic nerve over a 10-mm critical size defect. Indeed, whole genome gene expression analyses
confirm that the MPCS induces selective gene expression patterns and enhanced cells proliferation,
motility and myelination. We hypothesize that the
radially aligned porosity of the MPCS promotes
nerve regeneration by inducing morphogenetic
stimuli and orchestrating cell behaviour towards a
physiological regeneration mode.
We here establish the major cellular and molecular
mechanisms sustaining the effects of this novel
MPCS on peripheral nerve regeneration. Our findings open new perspectives towards the clinical
application of this micro-patterned scaffold, owing
to its ease of production, cost-effectiveness, favorable degradation rate and remarkable cell-instructing behavior.
Angelo Quattrini
Experimental neurophysiology
Brain recording and stimulation in assessing and modulating brain function
Our Unit develops and validate neurophysiological
methods for non invasive recording and stimulation
of the nervous system, for investigation and therapeutic purposes. From the investigational point of
view, functional measures can be used for detecting and monitoring nervous dysfunction to study
the physiopathology of neurological and psychiatric
disorders and to assess the response to treatment.
We investigated the respective contribution of EEG
source analysis, functional magnetic resonance
imaging (fMRI) and focal transcranial magnetic
stimulation (TMS) as non-invasive methods for localizing the primary motor cortex. Using co-registration of these technique for obtaining a functional
map of the hand motor representation, we demonstrated the usefulness of multimodal integration of
fMRI, EEG and TMS and the possibility to increase
EEG spatial resolution using fMRI information.
We also performed a functional investigation of cortical and subcortical circuitries involved in obsessive-compulsive disorder (OCD), using power
(low-resolution electromagnetic tomographyLORETA) and coherence (coupling of EEG bands)
analysis in drug-naïve patients. Using EEG, we
found dysfunctional circuitries involving structures
involved in a network considered important in the
generation of OCD symptomatology, comprising
the frontal lobe, insula, parietal and limbic regions.
OCD also had decreased inter-hemispheric coherence, indicating reduced functional coupling,
between delta and beta frequencies. These findings suggest that combined use of power and coherence analysis may provide functional measures
on different levels of involvement of cortico-subcortical circuits in neuropsychiatric disorders.
We also tested the possibility to perform translational investigation on the application of brain stimulation as a therapeutic tool in neurological
disorders. With this aim, we firstly performed a validation study in order to verify whether the application of weak transcranial direct current stimulation
(tDCS) to the mice brain leads to changes in corticospinal excitability. In humans, anodal tDCS has
been reported to enhance motor-evoked potentials
(MEPs) elicited by transcranial brain stimulation
while cathodal tDCS has been shown to decrease
57
them. We investigated the effects produced by
tDCS on mice motor cortex and found effects similar to those in humans. Although the site and
mechanisms of action of tDCS need to be more
clearly identified, the directionality of effects of
tDCS on mice MEPs is consistent with previous
findings in humans. The feasibility of tDCS in mice
suggests the potential applicability of this technique
to assess the potential therapeutic options of brain
polarization in animal models of neurological and
neuropsychiatric diseases.
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 longterm 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 Ras-ERK activity: drug addiction,
L-DOPA induced dyskinesia (LID) and the RasMAPK 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 Ras-GRF1, 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 (KRasG12V) 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
Role of adhesion in neuromuscolar disorders
Adhesion and cytoskeleton rearrangement play a
key role in neuromuscular development, function
and regeneration.
We are currently investigating the role of
Jab1/COP5, a proteosome subunit, which is modulated by adhesive signals. We revealed that
Schwann cell restricted inactivation of Jab1 affects
Schwann cell development, survival and interaction with axons. Schwann cells also present abnormal cytoskeleton rearrangement and adhesive
receptor expression. All these events result in dysmyelinating neuropathy.
We also demonstrated that the inactivation of vi-
mentin, an intermediate filament component of
Schwann cell and neuron cytoskeleton, causes
motor neuropathy and abnormally myelinated fibers.
This is, at least in part, due to the loss of vimentin
in neurons, which alters the neuregulin dosage. Abnormal remyelination is also observed when enzymes that usually rearrange the endoneurial
extracellular matrix after damage are inactivated.
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 cross-linker molecule that
re-connect myocytes to the basal lamina have
been delivered in mouse models of CMD. Treated
mice showed delayed deterioration of motor per-
formances and the amelioration of muscle tissue.
Stefano Carlo Previtali
Figure 9. Muscle section for laminin2 deficient mice treated with mesoangioblasts carrying the mini-agrin gene
(myc tagged). The injected muscles show diffuse engraftment of mesoangioblasts and expression of the mini-agrin
protein (myc in green).
Neuroimmunology Unit
Understanding the role and therapeutic potential of neural stem cells in
central nervous system diseases
The Neuroimmunology Unit is particularly interested
in understanding the physiopathological role and
the therapeutic potential of neural stem/precursor
cells (NPCs) in neurological disorders.
In the past years we have demonstrated that transplantation of NPCs in experimental multiple sclerosis and ischemic stroke is indeed able to induce a
functional improvement by playing a profound neuroprotective (immunomodulatory and neurotrophic)
effect. We are now investigating the best cell
source and transplantation route for improving the
therapeutic potential of such cells in order to foster clinical translation. Deriving NPCs from induced
pluripotent stem cells (iPS) is indeed a very promising source to obtain expandable autologous
NPCs. Ongoing experiments are comparing the efficacy of iPS- vs. embryo-derived NPCs to that of
adult NPCs in experimental multiple sclerosis and
spinal cord injury.
We are also trying to understand the physiopathological role and the factors regulating endogenous
neurogenesis during brain development and brain
pathology. We found that the β−Catenin signalling
plays a dual role in controlling cell proliferation/differentiation in the brain. Hipk1 was found to be the
crucial interactor able to revert the outcome of
βCatenin signalling in adult germinal niches. Using
a novel transgenic mouse line expressing the
CreERT2 under the control of abnormal spindlelike microcephaly-associated protein (AspM) promoter, we found that AspM-expressing RG cells
are multi-potent and that AspM descendants give
rise to proliferating progenitors in germinal niches of
both developing and post natal brains. Furthermore
when AspM expressing neural progenitor cells are
selective killed a severe derangement of the ventricular zone architecture and impairment of the
cortical lamination is seen thus demonstrating the
peculiar role of AspM in neurogenesis. Finally,
studying experimental stroke and epilepsy in the
Nestin transgenic mouse line in which NPCs can
be specifically ablated upon gancyclovir administration, we found that NPCs exert a fundamental
role in protecting the brain from excitotoxic damage.
Gianvito Martino
59
Figure 10. In the adult brain AspM expressing cells (in green the YFP reporter) migrate from the subventricular zone
(SVZ) along the rostral migratory stream (RMS) to the olfactory bulb (OB) to replenish granular neurons. Astrocytes
labeled by GFAP are shown in red. (Marinaro, Butti et al., PLoS ONE, 2011, 6(4): e19419).
Clinical neuroimmunology
The Unit of Clinical Neuroimmunology is still 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
2010 we have completed a study on a novel
mechanism of intercellular communication used by
glial cells to propagate pro-inflammatory signals in
the brain, namely shed vesicles. These newly described means of horizontal communication are
membranous cargo structures containing signals
heterogeneous in nature and significance. We described the possibility to detect and analyze shed
vesicles in the cerebrospinal fluid of mice (and patients), and in particular to investigate those of
myeloid origin. These findings have lead to further,
very relevant studies in a clinical setting, leading to
the characterization of novel biomarkers for both
inflammation and neurodegeneration. Concerning
other clinical research, we have completed a work
on the kinetic of Treg cells in MS patients, finding
that their increase is surprisingly associated clinical relapse. Further, we are still analyzing data concerning immunological markers in patients affected
by major psychoses, and we found a disimmune
signature associated to major depression. Finally
we have described a novel reactivity towards aldolase A in patients characterized by acute onset
movement disorder.
Roberto Furlan
CNS repair
Transplanted NPCs instruct phagocytes towards a tissue-protective mode
and regulate the healing of the severely contused spinal cord
Compelling evidence exists that neural stem/precursor cells (NPCs) possess peculiar therapeutic
plasticity. It is becoming in fact clearer that transplanted NPCs simultaneously instruct several
therapeutic mechanisms alternative to cell replacement. Current projects in the laboratory are
further exploring the cellular and molecular mechanisms regulating the therapeutic plasticity of
NPCs in complex CNS diseases such as multiple
sclerosis, and spinal cord injury.
With this study we interrogated the therapeutic
plasticity of NPCs after their focal implantation in
the severely contused spinal cord. We injected
syngeneic NPCs at the proximal and distal ends
of the contused mouse spinal cord, and performed extensive assessment of locomotor functions, gene expression, cell fate and interactions
of transplanted NPCs with endogenous cells, inflammatory infiltration and major pathological secondary events. We considered two different doses of NPCs and two treatment regimes - sub
acute [7 days post-injury (dpi)] or early chronic (21
dpi) - and used PBS-injected spinal cord injury
(SCI) mice as controls. Only the sub acute transplantation of NPCs ameliorated the recovery of locomotor functions of SCI mice. Transplanted
NPCs survived undifferentiated at the level of the
perilesion environment and established contacts
with endogenous phagocytes via cellular-junctional coupling. This was associated to significant
regulation of the expression levels of major inflammatory RNAs in vivo. Remarkably, transplanted
NPCs reduced the proportion of inflammatory
myeloid cells at the injury site – including M1-like
macrophages and dendritic cells – and, in turn,
led to the healing of the injured cord. We identify a
precise window of opportunity for approaches to
complex SCIs with therapeutically plastic somatic
stem cells and suggest that NPCs posses the
functional promise to correct the local environment from ‘hostile’ to ‘instructive’ for either the
healing or the regeneration past the lesion.
Stefano Pluchino
Neuroimaging research Unit
Normal functioning of the human brain
Empathy toward non conspecifics has different
neural representation among individuals with different feeding habits, perhaps reflecting different
motivational factors and beliefs.
Assessment of MS pathophysiology using structural and functional MRI
The accuracy of MRI diagnostic criteria for MS is increased when considering the presence of intracortical lesions (ICLs) on baseline scans from
patients at presentation with clinically isolated syndromes suggestive of MS.
Distinct patterns of regional distribution of gray
matter (GM) damage and T2-visible lesions are
associated with cognitive impairment in MS patients with different clinical phenotypes. The correspondence between lesion formation and GM at-
rophy distribution varies in the different forms of
MS.
The preservation of brain adaptive properties might
explain the favorable medium-term clinical outcome of pediatric MS patients. The progressive recruitment of cortical networks over time in patients
with the adult RR forms of the disease might result
in a loss of their plastic reservoir, thus possibly contributing to subsequent disease evolution.
MRI Assessment of CNS damage in neurodegenerative diseases
In early-onset Alzheimer’s disease (AD) patients,
the distinct regional distribution of white matter
(WM) atrophy reflects the topography of GM loss.
Regional patterns of WM tract damage occur in
patients with AD and patients with amnestic mild
cognitive impairment (aMCI) (see Figure 11), which
61
Figure 11. Results of voxel-based morphometry and tract-based spatial statistics analyses are overlaid onto a
common reference image (i.e., the canonical single subject MRI provided by the Statistical Parametric Mapping
software) to show the anatomical localisation of grey matter (GM) atrophy (cyan) and white matter (WM) changes
(red) in patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). WM abnormalities
correspond to significant axial diffusivity (D) changes in both groups. Of note, in aMCI patients there is a
widespread increase of axial D with a relatively spared GM. From Agosta et al., Radiology 2011;258:853-63.
Epub 2010 Dec 21.
may reflect the advanced phase of a secondary
degenerative process and an association, especially in the early phases of the disease, with primary WM tract damage over and above GM
abnormalities.
Major anatomical differences between patients with
Richardson’s syndrome (PSP-RS) and progressive
supranuclear palsy-parkinsonism (PSP-P) exist.
Such a different topographical distribution of tissue
damage may account for the clinical differences
between these two conditions.
Massimo Filippi
Neuroimaging of CNS white matter
In vivo assessment of MS pathophysiology using
structural and functional MRI
Distinct patterns of regional distribution of gray matter (GM) damage and T2-visible lesions are associated with cognitive impairment in multiple
sclerosis (MS) patients with different clinical phenotypes.
Thalamic atrophy is correlated with long-term accumulation of disability in MS patients. White matter (WM) lesions are likely to contribute to the loss
of tissue seen in the thalamus of these patients.
A dysfunction of the anterior components of the
default-mode network may be among the factors
responsible for the accumulation of cognitive
deficits in patients with progressive MS.
Compared with healthy controls, primary progressive (PP) MS patients have abnormal recruitment
in several areas of the sensorimotor network, which
is correlated with the structural damage to the WM
tracts connecting these regions.
In PPMS, an increased recruitment of cognitive-related networks might represent a functional reserve
with the potential to limit the severity of cognitive
impairment.
The preservation of brain adaptive properties might
explain the favorable medium-term clinical outcome of pediatric MS patients.
The movement-associated pattern of activations
seen in benign MS resembles that of healthy people, and its abnormalities are restricted to the sensorimotor network.
sual pathways, but extends posteriorly to the optic
radiation and the primary visual cortex.
MRI Assessment of CNS damage in migraine and
optic neuropathies
Motor learning results in structural GM changes of
different brain areas which are part of specific neuronal networks and tend to persist after training is
stopped. The scheme applied during the learning
phase influences the pattern of such structural
changes.
Maria Assunta Rocca
In patients with cluster headache a diffuse abnormality of brain functional connectivity is present,
which extends beyond the antinoceptive system.
Brain damage in patients with Leber’s Hereditary
Optic Neuropathy is not limited to the anterior vi-
Healthy brain function
Figure 12. Spatial patterns (A) and mean values of the average Z-scores of resting state activity (B) in the default
mode network in healthy controls (white), primary progressive multiple sclerosis (MS) (dark grey), and secondary
progressive MS (light grey). A reduction of the fluctuations within the anterior portions of the network is present in
patients in comparison to controls.
Human inherited neuropathies Unit
Regulation of membrane homeostasis in myelination
In the last ten years, our research interest has been
mainly focused on inherited peripheral neuropathies, of which Charcot-Marie-Tooth (CMT)
neuropathies represent the more frequent forms.
Among CMTs, CMT4B1 is a severe autosomal re-
cessive demyelinating neuropathy, characterized
by formation of redundant myelin sheaths (myelin
outfolding) that likely degenerate causing demyelination and axonal problems. We previously reported that CMT4B1 is caused by loss of MTMR2
63
in human and created a faithful mouse model of
the disease. MTMR2 is a phospholipid phosphatase with a suggested role in intracellular trafficking. Why altered phospholipid levels and
consequent intracellular trafficking impairment
leads to CMT4B1 remains to be assessed. We recently identified a potential mechanism using in vivo
and in vitro models and proposed that Mtmr2 belongs to a molecular machinery that titrates membrane formation during myelination. According to
this model, myelin outfoldings arise as a consequence of the loss of negative control on the
amount of membrane produced during myelination. As component of this machineries are also expressed in oligodendrocytes, our research interest
has also recently extended to the control of myelination in the central nervous system.
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). Gliogenesis and the development of nervous system strictly depend upon interaction between neurons and glial cells. Glial cells promote
neuronal survival, regulate the organization of myelinated axons and promote axonal differentiation and
myelin sheath production. Axons promote glial cells
survival and development. 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.
We are now investigating the signals on the axon,
and the downstream signaling pathways intermediates they activate in myelinating glia. These molecules are important to mediate axo-glial interactions, regulate the generation and formation of glial
cells and ultimately, maintenance of the myelin
sheath. We have previously identified type III NRG1 as an essential instructive signal that controls the
ensheathment fate of axons in the PNS and promotes myelination in the CNS. Our studies indicate
that NRG1 type III is processed in the extracellular
region by the α-secretase TACE. Ablation of TACE
determines altered processing of axonal NRG1
type III, precocious and ectopic myelination, hypermyelination and enhanced activation of the PI3K pathway. In vivo ablation of TACE is sufficient to
rescue myelination of NRG1 type III haploinsufficient
mice. Further, inactivation of TACE in Schwann
cells in vitro and in vivo does not alter the timing or
amount of the myelin produced suggesting that
TACE activity is due to a neuronal autonomous
mechanism. Our results underscore the existence
of several components controlling myelination and
implicate secretases as key determinants in controlling NRG1 type III expression on the axon.
The identification of the axonal molecules involved
in myelination and manipulations and the signaling
pathway intermediates they activate, could be effective to develop therapies for demyelinating diseases in which the 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) to evaluate the safety and efficacy of newly-developed immunosoppressive (IS)
or immunomodulatory (IM) drugs (Fingolimod,
Laquinimod, Cladribine, Teriflunomide, Ocrelizumab) in patients with Multiple Sclerosis (MS)
with different disease phases.
We collected and analyzed clinical and laboratory
data on more than 1500 MS patients, treated with
first-line IM drugs, to identify the early predictors of
short-term (2 years) and long-term (5 years) clinical
efficacy. A brain MRI without any active lesions,
performed 6-12 months after the beginning of the
treatment, represents a good prognostic factor.
We were the promoting centre of an Italian study
to evaluate the safety and efficacy of Natalizumab
in clinical practice. The presence of JC virus antibodies and previous IS therapies represent the
bad prognostic factors, increasing the risk to develop PML. Moreover, we were involved in 3 international RCTs planned to assess the efficacy of
Glatiramer Acetate, Cladribine or High Dose â Interferon in delaying the conversion to MS after a
first clinical event. The 5-year PRECISE results
have been recently analyzed, confirming the long
lasting beneficial effects of the early use of Glatiramer Acetate. We also coordinated a RCT on the
long-term benefits of a sequential therapy with Mitoxantrone (MTX) followed by β Interferon on patients with bad prognostic factors in the early
phase of the disease. Moreover, we participated
in a national project on newly diagnosed MS patients, aiming at evaluating the need of information, and the level of satisfaction of both patients
and neurologists.
We were the promoting centre of a retrospective
study to evaluate the incidence of Acute
Leukaemia (AL) in MS 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.
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 or
of “Neuromyelite Optica Spectrum Disorder”, 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, coordinated by HSR, aimed at the definition of outcomes of efficacy and efficiency in the management of cerebrovascular pts, we confirmed the efficacy of thrombolysis as well as
the relevant role of more sophisticated imaging
techniques (angio-MR; angio-CT and brain
MR) in improving patients’ outcome;
b) National and International clinical trials evaluating therapeutic strategies in primary and secondary prevention. Among these studies,
HSR Stroke Unit is the coordinator center of
the WakeUp Stroke (WUS) trial, designed to
evaluate safety and efficacy of thrombolysis in
patients with arousal stroke.
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. Markers of
carotid plaque instability - in collaboration with
the Cardiovascular Department, we are implementing an international prospective study on
a large cohort of patients with a carotid stenosis > 50% (NASCET), who will be studied with
a multimodal approach for the in vivo evaluation of the carotid plaques and for the stratification of the risk of rupture, which will include
US studies, comprehensive of study of
carotid plaque echogenicity, trans-cranial
Doppler (TCD) for microembolic signal detection, and contrastenhanced US, as well as
positron emission tomography (PET)/computerized tomography (CT) with 11C-PK11195
ligand.
d) Characterization of genetic determinants of ischemic stroke risk with a whole genome approach using Illumina® Bead Station 500. We
have recruited almost 400 cerebrovascular pts
and we plan to reach 500 pts by mid 2012:
genetic characterization and association with
phenotype will follow. We are involved in an in65
ternational collaborative study on wholegenome genetic association with clinical characteristics of almost 1,000 patients affected
by cervical arterial dissection (CADISP). The
preliminary data just published regard the risk
profile and the response to thrombolysis of
dissected patients.
Maria Sessa
Memory disorders
Our Unit is involved in the study of cognitive disorders with different methodological approaches.
Our main objective is to achieve early and accurate diagnosis, from the integration of different information (neuropsychological, biological, neuroradiological, neurophysiological data). We work in
close collaboration with the Neuroimaging Research Unit (M. Filippi and F. Agosta) and Functional Neuroradiology Unit (A. Falini) to study structural and functional CNS changes in demented
patients, and also with the MAGICS Centre (L.
Leocani) where selected patients participate to an
experimental treatment with non-invasive deep
transcranial magnetic stimulation. An additional
approach with the Units of Clinical Neurophysiology (F.Minicucci) and Experimental Neurophysiology (L. Leocani) has been based on the study of
functional cortical changes occurring in
Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) patients using advanced techniques
for EEG analysis such as low-resolutions tomography (LORETA). Our interest is also focused on
genetic aspects of dementia: we are collecting
blood samples of patients affected by AD to create a clinical database and a biobank in order to
identify genetic factors involved in dementia (F.
Martinelli-Boneschi; Laboratory of Neurological
Complex Disorders). In the last years, an important objective is to identify early markers of dementia, particularly new cerebro-spinal fluid (CSF)
biomarkers as β-amyloid, tau and phosphorilatedtau proteins. These CSF biomarkers could be very
useful in the diagnosis of AD in the early stage of
disease and to differentiate it from other types of
dementia. We found significant group differences
analyzing CSF in 72 AD and 42 FTD patients. Data from patients with CSF analysis are currently
collected in an electronic database with follow-up
data, to be able to identify Mild Cognitive Impairment (MCI) subjects with high risk of conversion
into AD, which is essential for therapeutic strategies. With this respect we are also involved in an
innovative clinical trial where anti-amyloid antibodies (currently used by our and other groups in trials
on AD patients) are provided to MCI with high risk
of conversion; a low level of CSF β-amyloid is an
inclusion criteria for this study.
Giuseppe Magnani
Movement disorders
The Movement Disorder Unit of S. 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 sup-
pression (“geste antagoniste”) in cervical dystonia;
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). 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
Clinical studies in Neuromuscular Diseases are addressed to give the best medical supports to our
patients.
We completed:
1. an open study evaluating the efficacy of FKT
long term efficacy in pt with peripheral ataxia
demonstrated patient had a better autonomy
also six month later the stop of FKT
2. a multicentric controlled double blind clinical trial
on the 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
We are working on:
1. a clinical multicentric randomized double blind
trial for the efficacy of EPO in ALS
2. a Randomized, Double-Blind, Placebo-Controlled, Multicentre Study to Assess the Efficacy
on Spasticity Symptoms of a Cannabis Sativa
Extract in Motor Neuron Disease Patients
3. evaluation of corneal confocal microscopy neurophysiological studies and cutaneous biopsy in
sensory peripheral neuropathy
4. usefulness of peripheral nerve MRI in patients
with peripheral neuropathy.
Raffaella Fazio
Paroxysmal events
Epilepsy and ultrasound vascular diagnostics
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.
Long term EEG monitoring (LTM) is a well-established procedure in the evaluation of epilepsy patients. 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 patients.
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.
Headache
Our group is deeply involved in research concerning:
• the brain activity with non conventional MRI techniques to evaluate brain lesions associated with
migraine to understand the tissutal damage and
the cerebral activity and plasticity (functional MRI)
• the correlation between migraine and vertigo (migrainous vertigo) with otovestibular techniques
• the brain pathology in pediatric headaches to understand the tissutal damage in a prospectic
study
• the genetic aspects linked to migraine
• the non conventional approach to migraine
pathology (i.e. Botox in chronic headache, diet
and stress evaluation in pediatric headache).
Fabio Minicucci
67
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IF 2009: 9,432
Fasano, S; Bezard, E; D’Antoni, A; Francardo, V; Indrigo, M; Qin, L; Doveró, S; Cerovic, M; Cenci, MA and Brambilla, R. Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia. Proc. Natl.
Acad. Sci. U.S.A.: 2010; 107(50): 21824-21829 - Article
IF 2009:
Centonze, D; Muzio, L; Rossi, S; Furlan, R; Bernardi, G; Martino, G. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ.: 2010;
17(7): 1083-1091 - Review
IF 2009: 8,240
Rocca, MA; Ceccarelli, A; Rodegher, M; Misci, P; Riccitelli, G; Falini, A; Comi, G and Filippi,
M. Preserved brain adaptive properties in patients with benign multiple sclerosis. Neurology: 2010;
74(2): 142 - 149 - Article
IF 2009: 8,172
Astro, V; Asperti, C; Cangi, G; Doglioni, C and de Curtis, I. Liprin-α1 regulates breast cancer cell
invasion by affecting cell motility, invadopodia and extracellular matrix degradation. Oncogene: 2010;
Article in Press
IF 2009: 7,135
Benedetti, S; Previtali, SC; Coviello, S; Scarlato, M; Cerri, F; Di Pierri, E; Piantoni, L; Spiga, I;
Fazio, R; Riva, N; Natali Sora MG; Dacci, P; Malaguti, MC; Munerati, E; Grimaldi, LM; Marrosu,
MG; De Pellegrin, M; Ferrari, M; Comi, G; Quattrini, A; Bolino, A. Analyzing histopathological
features of rare charcot-marie-tooth neuropathies to unravel their pathogenesis. Arch. Neurol.:
2010; 67(12): 1498-1505 - Article
IF 2009: 6,312
Schulte, C and Racchetti G; D’Alessandro, R; Meldolesi, J. A New Form of Neurite Outgrowth
Sustained by the Exocytosis of Enlargeosomes Expressed under the Control of REST. Traffic: 2010;
11(10): 1304-1314 - Article
IF 2009: 6,255
Rossi, S; Innocenti, I; Polizzotto, NR; Feurra, M; De Capua, A; Ulivelli, M; Bartalini, S and Cappa SF.
Temporal dynamics of memory trace formation in the human prefrontal cortex. Cereb. Cortex: 2011;
21(2): 368-373 - Article
IF 2009: 6,979
Velikova, S; Locatelli, M; Insacco, C; Smeraldi, E; Comi, G and Leocani, L. Dysfunctional brain
circuitry in obsessive-compulsive disorder: Source and coherence analysis of EEG rhythms. Neuroimage: 2010; 49(1): 977-983 - Article
IF 2009: 5,739
Esposito, M; Ruffini, F; Bergami, A; Garzetti, L; Borsellino, G; Battistini, L; Martino, G and
Furlan, R. IL-17- and IFN-γ-secreting Foxp3+ T cells infiltrate the target tissue in experimental autoimmunity. J. Immunol.: 2010; 185(12): 7467-7473 - Article
IF 2009: 5,646
Masserdotti, G; Badaloni, A; Green, YS; Croci, L; Barili, V; Bergamini, G; Vetter, ML; Consalez,
GG. ZFP423 coordinates Notch and bone morphogenetic protein signaling, selectively up-regulating Hes5 gene expression. J. Biol. Chem.: 2010; 285(40): 30814-30824 - Article
IF 2009: 5,328
Benedetti, F; Poletti, S; Radaelli, D; Bernasconi, A; Cavallaro, R; Falini, A; Lorenzi, C;
Pirovano, A; Dallaspezia, S; Locatelli, C; Scotti, G and Smeraldi, E. Temporal lobe grey matter
volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase
kinase 3-β activity. Genes Brain Behav.: 2010; 9(4): 365-371 - Article
IF 2009: 3,795
Selected publications, INSPE
Cohen, JA; Barkhof, F; Comi, G; Hartung, HP; Khatri, BO; Montalban, X; Pelletier, J; Capra, R; Gallo, P; Izquierdo, G; Tiel-Wilck, K; De Vera, A; Jin, J; Stites, T; Wu, S; Aradhye, S; Kappos, L. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med.: 2010; 362(5):
402-415 - Article
IF 2009: 47,050
Filippi, M; Rocca, MA; Calabrese, M; Sormani, MP; Rinaldi, F; Perini, P; Comi, G; Gallo, P. Intracortical lesions: Relevance for new MRI diagnostic criteria for multiple sclerosis. Neurology: 2010;
75(22): 1988-1994 - Article
IF 2009: 8,172
Giovannoni, G; Comi, G; Cook, S; Rammohan, K; Rieckmann; P; Soelberg Sørensen, P; Vermersch, P; Chang, P; Hamlett, A; Musch, B; Greenberg, SJ; CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med.: 2010; 362(5): 416-426
- Article
IF 2009: 47,050
Visigalli, I; Delai, S; Politi, LS; Di Domenico, C; Cerri, F; Mrak, E; D’Isa, R; Ungaro, D; Stok, M;
Sanvito, F; Mariani, E; Staszewsky, L; Godi, C; Russo, I; Cecere, F; Del Carro, U; Rubinacci, A;
Brambilla, R; Quattrini, A; Di Natale, P; Ponder, K; Naldini, L and Biffi; A. Gene therapy augments
the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I
phenotype in the mouse model. Blood: 2010; 116(24): 5130-5139 - Article
IF 2009: 10,555
Centonze, D; Muzio, L; Rossi, S; Furlan, R; Bernardi, G; Martino, G. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ.: 2010;
17(7): 1083-1091 - Review
IF 2009: 8,240
69
71
Memory disorders
73
DIVISION
OF
METABOLIC AND
CARDIOVASCULAR SCIENCES
Research Units
Amino acid and stable isotopes Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 80
HEAD OF UNIT: Livio Luzi
RESEARCHERS: Stefano Benedini, Andrea Caumo, Roberto Codella, Ileana Terruzzi
FELLOWS: Chiara Martinelli, Anna Montesano, Pamela Senesi
Complications of diabetes –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 80
GROUP LEADER: Gianpaolo Zerbini
RESEARCHER: Anna Maestroni
PHD STUDENT: Silvia Maestroni
TECHNICIAN: Daniela Gabellini
Obesity and metabolic related diseases ––––––––––––––––––––––––––––––––––––––––––– 81
GROUP LEADER: Gianluca Perseghin
FELLOW: Guido Lattuada
TECHNICIAN: Francesca Ragogna
Bone metabolism Unit––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 82
HEAD OF UNIT: Alessandro Rubinacci
RESEARCHER: Isabella Villa
POST-DOCTORAL FELLOW: Emanuela Mrak
PHD STUDENT: Simona Bolamperti
CONSULTANTS: Giovanna Mignogna, Gianluigi Moro, Marcella Sirtori
TECHNICIAN: Rita Masullo
Coagulation service & thrombosis research Unit–––––––––––––––––––––––––––––––––––––––– 82
HEAD OF UNIT: Armando D’Angelo
RESEARCHERS: Luciano Crippa, Patrizia Della Valle, Annalisa Fattorini, Silvana Viganò
FELLOW: Giulia Pavani
TECHNICIANS: Elisabetta Pattarini, Francesca Sampietro
Cardiodiabetes & core Lab ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 83
HEAD OF UNIT: Emanuele Bosi*
GROUP LEADER: Lucilla D. Monti
FELLOW: Elena Galluccio
TECHNICIANS: Sabrina Costa, Barbara Fontana
Pediatric endocrinology research –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 83
HEAD OF UNIT: Giuseppe Chiumello*
GROUP LEADER: Stefano Mora
FELLOWS: Silvia Carlucci, Annalisa Donini, Silvia Genovese, Ilaria Zamproni
TECHNICIAN: Maria Puzzovio
75
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Diabetes and endocrinologyUnit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 85
PHYSICIANS: Alberto Davalli, Gabriella Galimberti, Roberto Lanzi, Marco Federico Manzoni,
Alessandro Saibene
RESIDENTS: Andrea Bolla**, Chiara Cappelletti**, Valentina Crippa**, Valentina Doria**, Ilaria
Formenti**, Alessandra Gandolfi**, Sara Madaschi**, Chiara Molinari**, Francesca Perticone**,
Cecilia Piani**, Annachiara Uccellatore**, Valentina Villa**
FELLOWS: Andrea Laurenzi, Alessandro Rossini
TECHNICIAN NUTRITIONIST: Monica Marchi
Cardio-metabolic and clinical trials ––––––––––––––––––––––––––––––––––––––––––––––––– 85
CLINICAL GROUP LEADER: Piermarco Piatti**
FELLOWS: Pietro Lucotti, Emanuela Setola, Ermal Shehaj
DATA MANAGER: Roberta Savi
RESEARCH NURSE: Michela Stuccillo
Gynecology and infertility Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 86
RESEARCHERS: Lucia De Santis, Paola Panina, Enrico Papaleo, Paola Viganò
FELLOWS: Alessandra Mugione**, Luca Pagliardini
Fetal-maternal medicine –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 86
CLINICAL GROUP LEADER: Maria Teresa Castiglioni
RESEARCHERS: Francesca Di Sebastiano, Susanna Rosa, Maddalena Smid, Luca Valsecchi
PHD STUDENT: Paolo Cavoretto
FELLOWS: Lara Di Piazza, Federica Pasi, Audrey Serafini
Pediatrics Unit
Clinical pediatric endocrinology ––––––––––––––––––––––––––––––––––––––––––––––––––––– 87
CLINICAL GROUP LEADER: Giovanna Weber*
RESEARCHERS: Stefania Di Candia, Gabriella Pozzobon, Gianni Russo, Maria Cristina Vigone
Diabetes and metabolic diseases in children and adolescents ––––––––––––––– 88
CLINICAL GROUP LEADER: Franco Meschi
RESEARCHERS: Karen Marenzi, Matteo Viscardi
CONSULTANT: Andrea Rigamonti
Neonatology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 88
CLINICAL GROUP LEADER: Graziano Barera
RESEARCHERS: Antonella Poloniato, Rosanna Rovelli
RESIDENT: Patrizia Corsin
Cardiovascular interventions Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 89
HEAD OF UNIT: Antonio Colombo
PHYSICIANS: Mauro Carlino, Alfredo Castelli, Alaide Chieffo, Cosmo Godino, Azeem Mohamed
Latib, Matteo Montorfano
FELLOWS: Giefrius Davidicius, Filippo Figini, Takagi Kensuke, Marco Mussardo, Joanne Shannon
TRIAL COORDINATOR: Angela Ferrari
Clinical cardiovascular biology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 89
HEAD OF UNIT: Domenico Cianflone*
PHYSICIANS: Enrico Ammirati, Nicole Cristell
POST-DOCTORAL FELLOW: Norma Maugeri (till March 2010)
RESIDENTS: Alessandro Durante, Antonio Mangieri
TECHNICIAN: Michela Banfi
Ischaemic heart disease, heart failure and echocardiography Unit ––––––––––––––––– 90
HEAD OF UNIT: Alberto Margonato
PHYSICIANS: Eustachio Agricola, Alberto Capelletti, Gabriele Fragasso, Andrea Macchi, Michele
Oppizzi
RESIDENTS: Michela Cera, Irene Franzoni, Monica Mazzavillani, 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 –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 91
HEAD OF UNIT: Alberto Zangrillo*
PHYSICIANS: Elena Bignami, Tiziana Bove, Luca Cabrini, Maria Grazia Calabrò, Sergio Colombo,
Remo Daniel Covello, Giovanni Landoni, Giovanni Marino, Federico Pappalardo, Anna Mara
Scandroglio
RESIDENTS: Massimiliano Greco, Giulia Maj, Giacomo Monti, Laura Ruggeri
POST-DOCTORAL FELLOWS: Giovanni Borghi, Elena Frati, Davide Nicolotti, Marina Pieri
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Simona Massani, Lara Sussani, Paola Zuppelli
Strategic research on heart failure
HEAD OF UNIT: Paolo Camici*
PHYSICIANS: Marco Mongillo**, Iacopo Olivotto, Roberto Spoladore**
POST-DOCTORAL FELLOWS: Laura Calvillo**, Massimiliano Mancini**
TECHNICIAN: Alberto Mira**
Structural heart disease Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 91
HEAD OF UNIT: Ottavio Alfieri*
PHYSICIANS: Stefano Benussi, Michele De Bonis, Francesco Maisano
FELLOWS: Federico Anzil, Andrea Guidotti, Davide Schiavi
Study and treatment of aortic disease Unit –––––––––––––––––––––––––––––––––––––––––––––– 92
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: Luca Apruzzi, Giovanni Coppi, Davide Logaldo, Daniele Mascia, Daniele Psacharopulo,
Enrico Rinaldi, Sara Spelta, Gianbattista Tshiombo
FELLOWS: Domenico Baccellieri, Luca Bertoglio, Chiara Brioschi, Barbara Catenaccio, Andrea
Kahlberg
Vision first Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 92
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
77
RESIDENTS: Luigi Berchicci**, Ingrid Bianchi**, Maria Lucia Cascavilla**, Umberto De Benedetto**,
Federico Di Matteo**, Silvia Giatsidis**, Jacopo Milesi**, Lea Querques**, Laura Regali**, Ilaria
Zucchiatti**
CONSULTANTS: Nicola Baccelli, Loredana Bonisolli, Elena Bruschi, Gabriella Cammarata, Claudio
Campa, Carlo Ciampi, Paola Ciasca, Annalisa Colucci, Alessandra Criscuoli, Marina Fiori,
Maddalena Forti, Marco Gagliardi, Matteo Ghidoni, Lauretta Guarisco, Francesca Legorini, Mara
Lorenzi**, Angela Malegori, Maria Pia Manitto, Elena Mantovani, Elisabetta Martina, Paolo Mauceri,
Stefania Mazzarella, Lisa Melzi, Elisabetta Miserocchi, Veronica Odazio, Matteo Prati, Andrea
Ramoni, Carmen Rojo, Marco Setaccioli, Monica Stoppani, Fabrizio Scotti, Alessandra Spinelli,
Gemma Tremolada
TECHNICIANS: Giorgio Alto, Alessio Buzzotta, Chiara Manclossi, Antonella Ribecca
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, diabetes and 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.
79
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 en-
docrine 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 plantderived proteins.
Livio Luzi
Reversibility of the microvascular complications of diabetes
Despite major efforts aimed to obtain the best
possible glucose control, along with the normalization of blood pressure levels, microvascular
complications of diabetes remain among the major causes of end stage renal failure and blindness in Europe. We hypothesize that the complications of diabetes may be the result, in predisposed individuals, of the toxic effect of glucose
on progenitor cells localized in target organs of diabetes such as the renal glomerulus and the retina. When identified, these cells could represent
the objectives of specific pharmacologic approaches aimed to the prevention, cure and remission of these complications. To verify this hypothesis we set up two projects:
1. Identification of podocyte progenitor cells (PPCs)
In case of hyperglicemia the podocytes, i.e. the
glomerular cells responsible for the filtering selectivity of the kidney, tend to die and to detach
from the basal membrane finally causing 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 stem cell
markers on the other, suggesting the presence
of PPCs inside the adult human kidney. We
have also successfully isolated and grew PPCs
in culture using a selective culture medium.
Characterization of PPCs in culture by immunofluorimetic and molecular techniques is
presently under way.
2. Endothelial progenitor cells (EPCs) and diabetic
retinopathy
The final stage of diabetic retinopathy, so called
proliferative retinopathy (PDR), is characterized
by the proliferation inside the retina of new,
leaky, capillaries causing hemorrhages and, if
untreated, retinal detachment. Whether EPCs
might be involved in the pathogenesis of PDR
is presently unknown. In line with this hypothesis and in collaboration with the Vision First Unit
of this Institute we have demonstrated that type
1 diabetic patients with established PDR and
those predisposed to the complication have an
increased activity of circulating EPCs. We are
now setting up an animal model of PDR to verify the possibility to prevent/cure diabetic
retinopathy by modulating the homing of EPCs
inside the diseased retina.
Gianpaolo Zerbini
Figure 13. Homogeneous distribution of podocytes (cells responsible for the filtering selectivity of the renal
glomerulus evidenced with an antibody against the podocyte-specific antigen Synaptopodin) in the normal
glomerulus (left panel). In case of diabetic nephropathy, glomeruli are progressively invaded by large amounts of
extracellular matrix (nodules of Kimmestiel Wilson) progressive forcing the podocytes to die or to move toward the
outside edge (right panel).
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 βcells responsible of the pathogenesis of obesity,
the metabolic syndrome and type 2 diabetes. 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 in-
creased epicardial fat and intracardiac fat accumulation is a major factor involved in diabetes-induced 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.
Additional efforts are to be performed to establish
whether some of our novel metabolic biomarkers
which were generated in these studies may be
useful to predict the prognosis (all-cause, cardiovascular, cancer and hepatic-related mortality
rates) of patients with metabolic diseases.
Gianluca Perseghin
81
Research Units
Aging bone: mesenchimal stem cells (MSC) presence, gene expression
and endocrine milieu
The Unit is engaged in the effort to evaluate MSC
availability and differentiation potential, biomolecular signaling and endocrine milieu characterizing the
bone undergoing to fragility fractures. To these purposes, three lines of research are carried out.
1. The possibility to stimulate MSC differentiation
capacity directly in the tissue of interest would
open new therapeutic strategies in senile osteoporosis which is characterized by impaired
osteoblast function in skeletal sites, such as the
femural neck, which fragility induces the most
severe outcome. Along this line of thought, our
study demonstrated that a fraction of MSC is
present in bone, independently of donors’ age
or gender, and maintains the capacity to differentiate. Our study has also indicated that aged
donors derived osteoblasts had reduced osteocalcin expression, thus opening the view of
senescence-associated intrinsic osteoblast dysfunctions. This was associated to the altered
balance of Wnt effectors and targets expressed
in bone previously shown, that impairs MSC
commitment towards osteogenesis. The observed gene expression profile was consistent
with the major features of aging bone.
2. Aging is associated to a relative reduction of
GH stimulus on bone that might undergo to estrogen modulation. We have therefore characterized GH-Estrogen interplay in bone by
demonstrating that 17β-estradiol (E2) is able to
positively modulate the GH intracellular signaling
in human osteoblast-like cells via STAT5 phosphorylation. This effect was associated to an increase of GH receptor amount and to the ubiquitination of SOCS2, which is one of the negative
regulators of GH signaling. Our data suggest the
presence of a complex regulatory tissue-specific
action of E2 on tissue responsiveness to GH.
3. By collaborative efforts with the University of Edinburgh, the Unit has completed a wide study of
mutation screening in Paget disease that has
identified two different mutations. Further evaluation will be performed in the relatives. A joint
study with the Unit of Nephrology also started
with the aim to characterize risk factors and DXA
parameters of aortic calcifications.
Alessandro Rubinacci
Coagulation service & thrombosis research Unit
More about new oral anticoagulant drugs
Our group has been interested from a long time in
the evaluation of new oral anticoagulant drugs.
Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute
deep-vein thrombosis (DVT) and for continued
treatment, without the need for laboratory monitoring. We participated in an open-label, randomized,
event-driven, non inferiority study that compared
oral rivaroxaban alone (15 mg twice daily for 3
weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or
12 months in patients with acute, symptomatic
DVT. In parallel, we also took part in a double-blind,
randomized, event-driven superiority study that
compared rivaroxaban alone (20 mg once daily)
with placebo for an additional 6 or 12 months in
patients who had completed 6 to 12 months of
treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety
outcome was major bleeding or clinically relevant
nonmajor bleeding in the initial-treatment study and
major bleeding in the continued-treatment study.
The study of rivaroxaban for acute DVT included
3449 patients: 1731 given rivaroxaban and 1718
given enoxaparin plus a vitamin K antagonist. Rivaroxaban had non inferior efficacy with respect to
the primary outcome (36 events [2.1%], vs. 51
events with enoxaparin–vitamin K antagonist
[3.0%]; hazard ratio, 0.68; 95% confidence interval
[CI], 0.44 to 1.04; P<0.001). The principal safety
outcome occurred in 8.1% of the patients in each
group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and
594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo
[7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39;
P<0.001). Four patients in the rivaroxaban group
had nonfatal major bleeding (0.7%), versus none
in the placebo group (P = 0.11). Rivaroxaban offers
a simple, single-drug approach to the short-term
and continued treatment of venous thrombosis that
may improve the benefit-to-risk profile of anticoagulation.
Armando D’Angelo
Cardiodiabetes & core Lab
Atherosclerosis is a process that may affect different vascular beds. Neointimal hyperplasia seems
to be dependent on reduction in nitric oxide activity that determines endothelial dysfunction and oxidative stress. Since vascular beds of the heart and
peripheral circulation are affected in a similar way
by risk and genetic factors, atherosclerosis may initiate and develop at multiple sites simultaneously.
At genetic level we found a strong association between eNOS gene variants and type 2 diabetes
and intra-stent restenosis. In 2010, to better understand the role of eNOS variants in the development of type 2 diabetes mellitus, we evaluated a
cohort of normal subjects and we performed genotyping for eNOS variants. We found that these variants associate with an increased risk for glucose
intolerance and a new diagnosis of type 2 diabetes
after OGTT associated with insulin resistance. We
started the evaluation of new variants of ANP gene
in patients with mitral valve disease, coronary,
carotid and peripheral vascular disease and we initiated the characterization of the metabolic and en-
dothelial differences between coronary and carotid
atherosclerosis. Preliminary data suggested that
coronary atherosclerosis is characterized by decreased adiponectin levels, insulin resistence and
a more proatherogenetic profile while an increased
prothrombotic state and higher platelet activation
seem to be present in patients with carotid vasculopathy. These two different pathways will be evaluate on monocytes and EPCs from the two
populations in study. In addition, we found that a
reduced number of EPCs associate with an increase of intima media thickness of carotid arteries
in subjects carrying eNOS variants, suggesting an
early atherosclerosis in these subjects. Other fields
of research are the evaluation of new candidate
genes, the definition of the molecular mechanisms
involved in early endothelial activation and genes
expression for inflammation and thrombosis in endothelial progenitors cells and monocyte to understand the pathogenesis of CARDIO-DIABETES.
Lucilla D. Monti
Pediatric endocrinology research
Osteoporosis is regarded as a condition of the elderly, but it is now clear that it has its antecedents
during childhood and adolescence. A major role in
the development of osteoporosis is the bone mass
gain occurring during growth. The concerted action of bone-forming cells (osteoblasts), and boneresorbing 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
Figure 14. Total body
bone density of an
adolescent girl
83
Research Units
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 participating in a
study aimed to the identification of genetic markers of a rare disorder of glucose metabolism: Con-
genital Hyperinsulinism of Infancy (CHI). We established a National Registry for this disease, and we
enrolled and studied over 40 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 clinical 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 is currently ongoing, having recruited 1000 participants in over 30 diabetes outpatient clinics
throughout Italy, and is expected to end in July
2011. Results will be available in late 2011.
Along the same theme, a trial investigating the
measurement of blood glucose by a novel
non-invasive laser based technology is underway.
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. 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. After a preliminary pilot trial, we conducted a mutlicentre European clinical trial where we demonstrated
that FREMS is a safe and efficacious in the
treatment of painful diabetic neuropathy, with
the evidence of associated enhancement of local tissue microcirculation.
4. Within the Cardio-Metabolic and Clinical Trials
Unit (part of the Diabetes and Endocrinology
Unit) a large number of phase III and some
phase II clinical trials are conducted, with more
than 400 on follow up during the year 2010.
The main focus is on new drugs for type 2 diabetes, but some investigations are also devoted to new interventions in diabetic complications, cardiovascular diseases and nutrition.
Emanuele Bosi
Cardio-metabolic and clinical trials
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. In this light, in patients with
heart valve disease, we demonstrated a high
prevalence of DM2 associated with increased
ANP and FFA levels. In 2010 we concluded the
integrated project CARDIO-DIABETES between
GPs and Scientific Institutes of the Milan Area for
the prevention of type 2 diabetes mellitus in patients with cardiovascular disease and their first
degree relatives, in the light of the Cardio-cerebro-vascular projects of the Lombardia region.
We found that CAD patients have metabolic alterations that if not correctly diagnosed and treated,
could determine a worst cardiovascular outcome.
In addition, first degree relatives of CAD patients
have an a higher prevalence of impaired glucose
tolerance and type 2 diabetes mellitus and it is important to construct a specific program for early
prevention, diagnosis and treatment in this class
of subjects.
To confirm the role of a nutrition treatment through
chronic oral L-arginine administration in the amelioration of insulin resistance and endothelial dysfunction, we evaluate IGT patients with metabolic
syndrome. In these patients, oral L-arginine supplementation was administered for 18 months
with a follow-up period of about 1 year. L-arginine
was able to ameliorate glucose tolerance and to
reduce the total progression to type 2 diabetes
mellitus, with also a beneficial effect on insulin resistance. In this light, we created a food with low
glycemic index and L-arginine aggregated with an
85
innovative sonication process. A patent was filed
in October 2010.
The Cardio-Metabolic and Clinical Trials Unit is also involved in the largest and major world-wide
sponsored Clinical Trials for the prevention and
cure of DM2 and CAD.
Piermarco Piatti
Gynecology and infertility Unit
• The Unit aims to become a strategic reference
centre in the field of assisted reproduction,
combining clinical and scientific expertise
across different areas of infertility (i.e. endocrinology, endometriosis, andrology and oncology)
• The Unit collaborates with Laboraf and the University of Modena in the characterization of the
role of Anti-Mullerian Hormone as a prognostic
marker of fertility.
• The Unit remains primarily involved in both clinical and applied research with the final aim to increase pregnancy outcome in couples undergoing assisted reproductive technologies.
❍ Our team completed two multicentre randomised control clinical trials on the efficacy
of different novel molecules. The first focused
on a novel method for subcutaneous progesterone administration; the second tested the
role of co-treatment (r-FSH + r-LH) in the approach to “poor prognosis patients”.
❍ At present, we are the first Italian IVF unit conducting trials on nutraceuticals (i.e. inositol
and melatonin) in the reproductive field, with
the aim of ameliorating the outcome of both
patients with polycystic ovary syndrome and
poor prognosis patients.
• Cryopreservation of fertility in patients at risk of
premature ovarian failure, early menopause or
azoospermia. Open fields of studies are:
❍ Novel reproductive options for cancer patients.
❍ Ovulation induction protocols for young patients with severe endometriosis.
❍ Amelioration of technical procedures for cryopreservation of gametes and gonadal tissues
represent the most important experimental effort of the laboratory.
• Identification of new genomic parameters as well
as biomarkers critically involved in controlling embryo implantation after IVF.
❍ The non-classical HLA-G antigen and its functional polymorphisms in terms of differential
transcriptional expression and relationship with
tolerogenic properties of regulatory cells, and
microRNA signature. These studies are performed in women with a history of recurrent implantation failure undergoing IVF.
❍ Analysis of the molecular mechanisms governing the expression of HLA-G polymorphisms and the induction of tolerance will
provide us with new important tools for risk assessment of immune-related clinical IVF complications.
Massimo Candiani
Fetal-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 have started the recruitment 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 of this prospective study 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 compli-
cations. An additional group of women with type 1
diabetes, a disease of autoimmune etiopathogenesis, has been included.
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. Re-
cent 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 pathogen-
esis 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 insulinresistance. 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 late 2011 with new diagnostic criteria for GDM, introduced in May 2010.
Maria Teresa Castiglioni
Congenital Hypothyroidism (CH) pathogenesis is
still largely unknown, in particular for the forms associated with thyroid dysgenesis. In cooperation
with Milan University, we analyzed the role of the
Notch ligand Jagged1 in thyroid organogenesis:
we found that JAG1 gene inhibition directly impairs
thyroid development and can be responsible of
complex phenotypes in humans, including association of thyroid and cardiac malformations. We
continued also molecular studies focusing on
genes involved in iodide organification. New mutations of DUOX2 were identified: we are performing
functional studies and evaluating genotype-phenotype correlations.
The genetic basis of Congenital Hyperinsulinism
are not fully clarified. During our project funded by
MIUR in 2009 we potentiated the Italian Registry
Congenital Hyperinsulinism of Infancy with the aim
to contribute to advance the knowledge on the disease. To date, 40 families have been recruited. We
identified 13 mutations in ABCC8 and KCNJ11
genes (5 news mutations) and a novel mutation of
the HADH gene. In Prader Willi syndrome (PWS),
the most frequent syndromic obesity, the presence
of metabolic syndrome (MS) has not yet been es-
tablished. We performed a study to estimate the
frequency of MS: non-obese PWS showed low
frequency of MS and its components, while that
observed in obese PWS was very close to those
of obese controls, suggesting the crucial role of
obesity status.
Congenital Adrenal Hyperplasia (CAH) is a field of
application of less-invasive and more accurate
methods. We aim to determine salivary and urinary
steroid profile through LC-MS for diagnosis and follow-up of various forms of CAH. We are engaged
in some protocols on Turner syndrome that investigate the gonadal, thyroid and kidney function and
the psychological aspects of this condition. We are
studying patients with hypogonadotrophic hypogonadism from clinical and genetic perspective: in
two patients a mutation in candidate genes were
found. In patients with disorders of sex differentiation, characterized by atypical chromosomal, gonadic and anatomic development, we aim to
standardize pharmacologic tests execution and results interpretation in order to obtain a better diagnostic definition, together with genetic analysis.
Giovanna Weber
87
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) prevention of diabetes 2) technology in
diabetes 3) obesity in diabetic children. Our unit is
currently involved in a tertiary prevention study
sponsered by Diamyd. The study is a phase III, 3arm, randomized, double-blind, placebo-controlled, multicenter study, to investigate the impact
of diamyd on the progression of diabetes in patients newly diagnosed with type 1 diabetes mellitus. The primary objective is to evaluate the efficacy
of Diamyd compared to placebo in preserving endogenous insulin secretion as measured by Cpeptide. The secondary objective is to compare
diabetes status variables between Diamyd and
placebo before and after treatment, and to further
confirm the safety of Diamyd. Patients received 2
subcutaneous injections in a prime-and-boost regimen over a period of 30 days, followed by 2 additional single doses over a 9 month period.
Patients will be followed for a total of 30 months
with a blinded study period of 15 months and an
extension study period of 15 months.
More than 180 children treated with pump for continuous subcutaneous insulin infusion (CSII) are in
follow-up for many years and monitored for long
term results in term of HbA1c, acute complications, quality of life. Moreover we use continuous
glucose monitoring (CGMS) in children and adolescents and follow outpatients in the first combined application of CSII and CGMS. We are
comparing CSII and MDI in children < 6 yrs.
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.
We collaborate in Trialnet, primary and secondary
prevention study, (directed by Prof. Bosi) and with
Dr. Battaglia (DRI) in evaluating correlations between T-cell genotype and phenotype in children
affected by type 1 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
Figure 15. Preterm infant care
• Imaging: APICE OCT is an ongoing multi-center,
randomized trial evaluating the re-endothelization
of second generation (zotarolimus vs. everolimus)
drug-eluting stents by optimal coherence tomography (OCT).
• Complex Coronary Lesions: Outcomes following
drug eluting stent (DES) implantation vs. CABG in
unprotected left main coronary artery lesions
(ULMCA) at long term clinical follow up (5 years)
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). Recently 3 year otcome from SYNTAX have been
presented showing non inferiority of 1st generation DES vs CABG in major adverse cardiac and
cerebrovascular events in ULMCA setting. A new
randomized study, the EXCEL trial, will evaluate
the 2nd generation DES vs. CABG in ULMCA lesions in patients with a Syntaxscore less than 33.
• 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 (where 6 vs. 12 month dual antiplatelet
therapy is compared). EBC2 trial is comparing
simple vs. complex stenting approach in true bifurcation lesions after new generation DES. 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 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: the two devices with CE-mark, the balloon-expandable Edwards-Sapien valve and the
self-expanding CoreValve ReValving System, are
objective of observational trials and respectively,
the multi-center SOURCE registry is testing Edwards Sapien and ADVANCE is testing
CoreValve. Clinical and procedural data of both
devices are also collected in the OBSERVANT
trial: an Italian registry promoted by the Ministry of
Health. The outcomes of a percutaneous edgeto-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
Incremental prognostic value of inflammatory
markers on top of traditional risk factors in a
paired study of 878 STEMI and 878 controls in
three ethnic groups. We observed a statistically
significant difference whose clinical valu need further investigation. Conversely to prior observation
we also observed a wide overlap of levels of hsCRP among patients and controls. Furthermore
approximately 40% of patients in the very early
phase of STEMI have hsCRP levels below the 2.0
mg/dL threshold, thus challenging the currently
promoted preventive strategies. Conversely we
observed a subset of approx. 20% of STEMI patients who have circulating levels of IL-6 which are
5-10fold higher than normal. This observation is
not related to hother markers includind the
prospected infarct size. Subsequently we started
investigating the role of IL-6 in STEMI and its possible determinants.
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. Furthermore, activate
platelets induce the formation of temporary traps.
89
This phenomen appears reproducibily related
from the length of interaction, platelet number
and of the phagocytic capability of the neutrophils.
• Task 3 – Neutrophil/Platelet interaction in systemic inflammatory syndromes that could have a
vascular atherothrombotic components.
Cardiovascular rehabilitation and prevention
Newer approaches for monitoring patients during
the in-hospital cardiac rehabilitation.
We are employing standard commercial activity
and energy expenditure recording devices to evaluate Total Energy eXpenditure (TEx, Kcal/day) and
Active Energy eXpenditure (AEx represents total
Kcal/day used in activities >3 METS) as newer performance indicators for patients undergoing a resident cardiac rehabilitation program as an adjunct
or alternative to the standard six minutes walk test
(6MWT).
Domenico Cianflone
Ischaemic heart disease, heart failure and
echocardiography Unit
Our group is carrying out several lines of investigation in the 2 main fields of interest of the Unit: heart
failure and echocardiography.
are planning to investigate the potential therapeutic use of these cells in patients with end
stage heart failure.
Heart failure
Echocardiography
• 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 2010 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.
• Effects of beta-blockade administration in patients with biventricular heart failure – We are
starting a new study to evaluate the potential
detrimental effects of betablockade in patients
with bi-ventricular heart failure.
• Growth and differentiation of resident cardiac
stem cells – Aim of this project is the identification
and differentiation of resident cardiac stem cells
in patients with heart failure. In the near future we
• Mitral valve studies: several observational
prospective studies focusing on the pathogenesis, prognostic role and characterization of mitral
valve disease in patients with left ventricular dysfunction are in progress;
• Contrast Echocardiography: we are evaluating
the role of contrast enhanced echocardiography
in myocardial tissue characterization, aortic disease diagnosis, and its role during the thoracic
endovascular aortic repair procedures.
• 3D echocardiography: several trials regarding on
the additive value of 3D echocardiography compared to 2D echocardiography in the anatomical
definition of atrial septal defects, mitral valve disease and during percutaneous procedure are
ongoing.
• We are testing the role of lung ultrasound in the
follow up of patients with heart failure.
• We are about to create an “Ultrasound Cardiovascular Experimental Laboratory”, in which we
will develop: 1. Basic research on animal experiments to study novel diagnostic and therapeutic
targets for molecular contrast ultrasounds. 2. Development of the therapeutic approaches by
contrast ultrasound such as local drugs delivery
and monitoring of cell-based, particularly stem
cells therapy; 3. Clinical application of new generation of contrast molecular agents ie. for angiogenesis, inflammation and thrombosis.
Alberto Margonato
Organ protection in critically ill patients, Advanced
cardiac failure and mechanical supports Unit
Organ failure in critically ill patients is associated to
high morbidity and mortality. We are coordinating
large multicentre studies at the Italian level on numerous topics:
• treatment of refractory hypoxia in patients with or
without the H1N1 ARDS syndrome, in collaboration with the Italian ministry;
• 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: 1000 patients, double blind RCT);
• prevention of dialysis dependent acute renal failure 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: RCTs);
• safety and efficacy of desmopressin, factor XIII,
protein C zymogen and protein C activated in patients experiencing excessive bleeding or with
sepsis;
• anesthesiological challenges of the unfit patients,
ideal candidate to transfemoral artery aortic valve
implantation and of arrhythmia ablation;
• 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);
• With approximately 30 original papers and metaanalyses published on the above described topics in pubmed indexed journals yearly we’re the
most prolific Italian group publishing in anesthesia and intensive care journals and one of the
most prolific at the international level.
We are also editing an international journal “HSR
proceedings in Intensive Care and Cardiovascular
Anesthesia”, freely available on www.hsrproceedings.it and we organized the first international consensus conference in “reducing mortality in cardiac
anesthesia and intensive care”.
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. Mid- and long-term results of the procedures on tricuspid valve have been evaluated
and a randomized study has been developed to
establish indications for the correction of tricuspid
pathology. Surgical approaches alternative to
transplant have been investigated as therapies for
the last stage heart-failure. Surgical repair of the
mitral valve have been deeply investigated in the
context of dilatative cardiomyopathy, even associated to atrial fibrillation ablation and resynchronization therapy.
Heart valve disease
Innovative techniques to repair mitral and aortic
valve have been systematically evaluated. New im-
aging modalities have been applied and correlated
to the operative findings. Experimental adjustable
devices for mitral valve repair have been evaluated
in clinical studies and new adjustable devices, implantable with mininvasive approaches, have been
designed.
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. Morphologic and
structural changes of the cardiomyocytes in atrial
91
fibrillation have been investigated. Active contribution have been given to prepare the ESC guidelines for the treatment of atrial fibrillation.
Transcatheter valve therapy
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.
A multidisciplinary program for transcatheter aortic
Ottavio Alfieri
Study and treatment of aortic disease Unit
In 2010 the Vascular surgery Unit of the IRCCS
Ospedale San Raffaele has been involved in several clinical research studies regarding vascular
pathology, in particular on the treatment of aortic
disease:
• Zenith(R) Type B aortic dissection endovascular
system clinical study Protocol.
• Physician initiated multi-center Belgian-ItalianDutch tRial investigating Abbott(R) Vascular Iliac
Stents In the treatment of TASC A, B, C, & D iliac
lesions(BRAVISSIMO trial).
• Study of PERipheral Bypass GraFting: ProspECTive Evaluation of Fusion Peripheral Graft(TM) for
Above Knee Targets Clinical Study.
• the BIOVART project: in vitro generation of autologous vascular graft using bioengineering techniques. The study aims at recreate an
autologous vascular graft using a decellularized
human artery as a scaffold and patient’s marrow
stem cells.
• SAFROS: Patient Safety in Robotic Surgery. Aim
of the study is to define patient safety metrics, to
develop methods that abide by safety requirements and to demonstrate that a properly controlled robotic surgery can improve the level of
patient’s safety.
• Effect of tight fasting glycemic control using in-
sulin on the incidence of restenosis in patients
with type 2 diabetes submitted to peripheral angioplasty.
• Cerebrospinal fluid levels of HMGB-1 and the risk
of spinal cord ischemia in patients submitted to
open surgical or endovascular repair of the thoracic and thoracoabdominal aorta.
• Autologous transplantation of CD133+ bone
marrow stem cells for the treatment of critical ischemia of the lower limbs.
• A clinical study of safety and performance of the
Treovance(TM) stent-graft for patients with infrarenal abdominal aortic aneurysms.
• Innovation, a multicenter, open label, prospective, non-randomized study of INCRAFT(TM)
stent-graft in subjects with abdominal aortic
aneurysms.
• Zenith TX2(R) Low Profile TAA Endovascular Graft
Clinical Study.
• Study on the feasibility of treatment of below the
knee arterial lesions with new endovascular tools.
During 2010 the Vascular Surgery Unit has also
published 19 papers on peer reviewed journals, regarding the treatment of aortic aneurysmal disease
and other aspects of vascular pathology.
Roberto Chiesa
Vision first Unit
Medical Retina
CR: Several multicentre clinical trials for new therapeutic options with intravitreal compounds (antiVEGF agents or steroids) for Age-Related Macular
Degeneration (AMD), Diabetic Retinopathy (DR)
and Retinal Vein Occlusion.
Analyses of fundus autofluorescence responses in
chorioretinal dystrophies.
BR: Evaluation of the behaviour of Endothelial Progenitor Cells in DR and AMD in collaboration with
the Diabetes Complication Unit.
Study of the correlation between fundus autofluo-
rescence responses and morpho-functional characteristics.
Surgical Retina
CR: Evaluation of new therapeutic options: Enzymatic Vitreolysis with Autologous Plasmin.
BR: Set up of a Vitreous Biobank and investigation
of Endogenous Vitreal Ouabain in retinal diseases
in collaboration with Genomics of Renal Diseases
and Hypertension Unit.
Pediatric Ophthalmology
CR: Multicentre clinical trial to test efficacy and tol-
erance of Azytromicin vs Tobramicin in pediatric purulent bacterial conjunctivitis.
Neuro-Ophthalmology
CR: MRI evaluation of structural, functional brain
damage and cortical plasticity in Leber’s and Autosomal Dominant Hereditary Optic Neuropathies;
in Neuromyelitis Optica and Recurrent Idiopathic
Optic Neuritis, in collaboration with Neuroradiology
and Neuroimaging Research Units.
Role of MRI parameters to assess Thyroid-Associated Orbitopathy activity, in collaboration with Neuroradiology Unit
Evaluation of multisensory cortical integration in
Hereditary Cone Dystrophy by functional MRI and
DTI, in collaboration with Neuroradiology 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 operator reproducibility of nerve fiber layer thickness and topographic measurement of the optic nerve among
different Spectral Domain OCT instruments.
Evaluation Central Corneal Thickness reproducibility using new Spectral Domain OCT.
Evaluation of the role of retinal ganglion cells in the
development of epiretinal membrane using
SDOCT.
Ocular Immunology and Uveitis
CR: Evaluation of new biologic agents for the treatment of intraocular inflammation.
Evaluation of efficacy of systemic immunosuppressive therapy in RCT.
Analysis of pediatric uveitis associated with Juvenile Idiopathic Arthitis (JIA): treatment with anti-CD
20 monoclonal antibodies (Rituximab).
Ocular Oncology
CR: Evaluation of treatment with intralesional Rituximab in conjunctival lymphoma and Gamma
Knife Radiosurgery for treatment of choroidal
melanoma.
Glaucoma
CR: Clinical studies (multicentric and single center)
to test new medical and surgical therapeutic options in glaucoma management.
Francesco Bandello
Figure 16. The new OCT instruments allow histologic exam of the retina in vivo; in this case the vitreomacular
traction is perfectly detected.
93
Pellegrini, N; Valtuena, S; Ardigo, D; Brighenti, F; Franzini, L; Del Rio, D; Scazzina, F; Piatti, PM;
Zavaroni I. Intake of the plant lignans matairesinol, secoisolariciresinol, pinoresinol, and lariciresinol in
relation to vascular inflammation and endothelial dysfunction in middle age-elderly men and postmenopausal women living in Northern Italy. Nutr. Metab. Cardiovasc. Dis.: 2010; 20(1): 64-71 – Article
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Anderwald, C; Stadler, M; Golay, A; Krebs, M; Petrie, J; Luger, A; RISC Investigators. Impact of
family history on relations between insulin resistance, LDL cholesterol and carotid IMT in healthy
adults. Heart: 2010; 96(15): 1191-1200 – Article
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Kozakova, M; Palombo, C; Morizzo, C; Nolan, JJ; Konrad, T; Balkau, B; RISC Investigators. Effect
of sedentary behaviour and vigorous physical activity on segment-specific carotid wall thickness and
its progression in a healthy population. Eur. Heart J.: 2010; 31(12): 1511-1519 – Article
IF 2009: 9,800
Monti, LD; Lucotti, PCG; Setola, E; Rossodivita, A; Pala, MG; Galluccio, E; La Canna, G; Castiglioni, A; Cannoletta, M; Meloni, C; Zavaroni, I; Bosi, E; Alfieri, O; Piatti, PM. Effects of chronic elevation of atrial natriuretic peptide and free fatty acid levels in the induction of type 2 diabetes
mellitus and insulin resistance in patients with mitral valve disease. Nutr. Metab. Cardiovasc. Dis.:
2010; Article in press
IF 2009: 3,517
SID Gruppo di Studio Diabete e Aterosclerosi: Piatti, PM; Avogaro, A; Anfossi, G; Ardigò, D; Vigili
de Kreutzemberg, S; Inchiostro, S; Rivellese, AA; Trovati, M; Zambon, S; Zavaroni, I; AMD: Arcangeli, A; Gentile, S; ANMCO: Lettino, M; Mafrici, A; Uguccioni, M; ARCA: Bianchi, A; Cavallaro, V;
Monducci, I; SIC: Cadeddu, C; De Luca, G; SISA: Manzato, E. Consensus: Screening e terapia della cardiopatia ischemica nel paziente diabetico. Il Diabete: 2010; 22(4): 165-213
Perseghin, G. The role of non-alcoholic fatty liver disease in cardiovascular disease. Dig. Dis.:
2010; 28(1): 210 - 213 - Review
IF 2009: 1,487
Urbanek, K; Cabral-Da-Silva, MC; Ide-Iwata, N; Maestroni, S; Delucchi, F; Zheng, H; Ferreira-Martins, J; Ogórek, B; D’Amario, D; Bauer, M; Zerbini, G; Rota, M; Hosoda, T; Liao, R; Anversa, P; Kajstura, J; Leri, A. Inhibition of Notch1-dependent cardiomyogenesis leads to a dilated myopathy in
the neonatal heart. Circ. Res.: 2010; 107(3): 429-441 - Article
IF 2009: 9,214
European Association for Percutaneous Cardiovascular, Interventions; Wijns, W; Kolh, P; Danchin,
N; Di Mario, C; Falk, V; Folliguet, T; Garg, S; Huber, K; James, S; Knuuti, J; Lopez-Sendon, J; Marco, J; Menicanti, L; Ostojic, M; Piepoli, MF; Pirlet, C; Pomar, JL; Reifart, N; Ribichini, FL; Schalij, MJ;
Sergeant, P; Serruys, PW; Silber, S; Sousa Uva, M; Taggart, D; ESC Committee for Practice Guidelines; Vahanian, A; Auricchio, A; Bax, J; Ceconi, C; Dean, V; Filippatos, G; Funck-Brentano, C;
Hobbs, R; Kearney, P; McDonagh, T; Popescu, BA; Reiner, Z; Sechtem, U; Sirnes, PA; Tendera, M;
Vardas, PE; Widimsky, P; EACTS Clinical Guidelines Committee; Kolh, P; Alfieri, O; Dunning, J; Elia,
S; Kappetein, P; Lockowandt, U; Sarris, G; Vouhe, P; Kearney, P; von Segesser, L; Agewall, S; Aladashvili, A; Alexopoulos, D; Antunes, MJ; Atalar, E; Brutel de la Riviere, A; Doganov, A; Eha, J; Fajadet, J; Ferreira, R; Garot, J; Halcox, J; Hasin, Y; Janssens, S; Kervinen, K; Laufer, G; Legrand, V;
Nashef, SA; Neumann, FJ; Niemela, K; Nihoyannopoulos, P; Noc, M; Piek, JJ; Pirk, J; Rozenman,
Y; Sabate, M; Starc, R; Thielmann, M; Wheatley, DJ; Windecker, S; Zembala, M. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society
of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart
J.: 2010; 31(20): 2501-2555 - Article
IF 2009: 9,800
European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery; Camm,
AJ; Kirchhof, P; Lip, GY; Schotten, U; Savelieva, I; Ernst, S; Van Gelder, IC; Al-Attar, N; Hindricks, G;
Prendergast, B; Heidbuchel, H; Alfieri, O; Angelini, A; Atar, D; Colonna, P; De Caterina, R; De Sutter, J; Goette, A; Gorenek, B; Heldal, M; Hohloser, SH; Kolh, P; Le Heuzey, JY; Ponikowski, P; Rutten, FH. Guidelines for the management of atrial fibrillation: the Task Force for the Management of
Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J.: 2010; 31(19): 23692429 - Article
IF 2009: 9,800
Benussi, S; Galanti, A; Zerbi, V; Privitera, YA; Iafelice, I and Alfieri, O. Electrophysiologic efficacy of irrigated bipolar radiofrequency in the clinical setting. J. Thorac. Cardiovasc. Surg.: 2010;
139(5): 1131 - 1136 - Article
IF 2009: 3,063
Tamburino, C; Ussia, GP; Maisano, F; Capodanno, D; La Canna, G; Scandura, S; Colombo, A;
Giacomini, A; Michev, I; Mangiafico, S; Cammalleri, V; Barbanti, M; Alfieri, O. Percutaneous mitral
valve repair with the MitraClip system: Acute results from a real world setting. Eur. Heart J.: 2010;
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Alfieri, O; De Bonis, M. Mitral valve repair for functional mitral regurgitation: Is annuloplasty alone
enough? Curr. Opin. Cardiol.: 2010; 25(2): 114 - 118 - Review
IF 2009: 2,660
Lapenna, E; De Bonis, M; Verzini, A; La Canna, G; Ferrara, D; Calabrese, MC; Taramasso, M;
Alfieri, O. The clover technique for the treatment of complex tricuspid valve insufficiency: midterm
clinical and echocardiographic results in 66 patients. Eur. J. Cardio-Thorac. Surg.: 2010; 37(6):
1297 - 1303 - Article
IF 2009: 2,397
Natale, A; Raviele, A; Al-Ahmad, A; Alfieri, O; Aliot, E; Almendral, J; Breithardt, G; Brugada, J;
Calkins, H; Callans, D; Cappato, R; Camm, JA; Della Bella, P; Guiraudon, GM; HaIssaguerre, M;
Hindricks, G; Ho, SY; Kuck, KH; Marchlinski, F; Packer, DL; Prystowsky, EN; Reddy, VY; Ruskin, JN;
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Venice chart international consensus document on ventricular tachycardia/ventricular fibrillation ablation: Special article. J. Cardiovasc. Electrophysiol.: 2010; 21(3): 339 - 379 - Review
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Sharp, ASP; Michev, I; Maisano, F; Taramasso, M; Godino, C; Latib, A; Denti, P; Dorigo, E;
Giacomini, A; Iaci, G; Manca, M; Ielasi, A; Montorfano, M; Alfieri, O and Colombo, A. A new
technique for vascular access management in transcatheter aortic valve implantation. Catheter. Cardiovasc. Interv.: 2010; 75(5): 784 - 793 - Article
IF 2009: 2,363
95
97
DIVISION
OF
REGENERATIVE
MEDICINE,
STEM CELLS AND GENE THERAPY
Director:
Giulio Cossu
Associate Directors:
Fabio Ciceri, Luigi Naldini*
Research Units
Skeletal muscle development and therapy Unit –––––––––––––––––––––––––––––––––––––––– 105
HEAD OF UNIT: Giulio Cossu, ERC Advanced Grant
RESEARCHER: Graziella Messina
POST-DOCTORAL FELLOWS: Arianna Dellavalle, Hoshia Hidetoshi, Anna Pistocchi, Francesco
Saverio Tedesco
PHD STUDENTS: Sara Benedetti, Ornella Cappellari, Giovanni Maroli, Simona Rolandi-Maciotta,
Giuliana Rossi
TECHNICIANS: Stefania Antonini, Chiara Bonfanti, Diego Covarello (till May 2010), Anna Innocenzi,
Stefania Monteverde, Laura Perani, Rossana Tonlorenzi
Functional genetics of muscle regeneration ––––––––––––––––––––––––––––––––––––– 106
GROUP LEADER: Silvia Brunelli
POST-DOCTORAL FELLOWS: Stephanie François, Patrizia Pessina, Thierry Touvier, Paola
Zordan
PHD STUDENTS: Emanuele Azzoni, Valentina Conti
Neural stem cell biology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 106
GROUP LEADER: Rossella Galli
PHD STUDENTS: Daniela Corno**, Katayoun Hemmesi**, Laura Magri**, Stefania Mazzoleni**
Angiogenesis and tumor targeting Unit –––––––––––––––––––––––––––––––––––––––––––––––––– 107
GROUP LEADER: Michele De Palma, ERC Starting Grant
POST-DOCTORAL FELLOWS: Roberta Mazzieri, Ferdinando Pucci
PHD STUDENTS: Daniela Biziato**, Mario Leonardo Squadrito**
TECHNICIANS: Davide Moi, Anna Ranghetti
99
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY
Research Units/Clinical Research Units
Autoimmunity & vascular inflammation Unit –––––––––––––––––––––––––––––––––––––––––––– 108
HEAD OF UNIT: Angelo A. Manfredi*
POST-DOCTORAL FELLOWS: Valentina Canti, Norma Maugeri (from April 2010)
PHD STUDENTS: Lidia Bosurgi**, Alessandra Castiglioni**, Lucia Cottone**
TECHNICIAN: Annalisa Capobianco
Innate immunity and tissue remodelling –––––––––––––––––––––––––––––––––––––––––– 109
GROUP LEADER: Patrizia Rovere-Querini
POST-DOCTORAL FELLOWS: Gianfranca Corna, Elena Rigamonti
PHD STUDENTS: Lara Campana**, Michela Vezzoli**
TECHNICIAN: Antonella Monno
Cellular pharmacology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 110
HEAD OF UNIT: Emilio Clementi
POST-DOCTORAL FELLOW: Laura Bizzozero
PHD STUDENTS: Emma Assi, Denise Cazzato
FELLOWS: Nicoletta Cordani, Viviana Pisa
TECHNICIAN: Clara Sciorati
Experimental hematology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 111
HEAD OF UNIT: Chiara Bonini
RESEARCHER: Attilio Bondanza
POST-DOCTORAL FELLOWS: Elena Provasi**, Luca Vago**
PHD STUDENTS: Monica Casucci**, Nicoletta Cieri**, Maddalena Noviello**, Giacomo Oliveira**
FELLOW: Maria Rosaria Carbone
TECHNICIANS: Barbara Camisa, Zulma Magnani
Gene expression and muscular dystrophy Unit (Dulbecco Telethon Institute) ––– 111
GROUP LEADER: Davide Gabellini, ERC Starting Grant
POST-DOCTORAL FELLOWS: Sergia Bortolanza, Cristina Godio, Mariaelena Pistoni, Alexandros
Xynos
PHD STUDENTS: Daphne Cabianca**, Valentina Casà**, Claudia Huichalaf**, Marie Victoire
Neguembor**
Molecular and functional immunogenetics Unit ––––––––––––––––––––––––––––––––––––––– 112
HEAD OF UNIT: Katharina Fleischhauer
PHD STUDENTS: Pietro Crivello, Federico Sizzano, Cristina Toffalori
FELLOW: Cinzia Pultrone
TECHNICIAN: Laura Zito
Hematology and hematopoietic stem cell transplantation Unit ––––––––––––––––––––– 113
PHYSICIANS: Andrea Assanelli, Jacopo Peccatori
RESIDENTS: Alessandra Forcina, Raffaella Greco, Sara Mastaglio
POST-DOCTORAL FELLOWS: Daniela Clerici, Maria Teresa Lupo Stanghellini
STUDY COORDINATOR: Stefania Trinca
DATA MANAGER: Anna Sparano
Clinical Research Units/Research Units, HSR-TIGET
Immunohematology and transfusion medicine Unit ––––––––––––––––––––––––––––––––––– 113
HEAD OF UNIT: Silvano Rossini
RESEARCHERS: Laura Bellio, Oriana Perini
FELLOW: Antonio Scavo
PSIEP - Strategic Program of Pediatric Immunohematology –––––––––––––––––––––––– 114
HEAD OF UNIT: Maria Grazia Roncarolo*
PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Sarah Marktel
RESIDENT: Sara Napolitano
HSR-TIGET
The San Raffaele Telethon Institute
for Gene Therapy
Director:
Luigi Naldini*
Research Units
Gene transfer technologies and new gene therapy strategies Unit–––––––––––––––– 116
HEAD OF UNIT: Luigi Naldini*, ERC Advanced Grant
POST-DOCTORAL FELLOWS: Mario Amendola (till May 2010), 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 ––––––––––––– 116
GROUP LEADER: Angela Gritti
POST-DOCTORAL FELLOWS: Tiziano Di Tomaso (from August 2010)
PHD STUDENTS: Chiara Cavazzin, Annalisa Lattanzi, Margherita Neri**, Sara Santambrogio**
FELLOW: Beatriz Alcalà-Franco (till July 2010)
TECHNICIAN: Claudio Maderna
Hematopoietic stem cell gene therapy for lysosomal storage disorders –– 117
GROUP LEADER: Alessandra Biffi
POST-DOCTORAL FELLOWS: Alessia Capotondo, Ilaria Visigalli
PHD STUDENTS: Stefania Delai, Silvia Ungari**
FELLOW: Rita Milazzo
TECHNICIAN: Tiziana Plati
101
Research Units, HSR-TIGET
Safety of gene therapy and insertional mutagenesis –––––––––––––––––––––––––– 118
GROUP LEADER: Eugenio Montini
PHD STUDENTS: Daniela Cesana**, Marco Ranzani**
FELLOW: Jacopo Sgualdino
TECHNICIANS: Fabrizio Benedicenti, Pierangela Gallina, Samanta Oldoni (till April 2010)
BIOINFORMATICIANS: Stefania Merella, Enrico Rubagotti (till April 2010)
Gene transfer into stem cells Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 118
HEAD OF UNIT: Giuliana Ferrari*
POST-DOCTORAL FELLOW: Maria Rosa Lidonnici**
PHD STUDENT: Rossella Ierardi
TECHNICIANS: Giacomo Mandelli, Claudia Rossi, Francesca Tiboni
Immunological tolerance Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 119
POST-DOCTORAL FELLOWS: Andrea Annoni, Georgia Fousteri, Kevin Goudy
PHD STUDENT: Mahzad Akbarpour, Maura Rossetti
TECHNICIANS: Grazia Andolfi, Claudia Sartirana, Eleonora Tresoldi
From FOXP3 mutation to IPEX syndrome––––––––––––––––––––––––––––––––––––––––– 119
GROUP LEADER: Rosa Bacchetta
RESEARCHER: Barbarella Lucarelli
POST-DOCTORAL FELLOWS: Didem Aydin, Laura Passerini
PHD STUDENT: Sara Di Nunzio
FELLOW: Eva Rossi Mel
Tolerogenic dendritic cells –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 120
GROUP LEADER: Silvia Gregori
PHD STUDENT: Giada Amodio, Chiara Magnani
FELLOWS: Grazia Locafaro, Matteo Villa
TECHNICIAN: Daniela Tomasoni
Pathogenesis and therapy of ADA-SCID Unit ––––––––––––––––––––––––––––––––––––––––––– 120
HEAD OF UNIT: Alessandro Aiuti
POST-DOCTORAL FELLOWS: Luca Biasco, Aisha Vanessa Sauer
PHD STUDENTS: Immacolata Brigida, Nicola Carriglio
TECHNICIANS: Francesca Dionisio, Stefania Giannelli, Raisa Jofra Hernandez
Gene therapy for WASP/Omenn––––––––––––––––––––––––––––––––––––––––––––––––––––– 121
GROUP LEADER: Anna Villa
POST-DOCTORAL FELLOWS: Marita Bosticardo, Renata Ilde Mazzucchelli, Samantha
Scaramuzza
PHD STUDENTS: Maria Carmina Castiello, Marco Catucci, Michela Locci
TECHNICIANS: Elena Caldana, Elena Draghici
PCRU - Pediatric Clinical Research Unit ––––––––––––––––––––––––––––––––––––––––––––––––– 122
COORDINATOR: Alessandro Aiuti
PROJECT LEADERS: Alessandro Aiuti (ADA-SCID), Maria Grazia Roncarolo* (WAS),
Maria Sessa and Alessandra Biffi (MLD)
RESIDENTS: Federica Barzaghi, Costanza Evangelio, Francesca Ferrua, Valentina Finizio, Marco
Fossati, Marta Frittoli
FELLOW: Laura Lorioli
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Flavia Bondardo
RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi
103
Mission and vision - 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.
The Division maintains 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. Recruitment in areas such as hematopoietic stem cell biology and translational medicine should complement the existing plan and increase the chance of achieving the ambitious goals of
this plan.
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 is a multidisciplinary 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, directed by Giulio Cossu. The third pillar is represented by the clinical HSC Transplantation (HSCT) Unit, directed by F. Ciceri, that 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 are being and 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: 1) the pioneering of successful gene therapy trials of hematopoietic stem cell (HSC) therapy and of
adoptive cancer immunotherapy. Of special relevance is the start of phase I/II clinical trials in Duchenne
Muscular dystrophy with heterologous stem cells, Metachromatic leukodystrophy and Wiskott Aldrich
Syndrome with autologous, genetically corrected HSC (all these trials are “first in man”); 2) the development and validation of new gene transfer technologies; 3) the identification and characterization of new
stem cells, innate effector and immune regulatory 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.
Training opportunies - PhD programs, post-doctoral and resident fellowships.
Research Units
Skeletal muscle development and therapy Unit
Physiopathology of skeletal muscle development
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 transplantationin pediatric Duchenne patients: a phase
I/II clinical trial started on March 2011, while a preliminary trial to validate outcome measures in these
patients started on June 2009 and was completed
in July 2010. Future protocols foresee autologous
cell correction by either lentiviral vectors or human
artificial chromosomes (HAC) respectively expressing either 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). Other experiments
address the origin of mesoangioblasts during fetal
muscle histogenesis, their lineage relationship with
skeletal myoblasts and their fate using genetic lineage tracing. Results indicated that pericytes give
rise to skeletal muscle fibers and to satellite cells
during unperturbed post-natal development of the
mouse, although this contribution increases upon
muscle regeneration or in muscular dystrophy. On
the other hand, committed myoblasts can be reprogrammed to a pericyte fate by endothelium-derived signaling molecules, suggesting competition
between endothelium and muscle fibers in recruiting mesoderm progenitors to their developmental
fate.
Giulio Cossu
Figure 17. Transverse section of the Tibialis anterior of a dystrophic (dysferlinopathic) mouse, transplanted with
LacZ labeled mesoangioblasts (blue).
105
Research Units
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.
Following muscle injury necdin null mice showed a
significant defect in muscle healing while mice overexpressing necdin showed significantly increased
myofiber regeneration. We elucidated the role of
necdin in muscle showing that it accelerates differentiation and has an antiapoptotic activity (Deponti et al. JBC, 2007). We have also shown that
necdin is selectively expressed in the atrophic muscles of cachectic mice and gastric tumour patients
(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 (Sciorati et al., JCS, 2009; Pessina et al,
2010). Furthermore we were able to isolate a novel
protein that interacts with Necdin, CCAR1. In particular Necdin regulates CCAR1 protein degradation by promoting its ubiquitination and processing
through the proteasome (François et al, in preparation), thus inhibiting CCAR1 proaboptotic activity.
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, inhibit cell death
and muscles of α-Sarcoglycan 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 (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 various lineage, including ematopoietic, smooth and skeletal muscle
and contribute to muscle regeneration following
acute damage. We are studying this process in relation to cells of the innate immune system and to
molecules that promote stem cells mobilization and
self-renewal, such as nitric oxide.
Silvia Brunelli
Neural stem cell biology
Epidermal growth factor (EGF) receptor (-R) is one
of the most relevant molecular mediators of
glioblastoma multiforme (GBM). We demonstrated that EGFR expression in GBM identifies distinct classes of tumor-initiating cells (TICs) coexisting within the same tumor and each endowed
with different tumorigenic potential and specific
molecular phenotype. EGFR-expressing cells respond to tyrosine kinase inhibitors (TKIs), whereas
EGFRneg TICs do not. Thus, effective therapies
against GBM should also consider TKI-nonresponder EGFRneg TICs. To identify potential therapeutic targets in EGFRneg TICs, computationalbased selection of gene expression data has
been combined with the functional validation of
candidate genes by RNAi.
Medulloblastoma (MB) represents the most frequent pediatric brain tumor. To identify novel molecular targets involved in MB, we performed
functional and molecular comparisons between
distinct hindbrain neural stem cells (NSC) and MB
cancer stem cells (CSCs). This approach led us
to the identification of novel potentially relevant
mediators of MB. The selected genes have been
exploited to define NSC- and CSC-associated
gene signatures, which, by correlating the expression of specific gene(s) to patient outcome, frequency of disease relapse and response to therapy, might help implementing MB patient stratification and individualized treatments.
Tuberous sclerosis complex (TSC) is a dominantly
inherited disease with high penetrance, mostly affecting children. Brain involvement is invariably
present and is associated with severe clinical
manifestations. To date, medical treatment is
solely symptomatic. Thus, the identification of alternative molecular targets for TSC is urgent. We
recently generated a novel TSC mouse model, by
deleting Tsc1 selectively in neural stem cells
(NSCs). Mutant mice recapitulated several TSC
neuropathological and clinical features, as cortical
abnormalities and epilepsy. Mutant NSCs in vitro
showed reduced proliferation and abnormal neuronal differentiation. When transcriptionally profiled, mutant NSCs overexpressed many genes,
which are also detected in TSC lesions, suggesting a close relationship between the two entities.
Rossella Galli
Figure 18. Neurons obtained from neural stem cells isolated from the cortex at embryonic day 16.5
Angiogenesis and tumor targeting Unit
Macrophages and angiopoietin-2 in tumor angiogenesis and progression
Increasing data indicate that tumor-infiltrating
myeloid cells support tumor angiogenesis by regulating multiple proangiogenic pathways. We previously identified a subset of tumor-associated
macrophages that are required for tumor angiogenesis - the Tie2-expressing macrophages
(TEMs). TEM elimination from tumor-bearing mice
blunts tumor angiogenesis without affecting the recruitment of other myeloid subsets to the tumors.
Of note, TEMs’ gene expression signature is consistent with their enhanced proangiogenic and tissue-remodelling activity. Interestingly, these cells
express a number of proangiogenic factors other
than VEGF (e.g., SDF1), suggesting that they may
promote tumor angiogenesis in a VEGF-independent manner. TEMs, like endothelial cells (ECs), express the ANG receptor TIE2 and respond to
ANG2 stimulation in vitro. We then asked whether
ANG2, which is secreted by angiogenic tumor
blood vessels, could regulate the activity of TEMs
in mouse tumor models, MMTV-PyMT breast tu-
mor-prone mice. To this aim, we either neutralized
ANG2 pharmacologically or knocked-down the
TIE2 receptor specifically in TEMs by using a novel,
conditional gene knock-down vector platform. We
found that ANG2 blockade regresses the tumor
vasculature and inhibits the progression of latestage, metastatic MMTV-PyMT mammary carcinomas and RIP1-Tag2 pancreatic insulinomas. ANG2
blockade did not inhibit the recruitment of TEMs to
the tumors, but impeded (1) their upregulation of
Tie2; (2) association with blood vessels; and (3)
ability to restore angiogenesis in the tumors. Remarkably, conditional Tie2 gene knock-down in
TEMs was sufficient to decrease tumor angiogenesis. Our findings support a model wherein the
ANG2-TIE2 axis mediates cell-to-cell interactions
between TEMs and ECs that are important for tumor angiogenesis and can be targeted to induce
effective antitumor responses (Mazzieri et al., Cancer Cell Apr. 2011).
Michele De Palma
107
Research Units
Figure 19. Immunostaining of
NG2 (pericytes, green) and
CD31 (vascular endothelial
cells, red) of MMTV-PyMT
mammary tumors. The top part
of the image is from a tumor
treated with an ANG2neutralizing antibody, whereas
the bottom part of the image is
from an untreated tumor. Note
several NG2-positive pericyte
sheets lacking internal
endothelial cell lining after
ANG2 blockade, which
indicates regression of
established tumor blood
vessels. The image shows
three-dimensional rendering of
the confocal z-stacks, after
superimposition of multiple
confocal planes. From Mazzieri
et al., Cancer Cell: 2011;
19(4): 512–526. Cover image
by Cesare Covino (ALEMBIC,
San Raffaele Scientific
Institute).
Inflammation comprises the homeostatic response
to threats to tissue integrity, sterile injuries and infection. As such, inflammation has the potential to
eradicate invading pathogens and to repair damaged tissues. However, it may be deleterious, with
persistent inflammatory damage and degeneration.
The pattern of cell death and the characteristics of
cell stress in situ shapes several features of infiltrating leukocytes and antigen presenting cells that
actually dispose of cell remnants. Defects in the
initiation and execution steps of cell death such as
in the clearance of cell debris, mitochondrial damages and activation of autophagic pathways are involved in the origin of systemic autoimmune
diseases, in which the deregulated response to
cell stress/death behaves both as an initiator and
an amplifying circuit, contributing to the specific
clinical features of each disease. 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 and in general of the environmental cues
that transform regenerating cells in a trigger for selfsustaining autoimmune responses.
Angelo A. Manfredi
Figure 20. Interaction between activated human platelets (red) and neutrophils challenged with recombinant IL-8.
Nuclei are counterstained with Hoechst (blue color). Maugeri et al., unpublished
Macrophages play a dual role in damaged tissues: they enhance local injury, through their effectors functions, and they favour remodeling and
repair. The identification of the molecular code by
which macrophages shape the tissue response
to various stressful events, which can be partially
mimicked or tampered with, will provide novel
strategies for the treatment of various immunemediated 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 injuries of the peritoneum, as
a consequence of benign (endometriosis) and
malignant (ovary carcinoma) ectopic cellular
growth. Moreover, we are interested in the role of
innate immune responses in shaping the interaction between the mother and the developing embryo. We specifically focus on the cross-talk between macrophages and stem/precursor cells in
these models. We found that stem cells behave
both as immune modulated substrates and as
active modulators of the ongoing immune response: specifically, we are actively investigating
the molecular pathways by which the two cell
populations influence and reciprocally control migration, survival and differentiation, as well as their
function at sites of acute self-limiting, active remodeling or persistent, self-sustaining inflammation.
Patrizia Rovere-Querini
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Research Units
Figure 21. Vessel associated stem cells (mesoangioblasts, green color) efficiently differentiate into polynucleated
myofibers in the presence of IL-10 secreting macrophages (red color).
Cellular pharmacology Unit
Nitric oxide, mitochondria, and a pharmacological therapy for muscular
dystrophy
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) activity with nitric
oxide (NO release). We used both a novel NONSAIDs (NCX 320, nitroibuprofen) and the combination of ibuprofen and the NO donor isosrbide
dinitrate. Two murine models for muscular dystrophies (α-sarcoglycan null and mdx mice) showed
significant amelioration of the morphological, biochemical and functional phenotype in the absence
of secondary effects. The mechanisms of action of
NO responsible for its therapeutic efficacy are multiple and include, alongside inhibition of inflammation, cyclic GMP-dependent enhancement of mitochondrial energy metabolism, and a correction of
the latent mitochondrial dysfunction observed in
muscular dystrophies. In particular, NO inhibited mitochondrial fission, restoring the ability of mito-
chondria to fuse with each other and thus maintain
proper oxidative phosphorylation and ATP generation. Furthermore, inhibition of mitochondrial fission
by NO with formation of elongated mitochondria enhanced myogenesis. This, alongside direct effects
on proliferation is also responsible for an enhancement of the endogenous pool of myogenic precursor cells, an effect that contributes to the therapeutic
action of NO. Finally, NO inhibited by S nitrosylation
the activity of a specific type 2 histone deacetylase,
the inhibition of which has been shown to be therapeutic in muscular dystrophy. The new therapeutic strategy we propose is not selective for a subset
of mutations and provides ground for immediate
clinical experimentation. In addition, it has immediate applicability to humans as the drugs used are
approved for clinical use, and, in the case of ibuprofen, also in paediatric patients.
Emilio Clementi
Experimental hematology Unit
Cancer immunotherapy with genetically modified T lymphocytes
Adoptive cellular immunotherapy is a promising approach for cancer eradication. The potency of cellular adoptive immunotherapy has been revealed
by persistent and complete clinical responses obtained with allogeneic hemopoietic cell transplantation (HSCT) followed by the adoptive transfer of
donor T lymphocytes, and by initial clinical responses observed with adoptive transfer of tumor
specific cytotoxic T lymphocytes (CTL) in cancer
patients. However, major hurdles limit the safety
and efficacy of adoptive T cell therapy: 1. In the
context of allo-HSCT, donor T lymphocytes are
toxic and mediate the detrimental graft-versus-host
disease. 2. In the autologous setting high-avidity
CTLs specific for tumor-associated antigens (TAA)
are rare, due to immunological tolerance. Our
group exploits gene transfer technologies to overcome these limitations. In 2010:
1) We started a phase III randomized clinical trial to
validate the ability of donor lymphocytes expressing a suicide gene, in promoting immune
reconstitution and control of GvHD after allogeneic hematopoietic stem cell transplantation
from haploidentical donors. This trial, sponsored by Molmed s.p.a., was designed based
on promising results obtained during the phase
I-II TK007 clinical trial.
2) We designed a novel strategy based on zinc
finger nucleases (ZFNs) and viral vectors that
allows for the first time the complete editing of
the antigen specificity of primary human lymphocytes at the DNA level, by combining the
disruption of the endogenous TCR with the
transfer of a tumor-specific TCR.
3) We designed a novel strategy aimed at directing T cell specificities towards a molecule essential for leukemic stem cells homing in the
hematopoietic niche. To this, we constructed
lentiviral vectors encoding for a novel chimeric
antigen receptor (CAR), and thus expressed
the leukemia-directed CAR into primary T lymphocytes.
4) We compared selected T cell subpopulations
for their sensitivity to genetic manipulation, and
their abilities to expand, differentitate in potentanti-tumor effectors and self renew. We identified naïve T cells as the most potent T cell
subpopulation for genetic manipulation and
adoptive immunotherapy.
Chiara Bonini
Gene expression and muscular dystrophy Unit
We are 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. It 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 repeats, 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 4q35 genes. Among
these, we focused on FRG1 since its over-expression in mice, frogs and worms causes an
FSHD-like phenotype.
During 2010:
1) We found that Polycomb group epigenetic repressors (PcG) are associated to D4Z4 when
4q35 genes are repressed, while Trithorax
group epigenetic activators (TrxG) are associated to D4Z4 when 4q35 genes are de-re-
pressed. We found that this epigenetic switch
is regulated by a non-protein coding RNA produced by D4Z4 selectively in FSHD patients.
Our analysis will generate novel insights into
the biological role of DNA repeats and ncRNAs
in regulating chromatin structure in higher eukaryotes.
2) We found that FRG1 binds the histone methyltransferase Suv4-20h1 to inhibit muscle differentiation. Interestingly, the FRG1/Suv4-20h1
interactions is evolutionarily conserved in
Drosophila where dFrg1 function as an E(var) inhibiting Suv4-20h1 activity. This work is elucidating the pathways affected in FSHD providing
novel therapeutic targets for the disease.
3) Since FSHD is a dominant disease associated
to a gain-of-function mechanism, it is a highly
relevant target to test therapeutic applications of
RNA interference (RNAi). We used adeno-associated viruses expressing shRNA specific for
FRG1 (AAV-shFRG1) to test RNAi therapeutics
in the FSHD mouse model. We found that a single systemic delivery of AAV-FRG1 is safe and
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Research Units
causes a stable and long-term FRG1 knockdown determining a significant rescue of the
disease at histological and functional levels.
These studies are paving the way to develop effective therapies for FSHD.
Davide Gabellini
Molecular and functional immunogenetics Unit
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 2010, the following main achievements were made:
1) New clinical and in vitro evidence for two overlapping algorithms of non-permissive HLADPB1 disparities relevant for clinical outcome
of unrelated hematopoietic stem cell transplantation (HSCT). In 2009, we showed in an Italian
Registry study that two overlapping algorithms
of non-permissive HLA-DPB1 T cell epitope
(TCE) disparities involving 3 (TCE3) or 4 (TCE4)
groups of DPB1 alleles encoding a shared
TCE, is significantly associated with clinical outcome of transplantation. In 2010, these data
were confirmed in an independent cohort of
1281 unrelated HSCT facilitate through the
American Registry. In addition, we showed that
HLA-DPA1 disparity was not significantly involved in the algorithm. In 24 mixed lymphocyte
reactions between HLA-matched pairs mismatched only for HLA-DPB1, we showed that
non-permissive HLA-DPB1 disparities were associated with higher frequencies of responder
T cells, as compared to permissive disparities
(Sizzano et al., Blood 2010).
2) Characterization of genomic and expression
profiles of leukemia at diagnosis or relapse after
allogeneic HSCT. In 2009, we have shown that
selective de novo loss of mismatched HLA is a
frequent (40%) event in leukemia relapsing after
haploidentical HSCT. In an attempt to detect
additional targets of leukemia immunoediting, in
2010, we have started a collaborative project
with the Fondazione Filarete at the University of
Milan, to systematically analyze SNP and
transpcriptional expression profiles of leukemia
collected at diagnosis and relapse after allogeneic HSCT. The results obtained so far from
7 such paired samples suggest important
changes in the clonal architecture between
leukemia at diagnosis and relapse in 4/7 (57%),
with the emergence of a single, possibly less
immunogenic and more aggressive clone from
an at least bi-clonal population. These findings
open new possibilities for the identification of
new therapeutic targets for the prevention/treatment of leukemia relapse after allogeneic
HSCT.
Katharina Fleischhauer
Hematology and hematopoietic stem cell
transplantation Unit
The San Raffaele Hematology and Bone Marrow
Transplantation (BMT) Unit is higly integrated with
Dr. Bonini, Fleischhauer, 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 hematopoietic stem cells (HSC)
transplantation, performing since 2006 around
100 allogeneic tranplants/year. The Unit has longlasting experience in transplantation from family
mis-matched haploidentical donors, with programs of cell therapy with suicide-gene modified
donor T lymphocytes and cell therapy with IL-10
induced regulatory T cells for the control of Graftversus-Host Disease. Our aim is to develop new
conditioning regimens based on treosulfan for allogeneic hematopoietic stemcells transplantation
(HSCT) to reduce transplant related toxicity (Allotreo trial, Eudract 2005-005182-11), and to increase anti-leukemia activity (clofarabine-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-versus-Host
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 laboratory.
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,
maintain an accredited Immunohematology Reference Lab and provides education in the field of
Transfusion Medicine. ITMS is conducting a project, funded by Regione Lombardia, on the appropriateness of blood transfusion.
The ITMS is subdivided into three distinct subunits, each responsible for a particular process:
a) 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.
b) 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. 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.
c) 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.
Silvano Rossini
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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 2010 the Unit has performed
more than 70 pediatric allogeneic stem cell transplantations for thalassemia, sickle cell anemia, primary immunodeficiencies and acute leukemias.
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
using lentiviral- vector transduced hematopoietic
stem cells are ongoing. New clinical trials of gene
therapy for thalassemia and mucopolisaccaridosis
I are in preparation. Finally, the Program is implementing a cell therapy clinical study for Duchenne
muscular dystrophy (project leader Prof Cossu).
HSR-TIGET
The San Raffaele Telethon Institute
for Gene Therapy
The San Raffaele-Telethon Institute for Gene Therapy (HSR-TIGET) is a multi-disciplinary research Institute with strong emphasis on the development of gene transfer and cell therapy and their application to
the treatment of rare genetic disorders. It hosts approximately 100 researchers (5 Heads of Unit and 6
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 pathophysiological processes of the inherited diseases under study, which include primary immunodeficiencies and autoimmune disorders, hemoglobinopathies, leukodystrophies and other lysosomal
storage disorders; b) develop new gene transfer technologies for more efficient and safe genetic correction 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. Furthermore, HSR-TIGET has established a Pediatric Clinical Research Unit (PCRU) 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 HSR-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 (Aiuti, Bordignon and Roncarolo,
New Eng. J. Med. 2009). HSR-TIGET scientists, led by Luigi Naldini, have made essential contribution
to the development and improvement of lentiviral vectors, which have become one of the most widely
used tool in biomedical research and hold the promise of therapy for several human diseases. Two new
gene therapy trials for Metachromatic Leukodystrophy and Wiskott-Aldrich Syndrome have started in
spring 2010 in our Institute. They are among the first trials employing lentiviral vectors for HSC gene transfer. Towards this goal, HSR-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.
On October 2010, HSR-TIGET entered a strategic alliance with GlaxoSmithKline (GSK) regarding the
clinical development and commercialization of its pipeline of HSC-based gene therapies for monogenic
disorders. This first-of-its-kind agreement between a major pharmaceutical company and an academic
centre developing gene therapy provides HSR-TIGET with the skills and resources required to address
the regulatory hurdles and manufacturing needs to be encountered along the path towards registration
of the new therapies as Advanced Therapy Medical Products.
Other HSR-TIGET scientists, led by Maria Grazia Roncarolo, have made significant advances in the field
of immunological tolerance mediated by regulatory T cells and the potential application of these cells as
cell therapy of immune-mediated diseases.
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.
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Gene transfer technologies and new gene therapy
strategies Unit
Targeting gene transfer to improve the efficacy and safety of gene therapy
We have exploited microRNAs to post-transcriptionally regulate transgenes and demonstrated applications of this technology for the functional
profiling of miRNAs at the single cell level, selection of cell populations based on miRNA expression, and de-targeting transgene expression from
specific cell types. We identified miR-126 and miR130a as specific for human and mouse
hematopoietic stem cells (HSC). Upon differentiation, these miRNAs are rapidly down-regulated. We
incorporated target sequences for these miRNAs
into a vector, thus inhibiting its expression in HSC
and progenitors, while allowing it in the differentiated progeny. By exploiting miR-126 to stringently
regulate transgene expression, we achieved for the
first time successful HSC gene therapy model of
globoid leukodystrophy in the mouse model. In another application, miR142-regulated hepatocytetargeted vectors allowed to establish long-term
Factor IX expression in a dog model of hemophilia.
Engineered Zinc Finger Nucleases (ZFNs) are powerful new tools for gene targeting. We have optimized the application of ZFN-mediated gene
editing to several cell types, including human pri-
mary lymphocytes, fibroblasts, keratinocytes, neural stem cells and induced Pluripotent Stem cells
(iPSC), and demonstrated the feasibility, efficiency
and specificity of gene disruption, reaching up to
30% of the alleles, and site-specific integration,
reaching up to 10% transgene-positive cells, with
an overall 94% target specificity measured on bulktreated cell populations and in a large panel of single cell-derived clones. However, identification of
suitable genomic sites for transgene integration remained elusive. We studied the transcriptional and
epigenetic impact of different transgene expression
cassettes targeted by ZFNs into two putative suitable loci, CCR5 and AAVS1. Analyses of the loci
before and after mono- or bi-allelic integration allowed on site tailoring of the expression cassettes
to achieve robust and uniform transgene expression without inducing detectable transcriptional
perturbation of the targeted locus and its flanking
genes. These studies provide a framework for sustainable gene transfer that can be exploited in novel
experimental paradigms and safer therapeutic applications.
Luigi Naldini
Gene/Neural stem cell therapy for lysosomal storage
diseases
Combined gene/neural stem cell approaches for metachromatic and
globoid cell leukodystrophies
Deficiency of arylsufatase A (ARSA) and ß-galactocerebrosidase (GALC) cause Metachromatic
and Globoid Cell Leukodystrophies (MLD and
GLD), respectively. Glycosphingolipid storage in
lysosomes in the central and peripheral nervous
system (CNS, PNS) leads to demyelination and
neurodegeneration, which are worsened by neuroinflammation. Gene therapy (GT) has the potential to provide a permanent source of the deficient
enzyme, either by directly delivering the missing
enzyme in the CNS or by transplanting enzymeproducing cells. In this latter approach, the peculiar biology of neural stem cells (NSC) might be
exploited. The goal of our work was to develop
novel combined gene- and NSC-based approaches to correct the metabolic defect and to
restore tissue damage in murine models of
Leukodystrophies. We focused on Twitcher mice,
a relevant GLD model in which we also performed
pathophysiology studies, assessing the role of
GALC in regulating the function of NSC niches.
We showed that a single injection of lentiviral vectors coding for the GALC or ARSA genes in the
white matter of GLD and MLD mouse models, respectively, resulted in rapid, sustained and widespread expression of the functional enzymes in
the whole CNS, with reduction of tissue storage.
In addition, we gave proof of principle that neonatal intracerebral NSC transplantation provides rapid and long-lasting production of GALC in the
CNS of Twitcher mice, with reduction of storage,
amelioration of motor function and improvement in
survival. Finally, we showed an impairment in the
organization and function of neurogenic niches in
Twitcher mice, suggesting a role of GALC in regulating neurogenesis and gliogenesis during CNS
development. Overall these studies gave proof of
principle for feasibility and efficacy of intracerebral
GT and NSC-based therapy as potential approaches for the treatment of leukodystrophies,
also raising important points as regard the pathophysiology of leukodystrophies. We are currently
generating induced pluripotent cell lines from skin
fibroblasts of GLD and MLD patients, which will
be then into neural cells, constituting 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
Figure 22. Robust transduction and transgene expression following injection of a lentiviral vector expressing GFP in
Twitcher mice. (A) Low-magnification bright-field picture of a cresylviolet counterstained coronal brain section
showing the injection site (EC, arrow). (A’) Distribution of GFP positive cells at the site of injection 3 weeks after
vector injection. Scale bars: 1.5 mm (A), 0.75 mm (A’). (B) 3D reconstruction of the forebrain (gray), lateral
ventricles (light bue), white matter (light yellow) and GFP-transduced tissue (green) of the brain of a representative
mouse injected with a lentiviral vector expressing GFP analysed 20 days post-injection. Reconstruction was
obtained from sequential sections analyzed for stereology using the Neurolucida software.
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 have
implemented 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 animal model of metachromatic leukodystrophy (MLD), a severe dysmyelinating LSD. Based
on the results obtained and on an extensive safety
study, a clinical trial of HSC gene therapy for MLD
has started and the first patients were recently
treated. 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 and a clinical development plan for MPS
I has started. In the case of globoid leukodystrophy (GLD), we demonstrated that the diseasecausing 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
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Safety of gene therapy and insertional mutagenesis
We recently developed and validated a new in vivo
genotoxicity assay based on systemic vector injection into newborn tumor-prone Cdkn2a-/- mice
to address the genotoxic potential of different VSVG pseudotyped Lentiviral Vectors. Treatment with
an LV with SIN LTRs harboring the strong enhancer/promoter sequences in internal position
caused a significant acceleration in the time of
tumor onset with respect to mock-controls. Our
data also indicated that the presence of the ORF
downstream the enhancer/promoter sequences
has a major role in increasing the safety profile of
the SIN design. Analysis of >5000 integrations in
tumor-infiltrated tissues showed the presence of
several Common Insertion Sites (CIS), indicating
that the tumor onset acceleration is caused by insertional mutagenesis (Cesana et al., 2011 submitted).
We analyzed the LV integration profile in human
CD34+ hematopoietic stem progenitor cells transduced with a therapeutic LV, in vitro and in vivo after
engraftment in transplanted Rag2-/-IL2Rγ-/- mice.
The vector genomic integration profile obtained is
highly similar to the one for the ALD clinical trial. Despite the safety concerns raised by the presence of
LV CIS in the ALD clinical trial, our analysis highlights important differences with respect to known
genotoxic CIS. Indeed, the LV CIS in the ALD clinical trial and our human/mouse hematochimeras
clustered in megabase-wide genomic regions with
an overall higher integration frequency with respect
to other chromosomal regions. Differently, the distribution of integrations at genotoxic CIS mostly appear as a single sharp peak targeting a single
gene. Because the differences between the LV CIS
found in our pre-clinical and ALD studies and
known genotoxic CIS are consistent across different vector platforms it suggests that different
mechanisms other than genetic selection may
drive CIS formation. Indeed, it is unlikely that genetic selection would favor integrations deregulating cancer genes preferentially clustered in specific
genomic intervals and not the several other well
known oncogenes spread along the genome.
These findings imply that LV CIS are produced by
an integration bias for specific genomic regions
rather than by oncogenic selection (Biffi et al., 2011
Blood).
Eugenio Montini
Gene transfer into stem cells Unit
In vivo selection of hematopoietic stem cells by a truncated erythropoietin
receptor (tEpoR)
In the gene therapy of diseases affecting the
hematopoietic system, low frequency of
hematopoietic stem cells (HSCs) and their quiescent nature are major obstacles to a successful
therapeutic outcome. Transgenes that do not provide an intrinsic selective advantage require to be
associated with a selection marker. A potential selection strategy is the use of modified growth factor receptors, conferring a ligand-dependent selective advantage to transduced cells. We
showed that a truncated form of the erythropoietin
receptor (tEpoR) is able to provide a competitive
advantage to murine and human HSCs upon
transplantation into suitable recipients. Cellular
and molecular mechanisms of tEpoR activity in
transduced cells are unknown. We show that
cord blood-derived CD34 + cells expressing
tEpoR are significantly protected from apoptosis
induced by cytokine starvation. Affymetrix gene
expression profiling identified a specific set of in-
creased and decreased transcripts in cells expressing tEpoR, which include genes involved in
the control of apoptosis. To test if the in vivo competitive engraftment is due to expansion of the incoming stem cells pool, we performed a competitive repopulation experiment in transplanted mice.
We observed that LV-mediated expression of
tEpoR leads to competitive advantage of transduced HSCs in reconstituted irradiated recipients
promoting a 10-fold in vivo expansion of transduced HSCs compared to untransduced cells.
Experiments of transplantation using HSCs transiently expressing the tEpoR are ongoing. The hypothesis that tEpoR promotes engraftment of
transduced repopulating cells, increasing their in
vivo survival rather than inducing their proliferative
expansion, could have important safety implications for gene therapy.
Giuliana Ferrari
Immunological tolerance Unit
Regulatory T cells in promoting peripheral tolerance
Regulatory T (Treg) cells are recognized fundamental for the induction and maintenance of immune tolerance. Both naturally occurring Treg
(thymic derived; FOXP3+) and adaptive type 1 Tr
(Tr1) cells (induced in the periphery; IL-10++IL-4-)
have been demonstrated to be effective in controlling immune responses against a variety of antigen(Ag)s in vivo and in vitro. nTreg suppressor
function is strictly dependent on high expression of
FOXP3, whereas Tr1 cells suppress T cell responses through a cytokine-dependent mechanism. Strategies aim at generating Treg cells ex vivo
suitable for cell therapy as well as at promoting tolerance in vivo are currently under investigation.
We further characterized the mode of action of Tr1
cells and we demonstrated that Tr1 cells suppress
T-cell responses via a novel bystander mechanism
mediated by perforin and granzyme B production.
Selective depletion of myeloid APC by Tr1 cells,
during an active immune response, represents an
additional bystander mechanism of suppression
that amplifies the tolerogenic loop induced by IL-10
and TGF-β produced by Tr1 cells. We also developed an efficient protocol to generate homogenous population of Treg or Tr1 cells by FOXP3 or
IL-10 lentiviral (LV)-mediated gene transfer, respectively. Resulting cells are phenotypically and
functionally similar to the in vivo occurring counterpart. These results represent significant progress
towards the definition of new cell therapy protocols
for promoting/restoring tolerance in immune-mediated diseases.
In parallel, we developed a miR142-regulated LV
gene transfer platform, that by targeting Ag expression to hepatocytes enables induction of Agspecific tolerance that can not be broken by secondary Ag exposure. Results demonstrate that
establishment of tolerance – upon administration
of either integrase competent (IC)LV or integrase
defective (ID)LV – is associated with de novo induction of Ag-specific Foxp3+ Treg, likely through
a TGF-β dependent mechanism. These results
open new therapeutic perspectives for the use of
miR142-regulated LV platform in several applications ranging from gene replacement in the absence of adverse immune-responses for monogenic diseases, to Ag-specific immuno-regulatory
regimen for immune-mediated disorders.
From FOXP3 mutation to IPEX syndrome
IPEX syndrome as a model to study the mechanisms of Treg dysfunction
and to implement new cell/gene therapy strategies to control autoimmunity
Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a monogenic autoimmune disease with severe early onset,
due to mutations of the transcription factor FOXP3,
the master gene regulator of naturally occurring
regulatory T (nTreg) cells. Through genetic, epigenetic and functional studies of FOXP3 mutated T
cells isolated from IPEX patients or carrier mothers,
we have investigated the role of FOXP3 not only in
nTregs but also in T effector cells. 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. Our studies demonstrated that FOXP3 is essential for the
function and maintenance of nTregs rather than for
their differentiation, since FOXP3mut Tregs have
normal FOXP3 demethylation, thus are normally
“imprinted” as nTregs, despite they have impaired
suppressive function. Increasing evidences indi-
cate that nTreg dysfunction is not the only pathogenic event in IPEX patients. Indeed, we found that
IL-17 producing T cells are increased in the peripheral blood of IPEX patients and that FOXP3mut
nTregs partially contribute to this pool of pathogenic
cells, suggesting Treg/Th17 conversion as an additional pathogenic mechanism. Differential gene
expression profile between FOXP3 null and FOXP3
wt cells are currently ongoing to clarify the complex
molecular interactions responsible for the acquisition of suppressive function by FOXP3+ cells. To
validate new molecular targets of FOXP3, we have
available several tools, based on lentiviral-mediated
gene over-expression or knockdown.
Noteworthy, there are many patients with symptoms resembling IPEX and defective Tregs but
without FOXP3 mutations (IPEX-like). It is now well
established that FOXP3 gene transfer into conventional Teff cells conferred suppressive capacity
to human T cells, even in the presence of FOXP3
119
mutations. Therefore, we are implementing preclinical studies to promote the application of cell
and gene therapy approaches as a valid alternative to immunesuppression, in order to cure not
only IPEX patients but also those who suffer from
Tregs/Teff immune dysregulation of different origin.
Rosa Bacchetta
Tolerogenic human dendritic cells: molecular characterization and role in
promoting peripheral tolerance
Dendritic cells (DC) are critical players at the interface between innate and adaptive immunity. DC
patrol the extracellular milieu, uptake and process
antigens and, upon maturation, prime the adaptive
immunity against invading pathogens. It is now evident that DC play also a key role in limiting immunity and in promoting tolerance. Previous and
current work from our laboratory aims at elucidating
these mechanisms. Our group identified and characterized a new subset of human tolerogenic DC,
termed DC-10, present in vivo and inducible in vitro
from monocytes in the presence of IL-10. DC-10
secrete high amounts of IL-10, express high levels
of membrane-bound (mb)HLA-G1 and the tolerogenic immunoglobulin-like transcript (ILT)4 , and induce antigen-specific type 1 regulatory T (Tr1) cells,
well known to promote and maintain peripheral tolerance. Our work is currently focusing on:
• identifying a pattern of DC-10-specific markers
and further defining the tolerogenic role of DC10 in vivo. To this end we performed a gene ex-
pression profile of DC-10 and we identified a
number of gene up- and down-regulated in DC10 as compared to both immature and mature
DC. Once comprehensively characterized, DC10 might represent a critical and innovative tool to
dampen autoimmunity or promote tolerance.
• elucidating the impact of 3’UTR polymorphisms
of HLA-G on the tolerogenic potential of DC-10.
Several polymorphisms located in 3’UTR of HLAG gene might be indeed responsible for posttranscriptional regulation of HLA-G expression.
Preliminary results indicate that variants at 3’UTR
of HLA-G gene are associated with high or low
mbHLA-G1 expression on DC-10.
Results will provide the basis for a deep understanding of DC-10 role in tolerance and for elucidating the molecular mechanisms governing the
expression of HLA-G associated with polymorphisms and the induction of tolerance.
Silvia Gregori
Pathogenesis and therapy of ADA-SCID Unit
Adenosine deaminase (ADA)-SCID is characterized
by impaired lymphocyte development and function, as well as systemic organ damage due to
metabolic toxicity. Our aim is to acquire new information on the immune and non immune alterations
of this disease, which still remain largely unknown,
and to investigate the ability of different treatments
to correct them.
Autoimmune manifestations are frequently observed in the milder forms or after enzyme replacement therapy (ERT). We successfully
established a model in which ADA-/- mice treated
with ERT showed autoimmune manifestations and
auto-antibody production, while mice rescued with
bone marrow transplantation (BMT) and lentiviralmediated gene therapy (GT) were comparable to
wildtype. Since nTreg cells possess a unique biochemical signature to generate high adenosine
concentrations, we hypothesized that they might
be specifically affected in ADA-SCID. Indeed, we
found phenotypical and functional differences between nTregs isolated from ADA deficient mice and
patients with respect to controls. Autoantibody production is a characteristic of most autoimmune diseases. Since B cells displaying self-reactive
specificities are generally removed at different
checkpoints during development, we tested the reactivity to self-antigens of cloned antibodies from
ADA-SCID patients. Our data suggest defects in
both the central and peripheral B cell checkpoints,
resulting in a lack of counter-selection of self-reactive clones.
Neurological and behavioral abnormalities have
been observed in a significant proportion of ADASCID patients evaluated after BMT. To test if these
abnormalities are part of the disease phenotype we
studied the ADA metabolism in the brain and assessed behavioral abnormalities in the ADA defi-
cient mice. ADA-/- mice showed significant altered
explorational, motivational and emotional behavior
with an anxiety-like phenotype in the Open Field
and Dark/Light Box tests. Imbalances in Adenosine 2a receptor distribution in the ADA-/- brain
and decreased pain perception suggested a more
important role for Adora2a than Adora1 in the ADA/- behavioural phenotype. Our findings will improve
our knowledge on the pathogenesis of neurological alterations in ADA-SCID and their correction by
available therapies.
Alessandro Aiuti
Gene therapy for WASP/Omenn
Functional characterization of WASp deficient B cells and their role in
inducing autoimmunity
Wiskott-Aldrich Syndrome (WAS) is a monogenic
X-linked immunodeficiency also characterized by
thrombocytopenia, eczema, tumors and multiple
autoimmune manifestations. WAS is caused by
mutations impairing the expression or function of
the hematopoietic-specific WAS protein (WASp),
involved in actin cytoskeleton remodeling. Although the molecular bases of this primary immunodeficiency have been extensively studied,
the mechanisms underlying autoimmunity are still
puzzling. The evaluation of the role of WASp in B
cells and their contribution in the induction of autoreactive versus tolerogenic immune responses
would represent an important step towards the
understanding of the mechanisms underlying tolerance induction in WAS patients. We then set
out to evaluate the role of WASp in B cells in a
mouse model of WAS. We analyzed the serum of
adult was-/- mice and found an increased level of
Igs as compared to wt mice, in particular of IgG2a
subclass. This result was confirmed by ELISpot
on sorted Marginal Zone and Follicular B cells.
The presence of autoreactive B cells was supported by high titers of autoantibodies against dsDNA and tissue Ags in was-/- mice. In in vitro proliferation assays, was-/- B cells were hyper-proliferating to BCR-dependent and Toll Like Receptor
(TLR)-dependent stimuli in comparison to wt B
cells, although no difference in the expression of
TLRs was found. These data suggest that WASp
absence may affect the activation state of B cells.
Studies are ongoing to better characterize BCR
and TLR9 signaling pathways. In addition, preliminary studies on gene expression in was-/- B cells
are ongoing and indicate an increased expression
of genes involved in class-switch (AID and T-bet)
and of cytokine genes (IL-6 and IL-10). Studies
aimed at evaluating gene expression dynamics
after activation are also ongoing. The results of
these studies would be critical in understanding
the role of B cells in autoimmunity induction in
WAS patients.
Anna Villa
Figure 23. Improvement of splenic B cell follicle and MZ architecture in GT treated Was-/- mice. Spleen sections
from BMT wt (A), BMT was-/- (B) and GT mice (C) have been stained for anti-metallophilic macrophages MoMa
(blue signal) combined with IgM (brown signals) to identify marginal zone macrophages surrounding spleen follicles
and marginal zone B cells, indicated by arrows ( 20x original magnification).
121
Clinical Research Units, HSR-TIGET
PCRU - Gene therapy for Wiskott-Aldrich Syndrome
Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia, infections, autoimmunity and lymphomas. Gene
therapy with autologous hematopoietic stem cell
(HSC) could represent a valid alternative to allogenic
transplant for patients lacking an HLA-identical
donor. We previously demonstrated that a lentiviral
vector (LVV) encoding for human WAS under the
control of endogenous 1.6 kb promoter efficiently
corrected human and mouse cells. We then set up
a clinically applicable and efficient transduction protocol based on 24 hours of culture and 2 hits of
gene transfer (MOI 100) on CD34+ cells from normal donors and WAS patients bone marrow (BM) or
mobilized peripheral blood (MPB) to validate the
GMP grade LVV. Following gene transfer, WASp expression was restored in patients’ differentiated
cells, including megakaryocytes. Biodistribution
studies in immunodeficient mice showed that human transduced CD34+ cells were able to normally
engraft and differentiate. Analyses of vector integrations showed polyclonal integration patterns
whereas vector mobilization to host cells and transmission to germline cells of the LVV were excluded
by several molecular assays. A phase I/II gene therapy protocol aimed at studying safety, biological activity and efficacy was opened in April 2010. Patients will receive preconditioning with anti-CD20
monoclonal antibody and reduced intensity busulfan and fludarabin; ATG will be included in case of
autoimmune manifestations. The first patients was
recently treated with autologous BM and MPB derived CD34+ cells, showed a high gene transfer efficiency (88-92%) in clonogenic progenitors. The
patients did not experience toxicity, recovered well
from transient neutropenia and is currently independent from platelets transfusions, 6 months after
gene therapy. Initial engraftment analyses is showing the presence of vector transduced cells in multiple lineages in peripheral blood and BM, at higher
level in lymphoid lineage. WASp expression was detected in peripheral blood monocytes, platelets and
all lymphocyte lineages. Long-term assessment
study will provide key information on the safety and
efficacy of gene therapy for WAS patients using LVV
transduced HSC in combination with reduced intensity conditioning.
PCRU - ADA gene transfer into hematopoietic stem cells
for the treatment of ADA-SCID
SCID due to adenosine deaminase deficiency
(ADA-SCID) is characterized by impaired lymphoid
development and function, and systemic manifestation of metabolic toxicity. Since year 2000, we
have applied a gene therapy approach based on
γretroviral-mediated ADA transfer into autologous
bone marrow (BM) hematopoietic stem cells (HSC)
cells combined to reduced intensity conditioning.
Three children were treated within pilot trials and 12
in the context of a phase I/II clinical study which has
completed enrolment. At present, all 15 patients
treated with these protocols are alive (median follow
up 4.7 years; range 2.3-10.2), and 13 do not require enzyme replacement therapy (ERT). Gene
corrected ADA+ cells continue to be detected long
term in multiple lineages of the BM and peripheral
blood of patients, at higher levels in lymphocytes,
leading to efficient systemic purine metabolic detoxification. Immunological studies showed improved
T-cell counts and functions, leading to protection
from severe infections. Most patients discontinued
or reduced anti-microbial prophylaxis and IVIg were
stopped in 8 patients. Combined studies on phenotype, cell cycle and telomere length, indicate that
T-cell homeostatic expansion contributes to immune reconstitution at early time points, similarly to
BM transplant, and that gene therapy is not associated to senescence in the HSC compartment.
Four patients experienced clinical manifestations of
autoimmunity, which have been also observed in
patients with mild disease form or under ERT. No
insertional oncogenesis has been observed over a
long period of follow up, in agreement with a polyclonal pattern of vector integration and the lack of in
vivo skewing for potentially dangerous insertions.
The analysis of genomic distribution of retroviral
vector insertions in these patients in comparison to
those who received infusions of transduced mature
T cells showed that insertions are associated with
regions transcriptionally active as well as geneticchromatin state of target cells in vitro whereas their
in vivo distribution mirrors directly this preference
without particular biases. In summary, HSC gene
therapy of ADA-SCID has a favorable risk-benefit
profile and is effective in restoring normal purine metabolism and immune functions.
Alessandro Aiuti
PCRU - Clinical trial of gene therapy in metachromatic
leukodystrophy
Metachromatic Leukodystrophy (MLD), consequent to the deficiency of Arylsulfatase A (ARSA),
is characterized by severe dysmyelination for which
no effective treatments exist.
In the last seven years, we have studied the natural history of MLD on a large cohort of 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. The study has been designed in the perspective of the clinical translation of a gene therapy approach based on transplantation of
Hematopoietic Stem Cell transduced with a lentiviral vector containing the human ARSA cDNA. The
trial was approved by the Italian Superior Institute of
Health in March 2010 and by HSR Ethical Committee in April 2010. The study is of Phase I/II,
open, not randomized, prospective, comparative
with the non-contemporary population of controls
evaluated within the 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. Efficacy will be assessed
as reduction in the progression of 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 first patient has been
treated in May 2010. No serious adverse events
were observed; we noticed a complete
haematopoietic reconstitution and clinical stability
at the 9-month follow-up. Additional two patients
have just been treated in a pre-symptomatic
phase. We plan to treat a total of 8 patients, recruited internationally, in 3 years. Patients will be
followed for the safety and efficacy endpoint measures for 3 years within the clinical trial and thereafter lifelong for monitoring of safety.
Maria Sessa
123
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F; Traggiai, E; Villa, A. Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the
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A; Tonon, G; Refaldi, C; Cappellini, MD; Andreani, M; Lucarelli, G; Roncarolo, MG; Marktel, S;
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F; Traggiai, E; Villa, A. Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the
Rag2 mouse model of Omenn syndrome. J. Exp. Med.: 2010; 207(7): 1525-1540 - Article
IF 2009: 14,505
Gregori, S; Tomasoni, D; Pacciani, V; Scirpoli, M; Battaglia, M; Magnani, CF; Hauben, E and
Roncarolo, MG. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the
IL-10-dependent ILT4/HLA-G pathway. Blood: 2010; 116(6): 935-944 - Article
IF 2009: 10,555
IF 2009: 10,555
125
Skeletal muscle development and therapy Unit
Gene expression and muscular dystrophy Unit
127
Research Units
Molecular and functional immunogenetics Unit
129
DIVISION
OF
Immunology, Transplantation,
and Infectious Diseases
Director:
Ruggero Pardi*
Associate Director:
Adriano Lazzarin*
Research Units
Leukocyte biology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 139
HEAD OF UNIT: Ruggero Pardi*
RESEARCHER: Monica Fabbri
POST-DOCTORAL FELLOWS: Antonella Giammarresi, Raffaella Molteni, Martina Panattoni**
PHD STUDENTS: Carolina Lage Crespo**, Anna Lukacs**, Michela Palmisano, Michol Savio**
TECHNICIAN: Barbara Clissi
Cellular and molecular allergology –––––––––––––––––––––––––––––––––––––––––––––––– 140
GROUP LEADER: Samuele E. Burastero
PHD STUDENT: Mona-Rita Yacoub**
TECHNICIAN: Daniela Breda
Human virology––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 141
GROUP LEADER: Mauro S. Malnati
RESEARCHER: Silvia Heltai
PHD STUDENT: Lia Vassena**
FELLOW: Giulia Cassina
TECHNICIAN: Francesca Sironi
Infection and cystic fibrosis ––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 141
GROUP LEADER: Alessandra Bragonzi
POST-DOCTORAL FELLOWS: Cristina Cigana**, Ida De Fino
PHD STUDENTS: Irene Bianconi, Nicola Ivan Lorè, Moira Paroni
FELLOWS: Beatriz Alcalà-Franco (from August 2010), Elisa Pedretti
131
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES
Research Units
Protein engineering and therapeutics –––––––––––––––––––––––––––––––––––––––––––– 142
GROUP LEADER: Luca Vangelista
POST-DOCTORAL FELLOW: Massimiliano Secchi
γδ T cells in innate and adaptive immunity –––––––––––––––––––––––––––––––––––––– 143
RESEARCHER: Maria Raffaella Zocchi
FELLOWS: Paolo Canevali, Silvia Catellani
Infectious diseases Unit
HEAD OF UNIT: Adriano Lazzarin*
Immunobiology of HIV –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 144
GROUP LEADER: Lucia Lopalco
PHD STUDENTS: Lorenzo Diomede, Maria Luisa Visciano**
FELLOWS: Valeria Asti, Domenico Savarino
TECHNICIAN: Claudia Pastori
Immunological diagnostics of tuberculosis
GROUP LEADER: Claudio Fortis
AIDS immunopathogenesis Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 145
HEAD OF UNIT: Guido Poli*
RESEARCHER: Massimo Alfano
PHD STUDENTS: Luca Cassetta, Giulia Della Chiara, Samanta Mariani, Elisa Saba
Biocrystallography Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 145
HEAD OF UNIT: Massimo Degano
POST-DOCTORAL FELLOW: Claudia Minici
FELLOWS: Simone Battaglia, Francesca Giannese
TECHNICIAN: Paola Tornaghi
Cellular immunology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 146
HEAD OF UNIT: Matteo Bellone
PHD STUDENTS: Luca Generoso, Elena Jachetti**, Alessia Ricupito**, Nicolò Rigamonti**
FELLOW: Arianna Calcinotto
TECHNICIAN: Matteo Grioni
Dynamics of immune responses Unit –––––––––––––––––––––––––––––––––––––––––––––––––––– 147
GROUP LEADER: Matteo Iannacone, Armenise-Harvard Career Development Award
POST-DOCTORAL FELLOWS: Elena Tonti, Laura Sironi, Stefano Sammicheli,
Nereida Jiménez de Oya
PHD STUDENT: Donato Inverso**
FELLOWS: Angelo Amabile**, Maurizio Vacca**
Emerging bacterial pathogens Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 148
HEAD OF UNIT: Daniela Maria Cirillo
PHD STUDENT: Paolo Miotto, Elisa Schena**
FELLOWS: Emanuele Borroni, Alessia Di Nauta, Lucinda Furci, Paola Mantegani, Diego Zallocco
TECHNICIAN: Rossella Baldan
Research Units
Experimental immunology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 149
HEAD OF UNIT: Paolo Dellabona
RESEARCHERS: Giulia Casorati, Claudia De Lalla
PHD STUDENTS: Virginia Cecconi**, Maya Fedeli**, Francesca Gorini**, Nagabhooshan Hegde**,
Anna Napoletano**
FELLOWS: Anna Rinaldi, Michele Cosmo Romano
TECHNICIAN: Claudio Garavaglia
Immunopathology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 149
HEAD OF UNIT: Luca G. Guidotti, ERC Advanced Grant
RESEARCHER: Giovanni Sitia
POST-DOCTORAL FELLOWS: Ivan Brunetta, Mario Catarinella, Pasquale Creo
PHD STUDENT: Roberto Aiolfi
TECHNICIANS: Tiziana Cataudella, Diego Covarello (from June 2010), Pietro Di Lucia,
Amleto Fiocchi, Bruno Fiore, Marta Mainetti, Francesca Mingozzi
Lymphocyte activation Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 150
HEAD OF UNIT: Anna Mondino
POST-DOCTORAL FELLOWS: Chaitanya Ekkirala, Rodrigo Hess-Michelini
PHD STUDENTS: Teresa Manzo**, Karolina Pilipow**, Romana Tomasoni**
TECHNICIAN: Veronica Basso
Tumor immunology Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 151
HEAD OF UNIT: Maria Pia Protti
RESEARCHER: Lucia De Monte
POST-DOCTORAL FELLOWS: Giulia Di Lullo, Diego Marescotti
PHD STUDENT: Donato Calabrese**
TECHNICIAN: Giuseppe Consogno
Viral evolution and transmission Unit –––––––––––––––––––––––––––––––––––––––––––––––––––– 151
HEAD OF UNIT: Gabriella Scarlatti
POST-DOCTORAL FELLOWS: Mariangela Cavarelli, Simone Pensieroso
PHD STUDENTS: Stefania Dispinseri, Lara Mainetti
FELLOWS: Priscilla Biswas, Chiara Foglieni
TECHNICIAN: Monica Tolazzi
Viral pathogens and biosafety Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 152
HEAD OF UNIT: Elisa Vicenzi
POST-DOCTORAL FELLOWS: Tiziana Coradin, Anna Kajaste-Rudnitski
FELLOW: Andrea Di Pietro
TECHNICIAN: Silvia Ghezzi
133
Infectious diseases Unit
Management and antiretroviral treatment of HIV infection ––––––––––––––––––– 153
CLINICAL GROUP LEADER: Antonella Castagna
PHYSICIAN: Nicola Gianotti
FELLOWS: Francesca Cossarini, Vincenzo Spagnuolo
STUDY COORDINATOR: Elisabetta Carini
DATA MANAGER: Stefania Salpietro
STATISTICIAN: Laura Galli
TECHNICIAN: Andrea Galli
Neurovirology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 153
CLINICAL GROUP LEADER: Paola Cinque
PHYSICIANS: Simona Bossolasco, Francesca Ferretti
STUDY COORDINATOR: Ester Tuveri
TECHNICIANS: Arabella Bestetti, Manuela Testa
Study and treatment of hepatotropic viruses related diseases –––––––––––––– 154
CLINICAL GROUP LEADER: Caterina Uberti-Foppa
RESEARCHER: Giulia Morsica
POST-DOCTORAL FELLOWS: Sabrina Bagaglio, Hamid Ibrahim Hasson
FELLOW: Lucy Porrino
TRIAL COORDINATOR: Clara Ronchetti
Vaccine and immunotherapy –––––––––––––––––––––––––––––––––––––––––––––––––––––––– 154
CLINICAL GROUP LEADER: Giuseppe Tambussi
PHYSICIAN: Silvia Nozza
FELLOW: Manuela Pogliaghi
RESEARCH NURSE: Liviana Della Torre
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Vega Rusconi
TRIAL COORDINATOR: Elisa Gasparotto
TECHNICIAN: Andrea Galli
Clinical immunopathology and advanced medical therapeutics Unit–––––––––––––– 155
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, Luca Ferrante, Barbara Guglielmi,
Francesca Motta, Fulvio Salvo, Mirta Tiraboschi, Enrico Tombetti
CONSULTANT: Lorenzo Dagna**
Clinical transplant Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 155
HEAD OF UNIT: Antonio Secchi**
PHYSICIANS: Rossana Caldara, Chiara Gremizzi, Vera Paloschi
POST-DOCTORAL FELLOWS: Federica Cipriani, Francesca D’Addio, Alessandra Petrelli
CONSULTANT: Paolo Fiorina
Pancreatic tumors Unit: immunotherapy and β cell function substitution ––––––– 156
HEAD OF UNIT: Marco Braga*
PHYSICIAN: Renato Castoldi
RESIDENT: Nicolò Pecorelli
FELLOW: Federica Merlini
Gynecological cancers immunology –––––––––––––––––––––––––––––––––––––––––––––––––––––– 156
CLINICAL GROUP LEADER: Massimo Origoni*
PHYSICIANS: Luigi Caputo, Guia Carminati, Davide Ferrari
RESIDENTS: Francesca Occhi**, Marta Parma**, Chiara Stefani**
Immunology in liver neoplasms–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 157
CLINICAL GROUP LEADER: Luca Aldrighetti
PHYSICIANS: Marco Catena, Renato Finazzi
Obesity
RESEARCHER: Michele Paganelli
Gastroenterology Unit
Clinical hepato-gastroenterology –––––––––––––––––––––––––––––––––––––––––––––––––– 158
RESEARCHER: Mario Guslandi
Digestive pathophysiology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 159
RESEARCHER: Sandro Passaretti
Transplant surgery
RESEARCHER: Carlo Socci
135
DRI
Diabetes Research Institute
Director:
Luca G. Guidotti
Associate Director:
Emanuele Bosi*
Research Units
Diabetes research Unit
HEAD OF UNIT: Luca G. Guidotti
Experimental diabetes–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 161
GROUP LEADER: Marika Falcone
POST-DOCTORAL FELLOW: Vera Usuelli
PHD STUDENTS: Caterina Di Pietro**, Chiara Sorini**
TECHNICIAN: Alessandra Caputo
β cell biology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 161
GROUP LEADER: Lorenzo Piemonti
POST-DOCTORAL FELLOWS: Simona Marzorati, Leda Racanicchi
PHD STUDENTS: Elisa Cantarelli**, Antonio Citro, Valeria Sordi
FELLOW: Erica Dugnani
Cell imaging ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 162
HEAD OF UNIT: Alessandro Del Maschio*
GROUP LEADER: Maria Luisa Malosio
FELLOW: Cristina Brigatti**
Research Units/Clinical Research Units, DRI
Immune tolerance Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 163
GROUP LEADER: Manuela Battaglia, JDFR
PHD STUDENTS: Alessandra Ferraro, Nicola Gagliani
FELLOW: Andrea Valle
TECHNICIANS: Tatiana Jofra, Angela Stabilini
Islet transplantation ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 164
HEAD OF UNIT: Antonio Secchi*
CLINICAL GROUP LEADER: Paola Maffi
DATA MANAGER: Paola Magistretti
RESEARCH NURSE: Luisa Zamberletti
Prevention in Type 1 diabetes ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 164
CLINICAL GROUP LEADER: Luca Falqui
PHYSICIANS: Sabina Martinenghi, Matteo Rocco Pastore
RESIDENT: Laura Molteni
TRIAL COORDINATOR: Pauline Grogan
RESEARCH NURSE: Eleonora Bianconi
Epidemiology & data management––––––––––––––––––––––––––––––––––––––––––––––––– 165
Researcher: Marina Scavini
Childhood diabetes ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 165
RESEARCHER: Riccardo Bonfanti
RESIDENTS: Roseila Battaglino, Valeria Favalli, Giulio Frontino
Islet processing activity ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 166
SUPERVISOR: Lorenzo Piemonti
RESEARCHER: Rita Nano
FELLOWS: Raffaella Melzi, Alessia Mercalli
137
The Division of Immunology, Transplantation and Infectious Diseases (DITID) stems from a deeply integrated area of Institutional research at the San Raffaele, dating back to the inception of DIBIT and making up the scientific core of areas of intense clinical investigation, which include, but are not limited to,
cancer, type 1 diabetes, allergy, cell and solid organ transplantation and HIV infection. Although the contribution of a normal or deranged immune response to the pathogenesis of the above conditions is highly
heterogeneous, common themes emerge, thus justifying the creation of a scientific and cultural environment where pre-clinical models, technology platforms and specific know-how pertinent to immunology
can be optimized to achieve critical mass, to develop higher education programs and to promote innovative research outcomes, both in preclinical research and in the clinical settings.
Based on these premises, the comprehensive goal and unifying mission of the DITID is to harness the
immune response for the benefit of patients. To this aim, the DITID is fostering research efforts and development of new technologies aimed at dissecting the mechanisms underlying the immune response
to infectious agents, cancer- and transplantation-associated antigens, as well as the dysregulation of the
processes leading to peripheral tolerance to self-antigens. Validation of these basic discoveries will require
standardization of pre-clinical models and extensive analysis of human immune cells and tissues. The most
promising findings will be translated into proof-of-concept designs for phase I/II clinical trials.
To achieve its goals, the DITID will structure selected research activities into a limited set of Research
Programs, aimed at fostering interdisciplinary research and strong integration of pre-clinical and clinical
investigations. The Islet Transplantation Program (ITP) aims at achieving long-lasting insulin independence
in patients with type 1 diabetes (T1D) undergoing portal vein islet transplantation. Recognized experts in
islet transplantation, immunological tolerance, liver immunopathology and non-invasive imaging have been
brought together to address and modify innate and adaptive immune responses to islet transplants that
together prevent lifelong persistence of functional islets within the liver, as well as to identify potentially novel
and safer implantation sites.
The Program of Immunology and Bio-immunotherapy of Cancer (PIBIC) is promoted jointly by the DITID
and the Division of Molecular Oncology. The major goals of the PIBIC are twofold: i. a deeper understanding of the mechanisms underlying the tumor/immune system interactions; and ii. the provision of new
immunotherapy strategies that are rationally designed to increase significantly the therapeutic efficacy of
the current ones.
A third Program stems from the recognition of a critical mass of basic and applied investigators already
ongoing in this Division and in the Department of Infectious and Tropical Diseases on the role of CCR5
and its ligands in HIV infection and related clinical entities. The Program is named “Correlates of HIV-associated Immune Response Modulation” (CHARM). General goals of CHARM are the investigation and
exploitation of the role of CCR5 and its natural or chemical ligands in HIV infection and in infection-related
inflammation.
Finally, an inter-division R&D program for Advanced immuno-monitoring of patients undergoing Phase I
and II trials based on immunomodulation in cancer and infectious diseases has been recently launched
jointly with the Division of Molecular Oncology.
Research Units
Role of an adhesion-regulated modifier of cullin-based ubiquitin ligases in
parenchymal tissue homeostasis
During the last several years, our group has identified a multimolecular comlex named the Cop9
Signalosome (CSN) as a key intermediate in adhesion- and growth factor-induced proliferation.
By generating mice harboring a floxed
CSN5/JAB1 allele, we were among the first to
provide genetic evidence for the essential role of
the CSN in mammalian tissue homeostasis
(Panattoni M J. Exp. Med. 2008. 205:465). Overwhelming genetic evidence, including recent findings from our group, suggests that the CSN is a
positive regulator of CRL-dependent substrate
degradation in vivo. CSN5/JAB1 is essential for
viability in D. melanogaster, as are other CSN
subunits in various organisms, including the
mouse. Over the last year we have extensively
characterized the phenotype of mice in which
CSN5 has been deleted specifically in hepatocytes in postnatal life, by crossing our
CSN5flox/flox mice with a deleter strain expressing ALB-Cre (Panattoni, M. et al. ms in preparation). As a result of inactivation of the CSN, hepatocytes show evidence of cell cycle arrest (mostly
in the S/G2/M phase as judged by in vivo BrdU
incorporation experiments, not shown), with fre-
quent tetraploidy and polyploidy, along with “constitutive” signs of DNA damage (γH2AX+ foci) and
apoptosis (Figure 24 and data not shown). This
phenotype is reminiscent of an aberrant “oncogene-induced” type of response and can be
maximized by exposing CSN5 deficient livers to
growth-inducing stimuli during parenchymal regeneration. Gene expression profiling of c-Mycexpressing hepatocytes in the CSN5-deficient
background allowed us to identify a signature of
approximately 40 genes that are modulated by cmyc and epistatically interfered by the CSN. Interestingly, a preliminary assessment of this signature in samples of progressing liver cancer appears to clearly discriminate more aggressive tumors from benign liver nodules and early lesions.
Based on the above evidence we hypothesize
that the coordinate regulation of CRL complexes,
the CSN contributes to setting a threshold response to growth-promoting stimuli above which
cells sense DNA replicative stress and trigger an
oncogene-induced type of response, resulting in
cell cycle exclusion, cellular senescence and
apoptosis.
Ruggero Pardi
Figure 24. Evidence of DNA damage (accumulation of γ-H2AX histone) in livers from conditional KO for the CSN
(right panel) compared to wild type littermates (left panel)
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Research Units
Cellular and molecular allergology
Modulation of allergenicity by structurally-guided single point mutations
Recombinant allergens entered clinical practice as
highly performing diagnostic tools and also 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, i.e., the capability to
be recognized by IgE from allergic individuals, while
fully maintaining T-cell stimulatory potential. The latter is a property which has to be maintained for the
success of immunotherapy itself, which largely depends on the expansion of allergen-specific regulatory T cells. Conventional strategies to generate
these “allergoids” used to include extended deletions of B-cell epitopes and multiple mutations of the
allergen molecule. Alternatively, we recently developed (in collaboration with the Department of Experimental Medicine of the University of Parma) a
structurally-guided approach capable to destroy
crucial B cell epitopes by generating mutants minimally modified in terms of primary sequence but
dramatically affected in the overall protein structure.
We used a model based on an allergenic isoform
of the major urinary protein 2 from Mus musculus,
we cloned and expressed in Pichia pastoris. This
allergen (M16356, P11589, 1df3) was submitted
to the International Union of Immunological Societies allergen nomenclature sub-committee, which
is responsible in the naming and incorporation of
new allergens into the nomenclature, and attributed
the following code: Mus m 1.0102 (http://www.allergen.org/index.php). We found that Tyr120 is particularly important for the overall stability of Mus m
1.0102. Mutations at the level of this residue appear primarily responsible for alterations in the Hbonds 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 in
vitro and in vivo 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.
Samuele E. Burastero
Figure 25. Slab view of MUP2 crystal structure (1JV4, displayed in topology cartoon): W19 is visible at the bottom
of the hydrophobic cavity of the β-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 long quest for an efficacious vaccine against HIV-1
Background
The failure of anti HIV-1 vaccine strategy based on
the exclusive 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 T-cell 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 an
useful immunogen. Indeed, monomeric gp120 Env
fails to induce NAbs, whereas NAbs have the
unique ability to bind to the gp120 Env trimer.
Moreover, relevant epitopes of this oligomeric
structure are shielded by the 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.
Main results obtained in 2010
The Tat-specific response, the hallmark of EC and
LTNP individuals, is mainly directed against the Nterminus and the cistein-rich region of the protein in
which are encoded key aminoacidic residues involved in HIV-1 transactivation. Moreover, only in
EC/LTNP individuals the Tat-specific CD8 T-cellresponse is mainly polyfunctional and contains a
significant proportion of effector citotoxic CD8
cells.
The V1-deletion within the US077 gp160 protein
scaffold has been chosen for further testing in animal models. A HIV-1 derived Virus like particle
(VLP) strategy has been chosen to produce the
trimeric envelope structure used for rabbit immunisation. Four rabbits have been immunized and in all
animals the ∆V1gp160 construct elicited a strong
gp160-specific antibody response. Experiments to
evaluate the presence of neutralizing antibody titers
(NAb)are under way.
Mauro S. Malnati
Pseudomonas aeruginosa-host interactions in Cystic Fibrosis:
implications for pathogenesis and therapy
Pathogen recognition and induction of immune responses are important for efficient elimination of infection. However, life-threatening chronic infections
are maintained by bacterial patho-adaptive variants
that employ strategies to evade or modulate these
defences. The goal of our program is to elucidate
cellular and molecular mechanisms that are involved in the cystic fibrosis (CF) host-pathogen interactions with the aim of devising new therapeutic
approaches to treat respiratory infections.
Cellular and molecular mechanisms involved in P.
aeruginosa-host pathogen interactions.
The most effective strategy for hijacking genes involved in innate immune responses involves steric
shielding or modification of exposed molecules.
Comparing lipid A and peptidoglycan of sequential
strains isolated from CF patients, isolated during a
period of up to 7.5 years, we found specific struc-
tural modifications temporally associated with CF
lung infection. Both bacterial structures (LPS and
PGN) and whole cell bacteria of early and late clinical strains had different potencies when activating
host innate immunity. Late strains are prone to revise their interaction with host by dampening the
inflammatory response and activating pathways
relevant for damage and remodelling process.
Pathogenicity-adaptive mutations in P. aeruginosa
represent a genetic mechanism for enhancing
long-term bacterial persistence in the host. In the
last year, we have unveiled novel P. aeruginosa
patho-adaptive mutations by using a novel genomic approach (Pos-STM) in mice. Sequence
analysis in longitudinally P. aeruginosa isolates from
CF patients confirmed the signs of patho-adaptive
mutations within the genome and their clinical implications for the persistent lifestyle and disease
progression of the airway chronic infection.
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Research Units
Evaluation of novel molecules for treating respiratory infection and inflammation.
Murine model for acute and chronic infection,
along with mice genetically modified for the Cftr
gene, are a key asset in CF research. The Cystic
Fibrosis Animal Core Facility (CFaCore) provides
these murine models and supports the CF community testing novel therapeutic molecules. The
aim is to favor the translation of basic research projects into pre-clinical application.
Alessandra Bragonzi
Figure 26. Pseudomonas aeruginosa airways chronic infection in mice: histology and localization of bacterial cells
by immunoflorescence
Research in our laboratory focuses on molding
protein design, engineering and expression strategies into novel therapeutic interventions. Efforts are
devoted to HIV-1 entry inhibitors based on 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 particularly promising and innovative approach, based on the engineering of human
commensal bacteria, such as lactobacilli, to produce anti-HIV-1 protein therapeutics, a field in
which we are involved and committed. A further
aspect of HIV-1 entry inhibitors 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
various HIV-1 inhibitors. As a future purpose,
RANTES derivatives will be tested also in the context of inflammation, cancer and other pathologies.
In a different research area, we are trying to couple
structure-function knowledge on IgE and its receptors 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. Interestingly, in a research program co-directed with
Prof. Antonio Siccardi, we found that IgE is a potent
adjuvant in anti-tumor vaccination and Fc ε RI (the
high affinity receptor for IgE) the key mediator of the
anti-tumor effect. We are now evolving this system
by recruiting also tmIgE, a truncated version of
membrane-bound IgE (tmIgE) capable to bind and
activate Fc ε RI, as well as safe recombinant viral
vectors, such as recombinant MVA (modified vaccinia virus Ankara), engineered to express tmIgE.
Aside its adjuvanticity, we are investigating other
aspects of IgE as anti-tumor agent, including its
possible role as natural anti-tumor surveillant. Studies on the IgE system are enhanced by the use of
a rich battery of IgE-related transgenic mice. Finally,
we are planning the use of engineered commensal
bacteria inhabiting the intestine to combat various
diseases including worldwide pathological threats.
Luca Vangelista
Figure 27. Recombinant lactobacilli as an expression platform to screen novel RANTES mutants with potent antiHIV-1 activity
γδ T cells in innate and adaptive immunity
Involvement of γδ T cells in host defense against infections and
lymphomas
Among γδ T lymphocytes, that have been recognized as effectors of the so called stress immunity, 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 HIV-1 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 transcription factors and bear surface mole-
cules markers of Th1/Th17 cells (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-transretinoic acid or sodium valproate (Leukemia 2009,
23:642-648). 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. Also,
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 (Int J Cancer 2010).
On the other hand, in Hodgkin lymphomas, a
subset of Vδ1 T cells producing IL10 and with
regulatory properties seem to be localized in the
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Research Units
lymph nodes, due to the high production in situ of
TGFβ and to a lesser extent of IL6 (manuscript in
preparation). 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 host-virus 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
Figure 28. Humoral HIV
protective responses
identified in exposed to
HIV but uninfected
subjects. In particular,
the picture shows the
biological characteristics
of IgA antibodies
directed to gp41 and
CCR5.
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 topics
listed below.
Macrophage polarization and their role in the infection in the gut mucosa.
After our original observation that that both M1 and
M2 polarized MDM support less efficiently virus
multiplication, we have also observed that gut-mucosa associated macrophages contribute independently of T cells to the dysregulation of
biomarkers of inflammation and HIV replication in
the context of microbial translocation.
Genetic and T cell adaptive response in long-term
non progressors (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. In addition, we
have contributed significantly to the definition of In
regard to the immune responses, we have defined also that HIV-1 Nef-specific, memory
(CD45RO+) CD8 T cells secreting CCL4/MIP-1β,
but not IFN-γ, define the profile of the immune response of vs. normo-progressors.
Anti-HIV vaccine-preparedness studies.
In the context of the EC-funded “AVIP” initiative we
have contributed to the characterization of the genetic variants of HIV-1 circulating in South-Africa.
CCR5 usage and immunotherapy of HIV infection.
As follow-up study of a trial based on the intermittent administration of IL-2 together with combination antiretroviral therapy (cART), we have investigated its potential impact on the co-receptor use
by the circulating viral strains. We have observed
tha IL-2 “fixes” this property on the use of CCR5
that was maintained in a significantly higher proportion of individuals vs. those receiving cART only. This observation bears implication for the possibility of combining immunotherapeutic intervention and CCR5-antagonists.
Guido Poli
Biocrystallography Unit
Structural approaches against cancer, immune-mediated, and infectious
diseases
In the post-genomic era, a considerable effort is
put in the identification of target genes whose activity is relevant for human disease. The crystal
structure of the macromolecule encoded by the
gene is crucial information that provides an invaluable basis for the rational design of compounds
that may selectively bind to the gene product, and
specifically interfere with its activity.
Our unit focuses on the determination of the threedimensional structure of proteins and protein-ligand
complexes using X-ray crystallography. Our interest
range from enzymes crucial for the survival of
pathogens that are causative agents of infectious
diseases, to proteins involved in the pathogenesis
of neoplasies, and immune systems receptors.
We recently demonstrated that a Staphylococcal
enzyme with nucleoside hydrolase activity plays a
crucial role in the uptake pathway of components
for the biosynthesis of NAD+. Since S. aureus is
NAD-autotrophic, this enzyme is a highly amenable
target for a completely new class of antibacterial
compounds. We crystallized and determined the
structure of the staphylococcal NH enzymes, both
unliganded and in complex with a newly identified
micromolar inhibitor. These compounds are effective in reducing bacterial growth in culture, and are
currently being tested in animal models of infection.
The same family of enzymes is of central importance in the purine-auxotrophic Trypanosomes,
causative agents of Chagas’ disease and sleeping
sickness in humans. NHs bear the burden of providing the building blocks of DNA, RNA, and cofactors in these organism, and are hence obvious
yet overlooked targets for drug design. We determined the crystal structures of the three NHs from
T. brucei brucei, differing in specificity, and engineered isozyme-specific compounds that display
sub-nanomolar affinities and are strong candidates
as antitrypanosomal lead compounds.
We also developed, based on functional information from NH structure, a synthetic enzyme that activates a lowly toxic antineoplastic prodrug, and
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Research Units
greatly augments its efficacy in killing cancer cells.
Ongoing experiments in models in vivo demonstrate that large tumor masses can be dramatically
reduced with this gene-prodrug therapy.
Massimo Degano
Figure 29. Crystal structure of the trypanosomal IG-NH
enzyme. The homotetrameric arrangement of subunit is
characteristic of the nucleoside hydrolase enzyme
family, that are targets for antibacterial drug design and
are currently being tested in cancer suicide gene
therapy.
Harnessing the immune system against solid tumors
Our 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 a therapeutic tumor-specific immune response.
Monitoring the immune response against a tumor
associated antigen (TAA) in 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 selective immune tolerance. Indeed, tumor-bearing
mice still harbor TAA-specific T lymphocytes that
no longer respond to a specific vaccination.
To investigate immune mechanisms that impact
early on during tumor development, we have focused on invariant NKT (iNKT) cells, a subset of T
lymphocytes endowed with innate effector functions that aid in the establishment of adaptive immune responses, and play a spontaneous protective role against experimental tumors. We have
found that lack of iNKT cells in TRAMP mice results in the appearance of more precocious and
aggressive tumors that significantly reduce animal
survival. However, TRAMP mice bearing or lacking iNKT cells respond similarly to a TAA-specific
vaccination and develop tolerance to a TAA antigen at comparable rate. Hence, iNKT cells have a
critical role in the immune surveillance of carcinoma that is independent of tumor-specific immunity.
Considering the profound state of TAA-specific
immune tolerance that associates with PC progression in TRAMP mice, we have investigated
the possibility to “reload” the immune system by
allotransplantation. We have found that non-myeloablative minor histocompatibility mismatched
hematopoietic stem cell transplantation and donor
lymphocyte infusion of unmanipulated lymphocytes, combined with post-transplant tumor-specific vaccination circumvent tumor-specific tolerance allowing acute tumor rejection and the establishment of protective immune surveillance.
Hence, we have identified a strategy to overcome
cancer-associated immune tolerance, which also
represents the base for designing safer and more
effective transplantation strategies for solid tumors.
Matteo Bellone
Figure 30. In collaboration with Dr. Mondino’s group we have found that non-myeloablative minor histocompatibility
mismatched hematopoietic stem cell transplantation (fHCT) and donor lymphocyte infusion of unmanipulated
lymphocytes (DLI) associated with post-transplant tumor-specific vaccination (vax) prolong the survival of prostate
cancer-bearing TRAMP mice. TRAMP/fDLI/vax and TRAMP/vax mice were boosted monthly with the vaccine,
compared to wild type (WT)/fDLI/vax and TRAMP/PBS mice and analyzed for survival.
Dynamics of immune responses Unit
Our research program seeks to dissect the complex dynamics of host-virus interactions with a particular focus on the development and function of
adaptive immune responses. Since it is still beyond
the reach of even the most sophisticated in vitro
methodology to simulate the complex interplay of
physical, cellular, biochemical, and other factors
that influence cell behavior in microvessels and interstitial tissues, we make use of intravital microscopy. This technique is complemented by
more traditional molecular, cellular and histological
approaches, thus characterizing host-virus interactions at the molecular-, single cell- and whole
animal-level.
Ongoing projects in the lab include:
1. To characterize how viruses are handled within
draining lymph nodes upon peripheral inocula-
tion and how antiviral immune responses are
generated.
2. To dissect the cellular and molecular underpinnings of liver immunopathology (in collaboration
with Luca Guidotti).
3. To determine the influence of antigenic stimulation on the development and progression of
chronic lymphocytic leukemia and to characterize the behavior of leukemic cells in secondary
lymphoid organs and bone marrow (in collaboration with Federico Caligaris-Cappio and Paolo
Ghia).
4. To discover and characterize novel adjuvants for
adaptive immune responses.
Matteo Iannacone
147
Research Units
Figure 31. Multiphoton micrograph of
vesicular stomatitis virus (VSV)-eGFPinfected lymph node. VSV-eGFP infection
of lymph node induced green fluorescent
protein (GFP) expression in macrophages
but not in nerves (red). Blue depicts
second harmonic signal from collagen in
the lymph node capsule.
Emerging and re-emerging pathogens: Tuberculosis and multidrug
resistant nosocomial pathogens
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 TB
diagnosis, biomarkers and the role of small noncoding RNA in TB pathogenesis.
In the framework of the TMREST (EUFP7) and
TBChild (EDCTP) project we are performing the
final validation of a new automatic platform for rapid
diagnosis of malaria and tuberculosis.
Within the framework of the TBPANNET EU grants,
we established a European consortium with extensive experience in basic and clinical research
on MDR-TB, TB control and epidemiology.
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 MTBH37Rv
and the avirulent strain MbovisBCG were sequenced to identify unknown sRNAs in mycobacteria. We performed validation of candidates by
expression analysis and target prediction. Twenty
candidates have been confirmed by Northern blot.
We implemented the activities of our WHO laboratory for control of multidrug resistance TB Supranational supporting the implementation of TB
diagnosis in 12 middle-high burden TB Countries
world wide.
Molecular epidemiology and virulence 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 is the
predominant clone in the US and is emerging in
Europe. Studying 450MRSA strains 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 and ST228 3) toxigenic US300 related strains causing severe infections. We are studying the biofilm capacity
production and secretion of soluble factors.
C. difficile (CD) colitis is increasing in nosocomial
settings. CD 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. We are currently investigating the antibacterial role of defensins
against CD.
Daniela Maria Cirillo
Experimental immunology Unit
Investigating the tumor immunesurveillance by T lymphocytes specific for
lipid or peptide antigens
We aim at gaining mechanistic insights into two aspects of the immune response that have direct relevance to human health.
1. Development and function of CD1-restricted T
cells specific for lipid antigens
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 we have identified an iNKT
cell-specific miRNA signature. By whole transcriptomic analysis, we have defined mRNAs whose
expression is selectively modified in iNKT cells in
the absence of total miRNAs. Target identification
for the iNKT cell-specific miRNA signature is currently being performed by integrating multiple bioinformatic approaches. We are also investigating the
mechanisms by which iNKT cells control prostate
cancer growth in the mouse TRAMP model by
maintaining the anti-tumor profile of tumor-infiltrating
macrophages.
A second type of CD1 restricted T cells recognizes
endogenous lipid antigens presented by CD1a, b,
c and d. We have identified a leukemia-associated
lipid antigen that stimulates CD1c-restricted autoreactive T cells and are determining its distribution in primary leukemia blasts. Furthermore, we
are assessing the efficacy of human CD1 autoreactive T cell adoptive immunotherapy in immune
deficient mice grafted with human leukemia cells.
2. The antigenic landscape of the mutated tumor
antigenome
We have hypothesized that somatic mutations in
colorectal cancer genes (CRC CAN-genes) generate strongly immunogenic antigens and specific
immune responses in patients. By next generation
sequencing, we have identified somatic mutations
in the 40 most frequently mutated CRC CANgenes. Using reverse immunology, we have started
to determine the immunogenicity of the mutated
epitopes. The data obtained in the first CRC show
that a frameshift mutation in the APC tumor suppressor generates a tumor-unique immunogenic
epitope presented by HLA-DR to CD4+ T cells.
Paolo Dellabona
Immunopathology Unit
Immunopathogenesis of viral hepatitis
The hepatitis B virus (HBV) and hepatitis C virus
(HCV) are noncytopathic viruses causing immunemediated 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
complications (e.g. cirrhosis and hepatocellular
carcinoma, HCC) of these infections. The main objective of our Viral Hepatitis research program 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 designing
novel therapeutic approaches to prevent and cure
these diseases. The program takes advantage of
infected patients, proprietary mouse models of infection and new technological advances in the field
of live imaging (e.g. intravital microscopy). Using
these resources we plan to tackle a number of un-
resolved issues that comprise the means by which
virus-specific T cells traffic and recognize viral antigens within the normal, cirrhotic or cancerous livers
and the cellular/molecular basis for disease resolution. Pertinent to the latter we have recently
demonstrated that Kupffer cells, the intravascular
liver-resident macrophages, limit the severity of immunopathology during viral hepatitis by removing
apoptotic hepatocytes in a scavenger receptor-dependent manner. Having also recently described a
novel role for platelets in the pathogenesis of viral
hepatitis (i.e. platelets adhering to activated endothelium of the liver microcirculation become activated and promote the influx of pathogenic
virus-specific T cells into the organ parenchyma),
we are performing a large preclinical trial evaluating
the impact of anti-platelet therapy on the severity of
immune-mediated chronic liver injury and the development of HCC. Additional preclinical activities
149
Research Units
of our Unit include the implementation of novel
strategies attempting to cure established HCC,
such as the local delivery of anticancer drugs
through cell-based approaches involving the ma-
nipulation of tumor-infiltrating monocytes uniquely
express the angiopoietin receptor Tie2.
Luca G. Guidotti
We are interested in identifying strategies to overcome peripheral tolerance and augment T cell responses to tumors, and instead dampen
autoimmune manifestations. We combine single
cell-based analyses of T cell function in vivo with
their biochemical and molecular characterization in
vitro. We exploit both transplantable (TS/A-LACK)
and spontaneous (TRAMP: Transgenic adenocarcinoma of the mouse prostate) tumor model and
have developed active, adoptive and combined
immunotherapeutic strategies suitable of clinical
translation. Our studies support the notion that natural responses to the tumor might dampen vaccine-induced T cell responses (Schiering et al.
Cancer Res. 2010), and support the importance
of expanding tumor-specific T cell ex vivo for adoptive immunotherapy (Caserta et al., Eur. J. Immunol. 2010). In collaboration with the group of M.
Bellone we found that the combination of non myeloablative irradiation, allogeneic transplantation and
tumor-specific vaccination promotes potent CD4
and CD8 T cell responses able to cure mice of established prostate cancer (Hess et al. Cancer Res
2010; Manzo et al. In press). We have also shown
that therapeutic activity can be reproduced by the
use of autologous TCR-redirected T cells, genetically engineered to express TCR specific for either
tumor or minor histocompatibility antigens. Current
effort are focused in identifying the intratumoral distribution of TCR redirected T cells and in finding
strategies to control their functions. Among the
pathways important for T cell fate determination
(activation, proliferation and differentiation) we are
focusing on the role of Tuberous Sclerosis Complex and the mammalian Target of Rapamycin. We
found that T-lineage restricted inactivation of TSC1
and blocking mTOR signaling by Rapamycin respectively prevents proper T cell development and
TCR/CD28-induced T helper cell differentiation.
Mechanistically TSC appears critical for balancing
mTOR-dependent proliferation and survival, while
mTOR reveals capable of determining Ifng, Il4 and
Foxp3 transcription by controlling their promoter
methylation (Tomasoni et al., In press). We are currently exploiting these findings to define strategies
to manipulate T cell functions in vivo.
Anna Mondino
Figure 32. The image depicts
allogeneic CD4 (green) and CD8
(red) T cells infiltrating the stroma
and the prostatic epithelium of the
prostate of TRAMP mice
undergoing non myeloablative
transplantation and tumor-specific
vaccination.
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 previously reported in the blood of patients with
advanced melanoma patients and stage IB/III pancreatic cancer the presence of tumor antigen(TA)specific CD4+ Th2 cell response in the presence
of conserved CD4+ Th1 anti-viral immunity, suggesting that these patients do not suffer from generalized immunosuppression but rather they are
specifically impaired in antitumor immunity. Notably,
in pancreatic cancer Th2 immunodeviation in the
blood well correlated at the tumor site with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We therefore asked a) whether Th2
cells present at the tumor site have a role in disease progression and b) what leads to the tumor
related Th2 immune-deviation in pancreatic cancer. To address the first question we enumerated
GATA-3+ and T-bet+ lymphoid cells in tumor samples from 69 patients underwent surgical resection
for stage IB/III pancreatic cancer. We found that
GATA-3+ were predominant over T-bet+ cells in all
but one sample and identified the ratio of GATA3+/T-bet+ lymphoid cells as an independent prognostic factor of patient survival in multivariate
analysis. Indeed, patients with a ratio inferior to the
median value had a statistically significant prolonged overall survival. Second, we addressed the
mechanism that leads to Th2-type inflammation
and identified a complex cross-talk among tumor
cells, cancer associated fibroblasts (CAFs) and
DCs that implicates a) the secretion of pro-inflammatory cytokines (i.e., TNF-α and IL-1β) by tumor
cells with b) activation of CAFs to secrete the
thymic stromal lymphopoietin (TSLP), c) activation
by CAFs-derived TSLP of resident DCs with Th2
polarizing capability and which secrete Th2 attracting chemokines, and d) migration of TSLP activated TA-loaded DCs to draining LNs where Th2
cell priming occurs.
Maria Pia Protti
Antigenic and phenotypic characterisation of HIV-1 variants in
transmission and disease progression as target for vaccine development
Some HIV-1 variants are able to elicit a strong humoral virus-specific, broad neutralizing antibody response, providing fundamental proof-of-principle
that such a response can be elicited in vivo, and
thus may elicit these responses again if formulated
into an appropriate vaccine immunogen. To test for
this neutralizing antibody response we have identify patients focusing on specific cohorts with special traits; i.e. those with primary infection, long term
non progression (LTNP) and elite viral control. In
general neutralization as well as cross neutralization were rare in most of the individuals and titers
were low to medium. Elite Controllers and LTNP
were able to cross-neutralize multiple viruses in approximately 20% of cases. Only infected slow progressing children developed an autologus
neutralizing antibody response which increased in
breath to include also heterologous viruses within
2 years. The detailed analysis of the antibody
specificity from acute infection onwards in a set of
adult patients showed that the autologus neutralizing antibody response is directed only against few
early virus variants and their binding activity to selected regions of the gp120 and gp41. The phenotypic viral variation followed usually the
appearance of the neutralizing antibody response
supporting the role of this later one in inducing escape variants. We used the antigenic data together
with a detailed viral phenotypic and genotypic
analysis as basis for a genetic and functional database, which allowed to identify viral regions relevant for antigen optimisation and identification of
novel neutralization-sensitive epitopes as HIV-1
vaccine candidates to be forwarded for immunization of animals.
Gabriella Scarlatti
151
Research Units
Viral pathogens and biosafety Unit
Human Immunodeficiency Virus (HIV): virus-host interactions Influenza
Viruses: towards an universal vaccine
HIV
Influenza viruses
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. Indeed, TRIM22 significantly impaired HIV-1
replication by interfering with HIV-1 transcription
and independently of Tat and NF-κB LTR-driven
transcription. Current studies are ongoing to define the precise mechanism through the identification and characterization of TRIM22 partners and
mutants of both HIV-LTR and TRIM22 protein.
The immunogenicity of the new monovalent vaccine against 2009 pandemic influenza A/H1N1
was evaluated in a total of 192 individuals, including 44 HIV-1 positive individuals and 148 HIV-1negative healthy controls enrolled during the 2009
influenza vaccination campaign at the San Raffaele Scientific Institute. A single dose of monovalent MF59-adjuvanted 2009 influenza H1N1 vaccine induced an immune dominant response
against pandemic H1N1 virus in HIV-1 positive individuals reaching titers similar to those of HIV-1
negative subjects, although, the seroconversion
rate was negatively associated with HIV infection
and increasing age.
As heterosubtypic antibodies (Ab) that bind to
conserved regions of the influenza hemagglutinin
(H) protein may exist as part of a subdominant response and may widely cross-react with influenza
A viruses, we are evaluating the capacity of the
2009 pandemic influenza vaccine to elicit heterosubtypic Ab responses to identify, through the
isolation of human monoclonal Ab, those epitopes that elicit a broad response against group 1
and 2 influenza viruses. These studies will pave
the way for a universal vaccine.
Elisa Vicenzi
Management and antiretroviral treatment of HIV infection
It is a clinical research unit within the Department
of Infectious Diseases, 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, we participate to several national and international networks of HIV cohorts. To be part of these collaborations, our internal database (the Infectious Diseases Database (IDD-HSR)) is regularly updated.
Moreover, we use data from IDD-HSR for our 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 and it is also actively involved in proposing, coordinating and conducting investigator-driven independent, no-profit, randomised and nonrandomised clinical studies and committed to develop spin-off projects on the following:
1. Strategies for salvage therapy including maraviroc, etravirine and raltegravir as an effective
regimen in HIV infected subjects without remaining therapeutic options.
2. Holding regimens in patients without options by
using lamivudine monotherapy: the enrolment
in a pilot trial sponsored by AIFA is almost complete, results are expected for the end of the
year.
3. Simplification strategies in HIV infected patients
virologically suppressed. Two multicentric trials
comparing the effect of lopinavir/ ritonavir
monotherapy (MOLO) or atazanavir/ritonavir
monotherapy (MODaT)in first line therapy with
respect to standard of care have been opened
and are currently enrolling patients.
4. Cancer and HIV infection: description of longterm survival in HIV infected subjects with cancers, long-term immunological recovery in cancers survivors, immunereconstitution syndrome. A pilot trial investigating the interactions
between doxorubicin, protease inhibitors and
raltegravir in cases with lymphoma is currently
enorolling patients
5. Diabetes and HIV infection: focus on prevalence of diabetes in HIV infection in comparison
with the general population, early diagnosis of
glucose tolerance in HIV infected at high risk
with normal glucose value.
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 patients receiving antiretroviral treatment relates to the role of
the CNS as a reservoir for HIV and to the increased
prevalence of neurocognitive impairment (NCI). We
have shown that cerebrospinal fluid (CSF) markers
of immuneactivation, such as neopterin, CCL2 and
sUPAr are increased in untreated patients with NCI
compared to asymptomatic patients and also observed that both unimpaired and NCI treated patients have levels of these markers higher than
controls. Thus, it is likely that NCI in treated patients
results from persistent intrathecal immuneactivation despite apparently controlled viral replication.
PML is a progressive demyelinating disease occurring in patients with compromised immunity
caused by JC virus (JCV) infection of oligodendrocytes. The mechanisms leading to JCV reactivation and PML are mostly unknown. 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 B-cell and T cell responses against VP1,
and observed that, at the time of PML, patients
have lower IgG titres and lower T-cell responses
compared to controls and that responses tend to
increase following reversion of underlying immunosuppression. Thus the combined study of JCVspecific T and B cell responses can provide a tool
to recognize persons at risk to develop PML and
for subsequent disease monitoring.
Paola Cinque
153
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 antiHCV 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
Immunotherapy of HIV infection
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 non-responders.” However, the
proportion of patients experiencing immunologic
failure depends on how failure is defined, the observation period, and the CD4 T-cell count at start
of treatment.
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. 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.
The clinical research activity of Vaccine and Immunotherapy Research Center is currently focused
on the conduction of multicentric, internantional
phase I and phase II clinical trials employing IL-7 as
immunotherapy on HIV positive patients with poor
CD4 recovery under conventional antiretroviral
therapy.
Moreover, we are exploring a proof of concept
strategy (ERAMUNE-01 trial) that combines the
association of novel safe and very potent antiviral
therapy plus an immune experimental intervention
(IL-7) that would activate the latently infected cells
in order to purge the reservoir of HIV-infected pa-
tients while the antiviral combination would block
the spread of the virus. The concept will ultimately
test whether exhausting the HIV reservoir and ultimately obtaining virus eradication is feasible. If
successful, this would open the door for more in-
novative approachesthat would be capable of
eradicating the virus in a broader spectrum of patients.
Giuseppe Tambussi
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 of the involved pathogenic mechanisms. We are specifically interested in:
• the pathogenesis and clinical features of the
prototypic systemic autoimmune disease, Systemic Lupus Erythematosus;
• 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 pa-
tients with sustained systemic inflammation;
• the immunopathogenesis of fibrosis and vascular damage in scleroderma and associated conditions;
• 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
Planned transition to sirolimus-based therapy versus continued tacrolimusbased therapy in renal allograft recipients rapamune 0468E-4500-WW
Study Design
Patients screening - 14 days before through 14
days post transplantation (Tx)
- all patients initiated on tacrolimus + IMPDH inhibitor
Patients randomization - 90 to 150 days post
transplantataion
- patients will continue tacrolimus + IMPDH inhibitor
vs transition to sirolimus + IMPDH inhibitor
post Tx by on-therapy analysis (GFR measured
using iothalamate clearance)
• Secondary Endpoint (by on-therapy and intent
to treat analysis)
1. percent of patients who demonstrated a
>5ml/min/1.73m2 improvement in measured
GFR
2. percent of patients who demonstrated a
>5ml/min/1.73m2 improvement in calculated
GFR
3. measured GFR, calculated GFR and serum creatinine
4. slope of measured GFR and slope of calculated
GFR
5. change in Measured GFR, calculated GFR and
serum creatinine
Efficacy Endpoints
• Primary Endpoint
percent of patients who demonstrated a
>5ml/min/1.73 m2
1. improvement in measured glomerular filtration
rate (GFR) from randomization to 24 months
Selection of patients
• Screening - inclusion criteria
1. age ≥ 18 yrs
2. primary renal Tx recipients
3. those capable of having children provided that
agree to use method of birth control
The aim of the study is to evaluate feasibility, safety
and efficacy of the conversion from tacrolimus
based therapy to sirolimus based therapy in kidney transplanted patients.
Open-label, randomized, comparative, multi-center, multinational study.
155
4. those not capable of having children
• Screening - exclusion criteria
1. recipients of:
• previous renal Tx
• multiple organ Tx
• adult or pediatric en bloc kidney Tx
2. recipient who required or will require desensitization protocols
3. known history of:
• focal segmental glomerulosclerosis or membranoproliferative glomerulonephritis
• malignancy
• HIV
• Randomization - inclusion criteria
1. 90 to 150 days post Tx
2. Treatment with tacrolimus and IMPDH inhibitor
• Randomization - exclusion criteria
1. calculated GFR < 40 mL/min/1.73 m2
2. spot urin protein to creatinine ratio > 0.5
3. corticosteroid withdrawal/avoidance and did not
receive induction therapy
4. corticosteroid discontinued < 30 days before
randomization
5. acute rejection/interstitial fibrosis and tubular atrophy (using Banff 2007 criteria)
6. major surgery < 2 week prior randomization
7. active post-operative complication
Antonio Secchi
Pancreatic tumors Unit: immunotherapy and β cell
function substitution
Pancreatic cancer is the fourth leading cause of
cancer death and it has the worst prognosis among
malignancies. Peculiar is the tumor microenvironment characterised by an extensive desmoplasia
which favors tumor progression. In this fibrotic tissue we observed a predominant Th2 (GATA-3(+))
over Th1 (T-bet(+)) lymphoid infiltrate and we found
that the ratio of GATA-3(+)/T-bet(+) is an independent predictive marker of postoperative patient
survival: patients with a low ratio had a better prognosis, implying an active role for Th2 responses in
disease progression. We observed that Thymic
stromal lymphopoietin (TSLP), which favors Th2
cell polarization, was secreted by cancer-associated fibroblasts (CAFs). TSLP-containing supernatants from activated CAFs induced in vitro dendritic cells to secrete Th2-attracting chemokines,
and to acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were
expressed in the tumor and in the stroma, and
TSLPR-expressing DCs were present in the tumor
stroma and in tumor-draining but not in nondraining
lymph nodes. Collectively, this study identifies in
pancreatic cancer a cross talk between tumor cells
and CAFs, resulting in a TSLP-dependent induction
of Th2-type inflammation which associates with
reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis
in pancreatic cancer.
In the field of β-cell function substitution, the experience of islet autotransplantation is growing,
and our Institute is the only one in Italy where a
patient can undergo this procedure. Islet autotransplantation is indicated to improve postoperative glycemic control, when a portion of the gland,
not affected by neoplastic disease, has to be removed for technical reasons. Until now, sixteen
patients underwent islet autotransplantation with a
technical success rate of 100%. A randomised
study is ongoing on islet autotransplantation of the
left pancreas as an alternative to pancreatico-jejunostomy after pancreaticoduodenectomy with
high-risk pancreatic anastomosis.
Marco Braga
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, preneo-
plastic 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 GATA3+ in cervical tissues correlate with disease regression.
These data strenghten the tight correlation between immune response and HPV-related carcinogenesis.
More recently, attention has been forwarded to
emerging HPV genotypes (HPV 31) and their immunogenetic activity.
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 subpopulations and correlation with HPV and HIV
genital infection.
Massimo Origoni
Figure 33. Human Papillomavirus
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 patients 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 as-
signed 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 out-come, 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
157
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
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 expand 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 estab-
lished 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 evidencebased data.
Irritable bowel syndrome (IBS) is a functional disorder of gastrointestinal tract with a prevalence
around 7-15% of the general population in Western
Countries and of about 10% in the general population in Italy. Infectious gastroenteritis can trigger
long-lasting alterations in gut immunity and function and is considered to be the strongest environmental risk factors for IBS. Others as suggested
certain food components as triggers of symptoms
in IBS. Aim of our research is to evaluate the role of
a possible abnormal immune response to dietary
components in determining the symptoms of IBS,
applying the cytometric assay that quantifies basophils after stimulation with food allergens based
on cell-surface expression of CD63, recently
demonstrated to have a high level of sensitivity,
specificity and accuracy.
Mario Guslandi
Digestive pathophysiology
The gastro-esophageal- laryngopharyngeal reflux: from pathophysiology
to clinical management. The role of the new diagnostic tests
Gastroesophageal reflux disease (GERD) is defined
as a condition that develops when reflux of stomach contents causes troublesome symptoms
and/or complications. The manifestations of GERD
are classically described as heartburn and reflux,
which are often referred to as “typical GERD”.
However, GERD may also present atypically and is
referred to as extraesophageal syndrome. Common extraesophageal manifestations are hoarseness, globus, throat clearing, and cough; many
evidences show that the gastro-esophageal reflux
(GERD) may play a pivotal role in the pathogenesis
of the symptoms the so called laryngopharyngeal
Reflux (LPR).
Diagnostic approach to patients with extraesophageal reflux disease involved the use of insensitive tools, which have hampered the ability to
correctly identify patients at risk. In fact, empiric trial
using proton pump inhibitors (PPI) is still the recommended initial approach to the patients suspected of having reflux as the cause for
extraesophageal symptoms.
However, research shows conflicting evidence of
utility of empiric acid suppression for these symptoms and an objective test is necessary.
The ambulatory impedance/pH monitoring performed on or off therapy is the best test for studying the gastro-esophageal reflux but can be
misleading when the pH is measured in the pharynx.
In addition, up to now is unexplained why in some
patients the reflux reach the proximal esophagus.
Our aim is to study in this patients the esophageal
motility with a new manometric system with 36
pressure sensors that allows to perform an high
resolution manometry.
In addition we study the proximal reflux with a new
pH catheter for the detection of oropharyngeal acid
reflux. The Restech pH catheter uses a nasopharyngeal catheter to measure the pH in either liquid
or aerosolized droplets.
The goal of the study is to understand the physiopathology of the gastro-esophageal- laryngopharyngeal reflux.
Sandro Passaretti
159
DRI
Diabetes Research Institute
Type 1 diabetes (T1D) afflicts nearly 150,000 people in Italy, most of them children or young adults. Untreated, T1D is a lethal 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).
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 remain 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 a Scientific Advisory Board (Guido Pozza, Camillo Ricordi, Giuseppe Chiumello,
Massimo Trucco), two consultants (E. Bonifacio, Uni-Dresden; M. Von Herrath, Uni-San Diego) and is
composed of three Units of Basic Research (L. Piemonti, M. Battaglia, M. Falcone), three Groups of Clinical Research (P. Maffi, L. Falqui, R. Bonfanti) and three Cores (L. Piemonti/R. Nano, A. Esposito/F. De
Cobelli/M. Venturini and M. Scavini).
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;) and three external Cores (L. Monti, HSR; E. Bazzigaluppi, Laboraf; A. Sanna, LaboRaf), which closely interact with HSRDRI 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 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, DRI
Immune pathogenesis of Type 1 Diabetes
Genetic and environmental factors affect pathogenesis of autoimmune disease like Type 1 Diabetes (T1D) by altering innate immune regulatory
pathways whose function is to modulate the activation of self-reactive T lymphocytes. In fact, it recently emerged that innate immune cells such as
dendritic cells, mast cells and natural killer T cells
are central for prevention of autoimmunity. We
demonstrated that defects of those innate immune
reguatory cells contribute to the pathogenesis of
autoimmune T1D. Specifically, we found that the
crosstalk between dendritic cells and invariant NKT
cells mediated by SLAM-SLAM interaction is fundamental to maintain self-tolerance and it is defective in NOD mice that are prone to autoimmune
diabetes (Baev D.V. et al. J Immun 2008 and Caielli
S et al. J Immunol 2010). Recently, we investigated
the role in T1D of tolerogenic dendritic cells that reside in the gut mucosa and whose function is
modulated by environmental factors such as diet
and microbiota. In human T1D patients, we found
that those cells are defective and fail to induce peripheral differentiation of FoxP3+ Treg cells in the
gut (Badami E. et al. Diabetes, under revision). The
same defect is present in T1D-prone NOD mice
and, importantly, changes in the diet and/or microflora composition prevented autoimmune T1D
by restoring gut tolerogenic DC function in those
mice. We also found tha mast cells of NOD mice
fail to acquire a tolerogenic IL-10-secreting phenotype and contribute to the pathogenesis of autoimmune T1D with an overly inflammatory
phenotype (Gri G. et al. in preparation). Our future
goal is to link innate immune cell defects to T1D
pathogenesis and to develop molecular and cellular therapeutic approaches to restore their immune
regulatory function and prevent T1D. In the past
year, we generated a SLAM-containing retroviral
vector (SLAM_MIGR) to be used in vitro and in vivo
to transfect DCs restore their capacity to induce
regulatory iNKT cells. Moreover, we are generating
conditional knockout mice to delete mast cells
(Mcpt5-iDTR) and/or tolerogenic intestinal DCs
(CD103CD11c-iDTR) at different checkpoints in diabetes progression and assess their role in maintenance of peripheral tolerance towards pancreatic
islet antigens.
Marika Falcone
Figure 34. Tolerogenic effect of iNKT cells on DC maturation
β cell biology
β cell replacement in type 1 diabetes
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. 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. Our project focuses on creating conditions
that favour β cell expansion and survival in trans161
Research Units, DRI
planted and native environments
The somatic cell therapy for type 1 diabetes 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 propose to: (a) study bone marrow as
site for islet transplantation, (b) develop novel islet
survival strategies by modulating inflammation
specifically inhibiting pathways involving CCL2 or
IL-8, (c) Improve islet transplantation outcome by
cotransplantation of islets and feeder cells using
mesenchymal stem cells, (d) determine mechanisms of islet autoantigen immunization and destruction (e) identify a renewable source of cells to
be used to increase the transplantable β cell
mass.
Lorenzo Piemonti
Figure 35. PMN infiltration in hepatic tissue after islet iso-transplantation in diabetic wild type BALB/C mice. 24h
after transplantation, islets (Is) localized in the blood vessels of portal space (Vs). Intravascular thrombi were
consistently found around islets. Regions with abnormal cell shape and texture (Ischemic area, IschT) or necrotic
(NecT) wedge-shaped regions appeared (Left Panel) in normal tissue (NorT). PMN infiltration (stained in red by
napthol AS-D chloroacetate technique for esterase) was evident into necrotic hepatic tissue and around
transplanted islets (Right Panel).
Cell imaging
Imaging of iron oxide (Endorem®) labeled transplanted pancreatic islets by magnetic resonance
imaging, from bench to bedside
Non-invasive magnetic resonance imaging (MRI) of
pancreatic islets is an attractive option for the “realtime” 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 Endorem®, a clinically approved contrast agent, assessing safety and in vivo
MRI quality issues in a preclinical model. In collaboration with the Islet Transplant Program and the
Radiology Department, T1diabetic patients, were
transplanted intrahepatically with islets, of which a
fraction was labeled. MRI (T2*-weighted imaging)
allowed to visualize in the patients after transplantation (1, 2, 3, 7 days and once a month up to 1
year) hypointese spots associated with labeled
islets within the liver parenchyma. The MRI readout was correlated with metabolic measurements
of islet function (glycemia; C-peptide; insulin need;
HbA1c) and its usefulness in terms of prediction of
functional success or failure assessed.
Role of H2O2 production in insulin biosynthesis and
folding
Many signaling pathways regulating insulin synthesis and secretion are redox regulated, and hence
potential targets of H2O2. Despite its essential signaling roles H2O2 is toxic at high concentrations. β
cells express low levels of many antioxidant en-
zymes, an apparent paradox that could make them
vulnerable to H2O2. Upon glucose stimulation, the
endoplasmic reticulum (ER) of β cells must cope
with massive proinsulin synthesis and processing.
Since insulin biogenesis requires formation of disulfide bonds, proper oxidizing conditions need to be
maintained within the ER lumen. Perturbations in
redox homeostasis cause ER stress, aimed at reducing the protein load and increasing folding capacity. To investigate whether H2O2 is produced in
correlation with glucose-induced insulin production, we have used organelle-targeted, specific ratiometric sensors, based on HyPer, a fusion protein
between GFP and OxyR in transient and stable
pancreatic β cell models to monitor changes in
H2O2 levels in the ER lumen, in the mitochondria
and in the cytosol upon insulin biosynthesis induction.
Maria Luisa Malosio
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: a) characterize the immune responses occurring in the target organ of
T1D patients; b) dissect the immunological players
in charge of T1D development; c) define new clinical grade protocols for the expansion of human
Tregs; and d) 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. We observed up-regulation of Th17-cell immunity and functional defects
in the Tregs within the PLN of T1D subjects but not
in their blood. In addition, the proinsulin-specific
Treg-mediated control was altered in the PLN of diabetic patients but not in those of controls. b)
Analysis of peripheral blood collected from new
onset pediatric T1D patients showed a clear reduction of cells of the innate immunity. c) New
studies have now delineated a good manufacturing practice (GMP) protocol for rapamycin-based
human Tregs expansion. Importantly, these cells
are free of potentially-pathogenic effector T cells.
Finally, d) we found that antigen-specific Treg cells
transfer tolerance in a stringent model of islet transplantation and this tolerance is IL-10 mediated.
Conclusions: a) We provide evidences for an unbalanced immune-status in the target organ of
T1D subjects (i.e., pancreas draining lymphnodes) and treatments restoring the immune
homeostasis in the pancreas of these patients
represent a potential therapeutic strategy. b)
Functional studies are ongoing to better delineate
the role of the innate immunity in the pathogenesis of T1D. c) Rapamycin secures the ex vivo expanded human Treg cells and provide additional
justification for their clinical use in future cell therapy based trials. d) The definition of a clinical grade
protocol for the generation of antigen-specific human Tr1 cells is in progress to be used as cell
therapy in T1D patients undergoing pancreatic
islet transplantation.
Manuela Battaglia
163
Clinical Research Units, DRI
Islet transplantation
The clinical Islet Transplantation Program activity
has focused on the follow-up of patients who received islet transplant in previous clinical trial, the
continuation of ongoing clinical trials and the start
up of new lines of research.
Follow-up and continuation of ongoing clinical trials:
1. Edmonton protocol: 2/12 patients functioning after 8 years;
2. Pre transplant rapamycin treatment associated
to the Edmonton protocol: 5/10 patients still
functioning after 7 (2 patients), 6 (2 patients)
and 5 (1 patients) years;
3. Calcineurin inhibitor free immunosuppression
protocol (multicentre pilot trial): 2/8 patients functioning after 2 years;
4. Intra bone marrow islet infusion in patients not eligible for islet infusion in the liver: 5 procedure
were performed (2 cases of islet alone; 1 case
of islet after kidney; 2 cases of autotransplants).
These last patients showed sustained function in
terms of C-peptide;
5. In vivo magnetic resonance imaging of the transplanted islets: 1 new patient was included; 2/3
patients on follow-up are still functioning;
6. Islet and kidney transplant: 3 new patients;
7. Effect of islet transplantation alone on long-term
diabetes complications(i.e., early retinopathy,
neuropathy, carotid artery disease): data of all
patients on follow-up are being collected
prospectively and will be analyzed after the completion of a 5 years follow-up.
8. Prospective study of kidney function and incidence of cancer in patients who had received
islet transplant alone: all patients are on followup and data are analyzed periodically;
9. Islet autotransplantation in patients who underwent total pancreatectomy: 3/4 patients functioning; 10 new patients enrolled in the study.
New studies:
1. A phase 2 multicenter, randomized, open label,
parallel assignment, pilot study to assess the efficacy and safety of reparixin following a singleinfusion of islet in patients with type 1 diabetes
mellitus. 3 patients were included in the study
and underwent islet transplant;
2. Total pancreatectomy with islet autotransplantation as a superior alternative to pancreatoduodenectomy in patients at very high-risk of complications of the pancreatic anastomosis: a
single-center prospectic randomised clinical trial:
the study was approved by the Ethics Committee and one patient was enrolled and underwent
islet transplant;
3. Islet re-infusion in previously insulin-independent
patients to restore the insulin-free condition: 1
patient was included and underwent islet transplant.
Paola Maffi
Prevention in Type 1 diabetes
This research program embraces all the studies
aiming at defining the pathogenetic mechanisms of
induction and conservation of autoimmunity in humans and identifying strategies for halting and/or reversing the progression to clinically overt type 1diabetes. To pursue this line of research, in 2002, a
TrialNet Clinical Center was established at San Raffaele, with the continuous support of the Juvenile Diabetes Research Foundation (JDRF).
TrialNet is a NIH-supported network of clinical centres, investigators and core support facilities in the
US, Canada, United Kingdom, Italy, Finland and
Australia. The goals of TrialNet programs are to: further define epidemiology, natural history and risk factors in the development type 1 diabetes; the design
and implementation of clinical trials exploring agents
able to halt the progression of type 1 diabetes in recent-onset patients, and delaying or preventing the
development of the disease in individuals at risk.
The San Raffaele Center participated in studies
aimed at improving metabolic assessments in type
1 diabetes mellitus clinical trials, and in the Mycophenolate-Daclizumab (antiCD25) immunosuppresion clinical trial to preserve residual β-cell function in recent onset subjects. Ongoing studies
include: the natural history of development of type
1 diabetes; oral insulin for the prevention of diabetes
in relatives at risk. Under implementation are studies which will evaluate diabetes antigen (e.g. GAD)
parenteral administration for the prevention of diabetes in relatives at risk. An additional focus of the
Clinical Center 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.
Luca Falqui
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 and the Department of Metabolic
and Cardiovascular Sciences.
The Epidemiology and Data Management Core is
currently providing support to the following major
projects of the Diabetes Research Institute (DRI)
and the Islet Transplant Program:
a) a clinical trial testing safety, feasibility and efficacy of an immunosuppressive 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).
b) 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
less than 2 millimeters).
c) 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.
d) clinical research projects in diabetes and
pregnancy, including studies on pre-eclampsia in patients with pre-gestational diabetes,
screening for gestational diabetes and postpartum diabetes and early markers of fetal exposure to hyperglycemia during the pregnancy of women with pre-gestational diabetes.
e) a large multicenter clinical study on the effect
of self-monitoring of capillary glucose in patients with type 2 diabetes not treated with insulin (PRISMA Study).
f) pilot study to test a novel device for the noninvasive measurement of blood glucose in patients with diabetes.
Marina Scavini
Childhood diabetes
The Unit is dedicated to clinical research in the field
of diabetes in children and adolescents.
We follow 3 area of interest:
Immunology of type 1 diabetes
We have each year near 60-80 patients with type
1 diabetes at onset. We study this patients both
from humoral autoimmunity with antibodies and
cellular autoimmunity with a work on effector and
regulating T cell at onset of diabetes. This work is
done in collaboration with Battaglia’s team and with
Lampasona Lab. We have studied 20 patients for
T cells and we are following the residual β cell
function at 1 year from onset. Moreover we are
studing immunomodulation at onset of diabetes
with Gad vaccination and we treated 7 patients in
an international multicenter study.
We are working with Mario Negri in a study about
incidence and prevalence of type 1 diabetes in
Lombardy region. We received data from Varese
and Brescia and we are trying to define the epi-
demiology with a capture/recapture method.
We have a collaboration with Prof Barbetti and
ISPED diabetes study group for the analysis of non
autoimmune diabetes, and we published paper on
Mody, Insulin Mutation and neonatal diabetes.
New technology
We have studies about the introduction of new
technology for the treatment of children with diabetes. We are interested in the telemedicine and
the implementation of CSII with glucose sensors.
Microvascular complications
With the collaboration of Zerbini’s group and Prof
Lorenzi we are studying the prevalence of microvascular complications in our young adults and
we are planning an intervention trial with aspirin.
Riccardo Bonfanti
165
Clinical Research Units, DRI
Islet processing activity
IPF activity is dedicated to islet of Langerhans isolation from human pancreas
Allogenic transplant
IPF mission is to provide isolated human islets for
allo-transplantation in type 1 diabetic patients as
stated on the italian tissues transplant regulation.
Islets suitable for transplantation means that they
have been determined to meet all release specifications. At this purpose, IPF organized management with the target of ensuring that human islets
have the quality required for transplantation in humans.
Islet transplant represents a good model to study
different immunosuppressive strategy. IPF provide
islets for different clinical studies aimed to increase
the effectiveness of the islet transplant, to improve
islet engraftment and to achieve the immunological tolerance.
Autologous transplant
In patients with nonmalignant or malignant dis-
eases, undergoing completion or median pancreatectomy because of anastomosis leakage or impracticable anastomosis due to technical
difficulties and/or high risk of leakage, IPF provides
isolated islets from the remnant pancreas. Islets reinfused in the same patient allow to reach a
glycemic control also in case of completion pancreatectomy.
European Consortium Islet Transplant – Islet for Research
Islets from unsuccessful human islet isolation, 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, supported by JDRF, distributes
islet preparations not suitable for transplant, with
the aim to improve the research activities in diabetes.
Rita Nano
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International HIV Controllers Study. The major genetic determinants of HIV-1 control affect HLA
class I peptide presentation. Science: 2010; 330(6010): 1551-1557 - Article
IF 2009: 29,747
Pardi, R. Signal Transduction by Adhesion Receptors. Nature Education: 2010; 3(9): 38 - Article
Fornili, A; Giabbai, B; Garau, G and Degano, M. Energy Landscapes Associated with Macromolecular Conformational Changes from Endpoint Structures. J. Am. Chem. Soc.: 2010; 132(49):
17570-17577 - Article
IF 2009: 8,580
Iannacone, M; Moseman, EA; Tonti, E; Bosurgi, L; Junt, T; Henrickson, SE; Whelan, SP; Guidotti,
LG and von Andrian, UH. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature: 2010; 465(7301): 1079-1083 - Article
IF 2009: 34,480
Mondino, A; Dardalhon, V; Hess-Michelini, R; Loisel-Meyer, S; Taylor, N. Redirecting the immune
response: Role of adoptive T cell therapy. Hum. Gene Ther.: 2010; 21(5): 533-541 - Review
IF 2009: 4,202
Schiering, C; Guarnerio, J; Basso, V; Muzio, L and Mondino, A. Antigen-experienced CD4+ T
cells limit naïve T-cell priming in response to therapeutic vaccination in vivo. Cancer Res.: 2010;
70(15): 6161-6170 - Article
IF 2009: 7,543
Cecconi, V; Moro, M; Del Mare, S; Sidney, J; Bachi, A; Longhi, R; Sette, A; Protti, MP;
Dellabona, P and Casorati, G. The CD4+ T-cell epitope-binding register is a critical parameter
when generating functional HLA-DR tetramers with promiscuous peptides. Eur. J. Immunol.: 2010;
40(6): 1603-1616 - Article
IF 2009: 5,179
Sabin, C; Corti, D; Buzon, V; Seaman, MS; Lutje Hulsik, D; Hinz, A; Vanzetta, F; Agatic, G; Silacci,
C; Mainetti, L; Scarlatti, G; Sallusto, F; Weiss, R; Lanzavecchia, A; Weissenhorn W. Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to
the highly conserved heptad repeat 1 of gp41. PLoS Pathog.: 2010; 6(11): e1001195 - Article
IF 2009: 8,978
Gagliani, N; Jofra, T; Stabilini, A; Valle, A; Atkinson, M; Roncarolo, MG and Battaglia, M. Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant. Diabetes: 2010;
59(2): 433-439 - Article
IF 2009: 8,505
167
Franchini, S; Dagna, L; Salvo, F; Aiello, P; Baldissera, E and Sabbadini, MG. Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still’s disease. Arthritis
Rheum.: 2010; 62(8): 2530-2535 - Article
IF 2009: 4,152
Selected publications, DRI
Sordi, V; Melzi, R; Mercalli, A; Formicola, R; Doglioni, C; Tiboni, F; Ferrari, G; Nano, R;
Chwalek, K; Lammert, E; Bonifacio, E; Borg, D; Piemonti, L. Mesenchymal cells appearing in pancreatic tissue culture are bone marrow-derived stem cells with the capacity to improve transplanted
islet function. Stem Cells: 2010; 28(1): 140 - 151 - Article
IF 2009: 7,747
Gagliani, N; Jofra, T; Stabilini, A; Valle, A; Atkinson, M; Roncarolo, MG and Battaglia, M. Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant. Diabetes: 2010;
59(2): 433-439 - Article
IF 2009: 8,505
Caielli, S; Conforti-Andreoni, C; Di Pietro, C; Usuelli, V; Badami, E; Malosio, ML and Falcone;
M. On/off TLR signaling decides proinflammatory or tolerogenic dendritic cell maturation upon
CD1d-mediated interaction with invariant NKT cells. J. Immunol.: 2010; 185(12): 7317-7329 - Article
IF 2009: 5,646
Melzi, R; Mercalli, A; Sordi, V; Cantarelli, E; Nano, R; Maffi, P; Sitia, G; Guidotti, LG; Secchi,
A; Bonifacio, E; Piemonti, L. Role of CCL2/MCP-1 in islet transplantation. Cell Transplant.: 2010;
19(8): 1031-1048 - Article
IF 2009: 5,126
Lampasona, V; Petrone, A; Tiberti, C; Capizzi, M; Spoletini, M; Di Pietro, S; Songini, M; Bonicchio,
S; Giorgino, F; Bonifacio, E; Bosi, E; Buzzetti, R and for the Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study Group. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in
the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring
Autoimmune Diabetes (NIRAD) 4. Diabetes Care: 2010; 33(1): 104 - 108 - Article
IF 2009: 6,718
Human virology
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173
Management and antiretroviral treatment of HIV infection
Clinical immunopathology and advanced medical therapeutics Unit
β cell biology
175
DIVISION
OF
GENETICS AND
CELL BIOLOGY
Director:
Roberto Sitia*
Associate Director:
Marco E. Bianchi*
Research Units
Protein transport and secretion Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––– 182
HEAD OF UNIT: Roberto Sitia*
RESEARCHERS: Tiziana Anelli, Eelco Van Anken, Armenise-Harvard Career Development Award
POST-DOCTORAL FELLOWS: Jose Garcia-Manteiga, Stefano Vavassori
PHD STUDENTS: Margherita Cortini**, Francesca Fontana
FELLOWS: Milena Bertolotti, Imma Caserta, Federica Lari
TECHNICIANS: Claudio Fagioli, Elena Pasqualetto
Age related diseases–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 183
GROUP LEADER: Simone Cenci
POST-DOCTORAL FELLOWS: Elisa Benasciutti, Laura Oliva
PHD STUDENTS: Enrico Milan**, Niccolò Pengo**
FELLOW: Ugo Orfanelli
TECHNICIAN: Elisabetta Mariani
Molecular immunology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 184
GROUP LEADER: Antonio Siccardi
RESEARCHER: Maddalena Panigada
POST-DOCTORAL FELLOW: Francesco Gubinelli
PHD STUDENT: Andrea Barbieri
FELLOW: Elisa Nigro
TECHNICIAN: Elisa Soprana
177
DIVISION OF GENETICS AND CELL BIOLOGY
Research Units
Chromatin dynamics Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 185
HEAD OF UNIT: Marco E. Bianchi*
POST-DOCTORAL FELLOWS: Roberta Palumbo, Angela Raucci, Emilie Venereau
PHD STUDENTS: Antonella Antonelli, Jaron Liu
FELLOW: Luca Sessa
TECHNICIANS: Alessandro Catucci, Francesco De Marchis
In vivo Chromatin and transcription ––––––––––––––––––––––––––––––––––––––––––––––– 186
GROUP LEADER: Alessandra Agresti
POST-DOCTORAL FELLOWS: Barbara Celona
FELLOW: Lorenzo Caramel
Biology of myelin Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 187
HEAD OF UNIT: Lawrence Wrabetz
POST-DOCTORAL FELLOWS: Maurizio D’Antonio, Francesca Florio
PHD STUDENTS: Nicolò Musner**, Francesca Ornaghi**, Elisa Tinelli**, Domenica Vizzuso**
TECHNICIANS: Cinzia Ferri, Paola Saveri
Biomolecular mass spectrometry Unit ––––––––––––––––––––––––––––––––––––––––––––––––––– 188
HEAD OF UNIT: Angela Bachi
POST-DOCTORAL FELLOWS: Emanuele Alpi, Vittoria Matafora
PHD STUDENTS: Manuela Cuccurullo, Umberto Restuccia
FELLOW: Santosh Anand
TECHNICIAN: Angela Cattaneo
Gene expression Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 188
HEAD OF UNIT: Fulvio Mavilio
RESEARCHERS: Maria Pannese, Alessandra Recchia
PHD STUDENTS: Arianna Moiani**, Valentina Poletti**
FELLOW: Simona Capossela
TECHNICIAN: Serenella Sartori
Genetics of common disorder Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 189
HEAD OF UNIT: Daniela Toniolo
POST-DOCTORAL FELLOWS: Giorgio Pistis, Michela Traglia
FELLOWS: Salvatore Carrabino, Massimiliano Cocca, Corrado Masciullo
TECHNICIANS: Cinzia Sala, Fiammetta Viganò
Molecular basis of polycystic kidney disease Unit
(Dulbecco Telethon Institute) –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 189
HEAD OF UNIT: Alessandra Boletta
POST-DOCTORAL FELLOWS: Manila Boca, Isaline Rowe
PHD STUDENTS: Maddalena Castelli**, Monika Pema**
TECHNICIANS: Marco Chiaravalli, Gianfranco Distefano
Molecular genetics Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 190
HEAD OF UNIT: Francesco Blasi*
RESEARCHER: Daniela Talarico
POST-DOCTORAL FELLOW: Silvia D’Alessio
PHD STUDENTS: Patrizia Marzorati, Silvia Mori
FELLOWS: Ambra Crippa, Alessandro Gandelli
TECHNICIAN: Massimo Resnati
Research Units/Clinical Research Units
Molecular dynamics of the nucleus ––––––––––––––––––––––––––––––––––––––––––––––– 191
GROUP LEADER: Massimo Crippa
POST-DOCTORAL FELLOW: Monika Wozinska
FELLOW: Matteo Marinelli**
NeuroGlia Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 191
HEAD OF UNIT: Maria Laura Feltri
POST-DOCTORAL FELLOWS: Silvia Bogni, Ernesto Pavoni, Yannick Poitelon
PHD STUDENTS: Cristina Colombelli, Monica Ghidinelli**, Marilena Palmisano**,
Marta Pellegatta**
FELLOW: Alberto Merli
TECHNICIANS: Stefania Saccucci, Desirée Zambroni
Regulation of iron metabolism Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––– 192
HEAD OF UNIT: Clara Camaschella*
POST-DOCTORAL FELLOWS: Alessandro Campanella (from September 2010), Laura Silvestri**
PHD STUDENTS: Antonella Nai**, Alessia Pagani**
RESIDENT: Erika Poggiali**
Molecular genetics of renal disorders Unit (Dulbecco Telethon Institute) ––––––– 193
GROUP LEADER: Luca Rampoldi
POST-DOCTORAL FELLOW: Céline Schaeffer
PHD STUDENTS: Ilenia Bernascone**, Martina Brunati**
FELLOWS: Simone Perucca, Matteo Trudu
Dento-facial histopathology Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 195
HEAD OF UNIT: Enrico Gherlone*
PHYSICIANS: Paolo Capparé, Carlo Alberto Cortella, Roberto Crespi, Massimo Pasi, Giacomo
Santoro, Raffaele Vinci, Stefano Zandonella Necca
Genomics of renal diseases and hypertension Unit ––––––––––––––––––––––––––––––––––– 196
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: Irene Botticelli**, Guido Gatti**, Lino Merlino**, Marialuisa Querques, Francesco
Rainone**, Marco Simonini**, Francesco Trevisani**
FELLOWS: Lorena Citterio**, Simona Delli Carpini, Elisabetta Messaggio**
TECHNICIAN: Nunzia Casamassima
RESEARCH NURSES: Elena Brioni**, Marie Jankaricova
179
Tissue engineering and biomaterials ––––––––––––––––––––––––––––––––––––––––––––––––––––– 197
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
FELLOWS: Rosa Ballis, Marco Melato
Mission and vision - The Division of Genetics and Cell Biology (DGCB) aims at the mechanistic comprehension of biological and pathological 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 top priority.
Organization - DGCB consists of 14 basic and 3 clinical research groups, totaling over 140 staff. It occupies laboratory space in Dibit 1 and 2 buildings. 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 are engaged in inter-Divisional Research Programs and Institutional Facilities.
Goals - The major goal of our division is to foster curiosity-driven research and program projects aiming
to understanding the molecular and cellular bases of biological phenomena and human diseases, in the
believe that this will result in fueling translational research for the benefit of patients.
This is especially important for an Institute like ours, which expects basic and clinical research to synergistically flourish. The iterative process of translation is a key asset for DGCB. Our division aims at providing clinical sciences with novel concepts and protocols and at developing 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. The strong component of research on genetic diseases of
our division is an example: identifying mutational hotspots in patients, for instance, sheds light on basic
biological and cellular functions and allows for identification of novel bio-markers and therapeutical targets.
A second important aim of our division is to provide basic and translational research on cellular, molecular and genetic mechanisms with strong, reliable and state-of-the-art quantitative and high-throughput assays. To this end we work in close collaboration with the Center of Genomics, BioInformatics and
BioStatistics to develop state-of-the-art technological platforms for the scientific community. The Proteomic service and the Center for conditional mutagenesis represent successful examples of our strategy: they are at the technological forefront and are serving a vast number of intramural and external
scientists and clinicians.
Achievements - The numerous scientific achievements in 2010 are described in the sections devoted to
the single laboratories. Suffice here to recall the establishment and characterization of mouse models for
Charcot Marie Tooth and Polycystin or Uromodulin Associated Kidney Diseases, the identification of factors that promote or retard protein aggregation in cellular models of ER storage disorders, as well as novel
insights into the roles of adducin in the pathogenesis of hypertension, and of secreted HMGB1 in inflammation and epilepsy, and key discoveries on the molecular circuitry of mammalian iron metabolism
and related pathologies. Very satisfactory has been the activity of our technological platforms, Proteomics
and Center for Conditional Mutagenesis.
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. Many undergraduate student perform the experimental work for their Theses in DGCB laboratories. In 2010 several scientists visited DGCB laboratories for sabbatical or training periods. DGCB has hosted numerous well attended and
lively seminars, by both members and invitees.
181
Research Units
We explore the processes of oxidative folding, protein quality control and degradation in the early secretory compartment (ESC). 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), governed by the
pH gradient in ESC (Vavassori et al., submitted).
ERp44 regulates Ero1, IgM, adiponectin, Prx4 and
SUMF1 localization (Kakihana et al., submitted;
Cortini and Sitia, 2010 a, b) and IP3R1 activity
(Anelli, Bergamelli et al., submitted), integrating
redox and Ca2+ homeostasis (Anelli & Sitia, 2010).
We solved the structure of human Ero1α in its active and inactive conformations (Inaba et al., 2010)
and characterized the Ero1α-PDI interaction surface (Masui et al., 2011). Altogether, our findings
explain how disulfide bonds are vectorially and
specifically targeted to cargo proteins in the
crowded ER, and hyperoxidation is prevented. We
identified factors that control protein aggregation in
ESC, potential targets for ER storage and other
conformational diseases (Ronzoni et al., 2010;
Anelli and Sitia, 2010).
The lab also investigates the architectural (de novo
ER biogenesis) and functional (onset of Ig secretion and eventually apoptosis) changes during B to
plasma cell differentiation. We showed that differentiating B cells undergo a dramatic remodeling of
their antioxidant responses (Bertolotti et al., 2010;
Venè et al., 2010; Margittai & Sitia, 2010). Interestingly Chop is dispensable for plasma cell apoptosis (Masciarelli et al., 2010). We confirmed that
the proteasomal load vs capacity ratio dictates
sensitivity to bortezomib, a drug used against multiple myeloma and other plasma cell disorders
(Cenci & Sitia, 2011; Cenci, van Anken and Sitia,
2011; Fontana et al., in preparation). Our findings
pave the way to develop combinatorial treatments
- i.e. targeting autophagy or redox homeostasis for treating also resistant cells. The connections
between disulfide bond formation, protein secretion and oxidative stress identify novel targets for
manipulating (mal)adaptive stress responses (Masciarelli et al, 2010; Rubartelli & Sitia, 2009a, b), offering new therapeutic strategies agiainst ER
storage and conformational diseases, amyloidoses, myeloma and other cancers.
Roberto Sitia
Figure 36. Cellular responses to misfolded and aggregated proteins. Secretory proteins are co-translationally
translocated into the ER (entry) where they fold and assemble. Terminally misfolded proteins are recognized,
partially unfolded, dislocated, polyubiquitinated and eventually degraded by proteasomes (ER associated
degradation, ERAD). Likely unable to be retrotranslocated to the cytosol, protein aggregates can be sorted and
targeted to autophagy. The accumulation of misfolded proteins in the ER triggers the UPR cascade, which
transiently (and specifically) attenuates translation and positively regulates both ERAD and authophagy. If these
protection mechanisms are not sufficient, protein toxicity ensues and the cell undergoes apoptosis.
Figure 37. Model of the Ero1α -PDI pathway sustaining oxidative protein folding. Our data allowed us to
reconstruct the Ero1α -PDI catalytic cycle. that couples efficiency and fidelity of protein secretion.
a) Reduced PDI binds Ero1α : its hydrophobic pocket in the b’-domain recognized the protruding β-hairpin of
Ero1α such that the redox active site of the PDI a’-domain is preferentially oxidized.
b) Upon oxidation, PDI changes conformation. Oxidized PDI has lower affinity for Ero1α than for unfolded
substrate proteins.
c) Cargo proteins displace Ero1α and undergo PDI-catalyzed oxidation, leaving PDI reduced.
d) If correctly folded, the cargo protein dissociates from reduced PDI, which can reenter into step (a) for oxidation
by Ero1α. Should a non-native disulfide be inserted into the substrate, reduced PDI or other PDI-family member
proteins can isomerize the bond.
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 (Cenci and Sitia, 2007 and
2008; Cascio et al, 2008). Hence, our research
activity aims at understanding how normal and
malignant plasma cells cope with stress and proteasomal overload, investigating the mysterious
mechanisms regulating mammalian proteasome
biogenesis. The ultimate goal is to exploit proteotoxicity to identify novel targets against plasma
cell cancers (Cenci et al, 2010).
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). Ongoing wide-scope studies employ
functional
genomics,
proteomics
and
metabolomics, aiming at deciphering gene expression programs, degradation strategies and
metabolic trajectories of MM.
Parallel in vivo studies on the molecular mechanisms driving the differentiation and activity of osteoclasts, unique bone-resorbing cells, are unveiling novel links between adaptive immunity and
bone biology, of potential therapeutic interest
against bone-wasting conditions (Cenci et al,
PNAS 2003; Benasciutti et al, revised manuscript
submitted). Given the vicious connection between MM and bone cells, this model will be of
use to better understand the MM environment.
Simone Cenci
183
Research Units
Figure 38. Schematical representation of the load vs. capacity model as a determinant for sensitivity to
proteasomal inhibitors of MM cells. Multiple myeloma cell lines as well as primary CD138+ cells from patients
display different sensitivity to proteasome inhibitors. In both cell lines and patient derived cells, sensitivity was found
to correlate with the proteasomal load vs. capacity ratio. In resistant cells, the proteasomal capacity (depicted in
orange) exceeds the load of poly-ubiquitinated proteins (depicted in gray). Conversely, in sensitive cells, more
proteins are degraded by fewer proteasomes, generating long queues of poly-ubiquitinated proteins. The free
ubiquitin pool (depicted as white spheres) decreases, and many proteins that otherwise would be proteasome
substrates are no longer ubiquitinated. These proteins (depicted in dark blue) are stabilized, because they are no
longer ‘visible’ to the proteasome. Such stabilization of proteins may contribute to predisposing cells to apoptosis,
as has been shown for Ig-H, Bim, Bax and IkB α.
Three main projects are pursued.
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, the parallel construction of MVA and FPV recombinants
(that are not immunologically cross-reactive) allows
an efficient prime/boost strategy (Soprana et al.,
2011). The technology has led to the production
of a number of recombinants with potential applications in various fields of veterinary and human
medicine, notably in tumor and influenza vaccines
(human, avian, swine).
Survivin as a tumor marker for may diverse tumor.
Anti-survivin cytotoxic lymphocytes are described
in patients of many tumors (including mesothelioma, pancreatic ductal cancer, melanoma,
myeloma, CLL) indicating that there is no natural
tolerance against this molecule which is expressed
only by embryonic cells and by tumor cells where
it acts as a major anti-apoptotic effector. Increasing
the frequency of these effector cells might limit
tumor growth. Several trials are already in course,
using dendritic cells pulsed with survivin peptides.
In our approach, recombinant poxviruses expressing human or murine survivin have been produced
and are currently tested as preventive or curative
vaccines in a number of mouse tumor models, in
collaboration with several groups within the Institute.
Exploiting the adjuvant role of membrane IgE in cell
vaccines
Following our previous work (Reali et al., 2001;
Vangelista et al., 2005; Nigro et al., 2009), we have
obtained evidence that transgenic hyper-IgE mice
(in which the ε chain gene has been transplanted
in the γ-1 gene) are less susceptible to tumor
growth than wt mice and particularly so after a single round of tumor cell vaccination (practically ineffective in wt mice). Mice survivin the tumor
challenge show an antibody response at least partially of the IgE type (Nigro et al., in preparation).
The mechanism of protection (likely to include a T
cell response) is still under study.
Antonio Siccardi
The state of chromatin determines how specific
genes are expressed by different cells in the same
organism, which are genetically identical. 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). Our group studies in particular the
role of High Mobility Group Box 1 (HMGB1) in the
organization of chromatin (see ahead the report by
Alessandra Agresti).
HMGB1 also has an extracellular role: when leaked
out of necrotic cells it signals traumatic tissue damage and triggers inflammation, cell proliferation and
migration, innate and adaptive immune responses,
angiogenesis and eventually tissue repair.
During 2010, we showed that HMGB1 is released
by neurons and glial cells during epileptic activity,
and interacts with Toll-like receptor 4 (TLR4), a key
receptor of innate immunity. Antagonists of
HMGB1 and TLR4 retard seizure precipitation and
decrease acute and chronic seizure recurrence in
mouse models. Increased expression of HMGB1
and TLR4 in human epileptogenic tissue, like that
observed in the mouse models, suggests that
HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and
might be targeted to attain anticonvulsant effects
in epilepsies that are currently resistant to drugs.
We also showed that HMGB1 is released by keratinocytes during skin inflammation, and that the
interaction with TLR4 supports the development of
skin tumors.
Finally, we showed that HMGB1 is released by
mesothelial cells (cells lining the pleura) exposed
to asbestos. Asbestos exposure causes the development of mesothelioma, a devastating and incurable tumor. The release of HMGB1 induces
macrophages to secrete TNF-α, which triggers a
chronic inflammatory response that favors malignant transformation of mesothelial cells. HMGB1
levels in asbestos-exposed individuals are significantly higher than in nonexposed controls.
Our findings provide mechanistic links between
HMGB1 release, chronic inflammation,
and carcinogenesis. Inhibiting the chronic inflammatory response, especially by blocking HMGB1,
may interfere with the development of inflammation-associated cancers.
Marco E. Bianchi
Figure 39. Asbestos carcinogenesis. Asbestos causes necrotic cell death in mesothelial cells, which leads to the
release of HMGB1 into the extracellular space. HMGB1 release causes macrophages accumulation, inflammatory
responses and TNF-α secretion. TNF-α activates the NF-κB pathway, which increases mesothelial cell survival
after asbestos exposure. This allows mesothelial cells with asbestos-induced DNA damage to survive and, if key
genetic alterations accumulate, to eventually develop into malignant mesothelioma.
185
Research Units
In vivo Chromatin and transcription
Substantial histone reduction modulates genomewide nucleosomal
occupancy and global transcriptional output
Proper functioning of all living organisms depends
on maintenance of genomic information. The accommodation of 2m of DNA in the 10µ nucleus of
a human cell is made possible through its organization in a highly conserved structural polymer,
termed chromatin.
A dynamic chromatin structure, in terms of spatial
distribution of nucleosomes and proper reorganization during nuclear activities, is crucial to preserve cellular identity and to protect cells from
genomic instabilities. But what is known about nucleosome number? So far, the nucleosomes number has been tacitly considered a fixed parameter,
identical in all cell types. Surprisingly, our recent results indicate that nucleosome number in a nucleus is a controllable parameter, and that High
Mobility Group Box 1 protein (HMGB1) is the controller.
HMGB1 is an abundant chromatin component involved in nuclear transactions and fundamental for
the survival of the mouse. Mammalian cells lacking HMGB1 show a reduced content of core, linker
and variant histones, and a correspondingly reduced number of nucleosomes, possibly because
HMGB1 facilitates nucleosome assembly.
To understand how a cell deals with a reduction in
the number of nucleosomes, we turned to yeast,
which has NHP6A and -B proteins, closely related
to mammalian HMGB1. nhp6a/b mutant cells display genomic instability and hypersensitivity to
DNA-damaging agents. Indeed, they have a reduced amount of histones and fewer nucleosomes.
Nucleosome limitation in both mammalian and
yeast cells increases transcription globally and affects the relative expression of about 10% of
genes. In nhp6a/b cells the loss of more than 1
nucleosome in 4 does not affect nucleosomes position, but nucleosomal occupancy. The decrease
in nucleosomal occupancy is non-uniform, and
can be modelled assuming that different nucleosomal sites compete for available histones. Sites
with a high propensity to occupation are almost always packaged into nucleosomes both in wild type
and nucleosome-depleted cells; nucleosomes on
sites with low propensity to occupation are disproportionately lost in nucleosome-depleted cells.
We suggest that variation in nucleosome number,
by affecting nucleosomal occupancy both
genomewide and gene-specifically, constitutes a
novel layer of epigenetic regulation.
Alessandra Agresti
Figure 40. HMGB1depletion affects nucleosomal occupancy and transcription: Schematic representation of the
alterations in nucleosomal occupancy and transcription in cells lacking HMGB1 (HMGB1 mutant) as compared to
wild type cells. HMGB1 proteins are depicted in green, DNA as a grey wavy line, nucleosomes as blue ovals with
colour saturation proportional to their occupancy on DNA. Black and red arrows report on the extent of
transcription (PLoS Biology, 2011)
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, 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 (Figure 41) and activates protein quality
control pathways in myelinating Schwann cells of
peripheral nerve. Our recent data suggest that protein quality control unintentionally alters trafficking
of the P0 wildtype counterpart, the 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 41. P0S63del (green) accumulates in the endoplasmic reticulum (red) of Schwann cells only in MpzS63del
teased nerve fibers (arrows).
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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. In the last year we
have applied a label-free quantitative proteomic
technology to evaluate the differences at the protein level between B cells from Chronic Lymphocytic Leukemia patient with a bad versus good
prognosis. In this way we have identified and quantified more than a thousand of proteins, 20% of
which result to be statistically significantly regulated. A more in depth bioinformatic analysis is ongoing, to highlight the important pathways and
mechanisms differentially modulated in these two
sets of patients.
Moreover, we have also investigated how microRNA affects proteome changes in different cellular
models. Moreover, we are also investigating how
microRNA affects proteome changes in different
cellular models. In particular, we have evaluated
the effects of the regulation exerted by miR-124 in
a mouse model system, the neuroblastoma cell
line N2a. These cells are already known to be
able to differentiate into neuron-like cells after
serum starvation, through the induction of the
miR-124. To identify protein targets we have stably labeled the proteome of these cells via SILAC
technology (Stable Isotopic Labeling of cell culture), isolated the four main cellular compartments
(nucleus, cytoplasm, membranes and cytoskeleton), and we have been able to reliably identify
and quantify about 2200 proteins by high accuracy mass spectrometry, few hundreds of which are
statistically significantly up- or down-regulated in
the presence or absence of the mir-124, after
serum starvation. These modulated proteins have
been used for a bioinformatics analysis searching
both for in silico predicted miR-124 targets and
using Ingenuity Pathway Analysis software, a tool
that permits mapping the identified molecules into
known signaling pathways. Stratifying these data,
we have been identified two possible key players
of the differentiation of neuroblastoma cells into
neuron-like cells.
Angela Bachi
Figure 42. Proteome-wide accurate quantification.
Normalized protein ratios are plotted against summed
peptide intensities. The spread of the cloud is lower at
high abundance, indicating that quantification is more
precise. Each point, corresponding to an identified and
quantified protein, is colored by its ‘significance B’, with
blue crosses having values >0.05, red squares
between 0.05 and 0.01, yellow diamonds between
0.01 and 0.001 and green circles <0.001.
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 the genetic and epigenetic programs of somatic stem cells. High-throughput approaches are essential to study transcriptomes,
chromatin dynamics and the use of regulatory elements in the genome. Very few studies exist for somatic stem cells, defined retrospectively by the
nature of their progeny in vitro or in vivo. We have
developed a tool to map functional regions of chromatin in stem and progenitor cells, based on the
integration properties of the Moloney murine
leukemia virus (MLV). By using a deep sequencing
technology, we mapped >32,000 MLV integration
sites in the genome of human hematopoietic
stem/progenitor cells, and designed a detailed integration map throughout the genome. MLV integrations cluster in transcriptionally active,
cell-specific promoters and regulatory regions
bearing epigenetic marks of active or poised transcription and specialized chromatin configurations,
and allow the identifications of new regions with
putative regulatory function. Functional genome
mapping through retroviral “scanning” may be used
as a tool to identify regulatory regions involved in
the execution of stem cell genetic programs, providing a substantial contribution to a comprehensive description of the genetic and epigenetic
programs associated with stem cell functions.
Translational control is critical for gene regulation.
Wbscr1/eIF4H encodes a protein involved in the
process of protein synthesis at the level of the initiation phase. In human Wbscr1/eIF4H is located in
a region that is commonly deleted in patients affected by Williams-Beuren syndrome (WBS), a
neurodevelopmental disorder characterized by a
peculiar cognitive-behavioral profile. We generated
knockout mice for Wbscr1. The mice displayed
growth retardation, and reduction in body size. Behavioural studies performed on null mice showed a
severe impairment in spatial learning and associative fear-related memory formation. These alterations closely resemble phenotypes observed in
WBS patients. This model can be used to deeply
investigate the role of Wbscr1/eIF4H in WBS aetiopathogenesis.
Fulvio Mavilio
Genetics of common disorders Unit
One of the projects of the Unit involves the study of
the genetics of female reproductive life, including
age of menarche and menopause and female fertility and fecundity, phenotypes that have a significant genetic component and have become
relevant due to the postponement of first child
bearing occurring in most countries and the consequent infertility problems. We have collected a
large case control cohort and we have information
on reproductive life for all women participants in the
study of the genetic isolate INGI-ValBorbera. The
research involves the study of genetic association
of DNA variants in candidate genes identified by us
as well as genome wide association studies. We
have replicated the association of one gene identified in our group and we are participating in a large
consortium (the Reprogen Consortium). The first
published results are for age of menarche while the
study of menopause and early menopause are ongoing.
Also many of the other phenotypes regarding the
study of the genetically isolated population living of
INGI-ValBorbera, are now part of large international
collaborations for identification of common genetic
variation associated to hematological and iron related traits, kidney related phenotypes, blood pressure, TSH and thyroid related disorders and
several others. Preliminary studies suggest enrichment for rare variants in the isolated population
suggesting that it could become a very important
tool for identification of causative variants for many
of the phenotypes considered that could be identified more easily or exclusively in such special
populations.
Daniela Toniolo
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 Kid-
ney 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
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calcium channel, respectively. Our major interest is
on studying the normal function of PC-1 and how
its alteration causes cystogenesis.
PC-1 Interactors
We have an interest in identifying PC-1 interactors.
We have previously shown that PC-1 contains a
polyproline motif in its intracellular C-terminus mediating an interaction with the SH3 domain of
NPHP1, mutated in a different form of cystic kidney
diseases. In addition, we have recently found that
PC-1 interacts with a complex of polarity composed of aPKC and Par3, to control polarized cell
migration and to control proper tubular morphogenesis and diameter during renal development.
Finally, using a murine model system developed by
our lab, carrying a tagged version of endogenous
PC-1, we have initiated a Mass spectrometry approach to identify the PC-1 interactome.
mTOR dysregulation and renal cystogenesis
We have previously reported that PC-1 regulates
the mTORC1 cascade. Next, we have generated
a bona fide mouse model of ADPKD by inactivating the Pkd1 gene specifically in the kidney. In this
model we observe a biochemical upregulation of
the mTORC1 cascade. However, immunostaining
with an anti phospho-S6Rp antibody (surrogate
marker of mTORC1 activity) we found that only a
subset of cysts are positive, suggesting that
mTORC1 upregulation is not necessary for cysts to
form. Next, we inactivated the Tsc1 gene in the kidney and found that upregulation of mTORC1 occurs very early in the newborn kidneys whereas
cyst formation occurs much later. These data taken
together suggest that mTORC1 upregulation appears to be neither necessary nor sufficient for
cysts to form.
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 43. Apoptosis in E9.5 wt embryos (left) and Prep1i/i embryos (right), TUNEL reaction, whole mount.
Molecular dynamics of the nucleus
Role of unconventional myosin VI in prostate cancer
We have focused our attention on unconventional
Myosin VI (Myo6), a protein playing a prominent
role in prostate cancer by acting both in the cytoplasm and the nucleus.
By knocking down Myo6 in androgen-independent
prostate adenocarcinoma cells we observed a decrease in the tumor-forming potential of cells by
dramatically reducing their growth rate through a
putative epigenetic effect. Moreover, Myo6 depletion also affects the tumor phenotype by reducing
the ability of cells to migrate, invade and grow in
an anchorage-independent manner. Since therapies for androgen-independent prostate cancer
are currently lacking, Myo6 may represent a puta-
tive target for this stage of the disease.
We have also identified the genes whose expression is strongly affected by Myo6 depletion (transcriptome) in PC3 cells. To our surprise we found
that a substantial number mRNAs corresponding
to nuclear structural proteins (histones) are not only
strongly upregulated in the absence of Myo6, but
also present features that may affect their processing. This, in turn, may alter the timing of their
synthesis, normally associated with the early S
phase of the cell cycle, thus directing them to yet
unknown functions that we are currently investigating.
Massimo Crippa
NeuroGlia Unit
Adhesion molecules and signaling in peripheral nerve development and
myelin hereditary diseases
Schwann cells myelinate nerves, and contribute to
neuronal development, differentiation, integrity and
regeneration. Laminins, their receptors and the signals that they activate are required for 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, α dystroglycanopathies and Charcot-MarieTooth 4F.
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One morphogenetic process controlled by laminin
receptors is axonal sorting, the process by which
large axons to be myelinated are segregated by a
single Schwann cell. We have identified two α6β1
and α7β1 integrins and dystroglycan as the receptors important for radial sorting. We have
shown that these receptors act in sequence and
activate different signaling pathways to mediate radial sorting. We are now exploring if they bind different laminins in the Schwann cell basal lamina.
Among the signaling pathways that we have identified and are studying are small RhoGTPases such
as Rac1 and MAP kinases such as P38.
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 impaired adhesion of α6β4 integrin and dystroglycan. We are ex-
ploring genetically if α6β4 integrin promote myelin
stability through interactions with PMP22, mutated
in Charcot-Marie-Tooth 1A. Regarding dystroglycan, we showed that regulated proteolysis of dystroglycan by gelatinases (metalloproteinases 2 and
9) has a physiological role in organizing polarized
compartments in myelin. In hereditary and acquired
neuropathies, metalloproteinases 2 and 9 are upregulated, dystroglycan cleavage is augmented,
and we showed that this 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 is 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
Figure 44. Absence of dystroglycan in mouse Schwann cells cause an arrest in peripheral nerve development
(arrows in left: semithin sections sciatic nerves, B, or ventral roots, F) identical to those caused by lack of
dystroglycan-modifying enzymes fukutin and Large or the dystroglycan ligand laminin 211 in human congenital
muscular dystrophies and neuropathies. Center, B: by electron microscopy of sciatic nerves of mutant mice show
an arrest in the defasciculation of large axons (asterisks) during development. Right: dystroglycan appears first in
Schwann cells contacting these large axons by immunolectron microscopy. Thus, dystroglycan is likely the
relevant substrate and receptor whose function is altered in the neurological complications of human muscular
dystrophies.
The aim of our research is to understand the molecular pathways of cellular and systemic iron regulation in mammals and their dysregulation in iron
overload, deficiency and inflammation. Hepcidin is
the key regulator of systemic iron homeostasis and
its major inhibitor is the liver serine protease matriptase-2, encoded by TMPRSS6 gene. We have
previously shown that matriptase-2 downregulates
hepcidin cleaving from cell surface hemojuvelin,
the coreceptor of the BMP6 signaling pathway
which activates hepcidin transcription. Tmprss6ko mice have iron deficiency and we have shown
that Tmprss6-haploinsufficient mice are more susceptible to iron deficiency in conditions of increased iron requests. To verify whether
heterozygous TMPRSS6 nucleotide changes may
predispose to iron deficiency in humans we analyzed in vitro the activity of the common TMPRSS6
SNP rs 855791, that causes a non synonymous
(A736V) change in the protein and is associated
with variations of iron parameters in genome wide
association studies. Variant 736V showed a decreased hepcidin inhibitory activity in a luciferasebased assay in a dose dependent manner in
hepatoma cells transfected with hemojuvelin. In a
collaborative study, we confirmed these data in vivo
on a genotyped population which had serum hepcidin levels determined. Association studies
showed that 736V variant is associated with decreased serum iron and increased hepcidin levels
when hepcidin value is corrected for total body iron
(hepcidin/ferritin ratio). These results are relevant to
understand the genetic susceptibility to iron deficiency.
The Unit has contributed to two important achievements concerning cellular iron regulation in collaborative works: 1) to clarify the molecular
abnormalities of mitochondrial iron defects due to
glutaredoxin-5 deficiency in sideroblastic anemia,
results that revealed a previously unknown link between heme (hemoglobin) and iron sulfur cluster
production; 2) to define the differences in iron handling of inflammatory versus alternatively polarized
macrophages, that is relevant to characterize variations of iron metabolism in inflammation.
Clara Camaschella
Figure 45. Regulation of systemic iron homeostasis
Molecular genetics of renal disorders Unit
The main interest of our research 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 and calcium oxalate crystals-induced urothelial damage.
Mutations in uromodulin lead to uromodulin-associated kidney diseases (UAKD), a group of autosomal dominant 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 (Bernascone et al, Traffic
2006). This is consistent with the presence of uromodulin aggregates in the ER of tubular cells in kidney biopsies of patients and the dramatic reduction
of protein levels in patient urine.
We have recently generated the first transgenic
mouse model for UAKD (Bernascone et al, Hum
Mol Genet 2010). Transgenic mice that express
the C147W mutant uromodulin (TgUmodC147W),
corresponding to the well-established patient mutation C148W, were compared to expression193
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matched transgenic mice expressing the wild type
protein (TgUmodwt). TgUmodC147W mice recapitulate most of UAKD features, with urinary concentrating defect of renal origin and progressive
renal injury, i.e. tubulo-interstitial fibrosis with inflammatory cell infiltration, tubule dilation and specific damage of the thick ascending limb of Henle’s
loop, leading to mild renal failure. The key event in
the disease onset is accumulation of mutant uromodulin in the ER, that is evident at very early time
points and leads to ER hyperplasia.
Our data clearly demonstrate a gain-of-toxic function of uromodulin mutations providing insights into
the pathogenetic mechanism of the disease. TgUmodC147W mice represent a unique model where
to further investigate on the disease pathophysiology and test therapeutic strategies that might be
of relevance for other tubulo-interstitial or ER-storage disorders.
Luca Rampoldi
Dento-facial histopathology Unit
Our activity focused on biological features and clinical applications of dental implants and bone regenerative procedure for oral rehabilitations. To
preserve alveolar bone, avoiding invasive ridge
augmentation procedures, several biomaterials
were advocated immediately following tooth extraction to ensure the formation of alveolar bone
within the sites. Firstly, we studied the use of
xenogenic porcine bone grafts (PB) in fresh sockets by histomorphometric and in vivo gene expression profiling ex vivo in humans. Bone
specimens, obtained after 4 months, were analyzed by histomorphometry and RT-PCR. PB group
showed statistically significant (p<0.05) higher
mean vital bone (VB) and lower mean connective
tissue (CT) values than control (C) group. Real-time
RT-PCR analyses showed statistically significant
higher expression of ALP and the matrix formation
markers Collagen I and OPN in the PB group compared to the C group, whereas Runx2 and OPG
expression was comparable. Moreover, we analyzed the healing of an injectable mixture of nanoparticles of magnesium enriched hydroxyapatite
(MHA) in peri-implant defects in a Large White pig
model. At histologic and histomorphometric analy-
sis, test group reported statistically significant
higher values of bone area to implant contact (BIC)
and lower values of CT over time. Injectable MHA,
after 8 weeks, has been almost completely resorbed. Therefore we compared in humans the
use of synthetic MHA with PB grafts in fresh sockets. Four months after surgery, at histomorphometry, mean vital bone measurements reported
statistically significant differences (p<0.05) between MHA and C groups, and PB and C groups.
Not statistically significant differences were found
between MHA and PB groups. For residual graft
material values, not statistically significant differences were found between MHA and PB groups.
We demonstrated that such biomaterials are safe
and useful for bone regeneration prior to implant
insertion and prosthodontic rehabilitation.
Thus, we applied these findings in testing dental
implants with innovative protocols (immediate loading implants and in regenerated bone) in large populations of patients: from January to December
2010, we totally placed 471 implants in 153 patients, with a cumulative survival rate of 97.9%
Enrico Gherlone
Figure 46. Osteoid lamellar formation, stained in red, was present between implant surface and magnesiumenriched hydroxyapatite granules two weeks after healing. (original magnification x 32)
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Genomics of renal diseases and hypertension Unit
Target of prof. Paolo Manunta’s Unit -Genomics of
Renal Diseases and Hypertension- is to identify
networks that link genetic polymorphisms associated to blood pressure (BP) phenotypes, analyze
their interactions and assess the functional significance (effect size on the phenotype). Genetic heterogeneity, biological-environmental epistatic
interactions and the complex pathophysiology of
hypertension have so far hampered the clinical application of the genetic discoveries.
With the help of animal models (Milan rats) and
human cells we have shown that there are two
mechanisms underlying hypertension: Adducin
variants and plasma levels of Endogenous
Ouabain (EO).
Then, the attention was focused on humans identifying the relationship existing among genetic variants of enzymes of EO synthesis (LSS and
HSD3B1), EO transport (MDR1/ABCB1), Adducin1 and 3 and the response to a new antihypertensive drug,the rostafuroxin.
The presence of different combination of these
variants in never treated hypertensive patients defined their “genetic profile”.
The antihypertensive effect of rostafuroxin was on
average 14mmHg for systolic BP. This fall was predicted by the genetic profiles, while the response
to losartan and hydrochlorothiazide was not.
About a quarter of patients with essential hypertension is carrier of a profile (see figure 47). Since
the mechanisms inhibited by rostafuroxin also
cause organ damage related to hypertension, this
drug as well as effectively reduce BP may also reduce cardiovascular risk.
This innovative approach to the treatment of hypertension and its complications allows the development of a personalized therapy, able to act
without interfering with the physiological processes
that regulate BP.
After these meaningful results, we are adopting the
same approach to identify the genetic profiles of
other antihypertensive drug response (ACE inhibitor, diuretic) in two cohorts collected from our
Outpatient Clinic of Hypertension.
Other works in progress aim to predict and prevent
pathological conditions due to organ damage
caused by high BP (stroke, cardiac hypertrophy,
chronic renal failure) and the acute kidney impairment (AKI) after cardiac surgery.
Paolo Manunta
Figure 47. Effect on Systolic Blood Pressure (SBP) response after 5 weeks of rostafuroxin (all doses, black) or
placebo (white) in patients according to the presence or absence of the combination of genotypes in the genetic
profile. (a) All patients. (b) No previously treated patients. (c) All patients carrying the genetic profile (GLM: model, P
= 2.38 × 10−5; profile × therapy interaction, P = 3.23 × 10−6). (d) No previously treated patients carrying the
genetic profile (GLM: model, P = 3.1 × 10−8; profile × therapy interaction, P = 1.84 × 10−8). (e) Previously
treated patients carrying the genetic profile. Percentages refer to relative group of patients.
Tissue engineering and biomaterials
Tissue engineering for osteo-cartilaginous, meniscal and tendon tissue
One of the main problem related to structural tissues, like articular cartilage, meniscus or tendon, is
their inability or limited capacity of self-repair. The
main goal of our research activity is the development of tissue engineering strategies for the repair
and regeneration of damaged structural tissues.
We have recently developed of an engineered osteochondral composite for the repair of the cartilage and osteo-chondral lesions. We have focused
on engineering in vitro a biphasic composite made
of cellular cartilage scaffold and an osteo-biocompatible material. In collaboration with other laboratories, we are testing different biomaterials as
scaffold for the reparative cells. We have recently
tested in large animal the potential of these bi-phasic composites. One important aim of our research
is also the analysis of the importance of the level of
in vitro maturation of the engineered cartilage before the implantation in vivo. Additionally, we are
also testing the potential of fresh or expanded cells
with the addition of growth factors in the culture
medium for the synthesis of newly formed engineered cartilage tissue.
We are also conducting a series of experiments
with the attempt of characterizing the native juvenile
and adult meniscus, in term of morphological characteristics, biochemical composition and cellular
phenotype, 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. In
fact, tendons, like cartilage and meniscus, 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, peritenon and dermal fibroblasts. We
have also developed a lesion model in the rabbit
patellar tendon, that may allow testing the efficacy
of the engineered tendon for repairing lesion defect orthotopically.
Giuseppe M. Peretti
Figure 48. Immunofluorescence of engineered cartilage tissue. In red, the collagen type II fibers; in green, the
collagen type I fibers; in blue, the cell nuclei
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Maroso, M; Balosso, S; Ravizza, T; Liu, J; Aronica, E; Iyer, AM; Rossetti, C; Molteni, M; Casalgrandi, M; Manfredi, AA; Bianchi, ME and Vezzani, A. Toll-like receptor 4 and high-mobility group box1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med.: 2010; 16(4): 413 419 - Article
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Inaba, K; Masui, S; Iida, H; Vavassori, S; Sitia, R and Suzuki, M. Crystal structures of human Ero1a
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Nai, A and Pagani, A; Silvestri, L; Camaschella, C. Increased susceptibility to iron deficiency of
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Hentze, MW; Muckenthaler, MU; Galy, B; Camaschella, C. Two to tango: regulation of Mammalian
iron metabolism. cell: 2010; 142(1): 24-38 - Review
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Cattoglio, C; Pellin, D; Rizzi, E; Maruggi, G; Corti, G; Miselli, F; Sartori, D; Guffanti, A; Di Serio, C;
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Bernascone, I; Janas, S; Ikehata, M; Trudu, M; Corbelli, A; Schaeffer C; Rastaldi, MP; Devuyst,
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via a polyproline Motif/SH3 domain interaction and regulates the apoptotic response in mammals.
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Byrne, EM; Cousminer, DL; Gudbjartsson, DF; Esko, T; Feenstra, B; Hottenga, JJ; Koller, DL; Kutalik, Z; Li,n, P; Mangino, M; Marongiu, M; McArdle, PF; Smith, AV; Stolk, L; Van Wingerden, SH;
Zhao, JH; Albrecht, E; Corre, T; Ingelsson, E; Hayward, C; Magnusson, PKE; Smith, EN; Ulivi, S;
Warrington, NM; Zgaga, L; Alavere, H; Amin, N; Aspelund, T; Bandinelli, S; Barroso, I; Berenson,
GS; Bergmann, S; Blackburn, H; Boerwinkle, E; Buring, JE; Busonero, F; Campbell, H; Chanock,
SJ; Chen, W; Cornelis, MC; Couper, D; Coviello, AD; D’Adamo, P; De Faire, U; De Geus, EJC; De-
loukas, P; Doring, A; Smith, GD; Easton, DF; Eiriksdottir, G; Emilsson, V; Eriksson, J; Ferrucci, L;
Folsom, AR; Foroud, T; Garcia, M; Gasparini, P; Geller, F; Gieger, C; Gudnason, V; Hall, P; Hankinson, SE; Ferreli, L; He,ath AC; He,rnandez DG; Hofman, A; Hu, FB; Illig, T; Jarvelin, MR; Johnson,
AD; Karasik, D; Khaw, KT; Kiel, DP; Kilpelanen, TO; Kolcic, I; Kraft, P; Launer, LJ; Laven, JSE; Li, S;
Li,u J; Levy, D; Martin, NG; McArdle, WL; Melbye, M; Mooser, V; Murray, JC; Murray, SS; Nalls, MA;
Navarro, P; Nelis, M; Ness, AR; Northstone, K; Oostra, BA; Peacock, M; Palmer, LJ; Palotie, A;
Pare, G; Parker, AN; Pedersen, NL; Peltonen, L; Pennell, CE; Pharoah, P; Polasek, O; Plump, AS;
Pouta, A; Porcu, E; Rafnar, T; Rice, JP; Ring, SM; Rivadeneira, F; Rudan, I; Sala, C; Salomaa, V;
Sanna, S; Schlessinger, D; Schork, NJ; Scuteri, A; Segre, AV; Shuldiner, AR; Soranzo, N; Sovio, U;
Srinivasan, SR; Strachan, DP; Tammesoo, ML; Tikkanen, E; Toniolo, D; Tsui, K; Tryggvadottir, L;
Tyrer, J; Uda, M; Van Dam, RM; Van Meurs, JBJ; Vollenweider, P; Waeber, G; Wareham, NJ; Waterworth, DM; Weedon, MN; Wichmann, HE; Willemsen, G; Wilson, JF; Wright, AF; Young, L; Zhai, G;
Zhuang, WV; Bierut, LJ; Boomsma, DI; Boyd, HA; Crisponi, L; Demerath, EW; Van Duijn, CM;
Econs, MJ; Harris, TB; Hu,nter DJ; Loos, RJF; Metspalu, A; Montgomery, GW; Ridker, PM; Spector,
TD; Streeten, EA; Stefansson, K; Thorsteinsdottir, U; Uitterlinden, AG; Widen, E; Murabito, JM; Ong,
KK; Murray, A. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nature Genet.: 2010; 42(12): 1077 - 1085 - Article
IF 2009: 34,284
Giannandrea, M; Bianchi, V; Mignogna, ML; Sirri, A; Carrabino, S; D’Elia, E; Vecellio, M; Russo, S; Cogliati, F; Larizza, L; Ropers, HH; Tzschach, A; Kalscheuer, V; Oehl-Jaschkowitz, B; Skinner, C; Schwartz, CE; Gecz, J; Van Esch, H; Raynaud, M; Chelly, J; de Brouwer, APM; Toniolo, D
and D’Adamo, P. Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly. Am. J. Hum. Genet.: 2010;
86(2): 185 - 195 - Article
IF 2009: 12,303
Ferrandi, M; Molinari, I; Torielli, L; Padoani, G; Salardi, S; Rastaldi, MP; Ferrari, P; Bianchi, G. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 1:
Experimental studies. Sci. Transl. Med.: 2010; 2(59): - 59ra86 - Article
Lanzani, C and Citterio, L; Glorioso, N; Manunta, P; Tripodi, G; Salvi, E; Delli Carpini, S; Ferrandi, M; Messaggio, E; Staessen, JA; Cusi, D; Macciardi, F; Argiolas, G; Valentini, G; Ferrari, P;
Bianchi, G. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 2: clinical studies. Sci. Transl. Med.: 2010; 2(59): 59ra87 - Article
199
201
203
CENTER
FOR
TRANSLATIONAL
GENOMICS
AND BIOINFORMATICS
Director:
Giorgio Casari *
Research Units
Neurogenomics Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 207
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, Francesco Consolato, Sara Cottonaro
TECHNICIANS: Maurizio De Fusco, Celia Pardini
Biomolecular NMR Laboratory (Dulbecco Telethon Institute) ––––––––––––––––––––––– 208
HEAD OF UNIT: Giovanna Musco
POST-DOCTORAL FELLOWS: Francesca Chignola, Massimiliano Gaetani, Michela Ghitti,
Silvia Mari, Luca Mollica, Andrea Spitaleri
PHD STUDENTS: Valeria Mannella, Dimitrios Spiliotoupulos, Chiara Zucchelli
FELLOW: Giacomo Quilici
Genomic Unit for the diagnosis of human pathologies ––––––––––––––––––––––––––––––– 209
HEAD OF UNIT: Maurizio Ferrari*
RESEARCHERS: Sara Benedetti, Paola Carrera, Laura Cremonesi, Vito Lampasona
PHD STUDENT: Angela Brisci**
FELLOWS: Francesca Bruno, Emanuela Castiglioni, Vincenza Causarano, Chiara Di Resta,
Silvia Galbiati, Carlo Lombardoni, Francesca Rigo, Stefania Stenirri
TECHNICIAN: Nadia Soriani
Organelle biogenesis and motility Unit –––––––––––––––––––––––––––––––––––––––––––––––––– 209
HEAD OF UNIT: Maria Vittoria Schiaffino
POST-DOCTORAL FELLOWS: Tiziana Daniele, Ilaria Palmisano
PHD STUDENT: Angela Palmigiano**
Proteome biochemistry Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 210
HEAD OF UNIT: Massimo Alessio
POST-DOCTORAL FELLOWS: Sheila Alvarez-Fernandez, Carlo Vittorio Cannistraci
PHD STUDENTS: Marco Barbariga, Maria Sabina Pesca
FELLOW: Lara Hurley
TECHNICIAN: Antonio Conti
205
CENTER FOR TRANSLATION ALGENOMICS AND BIOINFORMATICS
Mission and vision - Our mission is to become an internationally recognized center in genomics and bioinformatics to loan the Institute towards integrative translational research. The Center aims to 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 six research units and two core facilities are included in the CGBB. The core
facilities (Genomics and Bioinformatics) are being setting up to provide state of the art services to scientists within HSR taking advantage of the Illumina Hi-Seq sequencer and microarray platforms, as well as
of a large dedicated bioinformatics computing cluster. All Units focus on the molecular pathogenesis of
diseases from different and 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) and integrative genomics and bioinformatics approaches to disease (Genomic Networks of Disease Unit). 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 is to provide HSR the skills and capacity to deliver high quality genomics and bioinformatics research and support. This has been achieved by aggregating research groups
already operating in these fields as well as investing in the required technologies.
Achievements - The Center has recently undergone significant growth due to strategic investments in both
technology and human resources. Specifically a new co-director was recently hired to spearhead the
bionformatics efforts within the Center and the two key facilities (genomics and bioinformatics). The necessary technology was recently purchased, including an Illumina Hi-Seq next-generation sequencer and
a high performance computing cluster (1,000 CPUs and 200TB of storage) dedicated to bioinformatics
analysis.
CTGB 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 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.
• A computational method for complex protein systems analysis was developed by the Proteome Biochemistry Unit High for identifying proteins differentially expressed in pathological and physiological conditions by2D and 3D electrophoretic systems.
• The Genomic Unit for the Diagnosis of Human Pathologies is involved in the development of a lab-ona-chip platform integrating a PCR amplification microreactor 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 - Finally the coordinator of the Bioinformatics Core Facility will be setting up 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; regular training courses.
CENTER FOR TRANSLATION ALGENOMICS AND BIOINFORMATICS
Research Units
Neurogenomics Unit
The mitochondrion as a hub for neurodegeneration
Two projects in the lab focus on neurodegeneration
from a specific mitochondrial point of view. The mitochondrial protease AFG3L2 forms homooligomeric and hetero-oligomeric complexes with
its partner paraplegin (m-AAA proteases), which
are in charge of protein quality control in the inner
membrane. Heterozygous mutations of AFG3L2
have been recently associated to a form of spinocerebellar ataxia (SCA28), while homozygous mutations are responsible for a novel progressive
myoclonic epilepsy-ataxia-polyneuropathy syndrome of childhood.
We developed a SCA28 mouse model, which
shows 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 is a mitochondrial kinase associated to a juvenile recessive form of Parkinson’s disease. The
project focuses on the characterization of the
PINK1 pathways through the identification of novel
specific interactors and substrates. Proteomic
analysis and yeast two-hybrid screening allowed
us to establish a panel of candidates that are now
opening new perspectives of PINK1 functions.
Into the molecular mechanism of familial hemiplegic
migraine type 2
Familial hemiplegic migraine (FHM2) is a Mendelian
severe form of migraine with aura caused by mutations of the α2 subunit of the Na+/K+ pump, encoded by the ATP1A2 gene. Our in vitro models
suggest a loss of function of FHM2 mutations. We
developed and characterized the first knock-in
mouse of FHM2model and defined that cortical
spreading depression (CSD), the molecular correlate of migraine aura, is facilitated in mutant mice.
Further insight in the molecular mechanism will
stem from the study of the conditional mutant that
shows astrocyte-specific expression of the α2
subunit.
Giorgio Casari
Figure 49. Dark cell degeneration (Purkinje’s neuron)
207
CENTER FOR TRANSLATIONALGENOMICS AND BIOINFORMATICS
Research Units
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. The
two main projects are: 1) Structural characterization of ligand-receptor interactions; 2) Structural
and dynamic characterization of novel chromatininteracting modules.
1. Integrin aVb3 is involved in angiogenesis, inflammation, and cancer.
It exerts its role interacting with proteins containing
an RGD motif. Recent drug design studies have
therefore focused on the development of RGDcontaining ligands for medical applications. A. Corti
has shown that also the isoDGR motif can compete with RGD in the binding to aVb3. We have
developed a computational method which combines Metadynamics and docking to predict and
fine-tune the conformation of isoDGR-based avb3
antagonists. Ligand-based NMR techniques on living cells have validated the predictions (Molmedcollaboration).
2. Methylation of lysine residues on histone H3 tails
regulates transcription.
The PHD finger is a histone binding module able
to decode the histone H3 methylated status. Au-
toimmune Regulator, a protein expressed in
mTEC and responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
contains two PHD fingers. We have solved the
structure of AIRE PHD fingers and have shown
that the first PHD finger binds with a non methylated histone peptide. The structure of the complex
provides 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 such as Sp140, involved in CLL,
and NSD1 involved in Sotos Syndrome. (TartuUniversity-Collaboration).
A new line of research is dedicated to
metabolomics, an emerging ‘omics’ field that provides an analytical description of the metabolites in
complex biological samples under disparate biological or environmental conditions. Ongoing projects focus on the metabolic profiling of B to plasma
cell differentiation (Sitia), metabolic profiling of
PKD1 -/- MEF cells (Boletta), exometabolome of
NPC cells (Pluchino-Cambridge), software development for the rapid identification of metabolites in
NMR spectra (Uni-Cambridge).
Giovanna Musco
Figure 50. Free Energy Surface (kJ/mol) of acCisoDGRC reconstructed by using metadynamic Center: A
representative bundle of structures extracted from the FES minimum bL are shown with blue lines. The center of
the cluster within the minimum is represented by yellow sticks. Right: HADDOCK model of the acCisoDGRC–avb3
binding site. The surfaces of integrin a and b subunits are represented in pink and pale cyan, respectively. The
side chains of avb3 and the ligand directly involved in binding are labeled with the one- and three-letter code,
respectively.
Genomic Unit for the diagnosis of human pathologies
The Unit applied advanced methodologies to molecular analysis of genes involved in several diseases, including neurologic and neuromuscular,
arrhythmogenic, pediatric surfactant deficiencies,
macular degeneration, neurodegeneration, iron metabolism, polycystic kidney, and myeloproliferative
disorders. We developed high throughput genotyping and performed case-control association
studies to correlate genome variation to disease
predisposition. Our approaches led to identification
of a variety of sequence variations and made possible a genotype-phenotype correlation in both
monogenic and multifactorial traits. We further implemented our studies on nucleic acids in maternal
plasma: we evaluated a panel of circulating DNA,
RNA and protein as potential markers for pathologies of pregnancy; we are also developing assays
for the identification of fetal paternally inherited mutations using co-amplification at lower denaturation
temperature-PCR (COLD-PCR) for noninvasive prenatal diagnosis of b-thalassemia. For assay miniaturization, we developed an integrated Lab-onChip platform for PCR and detection processes.
In the frame of the International Human Variome
Project we initiated the Neurogenetics Consortium
establishing strategic aims. Store and interpret the
DNA variation in a standardized way is likely to become a critical step in maximizing the impact of discovery on the understanding and treatment of human disease. This applies to the field of neurology
in particular as neurological dysfunction is implicated in many diverse human disorders and given
the complex genotype to phenotype relationships.
Molecular biology tools are also applied to research
in the field of autoimmunity. Currently, the main
focus of this research area is the development of
immunoassays for the detection of autoantibodies
and antigen specific B cells in patients and animal
models of type-1 diabetes. Recently developed
assays were applied to the characterization of autoantibody responses to several pancreatic β cell
antigens like Zinc Transporter 8 and IA-2 β, either
in the preclinical phase of the disease or in the
course of immunomodulatory therapy in the context of islet transplantation, or in patients affected
by LADA, a late onset slowly progressing form of
autoimmune diabetes.
Maurizio Ferrari
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 motility 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 inherited disorder characterized by severe visual defects, including reduction of visual acuity,
nystagmus, strabismus, photophobia, retinal hypopigmentation, foveal hypoplasia and misrouting
of the optic tracts, and and by the presence of giant
melanosomes (macromelanosomes) in skin
melanocytes and retinal pigment epithelium (RPE).
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),
including the ability to couple with heterotrimeric G
proteins and arrestins. However, in contrast to
canonical GPCRs, OA1 is not localized to the
plasma membrane, but is targeted to intracellular
organelles, namely melanosomes and lysosomes,
by specific sorting determinants. From this intracellular location OA1 appears to control not only the
correct biogenesis of melanosomes, as suggested
by their reduced number and abnormal size, but
also the motility of the organelles. In fact, in the absence of functional OA1, melanosomes are rare in
the perinuclear area and accumulate toward the cell
periphery, displaying a defect in microtubule-based
motility. These unique features indicate that OA1 is
a resident intracellular GPCR and suggest that it
might be activated by an intra-luminal ligand, possibly L-DOPA or other melanin-related compounds,
to regulate melanosome maturation and movement
in an organelle-autonomous fashion. In order to uncover the downstream effectors mediating the role
of OA1 in organelle transport, we used co-immunoprecipitation approaches, combined to protein identification by mass-spectrometry, and took
advantage of chimeric proteins, consisting of the
receptor fused to G-α-i or β-arrestins. Our results
suggest that both G-α-i and β-arrestins are implicated in OA1 signaling and that the microtubule cytoskeleton could represent the final effector of the
receptor.
Maria Vittoria Schiaffino
209
Research Units
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 tumoral antigens.
Auto-Ab directed against a surface metallo-protease have been found in colon cancer patients,
with higher frequency in patients with advanced
disease. Similar reactivity was observed in pancreatic cancer patients, but not in B-CLL patients.
Antibody-based proteomics to study cellular signalling networks
Reverse phase protein microarrays (RPPA) is a
technique that allows to analyze the abundance of
proteins and their phosphorylation status in patient
tumor on a high-throughput level exploiting specific
sets of Abs able to dissect different signalling pathways. We are using this approach in B-CLL and
multiple myeloma patients.
Neuro-proteomics
Protein pattern changes in cerebrospinal fluid
(CSF) of neurodegenerative diseases:
CSF being in contact with the brain contains pro-
teins 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 affected by Parkinson’s disease
showed different post-translational modifications of
proteins involved in the regulation of redox balance
that might be a target of oxidative stress damage.
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, and patients
affected by amyotrophic lateral sclerosis.
Massimo Alessio
Figure 51. Pixel-based analysis of multple 2-D electrophoresis images for the identification of protein expression
level changes.
Cannistraci, CV; Ravasi, T; Montevecchi, FM; Ideker, T; Alessio, M. Nonlinear dimension reduction
and clustering by Minimum Curvilinearity unfold neuropathic pain and tissue embryological classes.
Bioinformatics: 2010; 26(18): i531-i539 - Article
IF 2009: 4,926
Di Modugno, F; Mottolese, M; De Monte, L; Trono, P; Balsamo, M; Conidi, A; Melucci, E; Terrenato, I; Belleudi, F; Torrisi, MR; Alessio, M; Santoni, A; Nisticò, P. The Cooperation between hMena
Overexpression and HER2 Signalling in Breast Cancer. PLoS One: 2010; 5(12): e15852 - Article
IF 2009: 4,351
Schiaffino, MV. Signaling pathways in melanosome biogenesis and pathology. Int. J. Biochem. Cell
Biol.: 2010; 42(7): 1094-1104 - Review
IF 2009: 4,887
Mari, S; Invernizzi, C; Spitaleri, A; Alberici, L; Ghitti, M; Bordignon, C; Traversari, C; Rizzardi, GP;
Musco, G. 2D TR-NOESY experiments interrogate and rank ligand-receptor interactions in living human cancer cells. Angew. Chem.-Int. Edit. : 2010; 49(6): 1071 - 1074 - Article
IF 2009: 11,829
Wodarczyk, C; Distefano, G; Rowe, I; Gaetani, M; Bricoli, B; Muorah, M; Spitaleri, A; Mannella, V; Ricchiuto, P; Pema, M; Castelli, M; Casanova, AE; Mollica, L; Banzi, M; Boca, M; Antignac, C; Saunier, S; Musco, G and Boletta, A. Nephrocystin-1 forms a complex with polycystin-1
via a polyproline Motif/SH3 domain interaction and regulates the apoptotic response in mammals.
PLoS ONE: 2010; 5(9): e12719 - Article
IF 2009: 4,351
Michiorri, S; Gelmetti, V; Giarda, E; Lombardi, F; Romano, F; Marongiu, R; Nerini-Molteni, S; Sale,
P; Vago, R; Arena, G; Torosantucci, L; Cassina, L; Russo, MA; Dallapiccola, B; Valente, EM;
Casari, G. The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy.
Cell Death Differ.: 2010; 17(6): 962 - 974 - Article
IF 2009: 8,240
Benedetti, S; Previtali, SC; Coviello, S; Scarlato, M; Cerri, F; Di Pierri, E; Piantoni, L; Spiga, I;
Fazio, R; Riva, N; Natali Sora, MG; Dacci, P; Malaguti, MC; Munerati, E; Grimaldi, LM; Marrosu,
MG; De Pellegrin, M; Ferrari, M; Comi, G; Quattrini, A; Bolino, A. Analyzing histopathological
features of rare charcot-marie-tooth neuropathies to unravel their pathogenesis. Arch. Neurol.:
2010; 67(12): 1498-1505 - Article
IF 2009: 6,312
Bruno, F; Bonalumi, S; Camaschella, C; Ferrari, M and Cremonesi, L. The -582A>G variant of
the HAMP promoter is not associated with high serum ferritin levels in normal subjects. HaematolHematol. J.: 2010; 95(5): 849 - 850 - Letter
IF 2009: 6,416
Solla, P; Vannelli, A; Bolino, A; Marrosu, G; Coviello, S; Murru, MR; Tranquilli, S; Corongiu, D;
Benedetti, S; Marrosu, MG. Heat shock protein 27 R127W mutation: Evidence of a continuum between axonal Charcot-Marie-Tooth and distal hereditary motor neuropathy. J. Neurol. Neurosurg.
Psychiatry: 2010; 81(9): 958-962 - Article
IF 2009: 4,869
De Grijse, J; Asanghanwa, M; Nouthe, B; Albrecher, N; Goubert, P; Vermeulen, I; Van Der Meeren,
S; Decochez, K; Weets, I; Keymeulen, B; Lampasona, V; Wenzlau, J; Hutton, JC; Pipeleers, D;
Gorus, FK. Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2Î²) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of
rapid progression to clinical onset of the disease: implications for prevention trials. Diabetologia:
2010; 53(3): 517 - 524 - Article
IF 2009: 6,551
Lampasona, V; Petrone, A; Tiberti, C; Capizzi, M; Spoletini, M; Di Pietro, S; Songini, M; Bonicchio,
S; Giorgino, F; Bonifacio, E; Bosi, E; Buzzetti, R and for the Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study Group. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in
the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring
Autoimmune Diabetes (NIRAD) 4. Diabetes Care: 2010; 33(1): 104 - 108 - Article
IF 2009: 6,718
211
CTGB people
Genomic Unit for the diagnosis of human pathologies
213
IMAGING
EXPERIMENTAL CENTER
Director:
Carlo Tacchetti
Associate Director:
Alessandro Del Maschio*
Research Units
Mouse functional genetics Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 218
HEAD OF UNIT: Ottavio Cremona*
POST-DOCTORAL FELLOWS: Nunzia Passaro**, Elisa Sala**, Annunziata Venuto**
Clinical and experimental radiology Unit –––––––––––––––––––––––––––––––––––––––––––––––– 219
HEAD OF UNIT: Francesco De Cobelli*
PHYSICIANS: Antonio Esposito, Claudio Losio, Roberto Nicoletti, Pietro Panizza,
Massimo Venturini
TECHNICIAN: Tamara Canu
High technology in radiation therapy Unit ––––––––––––––––––––––––––––––––––––––––––––––– 219
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
215
IMAGING EXPERIMENTAL CENTER
Clinical Research Units/Service Units
Medical physics Unit ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 220
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: Gianluisa Sicignano, Antonello Spinelli
Molecular imaging Unit –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 220
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: Giuseppe Di Grigoli, Manuela Giglio, Valeria Masiello
PHD STUDENTS: Francesca Gallivanone, Cristina Monterisi, Eugenio Rapisarda, Silvia Valtorta
TECHNICIANS: Antonia Compierchio, Andrea Fabro, Paola Lanzoni, Carlo Pizzamiglio, Pasquale
Simonelli, Francesco Sudati, Mauro Vaghi
Neuroradiology research group –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 221
HEAD OF UNIT: Giuseppe Scotti*
GROUP LEADER: Letterio Salvatore Politi
PHYSICIANS: Simonetta Gerevini, Claudio Righi, Francesco Scomazzoni, Franco Simionato
FELLOW: Antonella Pagani
Service Units
ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center ––––––––– 223
HEAD OF UNIT: Fabio Grohovaz*
RESEARCHER: Maria Carla Panzeri
FELLOWS: Miriam Ascagni, Simona Maida
TECHNICIANS: Cesare Covino, Andrea Menegon
Intravital microscopy –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 224
HEAD OF UNIT: Luca G. Guidotti
RESEARCHERS: Matteo Iannacone, Giovanni Sitia
POST-DOCTORAL FELLOW: Laura Sironi
TECHNICIANS: Pietro Di Lucia, Francesca Mingozzi
Preclinical MRI –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 224
HEAD OF UNIT: Antonio Esposito
PHYSICIANS: Gianluca Perseghin, Letterio Salvatore Politi
RESEARCHER: Linda Chaabane
FELLOWS: Caterina Colantoni, Antonella Pagani, Anna Palmisano
TECHNICIAN: Tamara Canu
Mission - The mission of the Experimental Imaging Center (CIS, Centro di Imaging Sperimentale) is stratified into four different levels of intervention:
1. 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 multidisciplinary research activities and speed the development of biomedical research discoveries in the
campus.
2. Technology development: to promote and create an integrated platform for multidisciplinary activity in
R&D, involving biologists,chemists, physicists, computer scientists and clinician scientists, to develop
tools and technologies in biomedical imaging.
3. Competitive biomedical research: to support independent clinical and pre-clinical research and to foster translational research.
4. Partnerships with private research institutions: to provide a focal point of interaction with pharmaceutical and biotechnology industries to explore 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.
217
Research Units
Mouse models of endocytosis
Endocytosis is the process by which plasma membrane is internalized in the cell. In these years, a
great deal of effort has been put in characterizing
the molecular machinery of this membrane trafficking route. Studying the network of interactions
behind this process has made evident that endocytosis is actually a platform to localize, regulate
and even activate many other essential cellular
processes, including cell signaling, actin dynamics, nuclear transcription and neurotrasmission.
Our laboratory, in collaboration with the laboratory
of Pietro De Camilli (Yale University, USA), has pioneered a genetic approach in mammals to study
endocytic function. We recently discovered that
the ubiquitously expressed epsin1 and epsin2 cooperate in the activation of Notch signaling during
embryogenesis, acting as cargo-specific endocytic
adaptors for this signaling pathway. More recently,
together with the De Camilli lab, we showed that
epsin 3 is enriched and colocalized with clathrin
around apical canaliculi, the sites that control acidification of the stomach lumen via the exo-endocytosis of vesicles containing the H/K ATPase.
Deletion of the epsin 3 gene in mice did not result
in obvious pathological phenotypes in either the
stomach or other organs, possibly because of
overlapping functions of the other two epsins.
However, levels of EHD1 and EHD2, two membrane tubulating proteins with a role in endocytic
recycling, were elevated in epsin 3 knock-out
stomachs, pointing to a functional interplay of epsin
3 with EHD proteins in the endocytic pathway of
parietal cells. We suggest that epsin 3 cooperates
with other bilayer binding proteins with curvature
sensing/generating properties in the specialized
traffic and membrane remodeling processes typical of gastric parietal cells.
Ottavio Cremona
Figure 52. Electron microscopy localization of epsin 3 at coated pits and vesicles at the base of apical canaliculi.
Immunogold labeling of ultrathin frozen sections. H/K ATPase is localized, as expected, on intracellular
tubulovesicles (asterisks) in cimetidine-treated samples and on the surface of microvilli (arrows) in histamine-treated
cells. In both conditions, epsin 3 (polyclonal antibodies) and clathrin are found at the surface of invaginations
among microvilli and on underlying coated vesicles. (Scale bars, 100 nm.) (Ko G, et al., 2010)
Clinical and experimental radiology Unit
Our Unit is involved in many research projects:
• Breast Imaging. Innovative screening and secondary oncologic prevention program of breast
cancer in women of 40-49 yrs-old tailored and
based on the personal risk factors: we have already screened 792 women; our preliminary results demonstrated a breast cancer detection
rate in women 40-49ers higher (1,01%) than the
incidence reported by the Italian Cancer Registry
(0,15-0,2%).
• Cardiac imaging. Cardiomyopathies: we enrolled
50 patients with HCM in order to assess the
prognostic value of MR. We reported LV function
and energy homeostasis in patients with type 1
diabetes with and without microvascular complications. We demonstrated the utility of CT in
evaluation of coronary stents using new algorithm
acquisition allowing the possibility to save X-Ray
dose exposure.
• Clinical trials with new contrast agents. Singleand multicenter clinical trials have been conducted in cardiac and vascular diseases, breast
and orbital tumours in order to assess the efficacy of different contrast media.
• Diffusion-weighted MR Imaging. We evaluated
the accuracy of DWI in evaluation of response to
chemotherapy in patients with gastric, pancreatic and breast tumors.
• Cellular and molecular imaging. A 7T MR magnet
has been installed and is working with personnel
of the Unit. Many projects are running (see report
Preclinical MRI Unit).
• Imaging of islet transplantation in Humans. We
developed new techniques able to visualize labelled cells with MR and liver-focal-fatty changes
with ultrasound as an early sign of altered graft
function and retinal blood flow improvement at
Color Doppler as early sign of good graft function.
• Implementation of radiotherapy planning with imaging. We implemented MR, DWI MR and 4DCT techniques to improve target volume
definition in prostate, rectal and in pancreatic tumors.
• Gastric Esophageal Tumors (GET) imaging. we
focused our research on a prospective study
using MR, Endoscopic-US and MDCT in staging GET.
• Non-invasive characterization of tumour microvasculature with new non-invasive technique of
dynamic contrast enhancement MRI.
• Interventional Radiology. Innovative therapeutic
approaches, as for example new TACE in the
treatment of uveal melanoma liver mts using drug
eluting beads.
Francesco De Cobelli
High technology in radiation therapy Unit
Head & Neck
Prostate
Intensity modulated radiotherapy (IMRT) in radical
and adjuvant setting. New techniques of RT delivery as simultaneous integrated boost.Multimodality imaging for RT planning with MRI and CT/PET, to
identify tumour subvolumes potentially radioresistant to implement a dose escalation program.
Hypofractionated radical and postoperative (adjuvant, salvage) irradiation (RT) of prostate cancer
with Tomotherapy (TT) and Rapid Arc (RA).
Prospective evaluation of any difference in acute
toxicity between TT and RA.
Selective irradiation of isolated LN metastases with
TT in patients previously treated with definitive RT
or prostatectomy.
Our group leads the prospectic, multicentric, observational trial DUE-01 (granted by AIRC) investigating, on ≥ 1.000 patients from ≥ 10 italian and
foreign Centers, clinical and physico-dosimetric
predictors of erectile disfunction and urinary toxicity from RT.
Lung
Hypofractionated treatments for NSCLC.Multimodality imaging for planning with CT/PET and
CT/SPECT for the evaluation of lung perfusion, in
order to minimize side effects. Tomotherapy for
Pleural Mesothelioma and 4D imaging for target
and OARs definition.
Pancreatic Cancer
Phase I-II dose escalation trial Hypofractionated
Image-Guided RT in both radical and adjuvant pancreatic cancer. Definition of target volume by contrast enhanced 4D-CT/ PET in unresectable
pancreatic cancer
Rectal cancer
Comparison between moderately hypofractionated
RT with Tomotherapy and hyperfractionated 3DCRT in rectal adenocarcinoma as neoadjuvant treatment
219
Preoperative adaptive RT with Tomotherapy using
CT/ MRI for RT planning and adjuvant hypofractionated Image-Guided RT.
SNC neoplasms
Role of salvage Temozolomide for patients with
recurrent or metastatic pituitary adenoma(EORTC
trials). Gamma knife radiosurgery for brain metastases (one of the widest series currently available).
Paper concerning 373 patients treated at HSR in
press on IJROBP. Helical TT for skull base meningiomas not suitable for surgery nor radiosurgery.
Monoinstitutional prospective internal trial on cognitive impairment in patients undergoing Tomotherapy or gamma knife radiosurgery for skull
base meningiomas currently ongoing.
Nadia Di Muzio
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. 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 tumor/organ mobility
(4D technology); 4) the definition of adaptive strategies to modify treatment plans. A number of studies have been conducted evaluating the impact of
multi-modal approach in treatment planning optimization. Several collaborations with national and
international groups have been consolidated over
the last years; two large projects have been funded
by AIRC during the last two years and are currently
in progress.
2. Physics for imaging
University of Verona a novel molecular imaging approach called Cerenkov luminescence imaging
(CLI) for the in vivo imaging of small animals such
as mice. CLI is based on the detection of CR generated by β particles as they travel into the animal
tissues. As a further improvement of CLI a novel
tomography algorithm allowing to obtain 3D images from the detection of CR was developed.
A second research topic is the CT dose monitoring and modelling of the associated risks with a
particular attention to pediatric and heavvy follow
up patients.
The use of monochromatic X rays is the 3rd R&D
line of the MDP in collaboration with INFN.
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.
The radiation protection of the NMD is carried out
by the MPD with the use of the most advanced
methodologies for radiation monitoring. Since the
beginning of the 80’s the MPD staff is also enrolled
in the safety and quality assurance of Laser and
NMR equipments installed at HSR.
Riccardo Calandrino
The MPD has developed in collaboration with the
Molecular imaging Unit
The main research activities are focused on:
1) Implementation of quality procedure for the
preparation of radioligands for clinical research
protocols in agreement with requirements of
National and European authorities. Ligands radiolabeling 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 sympathet-
ic nervous system 11C-HED. 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 are still ongoing.
2) Development of a) a new fully 3D iterative (OSEM) reconstruction algorithm based on a Regularization Technique which also account for
the Point Spread Function of the PET system
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 18FFDG 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 of animal
model of dystrophia using 18F-FDG.
4) Assessment of the clinical role of PET/CT in
the staging and re-staging of different cancer
patients, by using 18F-FDG and 11C-Choline
as tracers. In particular, gynaecological and
prostate cancer patients have been evaluated
by 18F-FDG PET/CT and 11C-Choline
PET/CT, respectively.
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 neuroinflammation and for the in vivo imaging of opiate receptors binding.
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 2010 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 ad-
vanced MR-based imaging techniques of brain tumors and of inflammatory, demyelinating and dysmyelinating murine models of central nervous
system diseases. Using a human-grade 3T and
the small-animal 7T Magnetic Resonance Imaging
(MRI) 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 stro-
Figure 53. Fat Suppressed post-contrast T1-weighted
image showing an intra-orbital lymphoma
221
mal 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 hereditary 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
Service Units
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 applica-
tion 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 2010 are: 683 registered users
(345 active), 103 persons attending theorical/practical courses; 5819 hours of independent microscopes use.
Web resources:
www.sanraffaele.org/research/alembic
Fabio Grohovaz
Figure 54. Co-culture of murine
bone marrow derived
macrophages and
mesoangioblast stem cells
stained with Hoechst, Myosin,
CD11b (Lidia Bosurgi,
Autoimmunity and Vascular
Inflammation Unit – hSR). In Cell
acquisition Miriam Ascagni,
ALEMBIC - HSR
223
Research Units
Intravital microscopy
Up until now, the visualization of cellular and subcellular biological processes in animal models has
been limited to static imaging of sectioned tissues.
The advent of new technological improvements in
wide field epifluorescence single photon intravital
microscopy (1P-IVM) along with the specific features of two photon IVM (2P-IVM) provide - at last
- the opportunity to study cellular and sub-cellular
biological processes within the live host and with a
resolution power of few hundreds nanometers. The
inability of 1P-IVM to collect images in a “confocallike fashion” represents both a limitation (narrow
image quality as photons are collected also from
out-of-focus planes) and an advantage (fast speed
of acquisition of up to 200 frames/sec) when compared to 2P-IVM, which has high-resolution and 3D sectioning capabilities but usually acquires a
frame every 15-30 sec. Because of limited surgical access, and/or intrinsic anatomical features,
the much more limited depth penetration of 1P-IVM
(as compared to 2P-IVM) restrains IVM to certain
districts (e.g. lymph nodes, spleen, bone marrow,
pancreas, brain, etc) but not others (e.g. liver, cremaster muscle and various vascular beds). There-
fore, it appears that, when possible, 1P-IVM is the
best option for studying events that occur quite
rapidly (for instance cell adhesion to blood and
lymph vessels) and 2P-IVM is best suited to follow
slow-occurring phenomena (for instance cell extravasation and cell-cell interaction). Note also that
the visualization of districts such as popliteal lymph
nodes, bone marrow, cremaster muscle or brain
requires up-right microscopes, while visualizing the
liver involves the use of inverted machines. The IVM
Facility is intended to be a resource for the scientific community and, at present, it counts on two
machines (one dedicated to up-right 1P-IVM and
another one to inverted 2P-IVM). It will take at least
12 months to acquire/design/install the next machine (up-right 2P-IVM). The facility also provides
consulting activity absolutely essential to rule out
necessity/feasibility of a given approach, so that its
function will be primarily devoted to highly selected
projects that effectively benefit from the use of this
time-consuming and complex technology.
Luca G. Guidotti
Preclinical MRI
Functional preclinical imaging at 7T
The newborn Preclinical MRI Unit was recently established within the new Imaging Experimental
Center of the San Raffaele Scientific Institute. The
beating heart of the Unit is a small bore horizontal
7 Tesla magnet (Bruker; BioSpec 70/30) equipped
with phased array and volumetric coils allowing to
explore all anatomic regions of mice. An Isoflurane
based anaesthesia system and an MR compatible
physiologic monitoring system allow to immobilize
animals during in-vivo imaging, monitoring vital
functions and gating images acquisition. The complete non-invasiveness of MR imaging provides the
opportunity to perform longitudinal studies of the
same animal minimizing the experimental variability
and the number of required animals; moreover, the
wide diffusion of MRI in the clinical practice makes
this tool a perfect translation bridge between preclinical research and clinical trials. The Preclinical
MRI Unit includes a complete platform to perform
both morphological imaging in living mice and also
more advanced experiments including diffusion imaging, perfusion imaging and magnetic resonance
spectroscopy, which provide a wide range of mul-
tidimensional information regarding tissues physiology and physiopathology.
Tests for scanner validation as been performed in
the last months in collaboration with different research groups, in the subsequent fields of preclinical research:
• Quantitative Magnetic Resonance monitoring of
muscle damage/healing process through diffusion tensor imaging and T2-maps assessment
• Magnetic resonance follow-up of iron labelled
pancreatic islets
• Non invasive phenotypization of a mouse model
of chronic hepatitis/hepatocellular carcinoma
(HCC)
• MR imaging of Embryonic Stem Cells
• Non-invasive MR assessment of cartilage repair
• Functional and volumetric assessment of the
heart in mice
• MRI of cerebral ischemic stroke
• Characterization of mouse models of neuroferrinopathies
Antonio Esposito
Figure 55. In vivo cine magnetic resonance imaging of
a mouse heart. Diastolic and systolic images acquired
in the short-axis or four chamber long-axis planes using
intra-gate technique.
225
Giorgi, C; Ito, K; Lin, HK; Santangelo, C; Wieckowski, MR; Lebiedzinska, M; Bononi, A; Bonora, M;
Duszynski, J; Bernardi, R; Rizzuto, R; Tacchetti, C; Pinton, P; Pandolfi, PP. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science: 2010; 330(6008): 1247 1251 - Article
IF 2009: 29,747
Magnoni, M; Esposito, A; Coli, S; Scuteri, L; De Cobelli, F; Cianflone, D; Del Maschio, A and
Maseri, A. Two different mechanisms of myocardial ischemia involving 2 separate myocardial segments in a patient with normal coronary angiography. Circulation: 2010; 121(1): e1-e3 - Article
IF 2009: 14,816
Gregorc, V; Citterio, G; Vitali, G; Spreafico, A; Scifo, P; Borri, A; Donadoni, G; Rossoni, G;
Corti, A; Caligaris-Cappio, F; Del Maschio, A; Esposito, A; De Cobelli, F; Dell’Acqua, F; Troysi,
A; Bruzzi, P; Lambiase, A; Bordignon, C. Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours. Eur. J. Cancer: 2010; 46(1): 198-206 Article
IF 2009: 4,121
Esposito, A; De Cobelli, F; Belloni, E; Ravelli, S; Scotti, R; Sabbadini, MG; Del Maschio, A.
Magnetic resonance imaging of a hypereosinophilic endocarditis with apical thrombotic obliteration
in Churg-Strauss syndrome complicated with acute abdominal aortic embolic occlusion. Int. J. Cardiol.: 2010; 143(3): e48-e50 - Article
IF 2009: 3,469
Briganti, A; Passoni, N; Ferrari, M; Capitanio, U; Suardi, N; Gallina, A; Da Pozzo, LF; Picchio,
M; Di Girolamo, V; Salonia, A; Gianolli, L; Messa, C; Rigatti, P; Montorsi, F. When to Perform
Bone Scan in Patients with Newly Diagnosed Prostate Cancer: External Validation of the Currently
Available Guidelines and Proposal of a Novel Risk Stratification Tool. Eur. Urol.: 2010; 57(4): 551 558 - Article
IF 2009: 7,667
Bettinardi, V; Picchio, M; Di Muzio, N; Gianolli, L; Gilardi, MC; Messa, C. Detection and compensation of organ/lesion motion using 4D-PET/CT respiratory gated acquisition techniques. Radiother. Oncol.: 2010; 96(3): 311-316 - Review
IF 2009: 4,343
Politi, LS; Forghani, R; Godi, C; Giordano Resti, A; Ponzoni, M; Bianchi, S; Iadanza, A; Ambrosi, A; Falini, A; Ferreri, AJM; Curtin, HD; Scotti, G. Ocular adnexal lymphoma: Diffusionweighted MR imaging for differential diagnosis and therapeutic monitoring. Radiology: 2010;
256(2): 565-574 - Article
IF 2009: 6,341
IF 2009: 10,555
Spinelli, AE; D’Ambrosio, D; Calderan, L; Marengo, M; Sbarbati, A; Boschi, F. Cerenkov radiation
allows in vivo optical imaging of positron emitting radiotracers. Phys. Med. Biol.: 2010; 55(2): 483 495 - Article
IF 2009: 2,781
Boschi, F; Calderan, L; D’Ambrosio, D; Marengo, M; Fenzi, A; Calandrino, R; Sbarbati, A; Spinelli,
AE. In vivo 18F-FDG tumour uptake measurements in small animals using Cerenkov radiation. Eur.
J. Nucl. Med. Mol. Imaging: 2011; 38(1): 120-127 - Article
IF 2009: 4,531
Ko, G; Paradise, S; Chen, H; Graham, M; Vecchi, M; Bianchi, F; Cremona, O; Di Fiore, PP; De
Camilli, P. Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at
endocytic sites of apical canaliculi. Proc. Natl. Acad. Sci. U.S.A.: 2010; 107(50): 21511-21516 Article
IF 2009: 9,432
Iannacone, M; Moseman, EA; Tonti, E; Bosurgi, L; Junt, T; Henrickson, SE; Whelan, SP; Guidotti,
LG and von Andrian, UH. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature: 2010; 465(7301): 1079-1083 - Article
IF 2009: 34,480
Melzi, R; Mercalli, A; Sordi, V; Cantarelli, E; Nano, R; Maffi, P; Sitia, G; Guidotti, LG; Secchi,
A; Bonifacio, E; Piemonti, L. Role of CCL2/MCP-1 in islet transplantation. Cell Transplant.: 2010;
19(8): 1031-1048 - Article
IF 2009: 5,126
Cozzarini, C; Fiorino, C; Da Pozzo, LF; Alongi, F; Berardi, G; Bolognesi, A; Briganti, A, Broggi, S; Deli, A; Guazzoni, G; Perna, L; Pasetti, M; Salvadori, G; Montorsi, F; Rigatti, P and Di
Muzio, N. Clinical Factors Predicting Late Severe Urinary Toxicity After Postoperative Radiotherapy
for Prostate Carcinoma: A Single-Institute Analysis of 742 Patients. Int. J. Radiat. Oncol. Biol. Phys.:
2011 - Article in Press
IF 2009: 4,592
227
ALEMBIC
229
RESEARCH
PROGRAMMES
Brain Regeneration usIng medical Devices,
Gene vectors and stEm cells (BRIDGE)
Head of Research Program:
Gianvito Martino (ad interim)
Deputy Head of Research Program:
Luigi Naldini*
Participating investigators:
Alessandra Biffi, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Alessandra Bolino, INSPE - Institute of Experimental Neurology
Vania Broccoli, Division of Neuroscience
Gian Giacomo Consalez, Division of Neuroscience
Manolis Fanto, Division of Neuroscience
Roberto Furlan, INSPE - Institute of Experimental Neurology
Rossella Galli, Division of Regenerative medicine, Stem cells, and Gene therapy
Angela Gritti, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Letizia Leocani, INSPE - Institute of Experimental Neurology
Gianvito Martino, INSPE - Institute of Experimental Neurology
Pietro Mortini*, Division of Neuroscience
Luigi Naldini*, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Stefano Pluchino, INSPE - Institute of Experimental Neurology
Letterio Salvatore Politi, Imaging Experimental Center
Stefano Carlo Previtali, INSPE - Institute of Experimental Neurology
Angelo Quattrini, INSPE - Institute of Experimental Neurology
Carla Taveggia, INSPE - Institute of Experimental Neurology
Flavia Valtorta*, Division of Neuroscience
231
RESEARCH PROGRAMMES
BRIDGE is a three-years projects being structured
into 3 different work packages (WP). It has three
main aims:
1. to exploit premiere knowledge derived from stateof-the-art stem cell and gene therapy trials to be
conducted at HSR for a number of neuroinflammatory and neurodegenerative conditions;
2. to combine 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 inflammatory
and degenerative nervous system diseases;
3. to develop biological models allowing to track
gene expression and neural activity in the transplanted cells and the treated tissues.
Research activity
(WP1) Stem cell and gene therapy to promote neuronal regeneration
1. The safety and efficacy of neural stem/precursor
cell (NPC) transplantation and direct central
nervous system (CNS) gene delivery by means
of lentiviral vectors (LV) was demonstrated in
murine models of leukodystrophies.
2. Induced pluripotent stem cells (iPS) from
leukodystrophic patient’s fibroblasts with or without prior LV-mediated correction of the genetic
defect were obtained.
3. Enzyme deficiency drives functional changes of
NSC compartments in murine models of
leukodystrophies through the alteration of important biochemical signalling pathways, even
in the absence of overt lipid storage.
(WP2) Intrinsic and extrinsic regulation of progenitor integration into normal and diseased neural tissue
1. The mechanisms governing neural induction at
the peak of gastrulation reveal the intimate connection between signals arising from the developing mesendoderm and the shaping of the
neural tube.
2. The developmental mechanisms that set the
pace of neurogenesis in development ensuring
a balance between the maintenance of an undifferentiated progenitor pool and the onset of
neuronal maturation, and between neurogenesis and gliogenesis, are highly relevant to the
elaboration of strategies aimed at promoting
adult neurogenesis. 3. miRNA profiling on NPCs
during the differentiation process, selecting lineage- and cell specific miRNAs whose expression is enriched in the stem cell/early progenitor
cell compartment has been analysed.
(WP3) Extrinsic regulators of neuronal regeneration:
glial cells, environment and biomaterials
1. Recent studies demonstrate that the dosage of
axonal Neuregulin−1 (NRG1) type III regulates
the amount of myelin produced and may be involved in axonal regeneration. Our data indicates that alteration of a protease can modulate
the amount of active Neuregulin−1 (NRG1) type
III and cause hypermyelination.
2. We showed that the use of a micro-patterned
collagen scaffold, with peculiar porosity of the
tube wall, that allow near-complete recovery of
the morphological and physiological features of
a normal nerves.
3. It has been observed that the cell population believed to be at the crossroad between neuro-inflamation and neurodegeneration is represented
by the myeloid cells, i.e. microglia and
macrophages in the CNS and macrophages in
the PNS.
4. The influence of inflammatory mediators on
synaptic activity and, in general, on neuronal
homeostasis, is currently being investigated in
order to find new biomarkers for PNS and CNS
inflammation.
RESEARCH PROGRAMMES
Program in Immunology and Bio-immunotherapy of
Cancer (PIBIC)
Co-Heads of Research Program:
Paolo Dellabona and Giorgio Parmiani
Matteo Bellone, Division of Immunology, Transplantation, and Infectious Diseases
Chiara Bonini, Division of Regenerative medicine, Stem cells, and Gene therapy
Giulia Casorati, Division of Immunology, Transplantation, and Infectious Diseases
Angelo Corti, Division of Molecular oncology
Michele De Palma, Division of Regenerative medicine, Stem cells, and Gene therapy and HSR-TIGET The San Raffaele Telethon Institute for Gene Therapy
Paolo Dellabona, Division of Immunology, Transplantation, and Infectious Diseases
Angelo A. Manfredi*, Division of Regenerative medicine, Stem cells, and Gene therapy
Anna Mondino, Division of Immunology, Transplantation, and Infectious Diseases
Giorgio Parmiani, Division of Molecular oncology
Maria Pia Protti, Division of Immunology, Transplantation, and Infectious Diseases
Patrizia Rovere-Querini, Division of Regenerative medicine, Stem cells, and Gene therapy
Vincenzo Russo, Division of Molecular oncology
233
RESEARCH PROGRAMMES
Vision - Immunotherapy holds promise as innovative, targeted and non-toxic treatment of cancer.
The clinical efficacy of immunotherapy has progressively improved over the years, thanks to the
continuous incorporation into the clinic of the advancements in our understanding of the basic
mechanisms of the immune response against tumors. However, there still remain biological hurdles
that should be overcome to increase the fraction of
patients that can benefit from immunotherapy. The
Program in Immunology and Bio-Immunotherapy of
Cancer (PIBIC) brings together experts in the fields
of immunobiology, cancer biology and medical oncology to investigate fundamental aspects of tumor
immunology, harness them to implement immunotherapy strategies in pre-clinical animal models, and translate such studies into spontaneous
or sponsored phase I/II clinical. PIBIC also provides
a scientific forum and infrastructure to help widening the institutional research perspectives of the
role of the immune system in protection against
cancer.
Goals - The research performed in the PIBIC is
guided by the “bench-to bedside-to bench” principle, considering that patients unexpected responses in well designed clinical trials are valuable
human experiments. The major objectives of the
PIBIC are twofold: i. a deeper understanding of the
mechanisms underlying the tumor/immune system
interactions; and ii. the provision of new immunotherapy strategies that are rationally designed
to increase significantly the therapeutic efficacy of
the current ones.
Main achievements - The research of the pro-
gram is advancing towards the definition of new
classes of tumor associated antigens, derived from
somatically mutated proteins or from lipids synthesized by the abnormal metabolism of cancer cells.
Studies in the TRAMP transgenic model have identified a very efficient new strategy of adoptive immunotherapy for prostate cancer in which
allogeneic T cells transfer, HSC transplantation and
post-transplantation anti-tumor vaccination were
combined to achieve a remarkable clinical control
of the disease in the majority of the treated animals.
Improved strategies for adoptive immunotherapy
using transfer of tumor antigen-specific TCR are
being implemented using gene editing by designed
zinc finger nucleases and lentiviral vectors for
adoptive immune therapy of leukemia. A new
mechanism of tumor immunoescape has been
identified in melanoma, involving products of cholesterol metabolism that dampen DC function.
Progress has been made in the understanding of
the molecular pathways that lead to immune deviation in pancreatic cancer and the definition of the
role
of
Tie2-expressing
tumor-infiltrating
macrophages in determining a pro-tumor conditions in the microenvironment. The tumor-microenvironment remains the focus of new discoveries
made on the unexpected role of Chromogranin A
and its fragments in controlling tumor cell growth.
Furthermore, improvement of the targeting of angiogenic vascular endothelium by tumor-cytotoxic
cytokines is actively pursued. New results were
also obtained from the studies investigating the targeting of cancer stem/initiating cells in human
glioblastoma or mouse prostate cancer by antitumor T cell effectors to improve the efficacy of immunotherapy.
Clinical Immunotherapy Protocols
In addition to the participation in several company
sponsored trials testing new, molecularly targeted
agents, two spontaneous clinical studies have
been initiated in metastatic melanoma patients.
The first is a combination of the anti-vascular agent
NGR-hTNF and a peptide-based melanoma vac-
cine and the second a combination of the antiCTLA4 antibody Ipilimumab with the chemotherapy drug Fotemustine. Two and 12 patients have
been enrolled in the first and second study, respectively.
RESEARCH PROGRAMMES
Islet Trasplantation Program (ITP)
Lorenzo Piemonti and Paola Maffi
Manuela Battaglia, DRI - Diabetes Research Institute
Luca G. Guidotti, DRI - Diabetes Research Institute
Paola Maffi, DRI - Diabetes Research Institute
Maria Luisa Malosio, DRI - Diabetes Research Institute
Rita Nano, DRI - Diabetes Research Institute
Marina Scavini, DRI - Diabetes Research Institute
Vision - The mission of this program is to achieve
long-lasting insulin independence in patients with
type 1 diabetes (T1D) undergoing portal vein islet
transplantation. Recognized experts in islet transplantation, immunological tolerance, liver immunopathology and non-invasive imaging have
been brought together to address and modify innate and adaptive immune responses to islet transplants that together prevent lifelong persistence of
functional islets within the liver.
Goals - Aims of this program are:
1. to improve donor management, donor selection
criteria, organ recovery techniques and islet cell
processing techniques. Expected results: identification of more efficient islet cell processing to
maximize islet recovery.
2. to identify and standardize methods for the evaluation of islet preparations intended for transplantation in humans (ie cell composition, cell
viability, insulin secretion). Expected results:
identification and validation of predictor for islet
engraftment and post transplant function.
3. to identify strategies and drugs able to improve
235
RESEARCH PROGRAMMES
islet ‘engraftment’. Expected results: achieve
successful islet transplantation from one donor
to one recipient
4. to develop single or multi centre clinical trial to
test new immunosuppression and tolerogenic
strategies. Expected results: achieve successful islet transplantation without immunosuppression or with less toxic immunosuppressive
regimens.
5. provide islets for researchers. Expected results:
support research activity related to beta cell biology in Europe.
Main achievements - During the last year we:
• demonstrated that inhibition of CXCR2 is crucial
for improving islet engraftment and survival. On
this basis a clinical trial (NCT01220856) is ongoing testing CXCR2 inhibitor in association with
the conventional immunosuppressive therapy;
• developed an immunosuppressive treatment
compatible with the survival, function, and expansion of the transferred CD4 T regulatory type
1 (Tr1) cells;
• tested the safety and feasibility of islet autotransplantation in patients undergoing completion
pancreatectomy because of anastomosis leakage after pancreatoduodenectomy for nonmalignant or malignant diseases;
• tested safety and feasibility of bone marrow as
site for islet transplantation in humans.
Figure 56. Bone marrow hystology 1 year after singeneic islet infusion (C57B6 in C57B6 mouse). Red: insulin
staining
RESEARCH PROGRAMMES
Human Brain Invivo Mapping with neuroimaging
(BRAINMAP)
Head of Research Program:
Massimo Filippi*
Deputy Head of Research Program:
Andrea Falini*
Francesco Benedetti, Division of Neuroscience
Luigi Beretta*, Division of Neuroscience
Stefano F. Cappa*, Division of Neuroscience
Paola Cinque, Division of Immunology, Transplantation, and Infectious Diseases
Andrea Falini*, Division of Neuroscience
Massimo Filippi*, INSPE - Institute of Experimental Neurology
Roberto Gatti, Division of Neuroscience
Letizia Leocani, INSPE - Institute of Experimental Neurology
Giuseppe Magnani, INSPE - Institute of Experimental Neurology
Vittorio Martinelli, INSPE - Institute of Experimental Neurology
Daniela Perani*, Division of Neuroscience
Maria Assunta Rocca, INSPE - Institute of Experimental Neurology
Maria Sessa, INSPE - Institute of Experimental Neurology
237
RESEARCH PROGRAMMES
Vision - Due to their exquisite sensitivity, relative
non-invasiveness, and major technical advances,
neuroimaging techniques (mainly MRI and PET)
have become in the past couple of decades an irreplaceable way for the in vivo assessment of the
central nervous system in healthy and diseased
humans.
Goals - The Research Program “Human Brain Invivo Mapping with Neuroimaging” (BRAINMAP) is
aimed at: a) joining and strengthening the decennial expertise already developed in neuroimaging
at our Institute; and b) developing new research
lines in this field, through a multidisciplinary and
inter-departmental approach.
Main achievements - Gray matter (GM) volume
changes associated with motor learning were
mapped in young healthy individuals. Fifteen subjects were trained with goal-directed motor sequences, and 16 with non purposeful motor
actions of the right hand. Motor learning results in
structural GM changes of different brain areas
which are part of specific neuronal networks and
tend to persist after training is stopped.
Electroencephalography (EEG) source analysis,
functional magnetic resonance imaging (fMRI) and
focal transcranial magnetic stimulation (TMS) are
non-invasive methods for localizing human hand
primary motor area (M1) with good accuracy compared to direct electrocorticography results. Our
study confirmed the usefulness of multimodal integration of fMRI, EEG and TMS in localizing M1 and
the possibility to increase EEG spatial resolution
using fMRI information.
Default-mode network (DMN) abnormalities were
explored in patients with secondary progressive
and primary progressive multiple sclerosis (MS). A
dysfunction of the anterior components of the
DMN was found in progressive MS patients, which
can be among the factors responsible for the accumulation of cognitive deficits in these patients.
Brain damage in patients with Leber’s hereditary
optic neuropathy is not limited to the anterior visual
pathways, but extends posteriorly to the optic radiations and the primary visual cortex. Such a damage to the posterior parts of the visual pathways
may be due either to trans-synaptic degeneration
secondary to neuroaxonal damage in the retina
and optic nerve or to local mitochondrial dysfunction.
The diagnostic accuracy of apparent diffusion coefficient (ADC) for discriminating ocular adnexal
lymphomas (OALs) from other orbital mass lesions
was assessed. The study showed that ADC permits accurate diagnosis of OALs. Interval change in
ADC after therapy represents a helpful tool for predicting therapeutic response.
The effect of a GSK3-beta promoter single-nucleotide polymorphism (rs334558) on GM volumes
was studied in patients affected by chronic schizophrenia. Carriers of the less active C allele variant
showed significantly higher brain volumes in an
area encompassing posterior regions of right middle and superior temporal gyri. These results support the interest for GSK3-beta as a factor affecting
neuropathology in major behavioural disorders,
such as schizophrenia.
FMRI was used to measure brain activity in 1- to 3day-old newborns while they heard excerpts of
Western tonal music and altered versions of the
same excerpts. Music evoked predominantly righthemispheric activations in primary and higher order
auditory cortex. During presentation of the altered
excerpts, hemodynamic responses were significantly reduced in the right auditory cortex, and activations emerged in the left inferior frontal cortex
and limbic structures. These results demonstrate
that the infant brain shows a hemispheric specialization in processing music as early as the first
postnatal hours, and that the neural architecture
underlying music processing in newborns is sensitive to changes in tonal key as well as to differences in consonance and dissonance.
RESEARCH PROGRAMMES
Bone Physiopathology Program (BoNetwork)
Roberto Sitia* and Enrico Gherlone*
Alessandra Biffi, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Clara Camaschella*, Division of Genetics and Cell biology
Francesco Camnasio, Department of general and specialistic surgery
Simone Cenci, Division of Genetics and Cell biology
Roberto Crespi, Division of Genetics and Cell biology
Marina Ferrarini, Division of Molecular oncology
Elisabetta Ferrero, Division of Molecular oncology
Gianfranco Fraschini*, Division of Genetics and Cell biology
Federico Furlan, Emergency medicine
Roberto Gatti, Division of Neuroscience
Enrico Gherlone*, Division of Genetics and Cell biology
Stefano Mora, Division of metabolic and cardiovascular sciences
Giuseppe M. Peretti, Division of Genetics and Cell biology
Patrizia Rovere-Querini, Division of Regenerative medicine, Stem cells, and Gene therapy
Alessandro Rubinacci, Division of metabolic and cardiovascular sciences
Roberto Sitia*, Division of Genetics and Cell biology
Giovanni Tonon, Division of Molecular oncology
Giuseppe Vezzoli, Division of Genetics and Cell biology
Anna Villa, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Raffaele Vinci, Division of Genetics and Cell biology
239
RESEARCH PROGRAMMES
Vision - The skeleton evolved to provide a scaffold
for movement, a protective container for the central nervous system and the hematopoietic marrow, and a ubiquitous depot for precious minerals.
Skeletal homeostasis is ensured by continuous
mechano-sensing and remodelling operated by
bone-forming osteoblasts, of mesenchymal origin,
and bone-resorbing osteoclasts, monocyte-derived syncytia.
Involutional osteoporosis affects older women and
men in every population (35% postmenopausal
women and 19% men in caucasians). Pathologic
fractures reduce lifespan and cause severe disability. New strategies agasinst osteoporosis are
needed to promote healthy aging. The enormous
direct expenditures are rising with increased life expectancy.
Much bone cell biology and physiology remain unexplored. The identification of key ontogenetic, differentiation and signaling mechanisms shared by
bone and adaptive immunity opened a new exciting field, osteoimmunology- Identifying the
hematopoietic and skeletal stem cells and their
niches, understanding how osteoblasts and osteoclasts differentiate and operate, their derangement in bone wasting diseases, and how cancers
divert the bone microenvironment will provide novel
targets for osteoporosis and osteolytic cancers.
The integrated study of bone cell biology, stemness, and adaptive immunity promise to greatly expand our understanding of bone biology, enabling
us to identify new tissue- and cell-specific therapeutic targets, with key implications for the molecular and regenerative medicine of the skeleton.
Goals - The main goal of BoNetwork is to crosscontaminate basic (cell biology, genetics and immunology) and clinical areas.
Specific objectives include identifying the molecular and cellular bases of bone homeostasis; promoting joint efforts in cartilage and bone
engineering; improve bone regeneration in odon-
toiatrics; establishing potential molecular targets
and robust cellular and animal models for bone diseases; establishing solid core technologies (bone
histomorphometry and imaging); providing a solid
interface for pharmaceutical and nutriceutical companies.
Main achievements - In its first year of activity,
Bonetwork lists numerous achievements, including:
• The development of engineered tissues to investigate the effects of blood exposure on engineered cartilage, and of an osteochondral
composite (combining a bone material with an
engineered cartilage) for cartilage defects in large
animals.
• The characterization of the morphological and
biochemical modifications of the swine meniscus
during growth to develop a meniscal biological
substitute.
• New biomaterials (magnesium-enriched hydroxyapatite and xenogenic porcine bone grafts)
tested as bone substitutes in regenerative procedures for oral rehabilitation in animal and
human studies; these biomaterials proved safe
and useful for bone regeneration prior to implant
insertion and prosthodontic rehabilitation, allowing population-wide further studies.
• The identification and functional characterization
of gene variants of the calcium-sensing receptor
associated with human disease.
• The validation of mineral water as a source for
Ca2+ assumption in healthy subjects.
• The evaluation of antiretroviral drugs on the development of bone mass and metabolism derangements in HIV-infected children and
adolescents.
• The identification of a novel role of Class II Transactivator (a factor thought to be active solely in
antigen presenting cells) in osteoclast development providing a new paradigm in osteoimmunology.
RESEARCH PROGRAMMES
Figure 57. Osteoclasts are unique bone-resorbing syncytia hallmarked by multiple nuclei, a specific tartrateresistant acid phosphatase activity (left panel), and complex vesicular trafficking and protein homeostatic dynamics
that can be studied by immunofluorescent labeling with specific antibodies conjugated with different
fluorochromes (right panel). The mature osteoclasts shown in this image, were generated by culturing murine bone
marrow monocytes with the cytokines M-CSF and RANKL for 7 days (this image was produced by Elisa
Benasciutti and Bettina Mariani, in Simone Cenci’s lab at DGCB).
241
RESEARCH PROGRAMMES
Correlates of HIV-Associated Immune Response Modulation program (CHARM)
Paola Cinque and Guido Poli*
Massimo Alfano, Division of Immunology, Transplantation, and Infectious Diseases
Antonella Castagna, Division of Immunology, Transplantation, and Infectious Diseases
Paola Cinque, Division of Immunology, Transplantation, and Infectious Diseases
Nicola Gianotti, Division of Immunology, Transplantation, and Infectious Diseases
Luca G. Guidotti, Division of Immunology, Transplantation, and Infectious Diseases
Adriano Lazzarin*, Division of Immunology, Transplantation, and Infectious Diseases
Mauro S. Malnati, Division of Immunology, Transplantation, and Infectious Diseases
Giulia Morsica, Division of Immunology, Transplantation, and Infectious Diseases
Ruggero Pardi*, Division of Immunology, Transplantation, and Infectious Diseases
Guido Poli*, Division of Immunology, Transplantation, and Infectious Diseases
Gabriella Scarlatti, Division of Immunology, Transplantation, and Infectious Diseases
Giuseppe Tambussi, Division of Immunology, Transplantation, and Infectious Diseases
Caterina Uberti-Foppa, Division of Immunology, Transplantation, and Infectious Diseases
Luca Vangelista, Division of Immunology, Transplantation, and Infectious Diseases
Elisa Vicenzi, Division of Immunology, Transplantation, and Infectious Diseases
RESEARCH PROGRAMMES
Vision - After the discovery of HIV as the cause of
AIDS (1983) CD4 was soon identified as the primary receptor utilized by the virus to infect T lymphocytes and mononuclear phagocytes. However,
it took another 10 years to identify the second receptors (or co-receptors) for entry in the molecules
known as CXCR4 (firstly discovered) and CCR5.
CCR5 is indeed the main entry co-receptor for HIV
(R5 strains) and sustains the pandemics while
CXCR4 usage emerged in ca. 50% of individuals
infected with the viral subtype B, dominant in North
America, Europe and Australia. These strains are
frequently “dualtropic” R5X4 and currently represent a limitation for the clinical use of CCR5 antagonists.
CCR5 (as well as CXCR4) belongs to the superfamily of 7-transmembrane domains receptors
(also known as GTP-binding protein coupled receptors) whereas their ligands, chemokines, are
distinct from other cytokines both at the structural
level and, functionally, by their capacity of inducing
the migration of leukocytes. Thus, CCR5 is of crucial importance for inter-individual HIV-1 infection
and spreading for which reasons specific small
molecule inhibitors have been already developed
and approved for their use in clinical practice.
CCR5 is usually expressed at low to undetectable
levels in resting immune cells, except memory T
lymphocytes, whereas it is inducible by a variety of
pro-inflammatory and immunologically activating
signals. CCR5 binds to at least three natural ligands, the CC chemokines known as CCL3 (MIP1alpha), CCL4 (MIP-1beta) and CCL5 (RANTES).
In conclusion, CCR5 plays a major role both in mediating HIV entry as well as in regulating the immune response.
Goals - General goals of CHARM are the investigation and exploitation of the role of CCR5 and its
natural or chemical ligands in HIV infection and in
infection-related inflammation. The program stems
from the recognition of a critical mass of basic and
applied investigators already ongoing in this Division and in the Department of Infectious and Tropical Diseases on the role of CCR5 and its ligands
in HIV infection and related clinical entities. The
projects and their individual leaders have already
proven their validity and vitality in terms of dedicated scientific publications, grants and patents.
However, they have never been coordinated as an
internal network or program up to date. CHARM
has therefore the general goal to create such a network of knowledge and mutual exchange of information, and collaborations.
A second goal of CHARM is not subtract competence and resources to the individual participating
groups, but rather to promote their synergy, to
avoid duplicating efforts, and to seek for additional
funding and support both to individual projects
and, mostly, to the Program as a whole.
Main achievements - After less than 2 years since
its inception, CHARM has promoted several meetings among the PI and their affiliates, characterized
by open discussion mostly dedicated to the issue
of how to implement the quality of the interaction
between the basic scientist and the clinicians, unified by the common interest in the role of CCR5 in
HIV disease and related issues (such as the role of
CCR5 in HCV infection). In this period, a number of
individual grants have been obtained by several
members of the program and a broad project
(CHARM-001, “Class-sparing regimens for R5 HIV1 infected patients in salvage therapy: looking for a
robust CD4 gain“, PI: Prof. Adriano Lazzarin) involving several investigators has been submitted to
the “IRCCS-Ricerca Finalizzata” and it is pending
for revision.
243
RESEARCH PROGRAMMES
Figure 58. RANTES is a natural ligand of CCR5 and a powerful inhibitor of HIV-1 entry. By appropriate
modifications of RANTES N-terminus, this chemokine can be converted from a CCR5 agonist to an antagonist, an
ideal feature for AIDS therapy and prevention.
RESEARCH PROGRAMMES
Microenvironment and Genes in Cancers of the Blood
(MAGIC)
Paolo Ghia* and Giovanni Tonon
Massimo Alessio, Center for Translational Genomics and BioInformatics
Angela Bachi, Division of Genetics and Cell biology
Matteo Bellone, Division of Immunology, Transplantation, and Infectious Diseases
Rosa Bernardi, Division of Molecular oncology
Stefano Biffo, Division of Molecular oncology
Chiara Bonini, Division of Regenerative medicine, Stem cells, and Gene therapy
Andrea Brendolan, Division of Molecular oncology
Valeria R. Caiolfa, Division of Molecular oncology
Federico Caligaris-Cappio*, Division of Molecular oncology
Giulia Casorati, Division of Immunology, Transplantation, and Infectious Diseases
Simone Cenci, Division of Genetics and Cell biology
Fabio Ciceri, Division of Molecular oncology; Division of Regenerative medicine, Stem cells, and
Gene therapy
Angelo Corti, Division of Molecular oncology
Michele De Palma, Division of Regenerative medicine, Stem cells, and Gene therapy and HSR-TIGET The San Raffaele Telethon Institute for Gene Therapy
Paolo Dellabona, Division of Immunology, Transplantation, and Infectious Diseases
Claudio Doglioni*, Division of Molecular oncology
Marina Ferrarini, Division of Molecular oncology
Andrés Jose Maria Ferreri, Division of Molecular oncology
Elisabetta Ferrero, Division of Molecular oncology
Katharina Fleischhauer, Division of Regenerative medicine, Stem cells, and Gene therapy
Paolo Ghia*, Division of Molecular oncology
245
RESEARCH PROGRAMMES
Luca G. Guidotti, Division of Immunology, Transplantation, and Infectious Diseases
Eugenio Montini, HSR-TIGET - The San Raffaele Telethon Institute for Gene Therapy
Marta Muzio, Division of Molecular oncology
Ruggero Pardi*, Division of Immunology, Transplantation, and Infectious Diseases
Giorgio Parmiani, Division of Molecular oncology
Maurilio Ponzoni, Division of Molecular oncology
Maria Pia Protti, Division of Immunology, Transplantation, and Infectious Diseases
Vincenzo Russo, Division of Molecular oncology
Roberto Sitia*, Division of Genetics and Cell biology
Giovanni Tonon, Division of Molecular oncology
Vision - Recent breakthrough in cancer research
have reinforced the view that any progress toward
the cure of cancer arise from a deep understanding of their pathogenesis. Blood cancers arise
when cells reproduce unrestrainedly due to genetic
abnormalities in multiple genes that control cell division, differentiation, survival or programmed cell
death. On the other side, it is emerging more and
more clearly that the tumor microenvironment provides critical stimuli conferring to malignant cells a
growth advantage and an extended survival. Signals from the tumor microenvironment are a major
hurdle to cancer cell eradication and have become
an attractive target for treatment strategies that aim
at perturbing the nurturing capacity of tumor cell milieu. Causal genes and the microenvironment concur to shape the ultimate phenotype of individual
patients, i.e. their clinical presentation, natural history and drug resistance.
In this program, among blood cancers, we focused
on B lineage neoplasias, as the interaction between genetically abnormal malignant cells and a
dysregulated microenvironment has been shown to
be key in the pathogenesis of these malignancies,
with a focus on acute lymphoblastic leukemia (ALL),
chronic lymphocytic leukemia (CLL), Non-Hodgkin
Lymphomas (NHL) and multiple myeloma (MM).
Despite major therapeutic advances, all these tumors are presently incurable. We argue that effective and ultimately curative therapies for these diseases could only emerge from targeting
simultaneously the tumour cell its microenvironment interactions.
Goals - The specific aim of the proposed program
is to understand the basic biological mechanisms
of blood cancers and translate the findings into clinical reality thereby improving both diagnosis and
treatment. To this end the proposal is built around
4 tightly-interconnected Tasks, focused on:
1. novel therapies;
2. optimizing existing therapies and improving quality of life;
3. novel targets;
4. new cellular protagonists.
The aims of Task 1 are to: a) perform “ready-to-go”
preclinical studies on promising inhouse compounds and targets that are ready to be enlisted in
pre-clinical proof-of-principle studies, some indeed
on the verge of phase I/II clinical trials; b) preclinically validate targets and compounds emerging
from the efforts of the other programs and c) to
straightforwardly translate these tools into phase I/II
clinical trials. Moreover, within this program we plan
to d) develop, validate and apply molecularly-defined prognostic and predictive markers that will be
used to design strategies for personalized treatment.
The aims of Task 2 are to optimize existing treatments sparing toxicity and to target the major complications, thereby improving the patients’ quality of
life.
Task 3 and 4 are more exploratory and are conceived to fuel Programs 1, 2 in the whole course of
the project. Task 3 aims are: a) to address the significance of novel dysregulated or mutated molecules present on the tumor cell surface, through
which proliferation and apoptosis signals triggered
by cross talk with the microenvironment are conveyed inside the cell; b) to comprehensively examine the pathways altered by the tumor cell/microenvironment cross talk.
The aims of Task 4 are to thoroughly investigate the
relative contribution of different nontumoral cell
types and their mechanisms including some that,
due to technical constraints or conceptual limitations, have not been examined in the past. We argue that a more comprehensive understanding of
such cells and mechanisms will lead to more effective treatments.
Main achievements - The program started at the
RESEARCH PROGRAMMES
end of 2010 and it has already managed to foster
extensive collaborations between basic scientists
and clinicians, through regular meetings, collection
and sharing of reagents and biological material and
the acquisition of dedicated, relevant research
funds.
247
FACILITIES
CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis –––––––– 250
HEAD OF UNIT: Lorenza Ronfani
FELLOWS: Lorenzo Benini, Ivana Benzoni, Rosanna Rinaldi
TECHNICIAN: Maria Luisa Pintonello
FRACTAL, Flow cytometry Resource, Advanced Cytometry Technical
Applications Laboratory ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 250
HEAD OF UNIT: Alessio Palini
BIOLOGISTS: Simona Di Terlizzi, Chiara Villa
TECHNICIANS: Emanuele Canonico, Ivan Muradore
CERMAC, Centre of Excellence of High Field Magnetic Resonance ––––––––––––––– 251
PHYSICIANS:Valeria Blasi, Andrea Falini*
RESIDENTS: Antonella Castellano**, Elisa Scola**
POST-DOCTORAL FELLOWS: Sara Cirillo, Roberta Longaretti, Silvia Polverigiani
PHD STUDENTS: Monia Cabinio, Paolo Vezzulli
FELLOW: Paola Scifo
TECHNICIAN: Antonella Iadanza
PROMIFA, PROtein MIcrosequencing FAcility ––––––––––––––––––––––––––––––––––––––––– 251
HEAD OF UNIT: Angela Bachi
FELLOW: Annapaola Andolfo
TECHNICIAN: Cinzia Magagnotti
Mouse histopathology ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 252
GROUP LEADER: Francesca Sanvito
TECHNICIAN: Martina Rocchi
249
FACILITIES
CFCM, San Raffaele-Telethon 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 Core Facility for Conditional Mutagenesis (CFCM) is operative from 1999. During
this time CFCM provided to the Scientific Community more than 400 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 set up the De Novo ES cells Isolation from
wild type and mutant blastocysts. ES cells derived
from transgenic mice represent important tools for
the analysis of the mutation of interest. Moreover,
Researchers have the possibility to differentiate
mutant ES cells in all cell lineage for further characterization.
More information can be found at the site
http://www.sanraffaele.org/CFCMn.html
Lorenza Ronfani
FRACTAL, Flow cytometry Resource, Advanced Cytometry
Technical Applications Laboratory
The Flow cytometry Resource and Advanced Cytometry 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 Im-
munophenotyping, 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 2010 the facility
achieved ISO 9001:2008 Certification for the
processes of Cell Sorting, Assisted Analysis and
Training. Additionally, the facility supported over
400 Researchers, performed more than 1400 cell
sorts and logged over 10,000 hours of analytical
instrument time.
Alessio Palini
Figure 59. Blue laser
FACILITIES
CERMAC, Centre of Excellence of High Field Magnetic
Resonance
The Center of Excellence is built around a High
Field Magnet (3Tesla) dedicated to research in the
field of neurosciences. It was financed by an original grant of the Ministry of University and Ministry
of Health
Scientists of different disciplines work together carrying on projects concerning development and validation of functional MR techniques and their
application in the field of neuroradiology, neurology,
neurosurgery, psichiatry, psichology and cognitive
neurosciences.
Advanced MR techniques are employed to investigate normal brain development and function with
special focus on myelination process, music comprehension, white matter connections, language
areas and mirror neuron system. The same tech-
niques are used to characterize morphological,
structural and functional modifications related to
degenerative, inflammatory, neoplastic and vascular diseases. A novel approach to psychiatric diseases has been enabled by the noninvasive MR
capabilities.
More than eighty papers have been published in
major international journals during the last five
years.
The Center is site for postgraduate and PhD training in neuropsychology, cognitive neuroscience,
neurology and psychiatry. Medicine, Psichology,
Biotechnology and Physiotherapy students complete their thesis at CERMAC.
Giuseppe Scotti
ProMiFa, PROtein MIcrosequencing FAcility
The Protein Microsequencing Facility provides different analytical services aimed at structurally characterizing peptides and proteins using analytical
HPLC systems, 2D gel electrophoresis apparatus
and mass spectrometers.
Our Facility offers the possibility to: characterize
proteins/peptides by determining their MW and
amino acidic composition; define PTMs (posttranslational modifications) of proteins, including
type and site; identify each individual component
within complex protein mixtures derived from biological samples, including serum, plasma, urine,
whole cells and cellular secretion products, thus
providing important insights into molecular mechanisms behind cellular processes. Differential protein expression profiles and biomarker identification
can be carried out by 2DE followed by gel imaging.
Proteins, fractionated on 1D/2D-electrophoresis,
are in situ digested and analysed by MS spectrometry. The resulting mass signals are then used
to search for protein databases. As an alternative,
protein mixtures can be digested and then fractionated by nano-liquid chromatography, combined
to ESI mass spectrometry and MS/MS, to perform
proteomic profiling of biological samples.
All the services comprise appropriate scientific
consultancy, interpretation of the results, a report
on the analytical data signed by the service coordinator (on demand).
The Facility is intended to be a resource for both
local and extramural scientific community.
Instrumentation
• Thermo Scientific LTQ Orbitrap XL mass spectrometer equipped with an Easy nLC Proxeon
Biosystems
• PE-Sciex Q-Star Pulsar quadrupole -TOF mass
spectrometer equipped with nanospray off-line
source and on-line nLC Agilent 1100 Series
• Voyager DE-STR MALDI-TOF mass spectrometer
• Beckmann HPLC systems equipped with different kinds of columns
• GE Healthcare 2DE gel apparatus
• Perkin Elmer ProXPRESS Imaging System
• 2DE Image analysis software ProGenesis, Nonlinear Dynamics
• 2DE Image analysis software SameSpots (update of ProGenesis), Nonlinear Dynamics
More information can be found at: www.sanraffaele.org/58228.html
Angela Bachi
251
FACILITIES
Figure 60. Tandem mass spectrum of the reported peptide.
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, in order to evaluate the presence of morphological alterations in mouse models
of human disease.
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
and with research groups from other Institutes 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.
The increasing requests and the urgent requirement to generate a reference center for the
histopathological analysis of mouse models of disease of high predictive value is spurring a gradual
development of resources and technical knowhow, i.e. tissue microarrays production, DNA and
RNA extraction from selected microdissected samples.
Francesca Sanvito
FACILITIES
Figure 61. CD31 expression in murine
angiosarcoma.
253
FACILITIES
FRACTAL, Flow cytometry Resource, Advanced Cytometry Technical Applications Laboratory
FACILITIES
PROMIFA, PROtein MIcrosequencing Facility
255
THE CLINICAL DEPARTMENTS
257
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: Stefano Benussi, Michele De Bonis, Francesco Maisano, Alessandra
Rossodivita
CLINICAL UNIT COORDINATOR: Alessandro Castiglioni
PHYSICIANS: Irina Arendar, Andrea Blasio, Paolo Denti, David Ferrara, Andrea Fumero, Antonio
Grimaldi, Giuseppe Iaci, Giovanni Laino, Elisabetta Lapenna, Stefano Moriggia, Simona
Nascimbene, Maria Grazia Pala, Alessandro Verzini
RESIDENTS: Maria Chiara Calabrese, Micaela Cioni, Enrica Dorigo, Andrea Giacomini, Maurizio
Taramasso
FELLOWS: Federico Anzil, Andrea Guidotti, 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, Alessandro Durante
HEAD OF UNIT: Antonio Colombo
CLINICAL UNIT LEADERS: Mauro Carlino, Alaide Chieffo, Matteo Montorfano
PHYSICIANS: Alfredo Castelli, Cosmo Godino, Azeem Mohamed Latib
FELLOWS: Giefrius Davidicius, Filippo Figini, Marco Mussardo, Joanne Shannon, Kensuke Takagi
TRIAL COORDINATOR: Angela Ferrari
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
259
Clinic for primary and secondary cardiomyopathy
HEAD OF UNIT: Paolo Camici*
PHYSICIANS: Enrico Ammirati**, Sara Benedetti, Iacopo Olivotto, Roberto Spoladore**
RESIDENTS: Rachele Contri, Alessandro Durante**, Daniela Piraino**
FELLOWS: Alessia Faccini, Valentina Guida
Arrhythmia Unit and electrophysiology laboratories
HEAD OF UNIT: Paolo Della Bella
CLINICAL UNIT LEADERS: Giuseppe Maccabelli, Patrizio Mazzone
PHYSICIANS: Caterina Bisceglia, Manuela Cireddu, Simone Gulletta, Gabriele Paglino, Simone Sala,
Nicola Trevisi
CONSULTANTS: Maria Avitabile, Alessandra Marzi, Nicoleta Sora, Pasquale Vergara
RESIDENTS: Francesca Baratto, Giuseppe Ciconte, Andrea Radinovic
TECHNICIAN: Raimondo Bellanca
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: Daniela Piraino, Roberto Spoladore
Functional rehabilitation
HEAD OF UNIT: Alessandra Raschi
Intensive Care Unit (ICU) and Post Operatory Care Unit (POCU)
CLINICAL UNIT COORDINATORS: Tiziana Bove, Maria Grazia Calabrò, Giovanni Landoni, Federico
Pappalardo, Anna Mara Scandroglio
PHYSICIANS: Elena Bignami, Francesco Cama, Andrea Carozzo, Francesca Cavenago, Guglielmo
Cornero, Remo Daniel Covello, Antonella Crescenti, Monica De Luca, Greta Fano, Rossana Fiori,
Annalisa Franco, Giovanna Frau, Chiara Gerli, Silvio Magrin, Giovanni Marino, Giulio Melisurgo,
Roberta Mennella, Melissa Messina, Fabrizio Monaco, Jaques N’Zepa Batonga, Massimiliano
Nuzzi, Ornella Sottocorna
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: Annamaria Gremmo, Piergiorgio Muriana, Silvia Raimondi Cominesi, Stefano Sestini
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: Luca Apruzzi, Giovanni Coppi, Davide Logaldo, Daniele Mascia, Daniele Psacharopulo,
Sara Spelta, Gianbattista Tshiombo
FELLOWS: Domenico Baccellieri, Luca Bertoglio, Chiara Brioschi, Barbara Catenaccio, Andrea
Kahlberg
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 wellas patients with chronic diseases admitted
electively are submitted 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.
261
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*, Francesco Deni, Renato Finazzi, Emiliano
Giorgi, Gilberto Mari, Michele Paganelli, Danilo Parolini, Sandro Passaretti, Carlo Socci
Gastroenterologic surgery
CLINICAL UNIT LEADERS: Saverio Di Palo, Elena Orsenigo
CLINICAL UNIT COORDINATOR: Paola De Nardi
PHYSICIANS: Andrea Marco Tamburini, Andrea Vignali
FELLOWS: Michele Carvello, Francesco Luparini, Alessio Mocci, Jacopo Nifosi, Maria Chiara
Salandini
RESIDENTS: Damiano Chiari, Francesca Muffatti, Serena Pozzi
General and pancreatic surgery
HEAD OF UNIT: Valerio Di Carlo*
CLINICAL UNIT LEADERS: Marco Braga*, Marco Cristallo
PHYSICIANS: Gianpaolo Balzano, Renato Castoldi, Marco Stella, Walter Zuliani
RESEARCHER: Lorenzo Piemonti
RESIDENTS: Massimiliano Bissolati, Vanessa Capitanio, Giovanni Capretti, Cristina Gilardini, Nicolò
Pecorelli, Gregorio Stratta
FELLOWS: Cristina Ridolfi, Federica Merlini
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 Maria Castoldi, Pietro Ciampi, Alessandro De Ponti, Dario
Fracassetti, Valeri Maltsev, Davide Mandelli, Umberto Mezzadri, Gianluigi Moro, Paola Rivoltini,
263
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, Antonella Putignano, Sabrina Testoni,
Cristian Vailati
CONSULTANTS: Maura Corsetti, Antonella Giussani, Gianni Mezzi, Maria Chiara Petrone, Elena
Radice
VISITING PROFESSOR: Giulia Martina Cavestro
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, Cinzia
Elisabetta De Grandis, Alessandra Garassino, Daniela Larato, Renato Meani, Alessandra Mello,
Francesca Presti, Lorenzo Quario, Raffaella Reineke
CLINICAL UNIT LEADER: Sergio Colombo
PHYSICIANS: Paolo Federico Beccaria, Pier Carlo Bergonzi, Luca Cabrini, Carlo Leggieri, Daniela
Mamo, Elena Moizo, Milena Mucci, Davide Salaris, Massimo Zambon
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 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.
Fields of research
The Department of Surgery has a long and distinguished history of surgical research that is recognized
nationally and internationally. Clinical trials not available elsewhere are offered for a variety of surgical diseases, giving hope to patients with critical illness who were once considered untreatable. The research
mission is to generate new knowledge of the scientific basis of surgically-related disease and to provide
outstanding scientific training for the surgeons and surgical scientists of the future. The key focus of the
Department of Suregry is the development and application of molecular/genetic biomarkers for the diagnosis, prognosis and prediction of treatment response of gastrointestinal tumors. The primary objectives are: 1) To be on the cutting edge of surgical research; 2) To help develop new applications to clinical
care; and 3) To provide outstanding research training for surgical residents and surgical scientists.
Carlo Staudacher
265
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: Benedetta Basta, Fabio Bernasconi, Maria Rosa Calvi, Marco Cerri, Antonella Cipriani,
Assunta De Vitis, Cristina Frascoli, Luigi Gioia, Elisabetta Grandi, Karin Iemi, Maurizio Mungo,
Alfredo Ravizza, Francesco Ruggieri, 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, Luigi Berchicci, Paolo Bettin, Ingrid Bianchi,
Stefania Bianchi Marzoli, Elena Bruschi, Gabriella Cammarata, Claudio Campa, Maria Lucia
Cascavilla, Carlo Ciampi, Paola Ciasca, Marco Codenotti, Annalisa Colucci, Alessandra Criscuoli,
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, Stefania Mazzarella, Paolo
Mauceri, Lisa Melzi, Jacopo Milesi, Elisabetta Miserocchi, Giulio Modorati, Veronica Odazio,
Matteo Prati, Lea Querques, Andrea Ramoni, Laura Regali, Carmen Rojo, 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: Giulio Ferrari, Federica Ferrario, Chiara Insacco, Stanislav Matuska, Giorgio
Paganoni, Elena Scandola, Maurizia Viganò
TECHNICIAN: Alessandra Battinelli
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, Salvatore Toma
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 integrates the clinical and research activities of six clinical “operative units” dedicated to pathology of: head and neck, auditory system, Central Nervous System (brain and
spinal cord), visual system.
Clinical activity and areas of excellence
From diagnosis to treatment, the areas of clinical excellence of the Department are:
Advanced neuroradiological techniques
Four high field magnetic resonance units (three 1.5T and one 3.0T units) perform more than 12.000 MRI
per year in children and adults. Presurgical functional studies (activation, tractography) are performed on
a regular basis for surgery of brain gliomas.
Pediatric MRI studies are performed in fetuses at risk, premature newborns, infants and children, both on
an outpatient basis in sedated or awake children and in emergency and inpatient basis.
Interventional Neuroradiology addresses endovascular treatment of aneurysms, arteriovenous malformations of the brain and spinal cord, fistulae, carotid stenosis. A wide variety of coils, stents and different
types of glue are in regular routine use. All procedures are performed in strict consultation and cooperation with neurosurgery and neurointensive care units.
Neurosurgery
The clinical hallmarks of neurosurgery are:
• pituitary and base of the skull tumors. The treatment of pituitary lesion is coordinated with the clinicoendocrinological support available within the department unit. Brain gliomas are operated with the sup267
port of functional MRI studies and tractography when needed and are followed in cooperation with
neurooncology for chemotherapy, and radiotherapy units. Aggressive and extensive skull base tumors
are operated in cooperation with otolaryngology department.
• Radiosurgery is performed on a wide range of lesions from brain AVM’s to skull base tumors and brain
metastasis with a very active gamma knife up to date equipment operated on a multidisciplinary basis.
Spine surgery and peripheral nervous system surgery are also performed.
Otolaryngology
The unit is characterized by a very intense surgical activity mainly addressed to neck malignancies (tumors
of the larynx, pharynx, thyroid), paranasal sinuses, oropharyngeal cavity, base of the skull.
Rehabilitation of patients submitted to laryngectomy and evaluation and treatment of patients with disturbed vestibular system and vertigo are among the non surgical clinical activities.
Ophthalmology
Organised in two vision units, one of which dedicated to the cornea and ocular surface, the ophthalmological activity is intense and addresses the following fields of pathology:
pediatric ophthalomology, retinal surgery, ocular oncology with a particular interest in orbital lymphomas,
advanced diagnostic imaging with evaluation of nerve fiber layer thickness, corneal thickness, retinal ganglion cells in the development of epiretinal membrane. Neuroophthalmology is particularly active in studying and treating inflammatory and hereditary optic neuropathies.
Neurointensive care
The neurointensive care unit provides support to the surgical activity of all the units of the department, neurosurgery, ophthalmology, otolaryngology and of the interventional procedures in Neuroradiology as well
as sedation of children and adults for diagnostic neuroradiological procedures.
Treatment of comatose patients and of severe brain trauma cases is one of the fields of excellence of the
unit.
Giuseppe Scotti
DEPARTMENT
INFECTIOUS DISEASES OF
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, Francesca Cossarini, Lorenzo Diomede, Giovanni Gaiera,
Andrea Galli, Giulia Gallotta, Hamid Ibrahim Hasson, Maria Rita Parisi, Annamaria Pazzi, Cecilia
Pizzocolo, Deborah Ratti, Clara Ronchetti, Vega Rusconi, Flavia Salmaso, Stefania Salpietro,
Chiara Tassan Din, Giovanna Travi
FELLOWS: Laura Alagna, Sabrina Bagaglio, Francesca Ferretti, Manuela Pogliaghi, Lucy Porrino,
Vincenzo Spagnuolo
TECHNICIANS: Arabella Bestetti, Manuela Testa
RESEARCH NURSES: Alba Bigoloni, Liviana Della Torre, Concetta Vinci
STUDY COORDINATORS: Elisabetta Carini, Elisa Gasparotto, Clara Ronchetti, Vega Rusconi
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.
The ongoing clinical research lines include: the pathogenesis and management of HIV drug-resistance,
269
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 and it is active as a reference centre for research, diagnosis and managment of JCV-related progressive multifocal leucoencephalopathy.
The Department Director is the National coordinator of the Healthy Ministry Italian guidelines on the use
of antiretroviral drugs and diagnostic-clinical management of persons with HIV-1 infection. Members of
the Department are involved as committee members in the Italian guidelines on HIV infection, the European AIDS Clinical Society Guidelines for treatment of HIV infected adults in Europe and the NIH-CDCHIVMA/IDSA Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults
and Adolescents.
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 2010, several 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, with the Department involved in 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 (International Network of HIV Cohorts). The Department is also
collaborating with Regione Lombardia to investigate treatment strategies for HIV infection aiming to reduce
health costs without jeopardizing treatment efficacy.
The Department coordinates International Network for Strategic Initiatives in Global HIV Trials (INSIGHT),
an NIH- funded consortium, that from the year 2000 to the end of the studies in 2009 has coordinated
all the main international studies on interleukin-2 administration in HIV+ patients. In the last years, additional interests include vaccines and Interleukin-7 use in HIV+ patients. Interleukin-7 use represents a
novel approach in HIV+ immunological non-responders and HCV+ patients. Moreover, through the participation in the ERAMUNE study, the chance to cure HIV infection is currently explored with an eradication of HIV infection project.
The institute is collaborating with national and international research on the development of new treatment
strategies of viral hepatitis co-infections in HIV positive people. In addition to clinical trials, the ongoing clinical research includes the pathogenesis and management of HCV drug-resistence. The department is also
involved in programs with the aim to investigate links between biological, psychological and social aspect
of HIV. The institute is one of the most active participants in EUROSUPPORT projects of European Community, a network of research in the area of sexual and reproductive health needs of people living with
HIV/AIDS
Within San Raffaele Hospital, 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. Particularly, the recent emerging of bacteria whit new mechanisms that confers resistance to
various antibiotics, forces to improve and control the quality and appropriateness of antimicrobials prescriptions in hospital. In this contest, the Department has the leading role, in cooperation whit the Hosp
Pharmacy and the Microbiology Lab, to develop and implement the Antimicrobial Management Program.
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 front-line activity in the management of HIV infection and high level clinical science outputs, 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, Andrea Rigamonti, 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, Arianna Passoni,
Alessandra Perduca, 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, Stefania Luchini
PHYSICIANS: Giada Almirante, Luigi Caputo, Anna Cardani, Paolo Cavoretto, Patrizia De Marzi,
Francesca Di Sebastiano, Davide Ferrari, Susanna Filippis, Luca Gandini, Elisabetta Garavaglia,
Paolo Giardina, Elena Marsiglio, Fabio Mauro, Michela Molgora, Nicoletta Panacci, Enrico Papaleo,
Micaela Petrone, Maria Teresa Potenza, Emanuela Rabaiotti, Susanna Rosa, Maddalena Smid,
Simona Vailati
RESEARCHER: Massimo Origoni*
BIOLOGISTS: Federico Calzi, Lucia De Santis, Paola Panina, Elisa Rabelotti, Paola Viganò
CONSULTANTS: Rossana Cairone, Raffaella Chionna, Rossana Favia, Marzia Frateschi, Fiorenza
Lagona, Silvia Maddalena, Massimo Pileri
RESIDENTS: Diana Del Prato**, Lara Di Piazza**, Francesca Di Puppo**, Cinzia Gentile**, Francesca
Occhi**, Jessica Ottolina**, Marta Parma**, Federica Pasi**, Francesca Pella**, Paola Persico**,
Anna Redaelli**, Audrey Serafini**, Chiara Stefani**
271
Pediatric immuno-hematology Unit
CLINICAL UNIT LEADER: Sarah Marktel
PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Alessandra Biffi
RESIDENTS: Federica Barzaghi, Costanza Evangelio, Francesca Ferrua, Marta Frittoli, Valentina Finizio,
Marco Fossati, Sara Napolitano
CHARGE NURSE: Clara Soliman
RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi
Obstetrics and Gynecology unit
The scientific and clinical activities of the Obstetrics and Gynecology Unit have involved four main areas:
1. Gynecological Surgery. The Unit is pilot centre for the diagnosis and treatment of endometriosis with
a multidisciplinary approach and the most advanced minimally invasive surgical techniques. Other activities include day surgery procedures, conservative and demolitive laparotomies, laparoscopies, 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.
2. Obstetrics and Fetal Medicine. In 2010, the delivery assistance (1983 deliveries) included 65% vaginal deliveries and 35% caesarean sections. Treatment and care are provided to patients with normal and
high-risk pregnancies - gestational and pre-gestational diabetes, hypertension, autoimmune diseases,
thrombophilia and recurrent abortion. In 2010, 3500 outpatient obstetric evaluations have been performed and 500 prenatal diagnoses were carried out.
3. Reproductive Sciences. The Infertility Unit combines the clinical and scientific expertise across different areas of infertility (endocrinology, andrology, oncology). The team completed two multicentre randomised control clinical trials on the efficacy of subcutaneous progesterone, and rFSH/rLH treatment on
the outcome of ovulation induction protocols. Cryopreservation of fertility is offered to patients at risk of
premature ovarian failure (cancer, severe endometriosis) with innovative techniques for cryopreservation
of gametes and gonadal tissues. One major research focus is the identification of new genomic biomarkers critically involved in controlling embryo implantation after IVF, including the HLA-G antigen and its
functional polymorphisms in relationship with tolerogenic cells.
4. Cancer Prevention. A low frequency of virus-specific T cells have been demonstrated in HPV-18+ patients with pre-neoplastic lesions. Higher relapse rate were found after surgical treatment in these cases,
strengthening the correlation between immune response and HPV-related female genital carcinogenesis.
Pediatrics and neonatology unit
Neonatology
Maturative study of the Central Nervous System
It is a very fascinating field of research: thanks to the use of innovative approaches, such as Diffusion Tensor Imaging and Functional MRI, it is possible to quantify the anatomic and functional evolution of the brain
of the preterm babies. Our group co-operates with the department of Pediatric Neuroradiology for the application of the latest imaging techniques and to valuate the clinical feasibility.
Metabolic and clinical outcome of infants born pre-term or from mothers with diabetes
Infants born from pregnancies complicated by pre-gestational or gestational diabetes, whose clinical conditions are often similar to those of uncomplicated pregnancies, need more characterization in order to
better define their long-term clinical and metabolic outcome. Body composition and bone mineralization
are innovative fields of research, that we are exploring in such babies along with growth and neuro-psychologic development. The aim of the study is to evaluate the impact of pre-gestational conditions on
extra-uterine growth. Results are than compared with normal babies an with infants born pre-term or
small for gestational age.
Diabetes and metabolic diseases in children and adolescents
The aim of the unit is clinical research in children and adolescents with type 1 diabetes. with 3 main lines
of study: 1) prevention of diabetes 2) technology in diabetes 3) obesity in diabetic children.
We participate in a tertiary prevention study (phase III, 3-arm, randomized, double-blind, placebo-controlled, multicenter study), with the primary objectives to evaluate the efficacy of Diamyd ( anti GAD vaccination) compared to placebo in preserving endogenous insulin secretion and to further confirm the
safety of Diamyd.
More than 180 children treated with pump for continuous subcutaneous insulin infusion (CSII) are monitored for long term results together with the use continuous glucose monitoring (CGMS) .ren and adolescents and follow outpatients in the first combined application of CSII and CGMS. We are comparing
CSII and MDI in children < 6 yrs.
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.
We collaborate in Trialnet, primary and secondary prevention study, (Prof. Bosi) and with Dr. Battaglia
(TIGET-DRI) in evaluating correlations between T-cell genotype and phenotype in children affected by
type 1 diabetes.
Congenital Hypothyroidism pathogenesis is still largely unknown, in cooperation with Milan University, we
analyzed the role of the Notch ligand Jagged1 in thyroid organogenesis: we found that JAG1 gene inhibition directly impairs thyroid development and can be responsible of complex phenotypes in humans.We
continued also molecular studies focusing on genes involved in iodide organification. New mutations of
DUOX2 were identified: we are performing functional studies and evaluating genotype-phenotype correlations.
The genetic basis of Congenital Hyperinsulinism are not fully clarified. To date, 40 families have been recruited. We identified 13 mutations in ABCC8 and KCNJ11 genes (5 news mutations) and a novel mutation of the HADH gene. In Prader Willi syndrome the most frequent syndromic obesity we performed a
study to estimate the frequency of metabolic syndrome: the results suggest the crucial role of obesity status.
Congenital Adrenal Hyperplasia is a field of application of less-invasive and more accurate methods. We
aim to determine salivary and urinary steroid profile through LC-MS for diagnosis and follow-up. We are
engaged in some protocols on Turner syndrome that investigate the gonadal, thyroid and kidney function
and the psychological aspects of this condition. We are studying patients with hypogonadotrophic hypogonadism from clinical and genetic perspective: in two patients a mutation in candidate genes were
found. In patients with disorders of sex differentiation, we aim to standardize pharmacologic tests execution and results interpretation in order to obtain a better diagnostic definition, together with genetic
analysis.
Giuseppe Chiumello
273
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: Andrea Bolla**, Chiara Cappelletti**, Valentina Crippa**, Valentina Doria**, Ilaria
Formenti**, Alessandra Gandolfi**, Sara Madaschi**, Chiara Molinari**, Francesca Perticone**,
Cecilia Piani**, Annachiara Uccellatore**, Valentina Villa**
FELLOWS: Andrea Laurenzi, Alessandro Rossini
NUTRITIONIST: Monica Marchi
TRIAL COORDINATOR: Pauline Grogan
RESEARCH NURSE: Eleonora Bianconi
Clinical transplantation
HEAD OF UNIT: Antonio Secchi*
CLINICAL UNIT LEADERS: Rossana Caldara, Paola Maffi
PHYSICIAN: Sabina Martinenghi
CONSULTANTS: Chiara Gremizzi, Vera Paloschi
RESIDENTS: Federica Cipriani, Francesca D’Addio, Alessandra Petrelli
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, Gabriella Cicenia, Emmanuel della Torre, Luca Ferrante, Barbara
Guglielmi, Alessandro Marinosci, Francesca Motta, Mirta Tiraboschi, Enrico Tombetti
Nephrology and dialysis
HEAD OF UNIT: Donatella Spotti
CLINICAL UNIT LEADERS: Paolo Manunta*, Giorgio Slaviero, Giuseppe Vezzoli
PHYSICIANS: Teresa Arcidiacono, Chiara Lanzani, Marco Melandri, Rita Quartagno, Maria Teresa
Sciarrone Alibrandi, Paola Stella
RESIDENTS: Irene Botticelli, Guido Gatti, Lino Merlino, Marialuisa Querques, Francesco Rainone,
Marco Simonini, Francesco Trevisani
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.
The Department of Internal Medicine is composed of four inpatient Clinical Units, a Day Hospital Service
and many Outpatient Clinics 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
275
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: Antonios Dakanalis, Valentina Di Mattei, Carola Iris Ferrari, Claudia Yvonne
Finocchiaro, Gianluca Franciosi, Serena Giuliani, Chiara Madinelli, Maria Rita Milesi, Chiara Motta,
Liliana Novella, Sara Peluso, Valeria Pezzani, Alessandra Pradella, Maria Monica Ratti, Eleonora
Sasso, Silvana Villa
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 LEADER: Stefano Erzegovesi
CLINICAL UNIT COORDINATORS: Maria Cristina Cavallini, Giuseppina Diaferia
PHYSICIANS: Cinzia Arancio, Alessandro Bernasconi, Marco Catalano, Silvia Cocchi, Angela Gabriele
FELLOWS: Emma Fadda, Elisa Galimberti, Riccardo Martone
Mood disorders
HEAD OF UNIT: Cristina Colombo*
CLINICAL UNIT LEADERS: Linda Franchini, Adelio Lucca, Raffaella Zanardi
PHYSICIANS: Barbara Barbini, Francesco Benedetti, Euridice Campori, Danilo Dotoli, Mara Cigala
Fulgosi, David Rossini
RESIDENTS: Dario Delmonte**, Clara Locatelli**, Alessia Malaguti**
Neurology
HEAD OF UNIT: Stefano F. Cappa*
CLINICAL UNIT LEADER: Sandro Iannaccone
PHYSICIANS: 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
Sleep disorders
HEAD OF UNIT: Luigi Ferini-Strambi*
PHYSICIANS: Mauro Manconi, Alessandro Oldani, Marco Zucconi
The first and main committment of the Department is to define and to developa 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.
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
277
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, Lucia Moiola, Mariaemma Rodegher, Maria Sessa,
Giulio Truci, Maria Antonietta Volontè
PHYSICIANS: Stefano Amadio, Giovanna Franca Fanelli, Roberta Guerriero, Silvia Mammi, Filippo
Martinelli-Boneschi, Stefania Medaglini, Maria Grazia Natali Sora, Grazia Maria Nuzzaco**,
Antonella Poggi, Marta Radaelli**, Nilo Riva**, Paolo Rossi, Luisa Roveri, Marina Scarlato, Maria
Carmela Spinelli**
RESIDENTS: Martina Absinta**, Valeria Barcella**, Damiano Baroncini**, Francesca Bianchi**,
Mariangela Bianco**, Francesca Caso**, Raffaella Chieffo**, Elisabetta Coppi**, Dacia Dalla
Libera**, Donatella De Feo**, Maria Grazia Deriu**, Federica Esposito**, Luisa De Toni
Franceschini**, Laura Ferrari**, Francesca Fumagalli**, Sebastiano Galantucci**, Chiara Ghidinelli**,
Giacomo Giacalone**, Clara Guaschino**, Elda Judica**, Sara La Gioia**, Emanuela Leopizzi**,
Giuseppe Liberatore**, Giulia Longoni**, Ignazio Diego Lopez**, Maria Merello**, Maria Josè
Messina**, Giulia Pavan**, Elisabetta Stefania Perego**, Luca Peruzzotti Jametti**, Marzia Romeo**,
Francesca Sangalli**, 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 rehabilitation. 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 pro-vide 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 dis-
ease 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 results of both the clinical and the research
activities of year 2010 remains satisfactory: 38 clinical trials have been approved and 69 trials are ongoing. Our Department is acting as Coordinating center for 10 clinical trials. During 2010 our Department
including the Research Units have reached a total of impact factor of approximately 395 – please refer
to the reports of each unit in this Scientific Progress Report. Moreover, there are 21 ongoing research
grants and 8 awards have been received by our physicians/researchers.
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
279
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, Manuela Pacchioni, Gilda
Rossoni
RESIDENTS: Chiara Miggiano, Federica Pozzi, Carlo Rossi, 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, Michela Tassara
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, Ornella Rimoldi, 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, Irene
Pescetelli, Pietro Spagnolo, Paola Vai
RESIDENTS: Pierpaolo Alongi, Cinzia Crivellaro, Elena Greco, Paola Mapelli, Rita Garcia Parra, Elena
Spinapolice, Ignazio Vilardi
FELLOWS: Elena Maria Andreolli**, Emilia Buriova, Giuseppe Di Grigoli, Elisa Galli, Giuliana Gelsomino,
Manuela Giglio, Claudia Francesca Maddé, Claudio Mannu, Valeria Masiello, Angelo Nacca,
Annalisa Pepe, Eugenio Rapisarda
PHD STUDENTS: Andrea Busdraghi, 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,
Stefano Mezzatesta, Giacomo Orlandi, Alice Piana, Jacopo Perego, Gabriele Raimondi, Riccardo
Rigamonti, Silvana Romano, Lucia Rozza, Pasquale Simonelli, 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: Nicola Alessandro Iacovelli, Brigida Pappalardi, Elisa Villa
TECHNICIANS: Fabio Baratto, Nietta Barricella, Roberta Bin, Rita Calaciura, Alessandro Capelli, Alberta
De Leonardis, Caterina Fiordelisi, Laura Longoni, Marilena Martulano, Lidio Palumbo, Diana Parutto,
Vincenzo Sacco, Giovannella Salvadori, Andrea Sbalchiero, Simone Selli, Antonella Soccio,
Alessandro Tavilla, Andrea Viale
The Department of Oncology aims at transforming everyday practice into protocol-based clinical activity to achieve optimization of care and acceleration of cure. The specific goals 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 is planned to be funnelled into 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 Cancer Center (HSR-ICC).
The Department includes the Divisions of Medicine 1Q, of Hematology and Bone Marrow Transplantation (BMT) and the Units of Medical Oncology, Radiotherapy and Nuclear Medicine. The number of beds
is 63, the personnel amounts to over 190 people including 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
2009 the Department has taken care of more than 4500 cancer patients and the outpatient service of
emergencies in oncology has been well set up. Furthermore ia) the Department has become full member of the ROL (Oncology Network of Lombardia Region) and the REL (Hematology Network of Lombardia
Region), iib) the Departmental Area of Lymphoid Tumors has been blooming with more than 200 new patients and 27 ongoing clinical trials, iiic) the BMT Unit has ranked among the firsts in Italy as for the number of allogeneic transplantations performed and div) 41 new clinical trials have been approved by the
Ethical Committee; overall 148 trials are running including numerous Phase I and Phase II trials. Blood,
281
thoracic, pancreas, brain tumors and melanoma are areas where the Department is especially active, not
to mention the urological cancers that are dealt with 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 is 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), the Network Italiano
BioImmunoterapia dei Tumori (NIBIT) and 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 (including physician-scientists) 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) Definition of new 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-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.
Federico Caligaris-Cappio
DEPARTMENT
OF
RADIOLOGY
Head of Department:
Alessandro Del Maschio*
DEPARTMENT AREA COORDINATORS: Francesco De Cobelli*, Maurizia Del Maschio, Roberto
Nicoletti, Pierluigi Paesano
Radiology HSR
HEAD OF UNIT: Alessandro Del Maschio*
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, Cinzia De Iorgi, Isabella
Fedele, Claudio Losio, Maurizio Papa
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 170000 diagnostic and interventional procedures (including emergency) per year.
The Department of Radiology is composed of many inpatient 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 Villa 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.
283
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. DiagnosticAngiography and Interventional Radiology
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
• Pancreatic and gastro-intestinal cancer’s imaging.
• Breast cancer imaging and screening
• Interventional Radiology
• Cellular and molecular imaging with a new 7T magnet dedicated to animal studies
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 it has been developed a tight cooperation on Magnetic resonance 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;
• 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 used different imaging
techniques, such 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 diabetic
patients who have undergone kidney or combined kidney-pancreas transplantation or islet-transplantation 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.
Alessandro Del Maschio
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: 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, Fabio
Castiglione, Dario Di Trapani, Ettore Di Trapani, Matteo Ferrari, Salvatore Grimaldi, Carmen
Maccagnano, Rayan Matloob, Federico Pellucchi, Giovanni Petralia, Lorenzo Rocchini, Francesco
Sozzi, Elena Strada, Manuela Tutolo, Luca Villa
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, Andrea Cestari, Luciano Nava
PHYSICIANS: Antonia Centemero, Andrea Losa, Tommaso Maga, Lorenzo Rigatti
CONSULTANTS: Nicolò Maria Buffi, Fabio Fabbri, Mattia Sangalli, Emanuele Scapaticci, Matteo
Zanoni
RESIDENT: Giovanni Lughezzani
285
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. In 2010, our department surpassed its objectives in terms of ward organization, clinical information organization and management, quality of clinical outcomes, and the level of patients’ satisfaction.
Fields of research
The clinical investigations performed in the most recent years leaded to the publication of 647 scientific
contributions for a overall citation index of 8374 (citation index last three years: 4003; h-index: 45) [Source
SCOPUS April 2011]. During the last 4 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.
In 2010, we actively participated in 6 multi-centric randomized-trials, as well as 7 multi-centric observational studies. Moreover, we continued to prospectively collect and analyze data from patients treated at
our institution. 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 have 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. In 2010, a biological bank was founded to permit collecting and analyzing tissue, blood, and urine samples from virtually all oncological patients for scientific research purpose.
Patrizio Rigatti
CLINICAL
SERVICES
Pathology –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 289
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 –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 289
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, 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, Emanuela
Castiglioni,Vincenza Causarano, Donata De Marco, Roberta Diotti, Chiara Di Resta,
Alessandra Foglio(*), Silvia Galbiati, Nadia Ghidoli, Carlo Lombardoni(*), Nicola
Maganetti, Gisella Moreno, Francesca Rigo(*), Diego Saita, Giuseppe Andrea Sautto,
Laura Solforosi, Stefania Stenirri
TECHNICIANS: Michela Sanpaolo, Francesca Sampietro(#), Nadia Soriani(*)
(*) reporting to the Center for Translational Genomics and BioInformatics
(#) reporting to the Division of Metabolic and Cardiovascular Sciences
Immunohematology and transfusion medicine service –––––––––––––––––––––––––––––– 290
HEAD OF UNIT: Silvano Rossini
CLINICAL UNIT LEADERS: Lorena Barzizza, Laura Bellio
PHYSICIANS: Cinzia Bargiggia, Alketa Bolentini, Katharina Fleischhauer, Salvatore
Gattillo, Lucia Malabarba, Milena Coppola, 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,
287
CLINICAL SERVICES
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 –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 290
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, Shikegi Kusamura, Andrea
Laurenzi, Francesco Luparini, Alessandro Marinosci, Federica Merlini, Federica Milani, Alessio
Mocci, Annamaria Pazzi, Elena Peretti, Alessandro Rossini, Roberta Varale
General intensive care –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 291
CLINICAL UNIT COORDINATOR: Paolo Silvani
Anesthesia ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 291
CLINICAL UNIT COORDINATORS: Massimo Caldi, Daniela Giudici
CLINICAL SERVICES
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 26.000 surgical, including 2500 cases of intraoperative frozen section consultations and 24.000 cytologic specimens
in 2010, encompassing most of the wide variety of
pathology scenario. We perform also a same day
diagnostic service for prostatic biopsies, in which
sampling, biopsy processing and reporting are
completed in about three hours. The diversity of
the specimen material is reflected in the special-
ized 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
Diagnostica e Ricerca San Raffaele (Laboraf) is the
Laboratory Medicine Unit that provides clinical laboratory services to the San Raffaele Hospital. Laboraf is organized as a department that includes:
Clinical Chemistry – Toxicology - Immunochemistry,
Haematology (in conjunction with the Immunohematology and Transfusion Medicine Service), Coagulation, Microbiology – Virology and Serology,
Clinical Molecular Biology and Cytogenetic, Autoimmune diseases. All these sectors are highly
specialized and continuously evolving. In 2010
Laboraf produced more about 7.25 millions of clinical analyses, for a total of almost 961000 patients.
In 2010 more than 100 new types of tests were introduced in various fields (allergology, microbiology
and virology, determination of therapeutic drugs
and drugs of abuse by mass spectrometry, new
tumor markers).
Besides clinical services Laboraf produces also research work in the field of Standardization in Clinical Chemistry and Microbiology and Virology.
1. Standardization in Clinical Chemistry. The development of a reference measurement procedure for the determination of Alkaline Phosphatase catalytic activity was completed and a
new project for the definition of a reference
measurement procedure for Pancreatic Lipase
started.
2. Microbiology. Molecular diagnosis of sepsis;
molecular diagnosis of systemic fungal infections; molecular diagnosis of sexually transmitted diseases.
3. Virology. Molecular diagnosis of viral agents of
acute respiratory diseases (myxoviruses, 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 neutralizing anti-HCV
and anti-Influenza A 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.
For research projects Laboraf collaborates also
with the research Center for Translational Genomics and BioInformatics, with the research Division of metabolic and cardiovascular sciences and
with the Department of Internal and specialistic
medicine.
Fernanda Dorigatti
289
CLINICAL SERVICES
Immunohematology and transfusion 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. ITMS is conducting a project, funded by Regione Lombardia, on the appropriateness of blood transfusion.
The ITMS is subdivided into three distinct subunits, each responsible for a particular process:
ing 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.
Blood Donation Center
Clinical Laboratory Diagnostics
The blood donation center sub-unit is responsible
for the collection and testing of blood to be transfused in-to 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.
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-hematologic malignancies.
Therapeutic Apheresis and Cellular Therapy
The Therapeutic Apheresis and Cellular Therapy
sub-unit is responsible for collecting and process-
Silvano Rossini
Emergency medicine
In 2010 the Emergency Department of San Raffaele Hospital provided care for 65.143 patients.
1,8% out of the triaged patients were given a red
code (that is, to be seen immediately in the resuscitation area). 155 of them were given a yellow
code (that is, to be seen within 30 minutes of arrival). The largest amount of them (85,8%) were
given lower priority (green code, that means to be
seen within 1 hour of arrival). Only 5,5% of them
were given a white code (that is, patients whose
conditions are not true emergencies). In 2010 we
have seen 21107 patients with medical problems,
15721 with surgical problems and 12225 with
minor trauma. 7561 children have been treated in
the pediatric area. In the dedicated area for obstetrics 5962 women received treatment.
9718 patients, after initial evaluation, were admitted
to different wards for further investigations and
treatments.
In 2010 488 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.
The first Italian edition of the MRMI course (Medical
Response to Major Incidents) has been held in October; some members of the Emergency Department were instructors together with members of
the International Faculty.
Staff members receive Emergency Medicine Upto-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.
CLINICAL SERVICES
In 2010 physicians attended the following meetings and courses: Simposio: L’utilizzo della tecnica
laparoscopica nella chirurgia d’urgenza, (Abano
Terme, October); Acute care Surgery Upgrade,
(Milano, October); Il trauma chiuso addominale
complicate: una sfida diagnostico-terapeutica,
(Paestum, May); International Meeting on Simula-
tion in Healthcare-( Phoenix, January); Trauma: Update and organization (Bologna: February; Rome:
June; Milan: December); ESTES( Bruxelles, May);
Congresso Nazionale SIMEU (Rimini, November).
Michele Carlucci
Our General ICU admitted 453 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 was 94%.
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.
The principal critical illnesses admitted to our unit
included:
• Trauma patients (11% 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 (62% 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 cardiac con-
gestive 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 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 safely perform 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 thera-
peutic 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
291
“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
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, Laura Sincinelli
JUNIOR DESK OFFICERS: Federico Porro
HEALTH ECONOMY ADVISOR: Marco Borgognoni
Clinical and Research Staff
Ricardo Riberio, Hospital São Rafael, Salvador, Brazil
Milena Soares, Hospital São Rafael, Salvador, Brazil
Martin Nsubuga, Director, St. Raphael of St. Francis Hospital Nsambya, Kampala, Uganda
Pius Okong, Head Research, St. Raphael of St. Francis Hospital Nsambya, Kampala, Uganda
Francesco Saul Aloi, Representative AISPO-San Raffaele, St. Raphael of St. Francis Hospital Nsambya,
Kampala, Uganda
Paul G. D’Arbela, St. Raphael of St. Francis Hospital Nsambya, Kampala, Uganda
Victoria Nakibuuka, Pediatrician, St. Raphael of St. Francis Hospital Nsambya, Kampala, Uganda
Klaus Reither, Swiss tropical and Public health institute, Bagamoyo 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 transplantation Unit
Consuelo Corti, Consultant, Hematology and bone marrow transplantation Unit
Valeria Calbi, Hematologist Cooperant, Hematology and bone marrow transplantation Unit
Giacomo Dell’Antonio, Medical Doctor, Pathology Unit
Simon Tiberi, Department of infectious disease
Francesca Occhi, Fellow Gynaecologist, Maternal and child health Department
Ottavio Alfieri, Head, Cardiovascular and thoracic surgery department
Antonio Grimaldi, Senior cardiologist, Cardio- thoracic -vascular Department
Francesco Arioli, Cardiologist, Cardio- thoracic -vascular Department
Enrico Ammirati, Cardiologist, Cardio- thoracic -vascular Department
Filippo Figini, Fellow cardiologist, Cardio- thoracic -vascular Department
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AISPO - SAN RAFFAELE IN THE WORLD
Andrea Radinovic, Fellow cardiologist, Cardio- thoracic -vascular Department
Santo Ferrarello, Fellow cardiologist, Cardio- thoracic -vascular Department
Anna Chiara Vermi, Fellow cardiologist, Cardio- thoracic -vascular Department
Francesco Maria Sacco, Fellow cardiologist, Cardio- thoracic -vascular Department
Fulvio Salvo, Support to Tibetan TB Programme - Dharamsala, India
Mario Mainero, Laparoscopy and Mini-invasive techniques Palestine
Alessandra Rossi, expert in MOVE program for rehabilitation Palestine
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
later has been involved in the management of a
tent-hospital and in building health centers. In
Uganda it has almost finalized a new OUT Patient
and Laboratory Department 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
and TB activities by implementing a negative pressure room. In Vietnam the University of Huè, Uni-
versity Vita-Salute San Raffaele and University of
Cagliari have initiated a center for the control of respiratory diseases. Other projects are implemented to face emergency or post-emergency
situations (due to war, natural disasters or epidemics) or to foster development of local health services.
INSEGNATE. Teaching is key to hand over knowledge. Courses, exchange programs, and ad
personam training are 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, EU, WHO, UNAIDS, Private Not for
Profit Foundation). In addition clinical, technical,
and administrative personnel of the San Raffaele
Institute 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.
Onco-hematology: reduction of child mortality
by cancer in Africa
The San Raffaele Haematology and Bone Marrow
Transplantation 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 in-
creasing diseases more hospitals and specialised
centres are needed. We developed 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 “Pathologist Oversees” (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 lymphoma 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 haematologist is giving educational training
to local staff for improving diagnosis from blood and
bone-marrow smear and for flow-cytometer analysis of blood cancers.
Cardiology: echocardiographic survey for prevention and
cure of rheumatic heart disease
A group of cardiologists from San Raffaele Hospital has established a cooperation programme and
study together with AISPO and the St. Raphael of
St. Francis Hospital Nsambya in Kampala, Uganda.
The aim of the study was to establish the prevalence of RHD (Rheumatic Heart Disease) in a representative sample of school pupils in Kampala,
the capital town of Uganda. RHD still accounts for
high morbidity and mortality in low- and middle-income countries developing countries. Beyond interview and physical examination, enrolled subjects
undergo echocardiography study, useful to detect
RHD’s valve lesions. So far, approximately 484
asymptomatic children have been screened and a
high prevalence of subclinical rheumatic lesions
has been observed. Careful echocardiography
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 collecting the epidemiological data on the prevalence of heart pathology in the local population. Up to now, more
than 300 individuals have been evaluated. Screening revealed a high prevalence of initial rheumatic
valve lesions in asymptomatic school-children of
Kampala. 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 Hospital in Milan 295
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 ten young patients of the
project have received heart surgery.
Uganda and Tanzania - Evaluation of new and emerging
diagnostics for childhood tubercolosis
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.
Democratic republic of Congo - Support to fight the large
endemic diseases HIV/AIDS, tubercolosis 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 HIV1 evolved during these years in the Democratic Republic of Congo?
297
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 cytological 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
Pathologist Overseas (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.
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.
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Steyaert, J; Grellier, P; Haemers, A; Degano, M; Maes, L;
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CH; Stuve, O; Wolinsky, JS; Ziemssen, T. Considerations
on discontinuing natalizumab for the treatment of multiple
sclerosis. Ann. Neurol.: 2010; 68(3): 409-411 - Letter
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P.78. Bernascone, I; Janas, S; Ikehata, M; Trudu, M; Corbelli, A; Schaeffer C; Rastaldi, MP; Devuyst, O; Rampoldi,
L. A transgenic mouse model for uromodulin-associated
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P.79. Bertelloni, S; Baroncelli, GI; Mora, S. Bone health in disorders of sex differentiation.. Sex. Dev.: 2010; 4(4-5): 270284 - Article
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P.80. Bertilaccio, MTS; Scielzo, C; Muzio, M; CaligarisCappio, F. An overview of chronic lymphocytic leukaemia
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P.81. Bertilaccio, MTS; Scielzo, C; Simonetti, G; Ponzoni,
M; Apollonio, B; Fazi, C; Scarfo, L; Rocchi, M; Muzio,
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IF 2009: 7,581
P.83. Bettinardi, V; Picchio, M; Di Muzio, N; Gianolli, L; Gilardi, MC; Messa, C. Detection and compensation of organ/lesion motion using 4D-PET/CT respiratory gated acquisition techniques. Radiother. Oncol.: 2010; 96(3): 311316 - Review
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P.84. Bettinardi, V; Picchio, M; Di Muzio, N; Gianolli, L;
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H; Shariat, SF; Graefen, M; Arjane, P; Duclos, A; Lattouf,
JB; Saad, F; Valiquette, L; Montorsi, F; Perrotte, P;
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P.86. Bianco, MA; Cipolletta, L; Rotondano, G; Buffoli, F; Gizzi,
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P.88. Bigot, P and Lughezzani, G; Karakiewicz, P; Perrotte, P;
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P.90. Bigot, P; Lughezzani, G; Bensalah, K; Rioux-Leclercq,
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carcinoma. Prospective study in 418 cases [Valeur pronostique des polyamines érythrocytaires dans le cancer du
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P.91. Binda, P; Morrone, MC; Burr, DC. Temporal auditory
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P.92. Boari, N; Roberti, F; Biglioli, F; Caputy, AJ; Mortini, P.
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P.93. Boido, D; Farisello, P; Cesca, F; Ferrea, E; Valtorta, F;
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P.94. Bolis, G; Scarfone, G; Raspagliesi, F; Mangili, G;
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Scambia, G. Paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with FIGO suboptimally resected stage III-IV epithelial ovarian cancer a multicenter, randomized study. Eur. J. Cancer: 2010; 46(16): 2905-2912
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IF 2009: 3,970
P.97. Borrow, P; Shattock, RJ; Vyakarnam, A; EUROPRISE
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P.98. Borsani, E; Albertini, R; Labanca, M; Lonati, C; Rezzani,
R; Rodella, LF. Peripheral purinergic receptor modulation
influences the trigeminal ganglia nitroxidergic system in an
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P.99. Borsani, E; Giovannozzi, S; Boninsegna, R; Rezzani, R;
Labanca, M; Tschabitscher, M; Rodella, LF. Nitroxidergic
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IF 2009: 1,234
P.100. Borzi, RM; Olivotto, E; Pagani, S; Vitellozzi, R; Neri, S;
Battistelli, M; Falcieri, E; Facchini, A; Flamigni, F; Penzo,
M; Platano, D; Santi, S; Facchini, A; Marcu, KB. Matrix
metalloproteinase 13 loss associated with impaired extracellular matrix remodeling disrupts chondrocyte differentiation by concerted effects on multiple regulatory factors.
Arthritis Rheum.: 2010; 62(8): 2370-2381 - Article
IF 2009: 4,152
P.101. Bosi, E. Time for testing incretin therapies in early type
1 diabetes? J. Clin. Endocrinol. Metab.: 2010; 95(6):
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P.102. Bosia, M; Anselmetti, S; Pirovano, A; Ermoli, E;
Marino, E; Bramanti, P; Smeraldi, E; Cavallaro, R. HTTLPR functional polymorphism in schizophrenia: Executive
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IF 2009: 2,823
P.103. Braga, M; Frasson, M; Zuliani, W; Vignali, A;
Pecorelli, N and Di Carlo, V. Randomized clinical trial of
laparoscopic versus open left colonic resection. Br. J.
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IF 2009: 4,077
P.104. Bragonzi, A. Fighting back: peptidomimetics as a new
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P.105. Brew, BJ; Davies, NWS; Cinque, P; Clifford, DB; Nath,
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P.106. Briganti, A; Gallina, A; Suardi, N; Capitanio, U; Tutolo, M; Bianchi, M; Passoni, N; Salonia, A; Colombo, R;
Di Girolamo, V; Guazzoni, G; Rigatti, P and Montorsi,
F. Predicting Erectile Function Recovery after Bilateral
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Montorsi, F. When to Perform Bone Scan in Patients with
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P.108. Briguori, C; Airoldi, F; Chieffo, A; Carlino, M; Montorfano, M; Colombo A. Renal function and drug-eluting
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P.109. Briguori, C; Testa, U; Riccioni, R; Colombo, A;
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P.110. Briguori, C; Visconti, G; Rivera, NV; Focaccio, A; Golia,
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IF 2009: 14,816
P.111. Bril, V; Banach, M; Dalakas, MC; Deng, C; Donofrio, P;
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P.112. Broggi, S; Fiorino, C; Dell’Oca, I; Dinapoli, N; Paiusco, M; Muraglia, A; Maggiulli, E; Ricchetti, F; Valentini, V;
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IF 2009: 4,343
P.113. Bruno, F; Bonalumi, S; Camaschella, C; Ferrari, M
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P.115. Budäus, L and Abdollah, F; Sun, M; Morgan, M; Johal, R; Thuret, R; Zorn, KC; Isbarn, H; Shariat, SF; Montorsi, F; Perrotte, P; Graefen, M; Karakiewicz, PI. Annual
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P.116. Budäus, L; Isbarn, H; Eichelberg, C; Lughezzani, G;
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P.117. Buono, M; Visigalli, I; Bergamasco, R; Biffi, A and Cosma, MP. Sulfatase modifying factor 1-mediated fibroblast
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IF 2009: 14,505
P.118. Burioni, R; Canducci, F and Mancini, N; Clementi,
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P.119. Burnett, D; Ceriotti, F; Cooper, G; Parvin, C; Plebani,
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M; Westgard, J. Collective opinion paper on findings of the
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IF 2009: 1,886
P.120. Burr, DC; Ross, J; Binda, P; Morrone, MC. Saccades
compress space, time and number. Trends Cogn. Sci.:
2010; 14(12): 528 - 533 - Short Survey
IF 2009: 11,664
P.121. Buscarini, E; Frulloni, L; De Lisi, S; Falconi, M; Testoni,
PA; Zambelli, A. Autoimmune pancreatitis: A challenging
diagnostic puzzle for clinicians. Dig. Liver Dis.: 2010;
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IF 2009: 2,972
P.122. Cabianca, DS and Gabellini, D. The cell biology of
disease: FSHD: copy number variations on the theme of
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P.123. Cabinio, M; Blasi, V; Borroni, P; Montagna, M; Iadanza, A; Falini, A; Cerri, G. The shape of motor resonance:
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P.124. Cabrini, L; Silvani, P; Landoni, G; Moizo, E; Colombo, S; Zangrillo, A. Noninvasive ventilation in H1N1-correlated severe ARDS in a pregnant woman: Please, be cautious!. Intensive Care Med.: 2010; 36(10): 1782 - Letter
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P.125. Caielli, S; Conforti-Andreoni, C; Di Pietro, C; Usuelli, V; Badami, E; Malosio, ML and Falcone; M. On/off
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P.126. Cainarca, S; Fenu, S; Ferri, C; Nucci, C; Arioli, P;
Menegon, A; Piemonti, L; Lohmer, S; Wrabetz, L;
Corazza, S. A photoprotein in mouse embryonic stem cells
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P.127. Calabrese, M; Filippi, M and Gallo, P. Cortical lesions
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P.128. Calabrese, M; Rocca, MA; Atzori, M; Mattisi, I; Favaretto, A; Perini, P; Gallo, P; Filippi, M. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset
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IF 2009: 9,317
P.129. Calandrino, R; del Vecchio, A; Parisi, R;Todde, S;
De Felice, P; Savi, A; Pepe, A and Mrskova, A. Measurements and evaluation of the risks due to external radiation
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IF 2009: 0,707
P.130. Caligaris-Cappio, F; Chiorazzi, N. Where is the biology of CLL leading us? Semin. Cancer Biol.: 2010; 20(6):
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IF 2009: 6,918
P.131. Camaschella, C; Strati, P. Recent advances in iron
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IF 2009: 2,371
P.132. Cambiaghi, M; Velikova, S; Gonzalez-Rosa, JJ;
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P.133. Camnasio, F; Scotti, C; Borri, A; Fontana, F; Fraschini,
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P.134. Cancrini, C and Ferrua, F; Scarselli, A; Brigida, I;
Romiti, ML; Barera, G; Finocchi, A; Roncarolo, MG;
Caniglia, M; Aiuti, A. Role of reduced intensity conditioning
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P.135. Canderan, G and Dellabona, P. T helper 17 T cells do
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P.136. Canderan, G; Gruarin, P; Montagna, D; Fontana, R;
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An efficient strategy to induce and maintain in vitro human
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P.137. Canducci, F; Marinozzi, MC; Sampaolo, M; Boeri,
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Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir. J. Antimicrob. Chemother.: 2010; 65(3):
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P.138. Cannistraci, CV; Ravasi, T; Montevecchi, FM; Ideker,
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IF 2009: 4,926
P.139. Cantoni, C; Fenoglio, C; Cortini, F; Venturelli, E; Villa, C;
Clerici, F; Marcone, A; Benussi, L; Ghidoni, R; Gallone, S;
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IF 2009: 3,832
P.140. Capello, D; Scandurra, M; Poretti, G; Rancoita, PMV;
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IF 2009: 4,597
P.141. Capitanio, U; Briganti, A; Gallina, A; Suardi, N; Karakiewicz, PI; Montorsi, F and Scattoni, V. Predictive models before and after radical prostatectomy. Prostate:
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IF 2009: 3,081
P.142. Capogna, G; Camorcia, M; Stirparo, S; Valentini, G;
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IF 2009: 1,847
P.143. Cappa, SF; Perani, D. Imaging studies of recovery
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IF 2009: 2,256
PUBLICATIONS
P.144. Cappelli, B; Aiuti, A. Gene therapy for adenosine
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IF 2009: 3,181
P.145. Capranzano, P; Sanfilippo, A; Tagliareni, F; Capodanno,
D; Monaco, S; Sardella, G; Giordano, A; Sangiorgi, GM
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IF 2009: 4,357
P.146. Caraceni, A; Cavaliere, F; Galante, D; Landoni, G. A
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IF 2009: 1,614
P.147. Carrabba, MG; Reni, M; Foppoli, M; Chiara, A;
Franzin, A; Politi, LS; Villa, E; Ciceri, F and Ferreri,
AJM. Treatment approaches for primary CNS lymphomas.
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IF 2009: 2,018
P.148. Carrara, S; Arcidiacono, PG; Mezzi, G; Petrone,
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IF 2009: 2,972
P.149. Casati, V; Romano, A; Novelli, E; D’Angelo, A. Tranexamic acid for trauma. Lancet: 2010; 376(9746): 10491050 - Letter
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P.150. Caselli, D; Cesaro, S; Ziino, O; Zanazzo, G; Manicone,
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Multidrug resistant pseudomonas aeruginosa infection in
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IF 2009: 6,416
P.151. Caserta, S; Alessi, P; Basso, V; Mondino, A. IL-7 is
superior to IL-2 for ex vivo expansion of tumourspecific
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P.152. Caserta, S; Kleczkowska, J; Mondino, A and Zamoyska, R. Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated
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P.153. Caso, F; Fiorino, A; Falautano, M; Leocani, L; Martinelli, V; Minicucci, F; Falini, A; Comi, G; Magnani, G.
Treatment of Wernicke’s encephalopathy with high dose of
thiamine in a patient with pyloric sub-stenosis: description
of a case. Neurol. Sci.: 2010; 31: 859-861 - Article
IF 2009: 1,120
P.154. Cassani, B; Poliani, PL; Marrella, V; Schena, F; Sauer,
AV; Ravanini, M; Strina, D; Busse, CE; Regenass, S;
Wardemann, H; Martini, A; Facchetti, F; van der Burg, M;
Rolink, AG; Vezzoni, P; Grassi, F; Traggiai, E; Villa, A.
Homeostatic expansion of autoreactive immunoglobulinsecreting cells in the Rag2 mouse model of Omenn syndrome. J. Exp. Med.: 2010; 207(7): 1525-1540 - Article
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P.155. Cassani, B; Poliani, PL; Moratto, D; Sobacchi, C; Marrella, V; Imperatori, L; Vairo, D; Plebani, A; Giliani, S; Vezzoni, P; Facchetti, F; Porta, F; Notarangelo, LD; Villa, A
and Badolato, R. Defect of regulatory T cells in patients
with Omenn syndrome. J. Allergy Clin. Immunol.: 2010;
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P.156. Cassol, E; Cassetta, L; Alfano, M and Poli, G.
Macrophage polarization and HIV-1 infection. J. Leukoc.
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P.157. Cassol, E; Malfeld, S; Mahasha, P; van der Merwe, S;
Cassol, S; Seebregts, C; Alfano, M; Poli, G and
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P.158. Castagna, A; Galli, L; Torti, C; D’Arminio Monforte, A;
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magnitude of short-term CD4+ T-cell recovery in HIV-infected patients during first-line highly active antiretroviral therapy. Antivir. Ther.: 2010; 15(2): 165 - 175 - Article
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P.159. Castiglioni, E; Finazzi, D; Goldwurm, S; Levi, S; Pezzoli, G; Garavaglia, B; Nardocci, N; Malcovati, L; Della Porta, MG; Gallì, A; Forni, GL; Girelli, D; Maccarinelli, F; Poli,
M; Ferrari, M; Cremonesi, L and Arosio, P. Sequence
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Chem. Lab. Med.: 2010; 48(10): 1415-1418 - Article
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P.161. Castoldi, G; Antolini, L; Bombardi, C; Perego, L; Mariani, P; Vigano, MR; Torti, G; Casati, M; Corti, A; Zerbini,
G; Valsecchi, MG; Stella, A. Oxidative stress biomarkers
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P.162. 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.
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P.163. Cattaneo, GM; Passoni, P; Sangalli, G; Slim, N;
Longobardi, B; Mancosu, P; Bettinardi, V; Di Muzio, N;
Calandrino, R. Internal target volume defined by contrastenhanced 4D-CT scan in unresectable pancreatic tumour:
evaluation and reproducibility. Radiother. Oncol.: 2010;
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P.164. Cattoglio, C; Maruggi, G; Bartholomae, C; Malani, N;
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M; Mavilio, F; Recchia, A. High-definition mapping of
retroviral integration sites defines the fate of allogeneic T
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P.165. Cattoglio, C; Pellin, D; Rizzi, E; Maruggi, G; Corti, G;
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De Bellis, G; Mavilio, F. High-definition mapping of retroviral integration sites identifies active regulatory elements in
human multipotent hematopoietic progenitors. Blood:
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P.166. Cavarelli, M; Karlsson, I; Ripamonti, C; Plebani, A;
Fenyo, EM; Scarlatti; G. Flexible use of CCR5 in the absence of CXCR4 use explains the immune deficiency in
HIV-1 infected children.. AIDS: 2010; 24(16): 2527-2533 Article
IF 2009: 4,909
P.167. Cavedini, P; Zorzi, C; Piccinni, M; Cavallini, MC and
Bellodi, L. Executive Dysfunctions in Obsessive-Compulsive Patients and Unaffected Relatives: Searching for a
New Intermediate Phenotype. Biol. Psychiatry: 2010;
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P.168. Ceccarelli, A; Rocca, MA; Neema, M; Martinelli, V;
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Filippi, M. Deep gray matter T2 hypointensity is present in
patients with clinically isolated syndromes suggestive of
multiple sclerosis. Mult. Scler.: 2010; 16(1): 39 - 44 - Article
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P.169. Ceccarelli, A; Rocca, MA; Valsasina, P; Rodegher,
M; Falini, A; Comi, G; Filippi, M. Structural and functional magnetic resonance imaging correlates of motor network dysfunction in primary progressive multiple sclerosis.
Eur. J. Neurosci.: 2010; 31(7): 1273 - 1280 - Article
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P.170. Cecconi, V; Moro, M; Del Mare, S; Sidney, J; Bachi,
A; Longhi, R; Sette, A; Protti, MP; Dellabona, P and Casorati, G. The CD4+ T-cell epitope-binding register is a
critical parameter when generating functional HLA-DR
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IF 2009: 5,179
P.171. Centemero, A and Rigatti, L; Giraudo, D; Lazzeri,
M; Lughezzani, G; Zugna, D; Montorsi, F; Rigatti, P
and Guazzoni, G. Preoperative Pelvic Floor Muscle Exercise for Early Continence After Radical Prostatectomy: A
Randomised Controlled Study. Eur. Urol.: 2010; 57(6):
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IF 2009: 7,667
P.172. Centonze, D; Muzio, L; Rossi, S; Furlan, R; Bernardi,
G; Martino, G. The link between inflammation, synaptic
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Cell Death Differ.: 2010; 17(7): 1083-1091 - Review
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P.173. Cera, M; Salerno, A; Fragasso, G; Montanaro, C;
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P.174. Cereda, A; Kravchuk, AV; D’Amato, A; Bachi, A;
Righetti, PG. Proteomics of wine additives: mining for the
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P.175. Cereda, S; Passoni, P; Reni, M; Vigano, MG;
Aldrighetti, L; Nicoletti, R and Villa, E. The cisplatin,
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P.176. Cereda, S; Reni, M; Rognone, A; Ghidini, M; Belli,
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IF 2009: 1,428
P.177. Ceriotti, F; Henny, J; Queraltó, J; Ziyu, S; Özarda, Y;
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P.178. Cerovac, V; Monteserin-Garcia, J; Rubinfeld, H; Buchfelder, M; Losa, M; Florio, T; Paez-Pereda, M; Stalla, GK;
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P.179. Cesca, F; Baldelli, P; Valtorta, F and Benfenati, F. The
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IF 2009: 9,140
P.180. Cesnik, E; Casetta, I; Turri, M; Govoni, V; Granieri, E;
Ferini-Strambi, L; Manconi, M. Transient RLS during
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IF 2009: 8,172
P.181. Cestari, A; Buffi, NM; Lista, G; Sangalli, M; Scapaticci, E; Fabbri, F; Lazzeri, M; Rigatti, P; Guazzoni, G.
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P.182. Cestari, A; Buffi, NM; Scapaticci, E, Lughezzani G;
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P.183. Cestari, A; Rigatti, L; Lughezzani, G and Guazzoni,
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IF 2009: 4,016
P.184. Charroux, B and Fanto, M. The fine line between waste
disposal and recycling: DRPLA fly models illustrate the importance of completing the autophagy cycle for rescuing
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P.185. Chaudhry, IB; Jordan, J; Cousin, FR; Cavallaro, R;
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P.186. Chersevani, R; Ciatto, S; Del Favero, C; Frigerio, A;
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P.187. Chieffo, A; Hoye, A; Mauri, F; Mikhail, G; Ammerer, M;
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P.188. Chieffo, A; Hoye, A; Mauri, F; Mikhail, GW; Ammerer,
M; Grines, C; Grinfeld, L; Madan, M; Presbitero, P; Skelding, KA; Weiner, BH; Mehran, R. Gender-based issues in
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P.189. Chiesa, R; Cappelli, B; Crocchiolo, R; Frugnoli, I;
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Biffi, A; Finizio, V; Aiuti, A; Broglia, M; Bartoli, A; Ciceri,
F; Roncarolo, MG; Marktel, S. Unpredictability of Intravenous Busulfan Pharmacokinetics in Children Undergoing
Hematopoietic Stem Cell Transplantation for Advanced Beta Thalassemia: Limited Toxicity with a Dose-Adjustment
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IF 2009: 3,149
P.190. Chiesa, R; Melissano, G; Marone, EM; Kahlberg, A;
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P.191. Chiesa, R; Melissano, G; Marone, EM; MarroccoTrischitta, MM; Kahlberg, A. Aorto-oesophageal and
Aortobronchial Fistulae Following Thoracic Endovascular
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P.192. Chiesa, R; Melissano, G; Tshomba, Y; Civilini, E;
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P.193. Chiesa, R; Tshomba, Y; Kahlberg, A; Marone, EM;
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Management of thoracic endograft infection. J. Cardiovasc. Surg.: 2010; 51(1): 15 - 31 - Review
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P.194. Chilosi, M; Doglioni, C; Murer, B; Poletti, V. Epithelial
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IF 2009: 1,056
P.195. Chun, FKH; Epstein, JI; Ficarra, V; Freedland, SJ; Montironi, R; Montorsi, F; Shariat, SF; Schroder, FH; Scattoni, V. Optimizing performance and interpretation of
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IF 2009: 7,667
P.196. Cicconi, P; Cozzi-Lepri, A; Castagna, A; Trecarichi,
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IF 2009: 2,878
P.197. Ciceri, F and Piemonti, L. Bone marrow and pancreatic islets: an old story with new perspectives. Cell Transplant.: 2010; 19(12): 1511-1522 - Review
IF 2009: 5,126
P.198. Citerio, G; Beretta, L; Stocchetti, N. Do we provide optimal care to patients with acute neurological injuries? Minerva Anestesiol.: 2010; 76(2): 155 - 156 - Letter
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P.199. Citterio, L; Lanzani, C; Manunta, P; Bianchi, G. Genetics of primary hypertension: The clinical impact of adducin polymorphisms. Biochim. Biophys. Acta-Mol. Basis
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P.200. Civilini, E; Melissano, G; Bertoglio, L and Chiesa, R.
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P.201. Clementi, M and Lazzarin, A. Human immunodeficiency virus type 1 fitness and tropism: Concept, quantification, and clinical relevance. Clin. Microbiol. Infect.: 2010;
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IF 2009: 4,014
P.202. Cocito, D; Paolasso, I; Antonini, G; Benedetti, L; Briani,
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P.203. Coffelt, SB; Lewis, CE; Naldini, L; Brown, JM; Ferrara,
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P.204. Coffelt, SB; Tal, AO; Scholz, A; De Palma, M; Patel, S;
Urbich, C; Biswas, SK; Murdoch, C; Plate, KH; Reiss, Y;
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IF 2009: 7,543
P.205. Cohen, JA; Barkhof, F; Comi, G; Hartung, HP; Khatri,
BO; Montalban, X; Pelletier, J; Capra, R; Gallo, P; Izquierdo, G; Tiel-Wilck, K; De Vera, A; Jin, J; Stites, T; Wu, S;
Aradhye, S; Kappos, L for the TRANSFORMS Study
Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med.: 2010; 362(5):
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IF 2009: 47,050
P.206. Colasante, G and Sessa, A. Last but not least: Cortical interneurons from caudal ganglionic eminence. J. Neurosci.: 2010; 30(22): 7449-7450 - Note
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P.207. Colleoni, S; Galli, C; Giannelli, SG; Armentero, MT;
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P.208. Colombo, B; Dalla Libera, D; Comi, G. Ocular pain: a
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IF 2009: 1,120
P.209. Colombo, R. Invasive bladder cancer and the role of
follow-up: should we consider the match over at radical
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P.210. Colombo, R. Words of wisdom. Re: treatment of nonmuscle invading bladder cancer: do physicians in the United States practice evidence based medicine? Eur. Urol.:
2010; 57(4): 730-731 - Comment
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P.211. Colombo, R; Naspro, R. Ileal Conduit as the Standard
for Urinary Diversion After Radical Cystectomy for Bladder
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P.212. Comi, G. Effects of disease modifying treatments on
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P.213. Comi, G; Abramsky, O; Arbizu, T; Boyko, A; Gold, R;
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PUBLICATIONS
Havrdová, E; Komoly, S; Selmaj, K; Sharrack, B; Filippi,
M; LAQ/5063 Study Group. Oral laquinimod in patients
with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized,
double-blind, parallel-group placebo-controlled study..
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P.214. Comi, G; O’Connor, P; Montalban, X; Antel, J; Radue,
EW; Karlsson, G; Pohlmann, H; Aradhye, S; Kappos, L.
Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult. Scler.: 2010; 16(2): 197 - 207 Article
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P.215. Corbo, V; Dalai, I; Scardoni, M; Barbi, S; Beghelli, S;
Bersani, S; Albarello, L; Doglioni, C; Schott, C; Capelli,
P; Chilosi, M; Boninsegna, L; Becker, KF; Falconi, M;
Scarpa, A. MEN1 in pancreatic endocrine tumors: Analysis
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P.216. Corna, G; Campana, L; Pignatti, E; Castiglioni, A;
Tagliafico, E; Bosurgi, L; Campanella, A; Brunelli, S;
Manfredi, AA; Apostoli, P; Silvestri, L; Camaschella, C;
Rovere-Querini, P. Polarization dictates iron handling by
inflammatory and alternatively activated macrophages.
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IF 2009: 6,416
P.217. Corrias, A; Mussa, A; Baronio, F; Arrigo, T; Salerno, M;
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Cassio, A. Diagnostic features of thyroid nodules in pediatrics. Arch. Pediatr. Adolesc. Med.: 2010; 164(8): 714719 - Article
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P.218. Corti, A. Chromogranin A and the Tumor Microenvironment. Cell. Mol. Neurobiol.: 2010; 30(8): 1163-1170 - Review
IF 2009: 2,107
P.219. Cortini, M and Sitia, R. ERp44 and ERGIC-53 synergize in coupling efficiency and fidelity of IgM polymerization
and secretion. Traffic: 2010; 11(5): 651-659 - Article
IF 2009: 6,255
P.220. Cortini, M and Sitia, R. From antibodies to
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IF 2009: 4,126
P.221. Covello, RD; Ruggeri, L; Landoni, G; Guarracino, F;
Bignami, E; Gonfalini, M; Virzo, I; Michev, I; Colombo,
A; Zangrillo, A. Transcatheter implantation of an aortic
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P.222. Cozzi, A; Rovelli, E; Frizzale, G; Campanella, A;
Amendola, M; Arosio, P; Levi, S. Oxidative stress and cell
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P.223. Cremasco, V; Benasciutti, E; Cella, M; Kisseleva, M;
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for development of a murine model of inflammatory arthritis
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P.224. Crépel, M; Jeldres, C; Perrotte, P; Capitanio, U; Isbarn, H; Shariat, SF; Liberman, D; Sun, M; Lughezzani,
G; Arjane, P; Widmer, H; Graefen, M; Montorsi, F; Patard,
JJ; Karakiewicz, PI. Nephron-sparing Surgery Is Equally Ef-
fective to Radical Nephrectomy for T1BN0M0 Renal Cell
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P.225. Crépel; M; Jeldres, C; Sun, M; Lughezzani, G; Isbarn,
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PI. A population-based comparison of cancer-control rates
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P.226. Crespi, R; Cappare, P and Gherlone, E. Fresh-socket implants in periapical infected sites in humans. J. Periodont.: 2010; 81(3): 378 - 383 - Article
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Catovsky, D; Houlston, RS. Inherited genetic susceptibility
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Santarpia, L; Trimarchi, F; Cannavo, S. Lymphocytic hypophysitis: Differential diagnosis and effects of high-dose
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P.235. Dacci, P; Dina, G; Cerri, F; Previtali, SC; Lopez, ID;
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P.236. Dacci, P; Riva, N; Scarlato, M; Andresen, I; Schmidt,
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P.237. Dagna, L; Girlanda, S; Langheim, S; Rizzo, N; Bozzolo, EP; Sabbadini, MG and Ferrarini, M. ErdheimChester disease: Report on a case and new insights on its
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P.238. D’Alessandro, R; Meldolesi, J. In PC12 Cells, Expression of Neurosecretion and Neurite Outgrowth are Governed by the Transcription Repressor REST/NRSF. Cell.
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Barbieri, M; Paolisso, G; Folli, F; Pontiroli, AE. Weight loss
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P.240. D’Amato, A; Bachi, A; Fasoli, E; Boschetti, E; Peltre,
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P.246. de Crevoisier, R; Fiorino, C; Dubray, B. [Dosimetric factors predictive of late toxicity in prostate cancer radiotherapy]. Cancer Radiother.: 2010; 14(6-7): 460-468 - Review
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Hutton, JC; Pipeleers, D; Gorus, FK. Predictive power of
screening for antibodies against insulinoma-associated
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P.249. De Marco, N; Iannone, L; Carotenuto, R; Biffo, S; Vitale, A; Campanella, C. P27BBP /eIF6 acts as an anti-apoptotic factor upstream of Bcl-2 during Xenopus laevis development. Cell Death Differ.: 2010; 17(2): 360 - 372 - Article
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P.250. De Marzi, P; Frigerio, L; Cipriani, S; Parazzini, F; Busci,
L; Carlini, L; Vigano, R and Mangili, G. Adjuvant treatment with concomitant radiotherapy and chemotherapy in
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P.251. De Nardi, P; Corsetti, M and Staudacher, C. Rectal
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epidemiology of KI and WU polyomaviruses in infants with
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P.259. Decembrino, L; D’Angelo, A; Manzato, F; Solinas, A;
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P.261. Del Giacco, L; Pistocchi, A; Ghilardi, A. prox1b activity
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P.263. Della Nave, R; Ginestroni, A; Tessa, C; Giannelli, M; Piacentini, S; Filippi, M; Mascalchi, M. Regional distribution
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P.265. Di Betta, E; Fariselli, L; Bergantin, A; Locatelli, F; Del
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P.266. Di Lullo, G; Soprana, E; Panigada, M; Palini, A;
Agresti, A; Comunian, C; Milani, A; Capua, I; Erfle, V;
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P.267. Di Modugno, F; Mottolese, M; De Monte, L; Trono, P;
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F; Torrisi, MR; Alessio, M; Santoni, A; Nisticò, P. The Cooperation between hMena Overexpression and HER2 Signalling in Breast Cancer. PLoS One: 2010; 5(12): e15852
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P.268. Di Nicolantonio, F; Arena, S; Tabernero, J; Grosso, S;
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P.269. Di Tomaso, T; Mazzoleni, S; Wang, E; Sovena, G;
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P.270. Dodero, A; Crocchiolo, R; Patriarca, F; Miceli, R;
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P.271. Dolcetti, R; Ponzoni, M; Ferreri, AJM and Doglioni,
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Hematol. Oncol.: 2010; 28(1): 1-2 - Editorial
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P.272. Donadoni, C and Bisighini, C; Scotti, L; Diomede, L;
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P.274. Donofrio, PD; Bril, V; Dalakas, MC; Deng, C; Hanna, K;
Hartung, HP; Hughes, R; Latov, N; Merkies, I; van Doorn,
P for the IGIV-C CIDP Efficacy (ICE) Study Group.
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P.275. Duckitt, R; Palsson R; Bosanska L; Dagna, L; Durusu
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P.276. Duckitt, R; Tanriover, MD; Bosanka, L; Dagna, L; Vardi,
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P.277. Dufour, C; Cappelli, B; Calvillo, M; Fioredda, F; Tonelli,
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P.278. Dumonceau, JM; Andriulli, A; Deviere, J; Mariani, A;
Rigaux, J; Baron, TH; Testoni, PA. European Society of
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P.279. Durham, SR; Emminger, W; Kapp, A; Colombo, G; de
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PUBLICATIONS
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T; Bandinelli, S; Barroso, I; Berenson, GS; Bergmann, S;
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Campbell, H; Chanock, SJ; Chen, W; Cornelis, MC;
Couper, D; Coviello, AD; D’Adamo, P; De Faire, U; De
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DF; Eiriksdottir, G; Emilsson, V; Eriksson, J; Ferrucci, L;
Folsom, AR; Foroud, T; Garcia, M; Gasparini, P; Geller, F;
Gieger, C; Gudnason, V; Hall, P; Hankinson, SE; Ferreli, L;
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Kilpelanen, TO; Kolcic, I; Kraft, P; Launer, LJ; Laven, JSE;
Li, S; Li,u J; Levy, D; Martin, NG; McArdle, WL; Melbye, M;
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M; Palmer, LJ; Palotie, A; Pare, G; Parker, AN; Pedersen,
NL; Peltonen, L; Pennell, CE; Pharoah, P; Polasek, O;
Plump, AS; Pouta, A; Porcu, E; Rafnar, T; Rice, JP; Ring,
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K; Tryggvadottir, L; Tyrer, J; Uda, M; Van Dam, RM; Van
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P.289. Esposito, M; Ruffini, F; Bergami, A; Garzetti, L;
Borsellino, G; Battistini, L; Martino, G and Furlan, R. IL17- and IFN-γ-secreting Foxp3+ T cells infiltrate the target
tissue in experimental autoimmunity. J. Immunol.: 2010;
185(12): 7467-7473 - Article
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P.290. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery; Camm, AJ; Kirchhof, P;
Lip, GY; Schotten, U; Savelieva, I; Ernst, S; Van, Gelder,
IC; Al-Attar, N; Hindricks, G; Prendergast, B; Heidbuchel,
H; Alfieri, O; Angelini, A; Atar, D; Colonna, P; De, Caterina,
R; De, Sutter, J; Goette, A; Gorenek, B; Heldal, M;
Hohloser, SH; Kolh, P; Le, Heuzey, JY; Ponikowski, P; Rutten, FH;, ESC, Committee for Practice Guidelines; Vahanian, A; Auricchio, A; Bax, J; Ceconi, C; Dean, V; Filippatos,
G; Funck-Brentano, C; Hobbs, R; Kearney, P; McDonagh,
T; Popescu, BA; Reiner, Z; Sechtem, U; Sirnes, PA; Tendera, M; Vardas, PE; Widimsky, P; Document Reviewers;
Vardas, PE; Agladze, V; Aliot, E; Balabanski, T; BlomstromLundqvist, C; Capucci, A; Crijns, H; Dahlöf, B; Folliguet, T;
Glikson, M; Goethals, M; Gulba, DC; Ho, SY; Klautz, RJ;
Kose, S; McMurray, J; Perrone, Filardi, P; Raatikainen, P;
Salvador, MJ; Schalij, MJ; Shpektor, A; Sousa, J; Stepinska, J; Uuetoa, H; Zamorano, JL; Zupan, I. Guidelines for
the management of atrial fibrillation: the Task Force for the
Management of Atrial Fibrillation of the European Society of
Cardiology (ESC). Europace: 2010; 12(10): 1360-1420 Review
IF 2009: 1,871
P.291. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery; Camm, AJ; Kirchhof, P;
Lip, GY; Schotten, U; Savelieva, I; Ernst, S; Van Gelder, IC;
Al-Attar, N; Hindricks, G; Prendergast, B; Heidbuchel, H;
Alfieri, O; Angelini, A; Atar, D; Colonna, P; De Caterina, R;
De Sutter, J; Goette, A; Gorenek, B; Heldal, M; Hohloser,
SH; Kolh, P; Le Heuzey, JY; Ponikowski, P; Rutten, FH.
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Guidelines for the management of atrial fibrillation: the Task
Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J.: 2010;
31(19): 2369-2429 - Article
IF 2009: 9,800
P.292. European, Association for Percutaneous Cardiovascular, Interventions; Wijns, W; Kolh, P; Danchin, N; Di, Mario,
C; Falk, V; Folliguet, T; Garg, S; Huber, K; James, S; Knuuti, J; Lopez-Sendon, J; Marco, J; Menicanti, L; Ostojic, M;
Piepoli, MF; Pirlet, C; Pomar, JL; Reifart, N; Ribichini, FL;
Schalij, MJ; Sergeant, P; Serruys, PW; Silber, S; Sousa
Uva, M; Taggart, D; ESC Committee for Practice Guidelines; Vahanian, A; Auricchio, A; Bax, J; Ceconi, C; Dean,
V; Filippatos, G; Funck-Brentano, C; Hobbs, R; Kearney,
P; McDonagh, T; Popescu, BA; Reiner, Z; Sechtem, U;
Sirnes, PA; Tendera, M; Vardas, PE; Widimsky, P; EACTS
Clinical Guidelines Committee; Kolh, P; Alfieri, O; Dunning, J; Elia, S; Kappetein, P; Lockowandt, U; Sarris, G;
Vouhe, P; Kearney, P; von Segesser, L; Agewall, S; Aladashvili, A; Alexopoulos, D; Antunes, MJ; Atalar, E; Brutel
de la Riviere, A; Doganov, A; Eha, J; Fajadet, J; Ferreira, R;
Garot, J; Halcox, J; Hasin, Y; Janssens, S; Kervinen, K;
Laufer, G; Legrand, V; Nashef, SA; Neumann, FJ; Niemela,
K; Nihoyannopoulos, P; Noc, M; Piek, JJ; Pirk, J; Rozenman, Y; Sabate, M; Starc, R; Thielmann, M; Wheatley, DJ;
Windecker, S; Zembala, M. Guidelines on myocardial
revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and
the European Association for Cardio-Thoracic Surgery
(EACTS). Eur. Heart J.: 2010; 31(20): 2501-2555 - Article
IF 2009: 9,800
P.293. Falconi, M; Zerbi, A; Crippa, S; Balzano, G; Boninsegna, L; Capitanio, V; Bassi, C; Di Carlo, V; Pederzoli, P.
Parenchyma-Preserving Resections for Small Nonfunctioning Pancreatic Endocrine Tumors. Ann. Surg. Oncol.:
2010; 17: 1621-1627 - Article
IF 2009: 4,130
P.294. Fallarini, S; Magliulo, L; Paoletti, T; de Lalla, C; Lombardi G. Expression of functional GPR35 in human iNKT cells.
Biochem. Biophys. Res. Commun.: 2010; 398(3): 420425 - Article
IF 2009: 2,548
P.295. Fanti, L and Testoni, PA. Sedation and analgesia in
gastrointestinal endoscopy: What’s new? World J. Gastroenterol.: 2010; 16(20): 2451-2457 - Article
IF 2009: 2,092
P.296. Fasano, S; Bezard, E; D’Antoni, A; Francardo, V; Indrigo, M; Qin, L; Doverò, S; Cerovic, M; Cenci, MA and
Brambilla, R. Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts
motor symptoms associated with L-dopa-induced dyskinesia.. Proc. Natl. Acad. Sci. U.S.A.: 2010; 107(50):
21824-21829 - Article
IF 2009: 9,432
P.297. Favaron, E; Bellodi, L; Biffi, S; Vanni, G; Zorzi, C;
Liperi, L; Perna, G. Acoustic startle response in panic disorder. Psychiatry Res.: 2010; 176(2-3): 254 - 256 - Article
IF 2009: 2,373
P.298. Favini, F; Giordano Resti, A; Collini, P; Casanova, M;
Meazza, C; Trecate, G; Ferrari, A. Inflammatory myofibroblastic tumor of the conjunctiva: Response to chemotherapy with low-dose methotrexate and vinorelbine. Pediatr.
Blood Cancer: 2010; 54(3): 483 - 485 - Article
IF 2009: 2,134
P.299. Fazi, C; Dagklis, A; Cottini, F; Scarfo, L; Bertilaccio,
MTS; Finazzi, R; Memoli, M and Ghia, P. Monoclonal B
cell lymphocytosis in hepatitis C virus infected individuals.
Cytom. Part B-Clin. Cytom.: 2010; 78B(SUPPL.1): S61-
S68 - Article
IF 2009: 1,727
P.300. Fenoglio, C; Scalabrini, D; Esposito, F; Comi, C; Cavalla, P; De Riz, M; Martinelli, V; Piccio, LM; Venturelli, E;
Fumagalli, G; Capra, R; Collimedaglia, L; Ghezzi, A;
Rodegher, ME; Vercellino, M; Leone, M; Giordana, MT;
Bresolin, N; Monaco, F; Comi, G; Scarpini, E; MartinelliBoneschi, F and Galimberti, D. Progranulin gene variability
increases the risk for primary progressive multiple sclerosis
in males. Genes Immun.: 2010; 11(6): 497-503 - Article
IF 2009: 4,222
P.301. Ferini-Strambi, L; Manconi, M. Treatment of restless
legs syndrome. Parkinsonism Relat. Disord.: 2010;
15(SUPPL. 4): S65-S70 - Article
IF 2009: 2,406
P.302. Fernandez-Diaz, LC; Laurent, A; Girasoli, S; Turco, M;
Longobardi, E; Iotti, G; Jenkins, NA; Fiorenza, MT;
Copeland, NG; Blasi, F. The absence of Prep1 causes
p53-dependent apoptosis of mouse pluripotent epiblast
cells. Development: 2010; 137(20): 3393-3403 - Article
IF 2009: 7,194
P.303. Ferrai, C; Xie, SQ; Luraghi, P; Munari, D; Ramirez, F;
Branco, MR; Pombo, A; Crippa, MP. Poised transcription
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Biol.: 2010; 8(1)e1000270: 1-16 - Article
IF 2009: 12,916
P.304. Ferrandi, M; Cusi, D; Molinari, I; Del Vecchio, L; Barlassina, C; Rastaldi, MP; Schena, FP; Macciardi F; Marcantoni, C; Roccatello, D; Peters, LL; Armelloni, S; Min, L;
Giardino, L; Mattinzoli, D; Camisasca, C; Palazzo, F; Manunta, P; Ferrari, P; Bianchi, G. α- and β-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA
nephropathy. J. Mol. Med.: 2010; 88(2): 203 - 217 - Article
IF 2009: 5,004
P.305. Ferrandi, M; Molinari, I; Torielli, L; Padoani, G; Salardi,
S; Rastaldi, MP; Ferrari, P; Bianchi, G. Adducin- and
ouabain-related gene variants predict the antihypertensive
activity of rostafuroxin. Part 1: Experimental studies. Sci.
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P.306. Ferreri, AJM; Illerhaus, G; Zucca, E; Cavalli, F on behalf of the International Extranodal Lymphoma Study
Group. Flows and flaws in primary central nervous system
lymphoma. Nat. Rev. Clin. Oncol. : 2010; 7(8): 1-2 - Letter
IF 2009: 8,075
P.307. Ferri, R; Manconi, M; Arico, D; Sagrada, C; Zucconi,
M; Bruni, O; Oldani, A; Ferini-Strambi, L. Acute
dopamine-agonist treatment in restless legs syndrome: Effects on sleep architecture and NREM sleep instability.
Sleep: 2010; 33(6): 793-800 - Article
IF 2009: 5,402
P.308. Ferri, R; Rundo, F; Manconi, M; Plazzi, G; Bruni, O;
Oldani, A; Ferini-Strambi, L; Zucconi, M. Improved
computation of the atonia index in normal controls and patients with REM sleep behavior disorder. Sleep Med.:
2010; 11(9): 947-949 - Brief Communication
IF 2009: 3,699
P.309. Fiaschi, T; Tedesco, FS; Giannoni, E; Diaz-Manera, J;
Parri, M; Cossu, G and Chiarugi P. Globular adiponectin
as a complete mesoangioblast regulator: Role in proliferation, survival, motility, and skeletal muscle differentiation.
Mol. Biol. Cell: 2010; 21(6): 848 - 859 - Article
IF 2009: 5,979
P.310. Ficarra, V; Benway, BM; Bhayani, SB; Rogers, CG;
Porter, JR; Guazzoni, G; Buffi, N; Mottrie, A. Reply from
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PUBLICATIONS
P.311. Filippi, M and Agosta, F. Imaging biomarkers in multiple sclerosis. J. Magn. Reson. Imaging: 2010; 31(4): 770 788 - Review
IF 2009: 2,770
P.312. Filippi, M and Rocca, MA. Novel MRI approaches to
assess patients with multiple sclerosis. Curr. Opin. Neurol.:
2010; 23(3): 212 - 217 - Review
IF 2009: 5,430
P.313. Filippi, M and Rocca, MA. Multiple sclerosis: monitoring long-term treatments in multiple sclerosis. Nat. Rev.
Neurol.: 2010; 6(8): 421-+422 - Short Survey
IF 2009: 6,362
P.314. Filippi, M; Agosta, F; Abrahams, S; Fazekas, F;
Grosskreutz, J; Kalra, S; Kassubek, J; Silani, V; Turner,
MR; Masdeu, JC. EFNS guidelines on the use of neuroimaging in the management of motor neuron diseases.
Eur. J. Neurol.: 2010; 17(4): 526 - 533 - Review
IF 2009: 2,510
P.315. Filippi, M; Ceccarelli, A; Pagani, E; Gatti, R; Rossi,
A; Stefanelli, L; Falini, A; Comi, G; Rocca, MA. Motor
learning in healthy humans is associated to gray matter
changes: A tensor-based morphometry study. Plos One:
2010; 5(4): e10198 - Article
IF 2009: 4,351
P.316. Filippi, M; Riccitelli, G; Falini, A; Salle, FD; Vuilleumier,
P; Comi, G; Rocca, MA. The brain functional networks
associated to human and animal suffering differ among
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e10847 - Article
IF 2009: 4,351
P.317. Filippi, M; Rocca, MA. MR imaging of gray matter involvement in multiple sclerosis: Implications for understanding disease pathophysiology and monitoring treatment efficacy. Am. J. Neuroradiol.: 2010; 31(7): 11711177 - Review
IF 2009: 3,296
P.318. Filippi, M; Rocca, MA. MRI and cognition in multiple
sclerosis. Neurol. Sci.: 2010; 31(Suppl 2): S231-S234 Article
IF 2009: 1,120
P.319. Filippi, M; Rocca, MA. Dirty-appearing white matter: A
disregarded entity in multiple sclerosis. Am. J. Neuroradiol.: 2010; 31(3): 390 - 391 - Editorial
IF 2009: 3,296
P.320. Filippi, M; Rocca, MA; Benedict, RH; DeLuca, J;
Geurts, JJ; Rombouts, SA; Ron, M; Comi, G. The contribution of MRI in assessing cognitive impairment in multiple
sclerosis.. Neurology: 2010; 75(23): 2121-2128 - Review
IF 2009: 8,172
P.321. Filippi, M; Rocca, MA; Calabrese, M; Sormani, MP;
Rinaldi, F; Perini, P; Comi, G; Gallo, P. Intracortical lesions:
Relevance for new MRI diagnostic criteria for multiple sclerosis. Neurology: 2010; 75(22): 1988 - 1994 - Article
IF 2009: 8,172
P.322. Fimognari, FL; Di Simone, S; Corsonello, A; Pastorelli,
R; Sampietro, F; Loffredo, L; Violi, F; D’Angelo, A. Poor
vitamin B6 status: A novel potential thrombotic factor in
chronic obstructive pulmonary disease. Nutr. Metab. Carbiovasc. Dis.: 2010; 20(9): e17-e18 - Letter
IF 2009: 3,517
P.323. Fiorina, P. ß-Cells step up in controlling the autoimmune response. Diabetes: 2010; 59(8): 1861-1864 Note
IF 2009: 8,505
P.324. Fiorina, P; Pietramaggiori, G; Scherer, SS; Jurewicz,
M; Mathews; JC; Vergani, A; Thomas, G; Orsenigo, E;
Staudacher, C; La Rosa, S; Capella, C; Carothers, A; Zerwes, HG; Luzi, L; Abdi, R; Orgill, DP. The mobilization and
effect of endogenous bone marrow progenitor cells in dia-
betic wound healing. Cell Transplant.: 2010; 19(11): 13691381 - Article
IF 2009: 5,126
P.325. Fiorini, C; Gola, A; Peloso, R; Longoni, A; Lechner, P;
Soltau, H; Strüder, L; Ottobrini, L; Martelli, C; Lui, R; Madaschi, L; Belloli, S. The DRAGO gamma camera. Rev. Sci.
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IF 2009: 1,521
P.326. Florence, E; De Wit, S; Castagna, A; Ribera, E; Hill, A;
Vanaken, H; Van Delft, Y; Marks, S. HIV RNA suppression
rates after 24 weeks of treatment with etravirine,
darunavir/ritonavir and raltegravir in the etravirine early access programme. Int. J. STD AIDS: 2010; 21(3): 224 225 - Letter
IF 2009: 1,050
P.327. Foglieni, B; Brisci, A; San Biagio, F; Di Pietro, P; Petralia, S; Conoci, S; Ferrari, M and Cremonesi, L. Integrated PCR amplification and detection processes on a
Lab-on-Chip platform: A new advanced solution for molecular diagnostics. Clin. Chem. Lab. Med.: 2010; 48(3): 329
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IF 2009: 1,886
P.328. Folli, F; Guzzi, V; Perego, L; Coletta, DK; Finzi, G; Placidi, C; La Rosa, S; Capella, C; Socci, C; Lauro, D; Tripathy,
D; Jenkinson, C; Paroni, R; Orsenigo, E; Cighetti, G; Gregorini, L; Staudacher, C; Secchi, A; Bachi, A; Brownlee,
M; Fiorina, P. Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients’ skin which
are normalized by kidney-pancreas transplantation. Plos
One: 2010; 5(3): e9923 - Research Article
IF 2009: 4,351
P.329. Forejtnikovà, H; Vieillevoye, M; Zermati, Y; Lambert, M;
Pellegrino, RM; Guihard, S; Gaudry, M; Camaschella, C;
Lacombe, C; Roetto, A; Mayeux, P; Verdier, F. Transferrin
receptor 2 is a component of the erythropoietin receptor
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2010; 116(24): 5357-5367 - Article
IF 2009: 10,555
P.330. Forlani, G; Giarda, E; Ala, U; di Cunto, F; Salani, M; Tupler, R; Kilstrup-Nielsen, C; Landsberger, N. The
MeCP2/YY1 interaction regulates ANT1 expression at
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Mol. Genet.: 2010; 19(16): 3114-3123 - Article
IF 2009: 7,386
P.331. Fornasiero, EF; Bonanomi, D; Benfenati, F; Valtorta,
F. The role of synapsins in neuronal development. Cell.
Mol. Life Sci.: 2010; 67(9): 1383-1396 - Review
IF 2009: 6,090
P.332. Fornili, A; Giabbai, B; Garau, G and Degano, M. Energy Landscapes Associated with Macromolecular Conformational Changes from Endpoint Structures. J. Am.
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IF 2009: 8,580
P.333. Fossati, A; Borroni, S; Eisenberg, N; Maffei, C. Relations of proactive and reactive dimensions of aggression to
overt and covert Narcissism in Nonclinical adolescents.
Aggressive Behav.: 2010; 36(1): 21 - 27 - Article
IF 2009: 1,698
P.334. Fossati, M; Cappelli, B; Biral, E; Chiesa, R; Biffi, A;
Ossi, C; Moro, M; Cirillo, DM; Clementi, M; Soliman, C;
Ciceri, F; Roncarolo, MG; Fumagalli, L and Marktel, S.
Fatal vancomycin- and linezolid-resistant Enterococcus
faecium sepsis in a child undergoing allogeneic
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IF 2009: 2,272
P.335. Fragasso, G; Marinosci, G; Calori, G; Palloshi, A;
Spoladore, R; Arioli, F; Bassanelli, G; Salerno, A;
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PUBLICATIONS
Margonato, A. Prognosis of mild/moderate chronic systolic heart failure. Int. J. Cardiol.: 2010; 145(3): 584 - 586 Letter
IF 2009: 3,469
P.336. Francese, R; Fiorina, P. Immunological and regenerative properties of cord blood stem cells. Clin. Immunol.:
2010; 136(3): 309-322 - Review
IF 2009: 3,863
P.337. Franchini, S; Dagna, L; Salvo, F; Aiello, P; Baldissera, E and Sabbadini, MG. Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset
Still’s disease. Arthritis Rheum.: 2010; 62(8): 2530-2535 Article
IF 2009: 4,152
P.338. Franchini, S; Dagna, L; Salvo, F; Aiello, P; Baldissera, E; Sabbadini, MG. Adult-onset Still’s disease: Clinical presentation in a large cohort of Italian patients. Clin.
Exp. Rheumatol.: 2010; 28(1): 41 - 48 - Article
IF 2009: 2,396
P.339. Fraschini, G; Ciampi, P; Scotti, C; Ballis, R; Peretti,
GM. Surgical treatment of chronic acromioclavicular dislocation: Comparison between two surgical procedures for
anatomic reconstruction. Injury: 2010; 41(11): 1103-1106
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IF 2009: 2,383
P.340. Freedman, MS; Bar-Or, A; Atkins, HL; Karussis, D;
Frassoni, F; Lazarus, H; Scolding, N; Slavin, S; Le Blanc,
K; Uccelli, A; MSCT Study Group. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult. Scler.: 2010; 16(4):
503-510 - Review
IF 2009: 3,279
P.341. Frenquelli, M; Muzio, M; Scielzo, C; Fazi, C; Scarfò,
L; Rossi, C; Ferrari, G; Ghia, P and Caligaris-Cappio,
F. MicroRNA and proliferation control in chronic lymphocytic leukemia: functional relationship between miR221/222 cluster and p27. Blood: 2010; 115(19): 39493959 - Article
IF 2009: 10,555
P.342. Friis-Møller, N; Thébaut, R; Reiss, P; Weber, R;
D’Arminio Monforte, A; De Wit, S; El-Sadr, W; Fontas, E;
Worm, S; Kirk, O; Phillips, A; Sabin, CA; Lundgren, JD;
Law, MG; DAD study group. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur. J. Cardiovasc. Prev. Rehabil.: 2010; 17(5): 491-501 - Article
IF 2009: 2,511
P.343. Frison, S; Crivello, P; Longhi, E; Andreini, E; Tivelli, M;
Serafini, M; Tagliaferri, C; Scalamogna, M; Poli, F. Description and molecular modeling of two novel HLA alleles:
HLA-A*0343 and A*0345. Hum. Immunol.: 2010; 71(6):
582-585 - Article
IF 2009: 2,550
P.344. Frisoni, GB; Galluzzi, S; Signorini, M; Garibotto, V;
Paghera, B; Binetti, G; Canu, E; Geroldi, C; Perani, D.
Preliminary evidence of validity of the revised criteria for
alzheimer disease diagnosis: Report of 2 cases. Alzheimer
Dis. Assoc. Dis.: 2010; 24(1): 108 - 114 - Article
IF 2009: 2,875
P.345. Fritsche, HM; Burger, M; Svatek, RS; Jeldres, C;
Karakiewicz, PI; Novara, G; Skinner, E; Denzinger, S;
Fradet, Y; Isbarn, H; Bastian, PJ; Volkmer, BG; Montorsi,
F; Kassouf, W; Tilki, D; Otto, W; Capitanio, U; Izawa, JI; Ficarra, V; Lerner, S; Sagalowsky, AI; Schoenberg, M; Kamat, A; Dinney, CP; Lotan, Y; Shariat, SF. Characteristics
and Outcomes of Patients with Clinical T1 Grade 3 Urothelial Carcinoma Treated with Radical Cystectomy: Results
from an International Cohort. Eur. Urol.: 2010; 57(2): 300-
309 - Article
IF 2009: 7,667
P.346. Frugnoli, I; Cappelli, B; Chiesa, R; Biral, E; Noe, A;
Evangelio, C; Fossati, M; Napolitano, S; Ciceri, F;
Roncarolo, MG and Marktel, S. Escalating doses of
donor lymphocytes for incipient graft rejection following
SCT for thalassemia. Bone Marrow Transplant. : 2010;
45(6): 1047-1051 - Article
IF 2009: 2,998
P.347. Frulloni, L; Falconi, M; Gabbrielli, A; Gaia, E; Graziani, R;
Pezzilli, R; Uomo, G; Andriulli, A; Balzano, G; Benini, L;
Calculli, L; Campra, D; Capurso, G; Cavestro, GM; De Angelis, C; Ghezzo, L; Manfredi, R; Malesci, A; Mariani, A;
Mutignani, M; Ventrucci, M; Zamboni, G; Amodio, A; Vantini, I; Italian Association for the Study of the Pancreas
(AISP); Bassi, C; Delle Fave, G; Frulloni, L; Vantini, I; Falconi, M; Frulloni, L; Gabbrielli, A; Graziani, R; Pezzilli, R; Capurso, IV; Cavestro, GM; De Angelis, C; Falconi, M; Gaia,
E; Ghezzo, L; Gabbrielli, A; Graziani, R; Manfredi, R; Malesci, A; Mariani, A; Mutignani, M; Pezzilli, R; Uomo, G; Ventrucci, M; Zamboni, G; Vantini, I; Magarini, F; Albarello, L;
Alfieri, S; Amodio, A; Andriulli, A; Anti, M; Arcidiacono, P;
Baiocchi, L; Balzano, G; Benini, L; Berretti, D; Boraschi, P;
Buscarini, E; Calculli, L; Carroccio, A; Campra, D; Celebrano, MR; Capurso, G; Casadei, R; Cavestro, GM; Chilovi,
F; Conigliaro, R; Dall’Oglio, L; De Angelis, C; De Boni, M;
De Pretis, G; Di Priolo, S; Di Sebastiano, PL; Doglietto,
GB; Falconi, M; Filauro, M; Frieri, G; Frulloni, L; Fuini, A;
Gaia, E; Ghezzo, L; Gabbrielli, A; Graziani, R; Loriga, P;
Macarri, G; Manes, G; Manfredi, R; Malesci, A; Mariani, A;
Massucco, P; Milani, S; Mutignani, M; Pasquali, C; Pederzoli, P; Pezzilli, R; Pietrangeli, M; Rocca, R; Russello, D; Siquini, W; Traina, M; Uomo, G; Veneroni, L; Ventrucci, M;
Zilli, M; Zamboni, G. Italian consensus guidelines for chronic pancreatitis. Dig. Liver Dis.: 2010; 42 Suppl 6: S381S406 - Article
IF 2009: 2,972
P.348. Fumagalli, M; Vergari, M; Pasqualetti, P; Marceglia, S;
Mameli, F; Ferrucci, R; Mrakic-Sposta, S; Zago, S; Sartori,
G; Pravettoni, G; Barbieri, S; Cappa, S; Priori, A. Brain
switches utilitarian behavior: Does gender make the difference? Plos One: 2010; 5(1): e8865 - Article
IF 2009: 4,351
P.349. Gacci, M; Ierardi, A; Rose, AD; Tazzioli, S; Scapaticci,
E; Filippi, S; Maggi, M; Nicita, G; Carini, M; Montorsi, F.
Vardenafil can improve continence recovery after bilateral
nerve sparing prostatectomy: Results of a randomized,
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P.351. Gagliani, N; Jofra, T; Stabilini, A; Valle, A; Atkinson,
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atazanavir-based therapy maintains control of HIV type-1
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[11C]choline positron emission tomography/computerized
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P.383. Giovannini, M; Aldrighetti, D; Zucchinelli, P; Belli, C;
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Chang, P; Hamlett, A; Musch, B; Greenberg, SJ; CLARITY
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P.388. Gratzke, C; Streng, T; Stief, CG; Downs, TR; Alroy, I;
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P.390. Graziottin, A. Menopause and sexuality: Key issues in
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Busch, R; Mayer, J; Hensel, M; Hopfinger, G; Hess, G;
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PL; Caligaris-Cappio, F; Seymour, JF; Berrebi, A; Jager,
U; Cazin, B; Trneny, M; Westermann, A; Wendtner, CM;
Eichhorst, BF; Staib, P; Buhler, A; Winkler, D; Zenz, T;
Bottcher, S; Ritgen, M; Mendila, M; Kneba, M; Dohner, H;
Stilgenbauer, S on behalf of an international group of investigators and the German Chronic Lymphocytic Leukaemia
Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic
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Women. Am. J. Cardiol.: 2010; 105(9): 1254 - 1260 - Article
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P.484. Lu, F; Carlino, M; Lu, C; Landoni, C; Lucignani G;
Fragasso, G; Di Bello, V; Margonato, A; Chierchia, SL;
Marzilli, M; Balbarini, A. Assessment of residual viability by
enoximone echocardiography in patients with previous myocardial infarction correlation with positron emission tomographic studies and functional follow-up. Echocardiography-J. Cardiovasc. Ultrasound Allied Tech.: 2010; 27(5):
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P.485. Lucca, A; Rossini, D; Malaguti, A; Zanardi, R; Magri,
L; Smeraldi, E. Use of electroconvulsive therapy in the city
of Milan: A naturalistic study. J. ECT: 2010; 26(2): 148 Letter
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P.486. Lucchini, G; Introna, M; Dander, E; Rovelli, A; Balduzzi,
A; Bonanomi, S; Salvade, A; Capelli, C; Belotti, D; Gaipa,
G; Perseghin, P; Vinci, P; Lanino, E; Chiusolo, P; Orofino,
MG; Marktel, S; Golay, J; Rambaldi, A; Biondi, A; D’Amico, G; Biagi, E. Platelet-lysate-expanded mesenchymal
stromal cells as a salvage therapy for severe resistant graftversus-host disease in a pediatric population. Biol. Blood
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P.487. Luciani, A; Villella, VR; Esposito, S; Brunetti-Pierri, N;
Medina, D; Settembre, C; Gavina, M; Pulze, L; Giardino,
I; Pettoello-Mantovani, M; D’Apolito, M; Guido, S; Masliah,
E; Spencer, B; Quaratino, S; Raia, V; Ballabio, A; Maiuri,
L. Defective CFTR induces aggresome formation and lung
inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat. Cell Biol.: 2010; 12(9): 863-875 Article
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P.488. Lughezzani, G; Briganti, A; Karakiewicz, PI; Kattan,
MW; Montorsi, F; Shariat, SF; Vickers, AJ. Predictive and
prognostic models in radical prostatectomy candidates: A
critical analysis of the literature. Eur. Urol.: 2010; 58(5):
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IF 2009: 7,667
P.489. Lughezzani, G; Budaus, L; Isbarn, H; Sun, M; Perrotte,
P; Haese, A; Chun, FK; Schlomm, T; Steuber, T; Heinzer,
H; Huland, H; Montorsi, F; Graefen, M; Karakiewicz, PI.
Head-to-Head Comparison of the Three Most Commonly
Used Preoperative Models for Prediction of Biochemical
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P.490. Lughezzani, G; Jeldres, C; Isbarn, H; Shariat, SF; Sun,
M; Pharand, D; Widmer, H; Arjane, P; Graefen, M; Montorsi, F; Perrotte, P; Karakiewicz, PI. A Critical Appraisal of
the Value of Lymph Node Dissection at Nephroureterectomy for Upper Tract Urothelial Carcinoma. Urology: 2010;
75(1): 118-124 - Article
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P.491. Lughezzani, G; Jeldres, C; Isbarn, H; Sun, M; Shariat,
SF; Widmer, H; Arjane, P; Graefen, M; Perrotte, P; Montorsi, F and Karakiewicz PI. Temporal stage and grade migration in surgically treated patients with upper tract
urothelial carcinoma. BJU Int.: 2010; 105(6): 799 - 804 Article
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Crepel, M; Rioux-Leclercq, N; Catros-Quemener, V; Moulinoux, JP; Bouet, F; Cipolla, B; Patard, JJ. The prognostic
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P.493. Lughezzani, G; Sun, M; Jeldres, C; Alasker, A; Budaus, L; Shariat, SF; Latour, M; Widmer, H; Duclos, A; Jolivet-Tremblay, M; Montorsi, F; Perrotte, P; Karakiewicz,
PI. Adenocarcinoma Versus Urothelial Carcinoma of the
Urinary Bladder: Comparison Between Pathologic Stage at
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P.494. Lughezzani, G; Sun, M; Perrotte, P; Alasker, A; Jeldres, C; Isbarn, H; Budaus, L; Lattouf, JB; Valiquette, L;
Bénard; F; Saad, F; Graefen, M; Montorsi, F and
Karakiewicz, PI. Comparative study of inguinal hernia repair
rates after radical prostatectomy or external beam radiotherapy. Int. J. Radiat. Oncol. Biol. Phys.: 2010; 78(5):
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P.495. Lughezzani, G; Sun, M; Perrotte, P; Jeldres, C;
Alasker, A; Isbarn, H; Budaus, L; Shariat, SF; Guazzoni,
G; Montorsi, F; Karakiewicz, PI. The European Network
327
PUBLICATIONS
for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancerstaging system: A North American validation. Eur. J. Cancer: 2010; 46(4): 713 - 719 - Article
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P.496. Lughezzani, G; Sun, M; Perrotte, P; Shariat, SF; Jeldres, C; Budaus, L; Alasker, A; Duclos, A; Widmer, H; Latour, M; Guazzoni, G; Montorsi, F; Karakiewicz PI.
Should Bladder Cuff Excision Remain the Standard of Care
at Nephroureterectomy in Patients with Urothelial Carcinoma of the Renal Pelvis? A Population-based Study. Eur.
Urol.: 2010; 57(6): 956 - 962 - Article
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P.497. Lughezzani, G; Sun, M; Perrotte, P; Shariat, SF; Jeldres, C; Budaus, L; Latour, M; Widmer, H; Duclos, A; Benard, F; McCormack, M; Montorsi, F and Karakiewicz PI.
Gender-related Differences in Patients With Stage I to III
Upper Tract Urothelial Carcinoma: Results From the Surveillance, Epidemiology, and End Results Database. Urology: 2010; 75(2): 321 - 327 - Article
IF 2009: 2,365
P.498. Lunghi, C; Binda, P and Morrone MC. Touch disambiguates rivalrous perception at early stages of visual analysis. Curr. Biol.: 2010; 20(4): R143-R144 - Letter
IF 2009: 10,992
P.499. Lupo Stanghellini, MT; Provasi, E; Bondanza, A; Ciceri, F; Bordignon, C and Bonini, C. Clinical impact of
suicide gene therapy in allogeneic hematopoietic stem cell
transplantation. Hum. Gene Ther.: 2010; 21(3): 241 - 250
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IF 2009: 4,202
P.500. Luscieti, S; Santambrogio, P; D’Estaintot, BL; Granier,
T; Cozzi, A; Poli, M; Gallois, B; Finazzi, D; Cattaneo, A;
Levi, S and Arosio, P. Mutant ferritin L-chains that cause
neurodegeneration act in a dominant-negative manner to
reduce ferritin iron incorporation. J. Biol. Chem.: 2010;
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P.501. MacCluer, JW; Scavini, M; Shah, VO; Cole, SA; Laston, SL; Voruganti, VS; Paine, SS; Eaton, AJ; Comuzzie,
AG; Tentori, F; Pathak, DR; Bobelu, A; Bobelu, J; Ghahate,
D; Waikaniwa, M; Zager, PG. Heritability of measures of
kidney disease among Zuni Indians: the Zuni Kidney Project. Am. J. Kidney Dis.: 2010; 56(2): 289-302 - Article
IF 2009: 5,152
P.502. Maffei, E; Palumbo, A; Martini, C; Meijboom, W;
Tedeschi, C; Spagnolo, P; Zuccarelli, A; Weustink, A; Torri, T; Mollet, N; Seitun, S; Krestin, GP; Cademartiri, F. Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without
revascularisation: registry data and review of multicentre trials. Radiol. Med.: 2010; 115: 368-384 - Article
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P.503. Magagnotti, C; Fermo, I; Carletti, RM; Ferrari, M;
Bachi, A. Comparison of different depletion strategies for
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P.504. Magli, A; Angelelli, C; Ganassi, M; Baruffaldi, F;
Matafora, V; Battini, R; Bachi, A; Messina, G; Rustighi,
A; Del Sal, G; Ferrari, S; Molinari, S. Proline isomerase
Pin1 represses terminal differentiation and myocyte enhancer factor 2C function in skeletal muscle cells. J. Biol.
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P.505. Magnoni, M; Esposito, A; Coli, S; Scuteri, L; De Cobelli, F; Cianflone, D; Del Maschio, A and Maseri, A.
Two different mechanisms of myocardial ischemia involving
2 separate myocardial segments in a patient with normal
coronary angiography. Circulation: 2010; 121(1): e1-e3 Article
IF 2009: 14,816
P.506. Maines, M; Landolina, M; Lunati, M; Lonardi, G; Pappone, A; Proclemer, A; Zanotto, G; Santini, M; Varbaro, A;
Vimercati, M; Valsecchi, S. Intrathoracic and ventricular impedances are associated with changes in ventricular volume in patients receiving defibrillators for CRT. PACE Pacing Clin. Electrophysiol.: 2010; 33(1): 64-73 - Article
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P.507. Maio, M; Nicolay, HJM; Ascierto, PA; Belardelli, F;
Camerini, R; Colombo, MP; Queirolo, P; Ridolfi, R; Russo,
V; Fonsatti, E; Parmiani, G. Sixth annual meeting of the
Italian network for tumor biotherapy (NIBIT), Siena, 16-18
October 2008. Cancer Immunol. Immunother.: 2010;
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P.508. Maio, M; Nicolay, HJM; Ascierto, PA; Belardelli, F;
Camerini, R; Colombo, MP; Queirolo, P; Ridolfi, R; Russo,
V; Fonsatti, E; Parmiani, G. Seventh annual meeting of
the Italian Network for Tumor Biotherapy (NIBIT), Siena, 1-3
October 2009. Cancer Immunol. Immunother.: 2010;
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IF 2009: 3,791
P.509. Malacarne, P; Boccalatte, D; Acquarolo, A; Agostini, F;
Anghileri, A; Giardino, M; Giudici, D; Langer, M; Livigni, S;
Nascimben, E; Rossi, C; Bertolini, G. Epidemiology of
Nosocomial infection in 125 Italian Intensive Care units.
Minerva Anestesiol.: 2010; 76(1): 13 - 23 - Article
IF 2009: 1,614
P.510. Mancini, N; Carletti, S; Ghidoli, N; Cichero, P; Burioni, R and Clementi, M. The era of molecular and other
non-culture-based methods in diagnosis of sepsis. Clin.
Microbiol. Rev.: 2010; 23(1): 235 - 251 - Review
IF 2009: 14,691
P.511. Manconi, M; Ferri, R; Sagrada, C; Punjabi, NM; Tettamanzi, E; Zucconi, M; Oldani, A; Castronovo, V and
Ferini-Strambi, L. Measuring the error in sleep estimation
in normal subjects and in patients with insomnia: Insomnia.
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IF 2009: 3,500
P.512. Mancosu, P; Sghedoni, R; Bettinardi, V; Aquilina,
MA; Navarria, P; Cattaneo, GM; Di Muzio, N; Cozzi, L;
Scorsetti, M. Semiautomatic technique for defining the internal gross tumor volume of lung tumors close to
liver/spleen cupola by 4D-CT. Med. Phys.: 2010; 37(9):
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P.513. Manenti, R; Tettamanti, M; Cotelli, M; Miniussi, C;
Cappa, SF. The neural bases of word encoding and retrieval: A fMRI-guided transcranial magnetic stimulation
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P.514. Manfredi, AA and Rovere-Querini, P. The mitochondrion - A Trojan horse that kicks off inflammation? N. Engl.
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P.515. Manfredi, AA; Rovere-Querini, P and Maugeri, N.
Dangerous connections: Neutrophils and the phagocytic
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2010; 17(1): 3-8 - Review
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P.516. Mangiavillano, B; Masci, E; Parma, B; Barera, G; Viaggi, P; Albarello, L; Tronconi, GM; Mariani, A; Testoni, S;
Santoro, T; Testoni, PA. Bulb biopsies for the diagnosis of
celiac disease in pediatric patients. Gastrointest. Endosc.:
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P.517. Mangili, G; Scarfone, G; Gadducci, A; Sigismondi, C;
PUBLICATIONS
Ferrandina, G; Scibilia, G; Vigano, R; Tateo, S; Villa, A;
Lorusso, D. Is adjuvant chemotherapy indicated in stage i
pure immature ovarian teratoma (IT)? A multicentre Italian
trial in ovarian cancer (MITO-9). Gynecol. Oncol.: 2010;
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IF 2009: 3,733
P.518. Mantegani, P; Tambussi, G; Galli, L; Tassan Din, C;
Lazzarin, A and Fortis, C. Perturbation of the natural killer
cell compartment during primary human immunodeficiency
virus 1 infection primarily involving the CD56bright subset.
Immunology: 2010; 129(2): 220 - 233 - Article
IF 2009: 3,276
P.519. Manunta, P; Messaggio, E; Casamassima, N; Gatti,
G; Delli Carpini, S; Zagato, L; Hamlyn, JM. Endogenous
ouabain in renal Na + handling and related diseases.
Biochim. Biophys. Acta-Mol. Basis Dis.: 2010; 1802(12):
1214-1218 - Review
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P.520. Marchesi, F; Piemonti, L; Mantovani, A; Allavena, P.
Molecular mechanisms of perineural invasion, a forgotten
pathway of dissemination and metastasis. Cytokine
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P.521. Marenzi, G; Giorgio, M; Trinei, M; Moltrasio, M; Ravagnani, P; Cardinale, D; Ciceri, F; Cavallero, A; Veglia, F;
Fiorentini, C; Cipolla, CM; Bartorelli, AL; Pelicci, P. Circulating cytochrome c as potential biomarker of impaired reperfusion in ST-segment elevation acute myocardial infarction.
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P.522. Margulis, V; Youssef, RF; Karakiewicz, PI; Lotan, Y;
Wood, CG; Zigeuner, R; Kikuchi, E; Weizer, A; Raman, JD;
Remzi, M; Roscigno, M; Montorsi, F; Bolenz, C; Kassouf, W; Shariat, SF. Preoperative multivariable prognostic
model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract. J. Urol.: 2010; 184(2):
453-458 - Article
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P.523. Mari, S; Invernizzi, C; Spitaleri, A; Alberici, L; Ghitti,
M; Bordignon, C; Traversari, C; Rizzardi, GP; Musco, G.
2D TR-NOESY experiments interrogate and rank ligand-receptor interactions in living human cancer cells. Angew.
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P.524. Marktel, S and Napolitano, S and Zino, E; Cappelli,
B; Chiesa, R; Poli, F; Crocchiolo, R; Ronchi, P; Rossini,
S; Ciceri, F; Roncarolo, MG and Fleischhauer, K.
Platelet transfusion refractoriness in highly immunized beta
thalassemia children undergoing stem cell transplantation.
Pediatr. Transplant.: 2010; 14(3): 393 - 401 - Article
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P.525. Marone, EM; Coppi, G; Tshomba, Y and Chiesa, R.
Eight-year experience with carotid artery stenting for correction of symptomatic and asymptomatic post-endarterectomy defects. J. Vasc. Surg.: 2010; 52(6): 15111517 - Article
IF 2009: 3,517
P.526. Maroso, M; Balosso, S; Ravizza, T; Liu, J; Aronica, E;
Iyer, AM; Rossetti, C; Molteni, M; Casalgrandi, M; Manfredi, AA; Bianchi, ME and Vezzani, A. Toll-like receptor 4
and high-mobility group box-1 are involved in ictogenesis
and can be targeted to reduce seizures. Nat. Med.: 2010;
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P.527. Martinelli-Boneschi, F; Esposito, F; Scalabrini, D;
Fenoglio, C; Rodegher, ME; Brambilla, P; Colombo, B;
Ghezzi, A; Capra, R; Collimedaglia, L; Coniglio, G; De Riz,
M; Serpente, M; Cantoni, C; Scarpini, E; Martinelli, V;
Galimberti, D; Comi, G. Lack of replication of KIF1B gene
in an Italian primary progressive multiple sclerosis cohort.
Eur. J. Neurol.: 2010; 17(5): 740 - 745 - Article
IF 2009: 2,510
P.528. Martino, G; Franklin, RJM; Van Evercooren, AB; Kerr,
DA and the Stem Cells in Multiple Sclerosis (STEMS) Consensus Group DA. Stem cell transplantation in multiple
sclerosis: Current status and future prospects. Nat. Rev.
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P.529. Masci, E; Mangiavillano, B; Parma, B; Mariani, A.
Avoiding duodenal endoscopic biopsies in celiac disease:
Are we going forward or looking to the past? Dig. Liver
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IF 2009: 2,972
P.530. Masciarelli, S; Fra, AM; Pengo, N; Bertolotti, M;
Cenci, S; Fagioli, C; Ron, D; Hendershot, LM; Sitia, R.
CHOP-independent apoptosis and pathway-selective induction of the UPR in developing plasma cells. Mol. Immunol.: 2010; 47(6): 1356 - 1365 - Article
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P.531. Masserdotti, G; Badaloni, A; Green, YS; Croci, L;
Barili, V; Bergamini, G; Vetter, ML; Consalez, GG.
ZFP423 coordinates Notch and bone morphogenetic protein signaling, selectively up-regulating Hes5 gene expression. J. Biol. Chem.: 2010; 285(40): 30814-30824 - Article
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P.532. Mastaglio, S; Lupo Stanghellini, MT; Bordignon, C;
Bondanza, A; Ciceri, F and Bonini, C. Progress and
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P.533. Matarrese, M; Bedeschi, P; Scardaoni, R; Sudati, F;
Savi, A; Pepe, A; Masiello, V; Todde, S; Gianolli, L;
Messa, C; Fazio, F. Automated production of copper radioisotopes and preparation of high specific activity
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P.534. Mattioli, F; Stampatori, C; Bellomi, F; Capra, R; Rocca,
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P.535. Mayo, SC; de Jong, MC; Pulitano, C; Clary, BM; Reddy, SK; Gamblin, TC; Celinksi, SA; Kooby, DA; Staley, CA;
Stokes, JB; Chu, CK; Ferrero, A; Schulick, RD; Choti, MA;
Mentha, G; Strub, J; Bauer, TW; Adams, RB; Aldrighetti,
L; Capussotti, L; Pawlik, TM. Surgical Management of Hepatic Neuroendocrine Tumor Metastasis: Results from an
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P.536. Mazzoleni, S; Politi, LS; Pala, M; Cominelli, M;
Franzin, A; Sergi Sergi, L; Falini, A; De Palma, M; Bulfone, A; Poliani, PL; Galli, R. Epidermal growth factor receptor expression identifies functionally and molecularly
distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. Cancer Res.:
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P.537. Mcmurchy, AN; Gillies, J; Allan, SE; Passerini, L; Gambineri, E; Roncarolo, MG; Bacchetta, R and Levings,
MK. Point mutants of forkhead box P3 that cause immune
dysregulation, polyendocrinopathy, enteropathy, X-linked
have diverse abilities to reprogram T cells into regulatory T
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329
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P.538. Meary, D; Leocani, L; Chieffo, R; Comola, M; Comi,
G; Baud-Bovy, G. Probing the control processes of the
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P.539. Melissano, G; Civilini, E; Bertoglio, L; Calliari, F;
Campos Moraes Amato, A; Chiesa, R. Angio-CT Imaging of the Spinal Cord Vascularisation: A Pictorial Essay.
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P.540. Melissano, G; Civilini, E; Bertoglio, L; Logaldo, D
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Toward a better understanding of endograft collapse after
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P.542. Melzi, R; Antonioli, B; Mercalli, A; Battaglia, M;
Valle, A; Pluchino, S; Galli, R; Sordi, V; Bosi, E; Martino, G; Bonifacio, E; Doglioni, C; Piemonti, L. Co-graft of
allogeneic immune regulatory neural stem cells (NPC) and
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P.543. Melzi, R; Mercalli, A; Sordi, V; Cantarelli, E; Nano,
R; Maffi, P; Sitia, G; Guidotti, LG; Secchi, A; Bonifacio,
E; Piemonti, L. Role of CCL2/MCP-1 in islet transplantation.. Cell Transplant.: 2010; 19(8): 1031-1048 - Article
IF 2009: 5,126
P.544. Merante, D; Menchini, F; Truitt, KE; Bandello, FM. Diabetic macular edema: correlations with available diabetes
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P.545. Merkies, IS; Hughes, RA; Donofrio, P; Bril, V; Dalakas,
MC; Hanna, K; Hartung, HP; Latov, N; van Doorn, PA;
Deng, C; ICE Study Group. Understanding the consequences of chronic inflammatory demyelinating polyradiculoneuropathy from impairments to activity and participation
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P.546. Mesaros, S; Rocca, MA; Sormani, MP; Valsasina, P;
Markowitz, C; De Stefano, N; Montalban, X; Barkhof, F;
Ranjeva, JP; Sailer, M; Kappos, L; Comi, G and Filippi,
M. Bimonthly assessment of magnetization transfer magnetic resonance imaging parameters in multiple sclerosis:
A 14-month, multicentre, follow-up study. Mult. Scler.:
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P.547. Meschi, F; Bonfanti, R; Rigamonti, A; Frontino, G;
Battaglino, R; Viscardi, M; Poscia, A; Chiumello, G. Patients’ evaluation of nocturnal hypoglycaemia with GlucoDay continuous glucose monitoring in paediatric patients.
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P.548. Messa, M; Congia, S; Defranchi, E; Valtorta, F; Fassio,
A; Onofri, F; Benfenati, F. Tyrosine phosphorylation of
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P.550. Micali, N; Longobardi, E; Iotti, G; Ferrai, C; Castagnaro, L; Ricciardi, M; Blasi, F and Crippa, MP. Down
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P.551. Michiorri, S; Gelmetti, V; Giarda, E; Lombardi, F; Romano, F; Marongiu, R; Nerini-Molteni, S; Sale, P; Vago,
R; Arena, G; Torosantucci, L; Cassina, L; Russo, MA;
Dallapiccola, B; Valente, EM; Casari, G. The Parkinsonassociated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ.: 2010; 17(6): 962 974 - Article
IF 2009: 8,240
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IF 2009: 3,503
P.621. Perseghin, G. The role of non-alcoholic fatty liver disease in cardiovascular disease. Dig. Dis.: 2010; 28(1): 210
- 213 - Review
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P.622. Perseghin, G. Exploring the in vivo mechanisms of action of glucokinase activators in type 2 diabetes. J. Clin.
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P.623. Peruzzotti Jametti, L; Ferrari, S; Politi, LS; Snider, S;
Mammi, S; Comi, G and Comola, M. Giant anterior
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for treatment and follow-up. Spine: 2010; 35(8): E322E324 - Article
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P.624. Pessina, P; Conti, V; Pacelli, F; Rosa, F; Doglietto,
GB; Brunelli, S and Bossola, M. Skeletal muscle of gastric cancer patients expresses genes involved in muscle regeneration. Oncol. Rep.: 2010; 24(3): 741-745 - Article
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P.625. Petrelli, A; Maestroni, A; Fadini, GP; Belloni, D; Venturini, M; Albiero, M; Kleffel, S; Mfarrej, BG; Del Maschio,
A; Maffi, P; Avogaro, A; Ferrero, E; Zerbini, G; Secchi, A
and Fiorina, P. Improved function of circulating angiogenic cells is evident in type 1 diabetic islet-transplanted
patients. Am. J. Transplant.: 2010; 10(12): 2690 - 2700 Article
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P.626. Petrone, MC; Arcidiacono, PG; Carrara, S; Albarello, L; Enderle, MD; Neugebauer, A; Boemo, C; Doglioni,
C; Testoni, PA. US-guided application of a new hybrid
probe in human pancreatic adenocarcinoma: an ex vivo
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IF 2009: 6,713
P.627. Petrone, MC; Arcidiacono, PG; Perri, F; Carrara, S;
Boemo, C; Testoni, PA. Chronic pancreatitis-like changes
detected by endoscopic ultrasound in subjects without
signs of pancreatic disease: do these indicate age-related
changes, effects of xenobiotics, or early chronic pancreatitis? Pancreatology: 2010; 10(5): 597-602 - Article
IF 2009: 2,195
P.628. Petzold, A; Mondria, T; Kuhle, J; Rocca, MA; Cornelissen, J; te Boekhorst, P; Lowenberg, B; Giovannoni, G; Filippi, M; Kappos, L; Hintzen, R. Evidence for acute neurotoxicity after chemotherapy. Ann. Neurol.: 2010; 68(6):
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AM; Barassi, A. Serum and urine trypsinogen activation
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P.630. Pezzilli, R; Zerbi, A; Di Carlo, V; Bassi, C; Delle Fave,
GF; Working Group of the Italian Association for the Study
of the Pancreas on Acute Pancreatitis. Practical Guidelines
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P.631. Picchio, M; Giovannini, E; Crivellaro, C; Gianolli, L;
Di Muzio, N; Messa, C. Clinical evidence on PET/CT for
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P.632. Picchio, M; Mangili, G; Samanes Gajate, AM; De
Marzi, P; Spinapolice, EG; Mapelli, P; Giovacchini, G;
Sigismondi, C; Vigano, R; Sironi, S; Messa, C. Highgrade endometrial cancer: Value of [18F]FDG PET/CT in
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P.634. Piemonti, L; Guidotti, LG and Battaglia, M. Modulation of early inflammatory reactions to promote engraftment
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P.635. Pierro, L; Giatsidis, SM; Mantovani, E and Gagliardi, M. Macular thickness interoperator and intraoperator
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P.638. Pistoni, M; Ghigna, C; Gabellini, D. Alternative splicing
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IF 2009: 5,559
P.639. Pluchino, S; Cusimano, M; Bacigaluppi, M; Martino,
G. Remodelling the injured CNS through the establishment
of atypical ectopic perivascular neural stem cell niches.
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IF 2009: 0,972
P.640. Poggi, A; Prevosto, C; Catellani, S; Rocco, I; Garuti, A;
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P.641. Poletti, S; Anselmetti, S; Bechi, M; Ermoli, E; Bosia,
M; Smeraldi, E; Cavallaro, R. Computer-aided neurocognitive remediation in schizophrenia: Durability of rehabilitation outcomes in a follow-up study. Neuropsychol. Rehabil.: 2010; 20(5): 659-674 - Article
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kinase-2 (Pank2) silencing causes cell growth reduction,
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based estimates of blood flow rate in doppler analysis: In
vivo validation by means of phase-contrast MRI. IEEE
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F; Pruneri, G; Gaidano, G; Capella, C; Zucca, E; Doglioni,
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lymphomas. Leuk. Res.: 2010; 34(9): e243-e245 - Letter
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P.653. Pouw, N; Treffers-Westerlaken, E; Mondino, A;
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Investigators. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis. J.
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P.661. Rama, P; Matuska, S; Paganoni, G; Spinelli, A; De
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ARR; Gough, J; Grimmond, S; Han, JH; Hashimoto, T;
Hide, W; Hofmann, O; Kawaji, H; Kubosaki, A; Lassmann,
T; van Nimwegen, E; Ogawa, C; Teasdale, RD; Tegner, J;
Lenhard, B; Teichmann, SA; Arakawa, T; Ninomiya, N; Murakami, K; Tagami, M; Fukuda, S; Imamura, K; Kai, C; Ishihara, R; Kitazume, Y; Kawai, J; Hume, DA; Ideker, T;
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Hayashizaki, Y. An Atlas of Combinatorial Transcriptional
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Italian study on treatment trends and outcomes of patients
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drug resistance and non-B subtypes prevalence among
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Rodegher, ME; Misci, P; Rossi, P; Falini, A; Comi, G;
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P.682. Roehrborn, CG; Siami, P; Barkin, J; Damiao, R; MajorWalker, K; Nandy, I; Morrill, BB; Gagnier, RP; Montorsi, F.
The Effects of Combination Therapy with Dutasteride and
Tamsulosin on Clinical Outcomes in Men with Symptomatic Benign Prostatic Hyperplasia: 4-Year Results from
the CombAT Study. Eur. Urol.: 2010; 57(1): 123-131 - Article
IF 2009: 7,667
P.683. Roetto, A; Di Cunto, F; Pellegrino, RM; Hirsch, E; Azzolino, O; Bondi, A; Defilippi, I; Carturan, S; Miniscalco, B;
Riondato, F; Cilloni, D; Silengo, L; Altruda, F; Camaschella, C and Saglio G. Comparison of 3 Tfr2-deficient murine
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P.684. Romagnoli, E; De Servi, S; Tamburino, C; Colombo,
A; Burzotta, F; Presbitero, P; Bolognese, L; Paloscia, L;
Rubino, P; Sardella, G; Briguori, C; Ettori, F; Franco, G; Di
Girolamo, D; Sheiban, I; Piatti, L; Greco, C; Petronio, S;
Loi, B; Lioy, E; Benassi, A; Patti, A; Gaspardone, A; Capodanno, D; Biondi-Zoccai, GGL; Sangiorgi, G for the I-BIGIS
Study Group Milan, Italy. Real-world outcome of coronary
bifurcation lesions in the drug-eluting stent era: Results
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P.685. Ronchi, P; Novelli, G; Colombo, L; Valsecchi, S;
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A; Villa, E; Danova, M. Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann. Oncol.: 2010;
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P.687. Ronzoni, R; Anelli, T; Brunati, M; Cortini, M; Fagioli,
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P.689. Ross, AL; Bråve, A; Scarlatti, G; Manrique, A; Buonaguro, L. Progress towards development of an HIV vaccine: report of the AIDS Vaccine 2009 Conference. Lancet
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P.690. Rossetti, M; Gregori, S and Roncarolo, MG. Granulocyte-colony stimulating factor drives the in vitro differentiation of human dendritic cells that induce anergy in naïve T
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Abnormal activity of the Na/Ca exchanger enhances glutamate transmission in experimental autoimmune encephalomyelitis. Brain Behav. Immun.: 2010; 24(8): 13791385 - Article
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P.692. Rossi, S; Gasparotto, D; Toffolatti, L; Pastrello, C; Gallina, G; Marzotto, A; Sartor, C; Barbareschi, M; Cantaloni,
C; Messerini, L; Bearzi, I; Arrigoni, G; Mazzoleni, G; Fletcher, JA; Casali, PG; Talamini, R; Maestra, R; Dei Tos, AP.
Molecular and clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size. Am. J.
Surg. Pathol.: 2010; 34(10): 1480-1491 - Article
IF 2009: 4,062
P.693. Rossini, D; Lucca, A; Magri, L; Malaguti, A; Smeraldi, E; Colombo, C; Zanardi, R. A symptom-specific
analysis of the effect of high-frequency left or low-frequency right transcranial magnetic stimulation over the dorsolateral prefrontal cortex in major depression. Neuropsychobiology: 2010; 62(2): 91-97 - Article
IF 2009: 2,147
P.694. Ruggeri, A; Ciceri, F; Gluckman, E; Labopin, M;
Rocha, V on behalf of Eurocord and Acute Leukemia
Working Party of the European Blood and Marrow
Transplant Group. Alternative donors hematopoietic stem
cells transplantation for adults with acute myeloid leukemia:
Umbilical cord blood or haploidentical donors? Best Pract.
Res. Clin. Haematol.: 2010; 23(2): 207-216 - Review
IF 2009: 3,134
P.695. Ruhrberg, C; De Palma, M. A double agent in cancer:
Deciphering macrophage roles in human tumors. Nat.
Med.: 2010; 16(8): 861-862 - Short Survey
IF 2009: 27,136
P.696. Rumi, E; Passamonti, F; Arcaini, L; Bernasconi, P; Elena, C; Pietra, D; Brisci, A; Arbustini, E; Cazzola, M; Lazzarino, M. Molecular remission after allo-SCT in a patient
with post-essential thrombocythemia myelofibrosis carrying
the MPL (W515A) mutation. Bone Marrow Transplant.:
2010; 45(4): 798 - 800 - Letter
IF 2009: 2,998
P.697. Sabin, C; Corti, D; Buzon, V; Seaman, MS; Lutje Hulsik,
D; Hinz, A; Vanzetta, F; Agatic, G; Silacci, C; Mainetti, L;
Scarlatti, G; Sallusto, F; Weiss, R; Lanzavecchia, A; Weissenhorn W. Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody
binding to the highly conserved heptad repeat 1 of gp41.
PLoS Pathog.: 2010; 6(11): e1001195 - Article
IF 2009: 8,978
P.698. Sachdeva, R; Jonsson, ME; Nelander, J; Kirkeby, A;
Guibentif, C; Gentner, B; Naldini, L; Bjorklund, A; Parmar,
M; Jakobsson, J. Tracking differentiating neural progenitors
in pluripotent cultures using microRNA-regulated lentiviral
vectors. Proc. Natl. Acad. Sci. U. S. A.: 2010; 107(25):
11602-11607 - Article
IF 2009: 9,432
P.699. Sagnelli, C; Uberti-Foppa, C; Pasquale, G; Coppola,
N; Albarello, L; Masiello, A; Doglioni, C; Lazzarin, A;
Sagnelli, E. Liver histology in HIV/hepatitis C-coinfected
and HCV-monoinfected patients with persistently normal
alanine aminotransferases. J. Acquir. Immune Defic. Syndr.: 2010; 54(1): 107 - 109 - Letter
IF 2009: 4,207
P.700. Saleri, N; Badoum, G; Ouedraogo, M; Dembele, SM;
Nacanabo, R; Bonkoungou, V; Cirillo, D; Pinsi, G; Matteelli, A. Extensively drug-resistant tuberculosis, Burkina
Faso. Emerg. Infect. Dis: 2010; 16(5): 840 - 842 - Article
IF 2009: 6,794
P.701. Salonia, A. Editorial Comment on: Paternity and Testicular Function Among Testicular Cancer Survivors Treated
with Two to Four Cycles of Cisplatin-Based Chemotherapy.
Eur. Urol.: 2010; 58(1): 140-141 - Editorial
IF 2009: 7,667
P.702. Salonia, A; Gallina, A; Briganti, A; Colombo, R;
Bertini, R; Da Pozzo, LF; Zanni, G; Sacca, A; Rocchini,
L; Guazzoni, G; Rigatti, P and Montorsi, F. Postoperative orgasmic function increases over time in patients undergoing nerve-sparing radical prostatectomy. J. Sex.
Med.: 2010; 7(1 PART 1): 149 - 155 - Article
IF 2009: 4,884
P.703. Salonia, A; Giraldi, A; Chivers, ML; Georgiadis, JR;
Levin, R; Maravilla, KR; McCarthy, MM. Physiology of
women’s sexual function: Basic knowledge and new findings. J. Sex. Med.: 2010; 7(8): 2637-2660 - Review
IF 2009: 4,884
P.704. Santoro, A; Pressiani, T; Citterio, G; Rossoni, G; Donadoni, G; Pozzi, F; Rimassa, L; Personeni, N; Bozzarelli,
S; Rossoni, G; Colombi, S; De Braud, FG; Caligaris-Cappio, F; Lambiase, A; Bordignon, C. Activity and safety of
NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma. Br. J. Cancer: 2010; 103(6): 837-844 - Article
IF 2009: 4,346
P.705. Santoro, A; Rimassa, L; Sobrero, AF; Citterio, G;
Sclafani, F; Carnaghi, C; Pessino, A; Caprioni, F; Andretta,
V; Tronconi, MC; Finocchiaro, G; Rossoni, G; Zanoni, A;
Miggiano, C; Rizzardi, GP; Traversari, C; Caligaris-Cappio, F; Lambiase, A; Bordignon, C. Phase II study of
NGR-hTNF, a selective vascular targeting agent, in patients
with metastatic colorectal cancer after failure of standard
therapy. Eur. J. Cancer: 2010; 46(15): 2746-2752 - Article
IF 2009: 4,121
P.706. Sardanelli, F; Boetes, C; Borisch, B; Decker, T; Federico, M; Gilbert, FJ; Helbich, T; Heywang-Kobrunner, SH;
Kaiser, WA; Kerin, MJ; Mansel, RE; Marotti, L; Martincich,
L; Mauriac, L; Meijers-Heijboer, H; Orecchia, R; Panizza,
P; Ponti, A; Purushotham, AD; Regitnig, P; Del Turco, MR;
Thibault, F; Wilson, R. Magnetic resonance imaging of the
breast: Recommendations from the EUSOMA working
group. Eur. J. Cancer: 2010; 46(8): 1296 - 1316 - Article
IF 2009: 4,121
P.707. Sarina, B; Castagna, L; Farina, L; Patriarca, F; Benedet-
337
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ti, F; Carella, AM; Falda, M; Guidi, S; Ciceri, F; Bonini, A;
Ferrari; S; Malagola, M; Morello, E; Milone, G; Bruno, B;
Mordini, N; Viviani, S; Levis, A; Giordano, L; Santoro, A;
Corradini P; Gruppo Italiano Trapianto di Midollo Osseo. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing
after autologous transplantation: a retrospective study
based on the time of HLA typing and donor availability.
Blood: 2010; 115(18): 3671-3677 - Article
IF 2009: 10,555
P.708. Scandurra, M; Rossi, D; Deambrogi, C; Rancoita, PMV;
Chigrinova, E; Mian, M; Cerri, M; Rasi, S; Sozzi, E; Forconi, F; Ponzoni, M; Moreno, SM; Piris, MA; Inghirami, G;
Zucca, E; Gattei, V; Rinaldi, A; Kwee, I; Gaidano, G;
Bertoni, F. Genomic profiling of Richter’s syndrome: Recurrent lesions and differences with de novo diffuse large Bcell lymphomas. Hematol. Oncol.: 2010; 28(2): 62-67 - Article
IF 2009: 1,869
P.709. Scarfo, L; Dagklis, A; Scielzo, C; Fazi, C; Ghia, P.
CLL-like monoclonal B-cell lymphocytosis: Are we all
bound to have it? Semin. Cancer Biol.: 2010; 20(6): 384 390 - Review
IF 2009: 6,918
P.710. Scattoni, V; Maccagnano, C; Zanni, G; Angiolilli, D;
Raber, M; Roscigno, M; Rigatti, P and Montorsi, F. Is
extended and saturation biopsy necessary? Int. J. Urol.:
2010; 17(5): 432 - 447 - Review
IF 2009: 1,158
P.711. Scattoni, V; Raber, M; Abdollah, F; Roscigno, M;
Deho, F; Angiolilli, D; Maccagnano, C; Gallina, A; Capitanio, U; Freschi, M; Doglioni, C; Rigatti, P; Montorsi,
F. Biopsy Schemes with the Fewest Cores for Detecting
95% of the Prostate Cancers Detected by a 24-Core Biopsy. Eur. Urol.: 2010; 57(1): 1-8 - Article
IF 2009: 7,667
P.712. Schettino, A; Lauro, LR; Crippa, F; Anselmetti, S;
Cavallaro, R; Papagno, C. The comprehension of idiomatic expressions in schizophrenic patients. Neuropsychologia: 2010; 48(4): 1032 - 1040 - Article
IF 2009: 4,345
P.713. Schiaffino, MV. Signaling pathways in melanosome
biogenesis and pathology. Int. J. Biochem. Cell Biol.:
2010; 42(7): 1094-1104 - Review
IF 2009: 4,887
P.714. Schiering, C; Guarnerio, J; Basso, V; Muzio, L and
Mondino, A. Antigen-experienced CD4+ T cells limit naïve
T-cell priming in response to therapeutic vaccination in vivo. Cancer Res.: 2010; 70(15): 6161-6170 - Article
IF 2009: 7,543
P.715. Schulman, CC; Irani, J; Morote, J; Schalken, JA; Montorsi, F; Chlosta, PL; Heidenreich, A. Testosterone Measurement in Patients with Prostate Cancer. Eur. Urol.: 2010;
58(1): 65-74 - Review
IF 2009: 7,667
P.716. Schulman, CC; Irani, J; Morote, J; Schalken, JA; Montorsi, F; Chlosta, PL; Heidenreich, A. Androgen-deprivation therapy in prostate cancer: A European expert panel
review. Eur. Urol. Suppl.: 2010; 9(7): 675-691 - Review
IF 2009: 2,358
P.717. Schulte, C and Racchetti G; D’Alessandro, R; Meldolesi, J. A New Form of Neurite Outgrowth Sustained by
the Exocytosis of Enlargeosomes Expressed under the
Control of REST. Traffic: 2010; 11(10): 1304-1314 - Article
IF 2009: 6,255
P.718. Scielzo, C and Bertilaccio, MTS; Simonetti, G;
Dagklis, A; Ten Hacken, E; Fazi, C; Muzio, M; Caiolfa,
V; Kitamura, D; Restuccia, U; Bachi, A; Rocchi, M; Ponzoni, M; Ghia, P and Caligaris-Cappio, F. HS1 has a
central role in the trafficking and homing of leukemic B
cells. Blood: 2010; 116(18): 3537-3546 - Article
IF 2009: 10,555
P.719. Scielzo, C; Ten Hacken, E; Bertilaccio, MTS; Muzio,
M; Calissano, C; Ghia, P; Caligaris-Cappio, F. How the
microenvironment shapes chronic lymphocytic leukemia:
The cytoskeleton connection. Leuk. Lymphoma: 2010;
51(8): 1371-1374 - Article
IF 2009: 2,397
P.720. Scola, E; Bozzali, M; Agosta, F; Magnani, G;
Franceschi, M; Sormani, MP; Cercignani, M; Pagani, E;
Falautano, M; Filippi, M; Falini, A. A diffusion tensor MRI
study of patients with MCI and AD with a 2-year clinical follow-up. J. Neurol. Neurosurg. Psychiatr.: 2010; 81(7):
798-805 - Article
IF 2009: 4,869
P.721. Scotti, C; Mangiavini, L; Boschetti, F; Vitari, F; Domeneghini, C; Fraschini, G; Peretti, GM. Effect of in vitro culture on a chondrocyte-fibrin glue hydrogel for cartilage repair. Knee Surg. Sports Traumatol. Arthrosc.: 2010;
18(10): 1400-1406 - Article
IF 2009: 1,674
P.722. Seresini, S; Origoni, M; Caputo, L; Lillo, F; Longhi,
R; Vantini, S; Paganoni, AM; Protti, MP. CD4+ T cells
against human papillomavirus-18 E7 in patients with highgrade cervical lesions associate with the absence of the
virus in the cervix. Immunology: 2010; 131(1): 89-98 - Article
IF 2009: 3,276
P.723. Serruys, PW; Onuma, Y; Garg, S; Vranckx, P; De
Bruyne, B; Morice, MC; Colombo, A; Macaya, C;
Richardt, G; Fajadet, J; Hamm, C; Schuijer, M; Rademaker, T; Wittebols, K; Stoll, HP on behalf of the ARTS II Investigators. 5-Year Clinical Outcomes of the ARTS II (Arterial
Revascularization Therapies Study II) of the Sirolimus-Eluting Stent in the Treatment of Patients With Multivessel De
Novo Coronary Artery Lesions. J. Am. Coll. Cardiol.: 2010;
55(11): 1093 - 1101 - Article
IF 2009: 12,640
P.724. Shanafelt, TD; Ghia, P; Lanasa, MC; Landgren, O;
Rawstron, AC. Monoclonal B-cell lymphocytosis (MBL): Biology, natural history and clinical management. Leukemia:
2010; 24(3): 512 - 520 - Review
IF 2009: 8,296
P.725. Shariat, SF; Bolenz, C; Karakiewicz, PI; Fradet, Y; Ashfaq, R; Bastian, PJ; Nielsen, ME; Capitanio, U; Jeldres,
C; Rigaud, J; Muller, SC; Lerner, SP; Montorsi, F; Sagalowsky, AI; Cote, RJ; Lotan, Y. P53 expression in patients
with advanced urothelial cancer of the urinary bladder. BJU
Int.: 2010; 105(4): 489 - 495 - Article
IF 2009: 2,865
P.726. Shariat, SF; Chade, DC; Karakiewicz, PI; Ashfaq, R; Isbarn, H; Fradet, Y; Bastian, PJ; Nielsen, ME; Capitanio,
U; Jeldres, C; Montorsi, F; Lerner, SP; Sagalowsky, AI;
Cote, RJ; Lotan, Y. Combination of Multiple Molecular
Markers Can Improve Prognostication in Patients With Locally Advanced and Lymph Node Positive Bladder Cancer.
J. Urol.: 2010; 183(1): 68-75 - Article
IF 2009: 4,016
P.727. Shariat, SF; Godoy, G; Lotan, Y; Droller, M;
Karakiewicz, PI; Raman, JD; Isbarn, H; Weizer, A; Remzi,
M; Roscigno, M; Kikuchi, E; Bolenz, C; Bensalah, K; Koppie, TM; Kassouf, W; Wheat, JC; Zigeuner, R; Langner, C;
Wood, CG; Margulis, V. Advanced patient age is associated with inferior cancer-specific survival after radical
nephroureterectomy. BJU Int.: 2010; 105(12): 1672-1677
- Article
IF 2009: 2,865
P.728. Shariat, SF; Svatek, RS; Tilki, D; Skinner, E;
PUBLICATIONS
Karakiewicz, PI; Capitanio, U; Bastian, PJ; Volkmer, BG;
Kassouf, W; Novara, G; Fritsche, HM; Izawa, JI; Ficarra, V;
Lerner, SP; Sagalowsky, AI; Schoenberg, MP; Kamat, AM;
Dinney, CP; Lotan, Y; Marberger, MJ; Fradet, Y. International validation of the prognostic value of lymphovascular
invasion in patients treated with radical cystectomy. BJU
Int.: 2010; 105(10): 1402 - 1412 - Article
IF 2009: 2,865
P.729. Sharp, ASP; Michev, I and Colombo, A. First transaxillary implantation of Edwards Sapien valve to treat an incompetent aortic bioprosthesis. Catheter. Cardiovasc. Interv.: 2010; 75(4): 507 - 510 - Article
IF 2009: 2,363
P.730. Sharp, ASP; Michev, I; Maisano, F; Taramasso, M;
Godino, C; Latib, A; Denti, P; Dorigo, E; Giacomini, A;
Iaci, G; Manca, M; Ielasi, A; Montorfano, M; Alfieri, O
and Colombo, A. A new technique for vascular access
management in transcatheter aortic valve implantation.
Catheter. Cardiovasc. Interv.: 2010; 75(5): 784 - 793 - Article
IF 2009: 2,363
P.731. Signorotto, P; del Vecchio, A; Montorfano, M;
Maisano, F; Giagnorio, M; Bellanca, R; Colombo, A
and Calandrino, R. Dosimetric data and radiation risk
analysis for new procedures in interventional cardiology.
Radiat. Prot. Dosimetry: 2010; 142(2-4): 201-208 - Article
IF 2009: 0,707
P.732. Siri, C; Cilia, R; De Gaspari, D; Villa, F; Goldwurm, S;
Catalano, M; Pezzoli, G; Antonini, A. Psychiatric symptoms in Parkinson’s disease assessed with the SCL-90R
self-reported questionnaire. Neurol. Sci.: 2010; 31(1): 35 40 - Article
IF 2009: 1,120
P.733. Sirri, A; Bianchi, V; Pelizzola, M; Mayhaus, M; Ricciardi-Castagnoli, P; Toniolo, D; D’Adamo, P. Temporal gene
expression profile of the hippocampus following trace fear
conditioning. Brain Res.: 2010; 1308: 14-23 - Article
IF 2009: 2,463
P.734. Sirtori, V; Corbetta, D; Moja, L; Gatti, R. Constraintinduced movement therapy for upper extremities in patients with stroke. Stroke: 2010; 41(1): e57-e58 - Short
Survey
IF 2009: 7,041
P.735. Sizzano, F; Zito, L; Crivello, P; Crocchiolo, R; Vago,
L; Zino, E; Fleischhauer, K. Significantly higher frequencies of alloreactive CD4+ T cells responding to nonpermissive than to permissive HLA-DPB1 T-cell epitope disparities. Blood: 2010; 116(11): 1991-1992 - Letter
IF 2009: 10,555
P.736. Smura, T; Ylipaasto, P; Klemola, P; Kaijalainen, S; Kyllönen, L; Sordi, V; Piemonti, L; Roivainen, M. Cellular tropism of human enterovirus D species serotypes EV-94,
EV-70, and EV-68 in vitro: implications for pathogenesis. J.
Med. Virol.: 2010; 82(11): 1940-1949 - Article
IF 2009: 2,470
P.737. Snyder, AM; Neely, EB; Levi, S; Arosio, P; Connor, JR.
Regional and cellular distribution of mitochondrial ferritin in
the mouse brain. J. Neurosci. Res.: 2010; 88(14): 31333143 - Article
IF 2009: 2,986
P.738. Socci, C; Orsenigo, E; Santagostino, I; Caumo, A;
Caldara, R; Parolini, D; Aldrighetti, L; Castoldi, R; Frasson, M; Carvello, M; Ghirardelli, L; Secchi, A; Di Carlo,
V and Staudacher, C. Pancreata from pediatric donors
restore insulin independence in adult insulin-dependent diabetes mellitus recipients. Transplant. Proc. : 2010; 42(6):
2068-2070 - Conference Paper
IF 2009: 0,994
P.739. Solla, P; Vannelli, A; Bolino, A; Marrosu, G; Coviello,
S; Murru, MR; Tranquilli, S; Corongiu, D; Benedetti, S;
Marrosu, MG. Heat shock protein 27 R127W mutation:
Evidence of a continuum between axonal Charcot-MarieTooth and distal hereditary motor neuropathy. J. Neurol.
Neurosurg. Psychiatry: 2010; 81(9): 958-962 - Article
IF 2009: 4,869
P.740. Sordi, V; Melzi, R; Mercalli, A; Formicola, R;
Doglioni, C; Tiboni, F; Ferrari, G; Nano, R; Chwalek, K;
Lammert, E; Bonifacio, E; Piemonti, L. Mesenchymal cells
appearing in pancreatic tissue culture are bone marrowderived stem cells with the capacity to improve transplanted islet function. Stem Cells: 2010; 28(1): 140 - 151 - Article
IF 2009: 7,747
P.741. Soria, A; Danise, A; Galli, L; Tiberi, S; Seminari, E;
Cossarini, F; Bigoloni, A; Marcotullio, S; Lazzarin, A;
Castagna, A. Viro-immunological dynamics in HIV-1infected subjects receiving once-a-week emtricitabine to
delay treatment change after failure: A pilot randomised trial. J. Clin. Virol.: 2010; 47(3): 253 - 257 - Article
IF 2009: 3,124
P.742. Soriano, V; Mocroft, A; Peters, L; Rockstroh, J; Antunes, F; Kirkby, N; de Wit, S; Monforte, A; Flisiak, R;
Lundgren, J; EuroSIDA. Predictors of hepatitis B virus
genotype and viraemia in HIV-infected patients with chronic hepatitis B in Europe. J. Antimicrob. Chemother.: 2010;
65(3): 548-555 - Article
IF 2009: 4,352
P.743. Sorrentino, R; Gherlone, EF; Calesini, G; Zarone, F. Effect of implant angulation, connection length, and impression material on the dimensional accuracy of implant impressions: An in vitro comparative study. Clin. Implant
Dent. Relat. Res.: 2010; 12(SUPPL. 1): e63-e76 - Article
IF 2009: 2,452
P.744. Spatola, CAM; Rende, R; Battaglia, M. Genetic and
environmental influences upon the CBCL/6-18 DSM-oriented scales: Similarities and differences across three different computational approaches and two age ranges. Eur.
Child Adolesc. Psych.: 2010; 19(8): 647-658 - Article
IF 2009: 1,651
P.745. Speliotes, EK; Willer, CJ; Berndt, SI; Monda, KL; Thorleifsson, G; Jackson, AU; Allen, HL; Lindgren, CM; Luan,
J; Magi, R; Randall, JC; Vedantam, S; Winkler, TW; Qi, L;
Workalemahu, T; Heid, I; Steinthorsdottir, V; Stringham, H;
Weedon, MN; Wheeler, E; Wood, AR; Ferreira, T; Weyant,
RJ; Segre, AV; Eestrada, K; Liang, L; Nemesh, J; Park, JH;
Gustafsson, S; Kilpelainen, TO; Yang, J; Bouatia-Naji, N;
Eesko, T; Feitosa, MF; Kutalik, Z; Mangino, M; Raychaudhuri, S; Scherag, A; Smith, AV; Welch, R; Zhao, JH; Aben,
KK; Absher, DM; Amin, N; Dixon, AL; Fisher, E; Glazer, N;
Goddard, ME; Heard-Costa, N; Hoesel, V; Hottenga, JJ;
Johansson, A; Johnson, T; Ketkar, S; Lamina, C; Li, S;
Moffatt, MF; Myers, RH; Narisu, N; Perry, JRB; Peters, MJ;
Preuss, M; Ripatti, S; Rivadeneira, F; Sandholt, C; Scott,
LJ; Timpson, NJ; Tyrer, JP; Van Wingerden, S; Watanabe,
R; White, CC; Wiklund, F; Barlassina, C; Chasman, DI;
Cooper, MN; Jansson, JO; Lawrence, RW; Pellikka, N;
Prokopenko, I; Shi, J; Thiering, E; Alavere, H; Sciarrone
Alibrandi, MT; Almgren, P; Arnold, A; Aspelund, T; Atwood, LD; Balkau, B; Balmforth, AJ; Bennett, AJ; BenShlomo, Y; Bergman, R; Bergmann, S; Biebermann, H;
Blakemore, AIF; Boes, T; Bonnycastle, L; Bornstein, SR;
Brown, MJ; Buchanan, TA; Busonero, F; Campbell, H;
Cappuccio, FP; Cavalcanti-Proenca, C; Ida Chen, YD;
Chen, CM; Chines, P; Clarke, R; Coin, L; Connell, J; Day,
I; Den Heijer, M; Duan, J; Eebrahim, S; Eelliott, P; Eelosua,
R; Eeiriksdottir, G; Eerdos, MR; Eeriksson, JG; Facheris,
MF; Felix, SB; Fischer-Posovszky, P; Folsom, AR;
Friedrich, N; Freimer, NB; Fu, M; Gaget, S; Gejman, PV;
339
PUBLICATIONS
Geus, EJ; Gieger, C; Gjesing, AP; Goel, A; Goyette, P;
Grallert, H; Grassler, J; Greenawalt, D; Groves, CJ; Gudnason, V; Guiducci, C; Hartikainen, AL; Hassanali, N; Hall,
A; Havulinna, A; Hayward, C; Heath, A; Hengstenberg, C;
Hicks, AA; Hinney, A; Hofman, A; Homuth, G; Hui, J; Igl,
W; Iribarren, C; Isomaa, B; Jacobs, KB; Jarick, I; Jewell, E;
John, U; Jorgensen, T; Jousilahti, P; Jula, A; Kaakinen, M;
Kajantie, E; Kaplan, L; Kathiresan, S; Kettunen, J; Kinnunen, L; Knowles, J; Kolcic, I; Konig, IR; Koskinen, S; Kovacs, P; Kusisto, J; Kraft, P; Kvaloy, K; Laitinen, J; Lantieri,
O; Lanzani, C; Launer, LJ; Lecoeur, C; Lehtimaki, T; Lettre, G; Liu, J; Lokki, ML; Lorentzon, M; Luben, R; Ludwig,
B; Magic; Manunta, P; Marek, D; Marre, M; Martin, NG;
McArdle, W; McCarthy, A; McKnight, B; Meitinger, T; Melander, O; Meyre, D; Midthjell, K; Montgomery, G; Morken,
MA; Morris, AP; Mulic, R; Ngwa, J; Nelis, M; Neville, MJ;
Nyholt, DR; O’Ddonnell, CJ; O’Rahilly, S; Ong, K; Ostra, B;
Pare, G; Parker, A; Perola, M; Pichler, I; Pietilainen, KH;
Platou, CP; Polasek, O; Pouta, A; Rafelt, S; Raitakari, O;
Rayner, N; Ridderstrale, M; Rief, W; Ruokonen, A; Robertson, NR; Rzehak, P; Salomaa, V; Sanders, AR; Sandhu,
M; Sanna, S; Saramies, J; Savolainen, MJ; Scherag, S;
Schipf, S; Schreiber, S; Schunkert, H; Silander, K; Sinisalo, J; Siscovick, DS; Smit, JH; Soranzo, N; Sovio, U;
Stephens, J; Surakka, I; Swift, AJ; Tammesoo, ML; Tardif,
JC; Teder-Laving, M; Teslovich, T; Thompson, JR; Thomson, B; Tonjes, A; Tuomi, T; Van Meurs, JBJ; Van OMen,
GJ; Vatin, V; Viikari, J; Visvikis-Siest, S; Vitart, V; Vogel, CI;
Voight, BF; Waite, L; Wallaschofski, H; Walters, B; Widen,
E; Wiegand, S; Wild, SH; Willemsen, G; Witte, DR; Witteman, J; Xu, J; Zhang, Q; Zgaga, L; Ziegler, A; Zitting, P;
Beilby, JP; Farooqi, IS; Hebebrand, J; Huikuri, HV; James,
A; Kahonen, M; Levinson, DF; MacCiardi, F; Nieminen,
MS; Ohlsson, C; Palmer, LJ; Ridker, P; Stumvoll, M; Beckmann, J; Boeing, H; Boerwinkle, E; BOmsma, DI;
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