scientific report - Ospedale San Raffaele

Transcript

San Raffaele Scientific Institute
Via Olgettina, 60
20132 Milano
Tel. 02 26431
www.sanraffaele.org
2008
SCIENTIFIC REPORT 2008
SCIENTIFIC REPORT
S C I E N T I F I C
R E P O R T
2008
COVER IMAGES
top left and right:
Unpublished image by Patrizia Rovere-Querini
(see Innate immunity and tissue remodelling, page 80)
top middle:
Unpublished image by Gian Giacomo Consalez (see Developmental neurogenetics Unit, pages 31-32)
bottom:
© 2009 American Society of Hematology
Cover image of a coming issue of Blood, 2009
Molteni, R; Lage Crespo, C.; Feigelson, S; Moser, C; Fabbri, M; Grabovsky, V; Krombach, F; Laudanna, C;
Alon, R and Pardi, R*
?-arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during
CXCR2-driven extravasation
Blood: 2009, May 8 (epub ahead of print)
doi: 10.1182/blood-2008-10-183699
* see Leukocyte biology Unit, page 101
Images 1. and 3. have been taken at the San Raffaele’s Advanced Light and Electron Microscopy BioImaging
Center (see ALEMBIC, page 160)
Some ot the images in this volume has been published in scientific papers:
Fig. 1, p. 20: Journal of the National Cancer Institute
Fig. 5, p. 45: PLoS One (in press)
Fig. 16, p. 120: Current Diabetes Reports
Fig. 23, p. 139: Nature Genetics
Fig. 26, p. 150: Nucleic Acids Research
Edited by the San Raffaele Library
Layout by Roberto Cremonesi
Printed by Grafiche Parole Nuove, Brugherio
INDEX - III
INDEX
INTRODUCTIONS
VII
Introduzione del Presidente
Introduction by the President
Introduction by the Scientific Director
Introduction by the Chief Operating Officer
IX
X
XII
XVI
San Raffaele Scientific Retreat 2008 photo gallery XVIII
3rd International Congress –
Aortic Surgery and Anesthesia “How to do it”
XX
Introduction by the General Director
Clinical Area
XXII
DIVISION OF MOLECULAR
ONCOLOGY
Introduction by the Directors
Research Units
Lymphoid malignancies Unit
B-cell neoplasia
Biology of multiple myeloma
Cell activation and signalling
Dynamic fluorescence spectroscopy in biomedicine
Lymphoid organ development
Preclinical models of cancer
Tumor microenvironment
Immuno-biotherapy of melanoma and
solid tumors Unit
Cancer gene therapy
Functional genomics of cancer Unit
Model genetics of membrane trafficking Unit
Molecular histology and cell growth Unit
Tumor biology and vascular targeting Unit
1
5
7
7
8
8
9
9
10
11
11
12
12
13
13
14
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
Clinical lymphoid malignancies
Gynecologic oncology
Medical oncology Unit - Clinical trials
Medical oncology Unit - Phase I and lung
cancer clinical trials
Urological Research Institute (URI)
14
15
15
16
17
17
18
18
19
19
20
20
21
DIVISION OF NEUROSCIENCE 23
Research Units
28
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
29
30
30
31
31
32
33
33
34
34
IV - SAN RAFFAELE SCIENTIFIC INSTITUTE
Acute brain protection, Acute post-operative pain,
Drugs and central nervous system Unit
35
Eye repair Unit
36
Cognitive neuroscience Unit
36
Experimental neurosurgery Unit
37
Functional neuroradiology Unit
37
In vivo Human molecular and structural
neuroimaging Unit
38
Neuroothology Unit
38
Psychiatry and clinical psychobiology
39
Sleep medicine
39
Clinical psychology
40
Motor function rehabilitation
40
INSTITUTE OF EXPERIMENTAL NEUROLOGY
(INSPE)
41
Introduction by the Director
Research Units
41
Experimental neuropathology
Experimental neurophysiology
Molecular genetics of behaviour
Neuromuscular repair
Neuroimmunology Unit
Clinical neuroimmunology
CNS repair
Neuroimaging research Unit
Neuroimaging of CNS white matter
Human inherited neuropathies Unit
Axo-glia interactions Unit
42
42
43
43
44
44
45
46
46
46
47
Inflammatory CNS disorders Unit
Cerebrovascular disorders
Memory disorders
Movement disorders
Neuromuscular disorders
Paroxysmal events
DIVISION OF METABOLIC
AND CARDIOVASCULAR
SCIENCES
47
48
49
49
49
50
Coagulation service & thrombosis research Unit
Cardiodiabetes & core lab
Pediatric endocrinology research
59
59
60
Diabetes and endocrinology Unit
Cardiodiabetes and clinical trials
Clinical pediatric endocrinology
Diabetes and metabolic diseases in children and
adolescents
Neonatology
Foetal-maternal medicine
Infertility
Cardiovascular interventions Unit
Clinical cardiovascular biology Unit
Ischaemic heart disease, heart failure and
echocardiography Unit
Organ protection in critically ill patients, advanced
cardiac failure and mechanical supports Unit
Structural heart disease Unit
Study and treatment of aortic disease Unit
Center for arrhythmia research
60
61
61
62
62
62
63
63
64
65
65
66
67
67
DIVISION OF REGENERATIVE
MEDICINE, STEM CELLS, AND
GENE THERAPY
71
Research Units
75
Skeletal muscle development and therapy Unit
Functional genetics of muscle regeneration
Gene expression and muscular dystrophy Unit
Molecular and functional immunogenetics
Neural stem cell biology
Autoimmunity & vascular inflammation Unit
Innate immunity and tissue remodelling
Cellular pharmacology Unit
Experimental hematology Unit
Angiogenesis and tumor targeting
76
76
77
78
78
79
80
80
81
81
53
Introduction
Research Units
56
Amino acid and stable isotopes Unit
Complications of diabetes
Obesity and metabolic related diseases
Bone metabolism Unit
57
57
58
58
Hematology and hematopoietic stem cell
transplantation Unit
Immunohematology and transfusion medicine Unit
PSIEP - Strategic Program of Pediatric
Immunohematology
THE SAN RAFFAELE TELETHON INSTITUTE
FOR GENE THERAPY (HSR-TIGET)
82
82
83
84
84
INDEX - V
Research Units
Gene transfer technologies and
new gene therapy strategies Unit
Gene/neural stem cell therapy for lysosomal
storage diseases
Hematopoietic stem cell based gene therapy for the
treatment of lysosomal storage disorders
Safety of gene therapy and insertional mutagenesis
Gene transfer into stem cells Unit
Immunological tolerance Unit
From FOXP3 mutation to IPEX syndrome
Tolerogenic dendritic cells
Pathogenesis and therapy of ADA-SCID Unit
Gene therapy for WASP/Omenn
Neurovirology
Vaccine and Immunotherapy
Clinical immunopathology and advanced medical
therapeutics Unit
Clinical transplant Unit
Gynecological cancers immunology
Immunology in liver neoplasms
Obesity
Pancreatic tumors: immunotherapy and β cell
function substitution
Clinical hepato-gastroenterology
Digestive pathophysiology
Transplant surgery
DIABETES RESEARCH INSTITUTE (DRI)
85
85
86
86
87
87
88
89
89
90
Pediatric Clinical Research Unit - Gene therapy
for Wiskott-Aldrich Syndrome
Pediatric Clinical Research Unit - ADA gene
transfer into hematopoietic stem cells for the
treatment of ADA-SCID
Pediatric Clinical Research Unit - Clinical trial of
gene therapy in metachromatic leukodystrophy
111
112
112
113
114
114
115
115
116
116
116
117
90
Research Units
117
91
Immune tolerance
Experimental diabetes
β cell biology
Cell imaging
118
119
119
120
92
DIVISION OF IMMUNOLOGY,
TRANSPLANTATION, AND
INFECTIOUS DISEASES
95
Research Units
100
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
Immunological diagnostics of tuberculosis
AIDS immunopathogenesis Unit
Biocrystallography Unit
Cellular immunology 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
101
102
102
103
103
104
105
105
106
106
107
107
108
109
109
110
110
111
Islet transplantation
Prevention in type 1 diabetes
Epidemiology & data management
Childhood diabetes
Islet processing activity
121
122
122
123
123
DIVISION OF GENETICS AND
CELL BIOLOGY
127
Research Units
130
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
131
131
132
132
133
134
134
135
136
136
137
137
138
VI - SAN RAFFAELE SCIENTIFIC INSTITUTE
Regulation of iron metabolism Unit
Molecular genetics of renal disorders Unit
139
139
Dento-facial histopathology Unit
Genomics of renal diseases and hypertension Unit
Tissue engineering and biomaterials
CENTER FOR GENOMICS,
BIOINFORMATICS AND
BIOSTATISTICS
140
141
141
THE CLINICAL
DEPARTMENTS
145
Research Units
146
Neurogenomics Unit
Theoretical biology
Biogenesis and motility of secretory organelles Unit
Genomic Unit for the diagnosis of human
pathologies
Proteome biochemistry Unit
Biomolecular NMR laboratory
147
147
148
CENTER FOR IMAGING
149
149
150
153
Introduction
154
Clinical and experimental radiology Unit
High technology in radiation therapy Unit
Molecular imaging Unit
Neuroradiology research group
155
155
156
157
FACILITIES
ALEMBIC, Advanced Light and Electron
Microscopy Bioimaging Center
CFCM, San Raffaele-Telethon Core Facility for
Conditional Mutagenesis
FRACTAL, Flow cytometry Resource, Analytical
Cytology Technical Applications Laboratory
CERMAC, Centre of Excellence of High Field
Magnetic Resonance
Mouse histopathology
Department of arrhythmology
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
Medical physics
Pathology
Laboratory medicine
Service of immunohematology and transfusion
medicine
Emergency medicine
General intensive care
Anaesthesia and neurointensive care Unit
161
161
162
165
166
167
170
172
174
176
178
180
182
183
185
187
188
190
190
191
191
192
192
193
159
160
160
PUBLICATIONS
Best papers 2008
List of 2008 publications
195
196
196
INTRODUCTIONS - VII
INTRODUCTIONS
INTRODUCTIONS - IX
Introduzione del Presidente
Sono particolarmente felice di presentare anche quest’anno il
lavoro dei nostri ormai numerosi ricercatori.
Sono convinto da sempre che non si può scegliere alcune linee di ricerca senza coltivare le molte altre. È perciò che mi
sento soddisfatto di vedere ormai una piattaforma scientifica
del San Raffaele di così vaste proporzioni.
Una piattaforma che comprende in una unità strettamente organizzata e integrata la ricerca di base, la ricerca traslazionale,
la ricerca clinica e applicata.
È chiaro che su questa base io aspiro ad una continuità, anzi
ad una intensificazione esplorativa in tutti i campi dello scibile
e questo perché l’Uomo: corpo, intelletto, spirito è una unità integrata, anche se le tre componenti sembrano essere tra loro
molto diverse.
Infatti, io credo che il rilancio del valore Uomo non può prescindere dalla unitarietà delle linee della di lui conoscenza, sia
come σοµα (corpo), νουs (intelletto), ψυχη (anima, spirito).
È questa la strada per farlo vivere sincrasicamente nell’ambiente e nel tempo.
Voglio anche aggiungere che l’Uomo per venire lucidamente
inteso va considerato per quello che egli è come sua genesi:
l’Uomo, cioè, non è un Ente in sé; è un Ente nell’Ente essenzializzato, cioè nel Creatore Dio che all’uomo ha comunicato per sinaptogenesi il suo potere di intelligere.
Da ciò la imprescindibilità di una struttura come il San Raffaele tipo “città dell’Uomo” dove le scienze, tutte le
scienze, sono di casa, sono cioè a disposizione di tutti. Anche le Scienze umanistiche, la Metafisica e cioè la Ontologia, la Antropologia, la Teodicea ecc. e con tutte le altre conoscenze che fanno dell’uomo: Uomo in progressione verticale.
La nostra Identità Universitaria, cioè altamente culturale, dev’essere per ogni suo componente il vero crocevia
della cultura universale.
È perciò che l’Uomo non può far senza di quell’Ente in sé che chiamiamo Dio e che si è rivelato nel Λογοs divino incarnandosi quale terminale facile all’uomo per giungere direttamente a Dio.
Cari ricercatori comprendete Voi tutto ciò?
Per comprenderlo occorre sapere amare.
Io, a novant’anni, ci sono quasi arrivato e ho tentato di descriverlo plasticamente nel Vostro Ciborio e nella
Vostra Cupola.
Vostro
Don Luigi Maria Verzé
Presidente e Rettore
X - SAN RAFFAELE SCIENTIFIC INSTITUTE
Introduction by the President
I am particularly delighted to present this Annual Report of the scientific research work carried on by the numerous researchers operating in our University and Research Centers.
I personally believe that it is impossible to choose a path of research while not following at the same time different others: a research is made out of different paths interweaved together. Thus, I cannot help but notice my
satisfaction in observing such an important and great scientific platform as San Raffaele is.
Such platform includes the basic research, the translational research and the clinic and applied researches into a joined unity.
It is clear that I aspire to a continuity of research between all the different fields of knowledge which are to be
interconnected on the basis that the human being – body, mind and soul – has to be considered an integrated
unity. Even though the three elements which shape the human being are very different from each other, they
compose a single blend.
Indeed, I strongly believe that the importance and the value of the human being has to be raised in the unity
of these three lines of knowledge, which pertain to the human being: the knowledge of the σοµα (body), the
knowledge of the νουs (mind), the knowledge of the ψυχη (soul).
This is the way necessary in order for the human being to live in space and time synchronously.
I would like to add that to understand what the human being is, it is necessary to consider him for what he is
in his/her genesis. In other words, the human being is not a being per se. On the contrary, the human being is a
being in the Absolute being, created by God and to whom God transferred his power of knowledge by way of
the synapses. As a consequence, the whole San Raffaele has to be shaped as a “city of the Human being”, where
different fields of sciences, of all kinds of science, are to be welcomed, that is: they are to be available to everybody. Even those humanistic sciences, such as Metaphysics – i.e. Ontology, Anthropology, Theodicy and so on
– are to be embraced together with those others which make the human being progressing forward, toward the
highness.
The identity of our University must be, to each of its members, the crossroad of the universal culture.
For these reasons, the human being can neither act nor do anything without God, who revealed himself in the
form of the divine Λογοs which can be easily grasped by each man and woman to arrive directly to God.
Dear researchers, do you understand all that I am saying here?
To understand it, it is necessary to have the capacity to love.
I am ninety years old and I can say I have almost achieved such capacity and I have tried to described it physically to you with Your newly built Ciborio and Your Dome.
Yours,
Don Luigi Maria Verzé
President and Chancellor
INTRODUCTIONS - XI
Scientific Directorate
SCIENTIFIC DIRECTOR: Maria Grazia Roncarolo
CHIEF OPERATING OFFICER: Maurizio Savi
HEAD OF SCIENTIFIC OFFICE: Giulio Negri
ASSISTANT TO THE SCIENTIFIC DIRECTOR: Laura Reiss
GRANT OFFICE: Paola Rebagliati, Riccarda Daneri
HEAD OF CLINICAL TRIAL OFFICE: Elisabetta Riva
Grazia Roncarolo
CLINICAL TRIAL OFFICE: Raffaella Biagetti, Giovanna Bombelli, Anna Negri,
Giliola Calori, Margherita Ianniello, Maria Rosa Mandelli, Rossella Stefani
HEAD OF BIOTECHNOLOGY TRANSFER OFFICE: Daniela Bellomo
BIOTECHNOLOGY TRANSFER OFFICE: Lucia Faccio, Paola Pozzi, Roberto Santarella,
Fabrizio Bacchi, Simona Locatelli
HEAD OF LIBRARY: Laura Tei
LIBRARY: Diego Maria Bertini, Francesco Curci, Elena Ponzi, Maria Samarati
Maurizio Savi
XII - SAN RAFFAELE SCIENTIFIC INSTITUTE
Introduction by the Scientific Director
The mission of the San Raffaele del Monte Tabor Foundation is to conduct innovative research benefiting the
care and cure of our patients and to provide state of the art education and training for new generations of doctors and scientists, with a high level of social responsibility.
The San Raffaele Scientific Institute (SRSI) was one of the first private hospitals established in Italy in 1971.
In 1972 it was granted by the Italian Ministry of Health the status of “Research Hospital” (IRCCS: “Istituto di
Ricovero e Cura a Carattere Scientifico”), with a main focus on diabetes and metabolic diseases. In 1992 a new
research building (42.125 sq m) was open to accommodate the Department of Biotechnology (DIBIT1). The
initial areas of research covered by DIBIT1 were genetics, cell biology and immunology while in the late 90’s
gene therapy, stem cell biology and molecular mechanisms of diseases were added. In recognition of its status as
a center of excellence in Molecular Medicine, in 2001 the Italian Ministry of Health granted the SRSI the status
of Molecular Medicine Research Institute. In 2006 the construction of a second (51.930 sq m) research building
(DIBIT2) was initiated to allow the much needed growth of the various SRSI research groups, to accommodate
the new, centrally organized, state of the art technology platforms supporting our research activities and importantly, to expand our translational research efforts in key disease areas such as regenerative medicine, neuroscience, cardiovascular and oncology. The construction of DIBIT 2 progressed amazingly fast, and several Research Units moved already in. At present approximately 660 scientists and technicians are working in DIBIT1
and DIBIT 2, including postdoctoral fellows, PhD students and undergraduate students. Furthermore, 20 associates provide research services. In addition, 670 physicians work in clinical research projects (see also introduction by Maurizio Savi, chief operating officer for research).
DIBIT1 and DIBIT2 are part of the San Raffaele Biomedical Science Park, which is the largest of its kind in
Italy and includes the San Raffaele Hospital, with more than 1350 beds, and the Vita-Salute San Raffaele University, which was established in 1996. The University hosts the faculties of medicine, psychology and philosophy and provides specialized post graduate courses, resident programs in various medical specialties, and international PhD programs in Cellular/Molecular Biology and Molecular Medicine.
INTRODUCTIONS - XIII
2008 was a year of important chances for SRSI. A new redefined research strategy and organization have been
designed and implemented to create optimal synergies between the different research areas, including clinical
research, to prepare us for the future challenges and to increase our competitiveness in the international scientific arena. In this new strategic vision, research represents the backbone of our institution and the intersection
that connects clinical and teaching activities. In this new model, research activities are consolidated in 6 Research Divisions whereas clinical activities are organized in 12 Clinical Departments (see also introduction by
Renato Botti, general director of clinical area). The Research Divisions are crossing many Clinical Departments
in a matrix model, in which research units and clinical units are fully integrated. In addition, 3 specialized Research Core and Centers have been established to meet the increasing need for state of the art imaging technologies, molecular pathology, functional genomics, proteomics and bioinformatics.
Research at the SRSI covers many disciplines, which include genetics, cell biology, stem cell biology, gene
therapy, immunology, and focuses on several diseases, which include cancer, transplant rejection, autoimmunity
and infections, neurodegenerative, cardiovascular and metabolic diseases. Research conducted in these areas
has the common goal to advance knowledge about molecular basis of diseases and to identify innovative therapies and new diagnostic options. The 6 Research Divisions and 3 Research Cores (see list at page XXIV) approved by the Board and implemented in 2008 represent existing areas of expertise and excellence as well as
new strategic area of research in which we want to invest for the future according to our strategic plan.
Within this new divisional organization, 3 major research Institutes continue to operate: the San Raffaele
Telethon Institute for Gene Therapy of Genetic Diseases (HSR-TIGET), which is pioneering gene therapy to
cure patients with monogenic diseases, the Institute for Experimental Neurology (INSPE), which investigates
the biological and molecular mechanisms underlying diseases of the nervous system with a strong focus on clinical translation, and the recently established Diabetes Research Institute (HSR-DRI) 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. Furthermore, the SRSI hosts several scientists belonging to the Dulbecco-Telethon
Institute (DTI) working on molecular and biological mechanisms of gene regulation and genetic diseases.
In 2008 we also defined the areas in which interdivisional and interdepartmental research programs have to
be consolidated or implemented.
The research Divisions are led by the Directors, appointed for three years and nominated by the President of
the Board of Directors, with the approval of the President of the Board of Director of the University Vita-Salute
San Raffaele.
A Scientific and Technical Committee has also been appointed to support the scientific and operating directors in the strategic research planning and in the definition of new initiatives.
In parallel to the implementation of this new research structure, the administrative and supporting research
structure was also extensively reorganized with the hiring of the Chief Operating Officer for research (see introduction by Maurizio Savi).
In this new organization, the administrative office, the research development and quality control office, the
grant office, the library, the office of biotechnology transfer and the office for clinical experimentation are under the direct responsibility of the scientific and operating directors.
2008 has been another very productive year for the SRSI.
The high productivity and quality of our research in 2008 is reflected by the total number and the total impact factor of our publications, with a remarkable number of manuscripts published in top level scientific journals, as illustrated in figures 1 and 2:
Publications and total Impact Factor 2006-2008
Publications 2006-2008 distributed in Impact Factor ranges
100%
3561,234
693
719
740
Percentage of publications
3870,073
3785,464
80%
65%
63%
62%
60%
40%
26%
28%
30%
20%
9%
10%
0%
2006
(average IF: 5,265)
2007
(average IF: 5,139)
Total IF 2006-2008
2008
(average IF: 5,230)
Publications 2006-2008
<5
5-10
≥10
Impact Factor ranges
2006
2007
2008
8%
XIV - SAN RAFFAELE SCIENTIFIC INSTITUTE
Furthermore, the close links and synergy between the Research Institute and the Hospital is documented by
the number and quality of our clinical trials, with around two hundreds clinical trials evaluated and approved
by our Ethical Committee and a significant proportion of investigator initiated trials in several therapeutic area,
as illustrated in the figures below:
Clinical trials evaluated by the HSR Ethical Committee in 2008
Pharmaceutical companies sponsored trials
No-profit groups sponsored trials
HSR investigators initiated trials
28%
50%
Pharmacological protocols
Observational procotols
Basic research protocols
Medical device protocols
1%
25%
55%
19%
22%
Clinical trials approved in 2008 by therapeutic area
Infectious diseases
Oncology/Hematology
Neurology
Diabetology
Cardiology/Arrhythmology
Urology
Ophthalmology
Anaesthesiology and intensive care
No-profit trials
Sponsored trials
8%
7%
1%
18%
3%
11%
8%
5%
1%
5%
11%
35%
35%
19%
14%
19%
The competitiveness of the SRSI is also demonstrated by its ability to attract funding not only from public
(Ministry of Health, Superior Institute of Health, Ministry of University and Research) but also from private
Italian sources (mainly Telethon, the Italian Association for Cancer Research and Bank Foundations) and from
international sources (e.g. European Community, European Research Council, American National Institute of
Health, World Health Organization, Association for International Cancer Research, Gates Foundation, Wellcome Trust, Juvenile Diabetes Research Foundation).
Finally, SRSI is an attractive partner for big pharmaceutical and biotechnology companies, as it is reflected by
the many collaborations with our scientists which were supported by the office of biotechnology transfer which
has the mission to create value from the intellectual property and know-how of the SRSI and Hospital.
These achievements have been made possible by the excellence of our scientists and clinicians, as also documented by the prestigious international awards won in 2008. In addition, the strong sense of community and
the synergy and cooperation between different teams were highlighted by our yearly Scientific Retreat where
basic and clinical scientists were brought together to discuss scientific progress and future plans. Finally, in
2008 a number of important educational initiatives, scientific events and prestigious international meetings
have been organized and hosted by our basic and clinical scientists.
INTRODUCTIONS - XV
LOOKING FORWARD
We are very much looking forward to occupy the new buildings and to use the new space to consolidate the
research divisions, to build state of the art technology platforms and to enter into new research areas.
SRSI will continue to be a multidisciplinary Institute, but we will also pay particular attention to invest into
research in diseases with a high unmet medical need and into therapeutic areas of increasing medical demand
such as oncology.
We will continue to strengthen our position as a leading center for translational medicine with strong links to
high quality clinical research. In this context, close collaborations between basic (fundamental) researchers,
clinical investigators and physician scientists will be strongly solicited and favored with the ultimate goal to apply new therapeutic principles, invented at the laboratory benches, as efficiently as possible to our patients.
We will continue to build expertise in the field of molecular and experimental medicine, including wide
genome analysis of complex diseases, stratification of patients by genotyping and phenotyping, farmacogenetics
and farmacogenomics.
We will implement a competitive postdoctoral program to attract international young scientists and foster international exchanges. In addition, we will establish a career path for physician scientists and young investigators.
I am confident that this research strategy and structure will further enhance SRSI’s position as an Institute of
excellence conducting innovative science in the field of Molecular Medicine, which at the end benefit our patients. In the coming future this strategy and structure will be presented to our internationally renowned scientific advisory board which will not only give us valuable suggestions but play a particular important role as we
establish high research standards.
The worldwide financial and economical crisis that looms over all of us as we write this scientific report
threatens the implementation of our new strategic research plan and organization. However, the unconditioned
support of our President, as well as the trust of our Board, the motivation of our research directors and the enthusiasm of our scientists and clinical researchers help us to be optimistic and confident that SRSI will continue
to grow and operate at the leading edge of biomedical research. In addition, the moral obligation and responsibility we have towards the younger generations of scientists and physicians to create an environment where they
will be allowed to grow and to build their careers gives us strength and determination.
I like to express my gratitude to the scientists, physicians, staff, post-doctoral fellows and students that with
their work, effort, enthusiasm and passion contributed to the research progress illustrated in this 2008 scientific report. I hope you will find our report interesting and inspiring.
Maria Grazia Roncarolo
Scientific director
XVI - SAN RAFFAELE SCIENTIFIC INSTITUTE
Introduction by the Chief Operating Officer
The San Raffaele Scientific Institute’s biomedical research covers several areas, all closely related to the theme
of Molecular Medicine, which brings together basic research, clinical research and healthcare with the common
goal of transferring preclinical research to the bedside and of translating scientific findings into innovative therapies.
With this global strategic vision, the San Raffaele Scientific Institute strives to enhance its position as a Center
of Excellence in Molecular Medicine by strengthening its infrastructure and redrawing its organization.
The new organization is the result of a project started in 2008 and it is based on a macro-structure processes
model, which aims at:
1.
Creating a common scientific direction inside the Opera, which inspires and supports the San Raffaele
Scientific Institute.
2.
Guaranteeing a complete integration between the main three areas of activities: scientific research,
health and education.
3.
Ensuring the sustainability of the Research Area on the basis of efficacy, efficiency and economy criteria.
4.
Creating an infrastructure and organization based on the individual value by promoting professional
valorization and establishing a working environment where people are able to develop and express
competences and expertise in the best way.
In order to reach these goals we have:
•
Identified the criteria and the rules for the establishment and functioning of the Research Divisions and
Research Cores.
•
Defined the modalities to implement efficient and valid guidelines for the organization of both scientific and administrative activities, establishing clear levels of managerial, administrative and technical responsibilities .
•
Ensured an efficient communication system and a flow of information continuously and efficiently
open to all users.
The San Raffaele Scientific Institute firmly believes in the value of communication and, since 2008, it has
strengthened its Marketing and Fund Raising Staff with the aim to improve the general knowledge on its activities, results and projects by using the main communication media, but also with the goal to better support its
funding possibilities by potentiating the relationships with the main National and International funding agencies for scientific research.
FOCUS ON SOME NUMBERS
RESEARCH - TOTAL REVENUES YEAR 2008
OTHER
REVENUES;
10,86%
OTHER REVENUES -YEAR 2008
EXTERNAL
SERVICES;
10,45%
RESEARCH INCOME - YEAR 2008
DONATIONS
INTERNAL SERVICES
SPONSORED
RESEARCH;
4,48%
DONATIONS;
38,59%
EXTERNAL
GRANTS;
43,78%
INTERNAL
SERVICES;
37,38%
RESEARCH
INCOME;
89,14%
RESEARCH INCOME
OTHER
INCOME;
13,58%
EXTERNAL SERVICES
CLINICAL
TRIALS;
7,84%
PUBLIC
FUNDS;
43,91%
OTHER INCOME
OTHER REVENUES
SPONSORED RESEARCH
CLINICAL TRIALS
PUBLIC FUNDS
EXTERNAL GRANTS
INTRODUCTIONS - XVII
BUILDING UP THE FUTURE
At the end of this year the new construction called “Dibit2” will be completed and equipped. These buildings
represent the “hearth” of the scientific long term vision of our Institute.
The construction consists of three buildings:
In the center there is the “Basilica” building, which, as its name suggests (taken from the Greek culture), represents a space where people can meet, interact, and discuss to advance scientific knowledge and promote scientific culture. In this block there are the Faculty of Medicine and Surgery and the Faculty of Psychological Sciences. Furthermore the advanced technological research based on DNA discovery and function will be conducted in this building by the Genetic and Cell Biology Research Division and the Research Center for Genomics, Bioinformatics and Biostatistics. The Research Center for Imaging and an Open Lab conceived as a
common area for the Research Divisions and the Clinical Groups will also be located in this area.
On each side of the Basilica there are two buildings. The first building is occupied by the Neurosciences Research Division and the Diagnostic Division; whereas the Research Division of Regenerative Medicine, Stem
Cells and Gene Therapy and the Research Division of Molecular Oncology will move into the second building.
The Research Division of Immunology, Transplantation and Infectious Diseases and the Metabolic and Cardiovascular Disease Division will maintain their actual location in Dibit1.
The total space dedicated to the research activity at San Raffaele will cover about 75.000 square meters with
about 1.350 operators: 660 for Basic Research Units, 670 for Clinical Research Groups and 20 for Facilities.
Maurizio Savi
Chief Operating Officer
XVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE
SAN RAFFAELE SCIENTIFIC RETREAT 2008
INTRODUCTIONS - XIX
XX - SAN RAFFAELE SCIENTIFIC INSTITUTE
3RD INTERNATIONAL CONGRESS - AORTIC SURGERY AND
ANESTHESIA “HOW TO DO IT”
Scientific promoter: prof. Roberto Chiesa
December 11-13, 2008
INTRODUCTIONS - XXI
Health Care Directorate
HEALTH CARE SUPERVISOR: Gianna Zoppei
GENERAL DIRECTOR: Renato Botti
HOSPITAL DIRECTOR: Roberts Mazzuconi
PLANNING & CONTROL DIRECTOR: Alessandro Longo
INFORMATION SYSTEMS DIRECTOR: Carla Masperi
PROCUREMENT & LOGISTIC DIRECTOR: Alberto Russo
HEALTH AREA PROJECT DEVELOPMENT DIRECTOR: Maria Romano
CUSTOMER SERVICE DIRECTOR: Riccardo Pizzo
TECHNICAL AREA DIRECTOR: Andrea Roma
E-SERVICES FOR LIFE AND HEALTH DIRECTOR: Alberto Sanna
PROMOTION & DEVELOPMENT MANAGER: Alberto Galliani
ORGANIZATION & DEVELOPMENT MANAGER: Margherita Gambaro
LEGAL OFFICE MANAGER: Piergiorgio Sammartino
Renato Botti
XXII - SAN RAFFAELE SCIENTIFIC INSTITUTE
Introduction by the General Director Clinical Area
San Raffaele Hospital is a private no-profit Foundation classified as Istituto di Ricovero e Cura a Carattere
Scientifico (Research Hospital). It is relentlessly pursuing its three interrelated lines of clinics, 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 2001 and renewed in 2004 and 2008.
San Raffaele IRCCS is a qualified hospital, which is well known in Italy for specific and relevant pathologies.
Furthermore it is recognized as a highly specialized Emergency Center and it is a teaching Hospital linked with
the Faculties of Medicine and Surgery and Psychology of the University Vita-Salute San Raffaele.
Its high quality medical assistance and the availability of a vast area of about 300.000 square metres have led
to a fast growth of the services provided by the Institute.
San Raffaele Hospital is part of the Italian National Health Service, in fact it has 1.397 beds accredited with
the National Health Service, 47 of them dedicated to the independent medical activities and 50 dedicated to
day surgery and day hospital treatments. In 2008 the San Raffaele Hospital’s activity counts 47.492 in-patients,
61.773 admittance at Emergency Room, more than 7.700.000 outpatients and diagnostic test. The Hospital
counts about 3.600 employees.
In January 2008, after the approval by the Board of Directors, the Hospital started to organize the medical
area in Clinical Departments. Due to the complexity of the Institution, this process required an effort for the
analysis and definition of area of aggregation, operation procedures and for the definition of the performance
indicators. The process is still ongoing, but almost completed. The goal of this new organizational model is to
integrate and coordinate the resources and the processes of the different Clinical Units, to render them more
flexible and efficient with regard to the structural and management costs, to improve their specific role in the
management of the patients and increase the quality of their medical activity.
At page XXIII is included the list of the Clinical Departments approved by the Board of Directors.
Such Areas, coordinated directly by the Health Direction, may enclose Units of different Clinical Departments and Units that not belong to Departments (Emergency Medicine, Services of Transfusion Medicine,
Pathological Anatomy). The objective of these areas is to promote standardization of the activities, to realize
common projects and synergies, to encourage the interexchange of human and technological resources, to promote communication between the Departments.
The activation of the 12 Clinical Departments was made possible thanks to the strict collaboration between
the medical areas and the San Raffaele’s management. All the procedures and processes were discussed and approved jointly, deriving from the common objective to increase the quality of the medical treatments and the efficiency of the Institute. The project management has been played and is played by the Health Direction, supported by the commitments of Board of Directors and General Direction.
The Clinical Departments are led by the Directors, appointed for three years and nominated by the President
of the Board of Directors, with the approval of the President of the Board of Director of the University VitaSalute San Raffaele. Each Director has been assigned several measurable objectives included in the so-called Cruscotto Dipartimentale. The Cruscotto Dipartimentale is aimed to monitor yearly the reaching of the goals assigned and the proper enforcement of the Department processes.
The Departmental Director is assisted by a Director Management Assistant (DMA), a person with management background, with the function to co-ordinate the Department as far as the administrative issues are concerned and to facilitate the relation 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 of the Departmental Model at the San Raffaele hospital is progressively reaching its goals
with regard to economic efficiency and clinical effectiveness mantaining the central role of the patient through
the full integration and co-sharing of the human, technologic and logistic resources.
Renato Botti
General Director Clinical Area
INTRODUCTIONS - XXIII
CLINICAL DEPARTMENTS
1.
Department of Arrhythmology
2.
Cardio-thoracic-vascular Department
3.
Department of General and Specialistic Surgery
4.
Head and Neck Department
5.
Department of Infectious Diseases
6.
Maternal and Child Health Department
7.
Department of Internal and Specialistic Medicine
8.
Department of Clinical Neuroscience
9.
Department of Neurology
10.
Department of Oncology
11.
Department of Radiology
12.
Department of Urology
CROSS DEPARTMENT AREAS
Clinical Laboratory Diagnostics
• Service of Immunohematology and Transfusion Medicine
• Pathology
• Laboratory Medicine
Imaging
• Radiology HSR
• Radiology SRT
• Neuroradiology
• Nuclear Medicine
Anesthesia and Resuscitation
• Intensive Care Cardiac Surgery
• General Intensive Care
• Neuro Intensive Care
• UTIC
Rehabilitation
• Neurologic Rehabilitation
• Orthopedic Rehabilitation
• Cardiovascular Rehabilitation
Emergency Medicine
On October 29th 2007, the Fondazione Centro San Raffaele’s Board of Directors has officially approved the
re-structure of the Clinical Area in Clinical Departments.
XXIV - SAN RAFFAELE SCIENTIFIC INSTITUTE
RESEARCH DIVISIONS AND CORES
1.
Division of Molecular Oncology
2.
Division of Metabolic and Cardiovascular Sciences
3.
Division of Neuroscience
4.
Division of Regenerative Medicine, Stem Cells, Gene Therapy
5.
Division of Immunology, Transplantation and Infectious Diseases
6.
Division of Genetics and Cell Biology
RESEARCH CORES
1. Experimental Imaging
2. Bioinformatics and Biostatistics
3. Pathology (not activated yet)
On March 7th 2008, the Fondazione Centro San Raffaele’s Board of Directors has officially approved the restructure of the Research Area in Divisions and Cores. This new structure is the result of over one year of activity of the Strategic Research Committee.
The matrix model
DC = Clinical Department
DR = Research Division
CR =Research Core
Research Divisions cross one or more Clinical Departments.
Research Cores cross both Clinical Departments and Research Divisions because of their technological value.
INTRODUCTIONS - XXV
INTERACTIONS bw RESEARCH AND CLINIC
Research
Divisions/Cores
Neurology
Clinical
Neuroscience
Molecular Oncology
Metabolic &
Cardio Vascular Sciences
Neuroscience
Regenerative Medicine,
Stem Cells & Gene Therapy
Immunology, Transplant.
& Infectious Diseases
Genetics &
Cell Biology
Imaging
Genomics,
Bioinformatics
& Biostatistics
Pathology
Clinical Departments
Internal
Medicine
Infectious
Diseases
Mother
& Child
Cardio Arrhythmology General & Radiology
Vascular
Spec. Surg.
Urology
Head &
Neck
Oncology
INTRODUCTIONS - XXVII
SCIENTIFIC REPORTS
La “squadra”
The Scientific Director, the Chief Operating Officer, the Directors and Associated Directors of the Research
Divisions, the Directors of the Institutes, and the Scientific and Technical Committee
DIVISION OF MOLECULAR ONCOLOGY - 1
DIVISION OF MOLECULAR ONCOLOGY
Director: Federico Caligaris-Cappio*
Associate Director: Giorgio Parmiani
Research Units
Lymphoid malignancies Unit
HEAD OF UNIT: Federico Caligaris-Cappio*
POST-DOCTORAL FELLOWS: Maria Teresa Sabrina Bertilaccio, Cristina Scielzo
PHD STUDENT: Michela Frenquelli**
FELLOWS: Benedetta Apollonio**, Giorgia Simonetti
B-Cells neoplasia
GROUP LEADER: Paolo Ghia*
POST-DOCTORAL FELLOW: Claudia Fazi**
PHD STUDENT: Antonis Dagklis
FELLOW: Lydia Scarfò
Biology of multiple myeloma
GROUP LEADER: Marina Ferrarini
POST-DOCTORAL FELLOW: Daniela Belloni
Cell activation and signalling
GROUP LEADER: Marta Muzio
PHD STUDENT: Stavroula Ntoufa
Dynamic fluorescence spectroscopy in biomedicine
GROUP LEADER: Valeria R. Caiolfa
POST-DOCTORAL FELLOW: Christian Hellriegel
FELLOW: Moreno Zamai
Lymphoid organ development
GROUP LEADER: Andrea Brendolan
PHD STUDENT: Laura Castagnaro
FELLOW: Elisa Lenti
GROUP LEADER: Rosa Bernardi
POST-DOCTORAL FELLOW: Nadia Coltella
PHD STUDENT: Ylenia Guarnerio**
TECHNICIAN: Federica Ferenderes
Tumor microenvironment
GROUP LEADER: Elisabetta Ferrero
PHD STUDENT: Lorenzo Veschini
2 - SAN RAFFAELE SCIENTIFIC INSTITUTE
Immuno-biotherapy of melanoma and solid tumors Unit
HEAD OF UNIT: Giorgio Parmiani
RESEARCHER: Cristina Maccalli
PHYSICIAN: Lorenzo Pilla
POST-DOCTORAL FELLOW: Tiziano Di Tomaso
TECHNICIAN: Gloria Sovena
Cancer gene therapy
GROUP LEADER: Vincenzo Russo
PHD STUDENTS: Raffaella Fontana**, Cristina Rainelli, Laura Raccosta
FELLOW: Maria Alessandra Meini
TECHNICIAN: Daniela Maggioni
Functional genomics of cancer Unit
HEAD OF UNIT: Giovanni Tonon
PHD STUDENTS: Aurora Negro**, Beatrice Rondinelli**
Model genetics of membrane trafficking Unit
HEAD OF UNIT: Ottavio Cremona*
POST-DOCTORAL FELLOWS: Simona Ferron, Elisabetta Raiteri, Alessandra Zatti
HEAD OF UNIT: Stefano Biffo
FORMER HEAD OF UNIT: Pier Carlo Marchisio*
POST-DOCTORAL FELLOWS: Daniela Brina , Stefano Grosso
PHD STUDENT: Viviana Volta
FELLOWS: Anne Beugnet, Simone Gallo, Elisa Pesce, Valentina Ruggeri
TECHNICIAN: Annarita Miluzio
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
HEAD OF UNIT: Pier Alberto Testoni*
PHYSICIANS: Lorella Fanti, Alberto Mariani, Edi Viale
RESIDENTS: Antonella Giussani, Chiara Notaristefano, Cristian Vailati
FELLOWS: Milena Di Leo, Sabrina Testoni
Endosonography: diagnostic and therapeutic endoscopic ultrasound
CLINICAL GROUP LEADER: Paolo Giorgio Arcidiacono
PHYSICIANS: Silvia Carrara, Gianni Mezzi, Maria Chiara Petrone
RESIDENT: Cinzia Boemo
Gastrointestinal surgical oncology Unit
HEAD OF UNIT: Carlo Staudacher*
PHYSICIANS: Paolo Aldo Raul Baccari, Paola De Nardi, Saverio Di Palo, Elena Orsenigo, Andrea Marco Tamburini,
Andrea Vignali
RESIDENTS: Maria Chiara Salandini, Ilaria Santagostino
PHD STUDENT: Alessandra Castiglioni**
FELLOWS: Michele Carvello, Paolo Gazzetta, Luca Ghirardelli, Shigeki Kusamura , Francesco Luparini Alessio Mocci,
Jacopo Nifosi
Head and neck oncology Unit
HEAD OF UNIT: Mario Bussi*
PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Matteo Trimarchi
RESIDENTS: Chiara Bellini, Beatrice Fabiano, Pietro Limardo, Paola Recanati
TECHNICIANS: Daniela Gherner, Barbara Ramella
Multidisciplinary group for thoracic surgical oncology
HEAD OF UNIT: Piero Zannini*
PHYSICIANS: Angelo Carretta, Paola Ciriaco, Giulio Melloni, Giampiero Negri*, Armando Puglisi, Carlopietro Voci*
RESIDENTS: Alessandro Bandiera, Michele Giovanardi, Annamaria Gremmo, Stefano Sestini, Antonio Tuoro
Oncogenesis in liver neoplasms Unit
HEAD OF UNIT: Gianfranco Ferla*
PHYSICIANS: Mvunde Mukenge, Michele Paganelli
RESIDENT: Eleonora Guzzetti
Onco-Hematology Unit
HEAD OF UNIT: Fabio Ciceri
PHYSICIANS: Massimo Bernardi, Consuelo Corti, Elena Guggiari, Francesca Lunghi, Matteo Carrabba, Magda Marcatti
RESIDENTS: Alessandro Crotta, Fabio Giglio, Simona Malato
POST-DOCTORAL FELLOW: Michela Tassara
TECHNICIAN: Roberta Mattarucchi
Pancreatic cancer Unit: biology and new therapeutic approaches
HEAD OF UNIT: Valerio Di Carlo*
PHYSICIANS: Gianpaolo Balzano, Walter Zuliani
RESIDENTS: Federica Milani, Cristina Ridolfi
FELLOW: Greta Grassini
Clinical lymphoid malignancies
CLINICAL GROUP LEADER : Andrès Jose Maria Ferreri
PHYSICIANS: Matteo Carrabba, Silvia Govi, Silvia Mappa
RESIDENT: Marta Bruno Ventre
TECHNICIAN: Arianna Vino
Gynecologic oncology
HEAD OF UNIT: Augusto Ferrari*
CLINICAL GROUP LEADER: Giorgia Mangili
PHYSICIANS: Patrizia De Marzi, Elisabetta Garavaglia, Micaela Petrone, Emanuela Rabaiotti, Riccardo Viganò
RESIDENTS: Cinzia Gentile, Serena Montoli, Francesca Pella
PHD STUDENTS: Jessica Ottolina, Cristina Sigismondi
Medical oncology Unit
HEAD OF UNIT: Eugenio Villa
Clinical trials
CLINICAL GROUP LEADER: Michele Reni
PHYSICIANS: Daniela Aldrighetti, Elena Mazza, Monica Ronzoni, Giordano Pietro Vitali
FELLOWS: Katia Bencardino, Stefano Cereda, Alessia Rognone
Phase I and lung cancer clinical trials
CLINICAL GROUP LEADER: Vanesa Gregorc
POST-DOCTORAL FELLOW: Carmen Belli
PHD STUDENTS: Anna Spreafico
FELLOWS: Monica Giovannini, Maria Grazia Viganò
URI, Urological Research Institute
HEAD OF UNIT: Patrizio Rigatti*
CLINICAL GROUP LEADER: Francesco Montorsi*
PHYSICIANS: Roberto Bertini, Alberto Briganti, Renzo Colombo, Marco Roscigno, Andrea Salonia, Vincenzo Scattoni,
Nazareno Suardi
RESIDENTS: Marco Bianchi, Umberto Capitanio, Andrea Gallina, Lorenzo Rocchini
URI Urological Research Institute, Ville Turro
HEAD OF UNIT: Giorgio Guazzoni*
CLINICAL GROUP LEADER: Francesco Montorsi*
PHYSICIANS: Nicolò Maria Buffi, Andrea Cestari, Luciano Nava, Emanuele Scapaticci
RESIDENT: Giovanni Lughezzani
* Professor at: Università Vita-Salute San Raffaele
** Università Vita-Salute San Raffaele
Oncology bears a particular potential
for translating research findings from
the laboratory into clinical applications.
Innovative strategies are urgently
needed in the areas of diagnosis, patient
risk stratification and treatment.
The focus of the Division is to develop
translational research programmes and
clinical research. The tenet of the Division is that any significant progress toward the cure of cancer can only be
based on an improved understanding of
its pathogenesis, which, in turn, will
lead to the development of improved
diagnostics and more rationale therapeutic interventions.
Federico Caligaris Cappio
Accordingly we aim at fostering extensive collaborations between basic scientists and clinicians. These collaborations will allow to conduct projects and achieve results otherwise
unattainable. Joint activities will accelerate the implementation of translational research through access
to a large number of patients and samples and combined resource platforms.
To this end the Division of Molecular Oncology intends:
a) to join efforts with the Clinical Department of Oncology to create a network organization, multidisciplinary teams and defined programmes for different tumors
b) to establish the collaborative use of resources and platforms with
other Research Divisions
c) to develop research programmes in specific areas of cancer where
we are internationally competitive
d) to establish infrastructure facilities that favour the Division development (patient’s data base, bio-bank, mouse and cell lines
registers)
e) to collaborate with other Research Divisions in establishing
technical platforms available for researchers and clinicians as
well
f) to establish a clinical trial unit especially devoted to Phase I and
I/II studies
Giorgio Parmiani
The activity will take advantage of existing competences and infrastructures that include:
• long-standing expertise, spanning from development and study of transgenic and KO mouse models to molecular and cellular systems for analysis of human (and mouse) cells in vivo and in vitro
• availability of mouse models in which various cellular components can be tracked by noninvasive
imaging technologies
• recent recruitments of scientists with experience in genomics and in preclinical modelling of cancer
• potential therapeutic reagents to be systematically analysed in a preclinical setting coupled with direct clinical experience in applying new therapies to patients
Four major areas of investigation have been identified and the research activity will develop along
these areas that will be implemented and potentiated:
a) Cancer Genetics
b) Cancer Microenvironment
c) Cancer Immunology and Immunotherapy
d) Cancer Stem Cells
Two scientific programs have been so far planned:
a) Strategic Research Program in Immunology and Bio-Immunotherapy of Cancer (PIBIC) that represents the merging of two previous programs and is co-organized with the Division of Immunology.
b) Microenvironment and Genes in Cancers of the Blood (MAGIC).
Research Units
LYMPHOID MALIGNANCIES UNIT
The principal aim of our Unit is to to dissect the elements responsible for the clinical presentation and the
natural history of Chronic Lymphocytic Leukemia (CLL). It is plausible to consider that besides “causal genes”
a number of other “influential genes” operate and that the products of all these genes interact with the microenvironment inducing proliferation, survival and clonal expansion of CLL cells within the tissues. The investigation of these elements is leading to the identification of molecules and mechanisms that could be exploited as potential therapeutic targets.
This has been approached by analyzing two major aspects. First, we have investigated the intracellular protein
HS1 and its role in controlling the CLL cell capacity to migrate and home to specific tissue compartments. Second, we have established new mouse models that may help analyzing the role of by-stander cells including stroma and accessory cells in favouring the proliferation, survival and accumulation of CLL cells within the invaded tissues.
We previously showed that the presence of hyperphosphorylated HS1 molecule, observed in a subset of CLL
patients, correlated with bad prognosis. In the current year we have started defining the functional role of HS1;
in vitro and vivo data indicate that HS1 play a key role in the regulation of leukemic B-cell cytoskeleton organization, which in turn controls the leukemic cell traffic, migration and homing to specific tissues; a protein
knock-down approach in human cells was complemented by the analysis of HS1 deficient mice. Next we have
established a new mouse model by crossing the classic “leukemic” EmuTCL1 transgenic mouse with HS1 deficient mice. This model suggests that the impairment of HS1 influences the localization and dissemination of
leukemic clones in a manner similar to the presence of hyperphosphorylated HS1 in humans. Third, we have
established and characterized a novel xenotransplanted mouse model by injecting the CLL cell line MEC1 into
adult immunodeficient rag2-/-g-/- mice. This xenotrasplant model may be proposed as a simple tool to explore
in vivo the leukemic tissue microenvironment and follow its interactions with CLL cells; it may also be explored
as a preclinical model of CLL for novel therapeutic approaches validation.
Federico Caligaris-Cappio
B-CELL NEOPLASIA
The main focus of our research is on tumors of mature B-cells and in particular on tumours of the chronic
type that are virtually incurable. In the past year, we aimed at identifying relevant molecules and pathways that
can be selectively targeted for therapeutic purposes in a patient-tailored fashion.
Strong evidence suggest that stimulation through the B-cell antigen receptor (BCR) is involved in the selection and expansion of the malignant clone in a number of chronic B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL). That notwithstanding, some CLL cases respond to the in vitro crosslinking of surface immunoglobulin with effective activation while others do not.
We have published that, in the CLL cases not responding to BCR ligation, leukemic cells express constitutively phosphorylated ERK1/2 and MEK1/2 together with NF-AT transcription factor transactivation in the
absence of AKT activation. This molecular profile recapitulates the biochemical signature of anergic murine B
cells and interestingly significantly correlates with a low stage disease at diagnosis.
The binding of each particular antigen to a leukemic BCR may provide either anergizing or activating stimuli,
being likely responsible for different biological and clinical behaviour.
The actual stage of the natural history of CLL at which the antigenic exposure occurs is poorly defined. As we
and others have identified the presence of monoclonal B cells (MBL) resembling CLL cells and circulating in
the peripheral blood of otherwise healthy individuals, we aimed at characterizing the immunoglobulin receptors and repertoire expressed by these cells, in order to identify features that are associated with the risk of
leukemic evolution. We studied MBL in the general population, where these cells account for a minority of all
circulating B cells and we showed that the IGHV gene usage is not CLL-biased. These findings suggest that the
detection of MBL does not indicate, in most cases, a pre-leukemic state. The presence of few unmutated and
stereotyped cases suggests that some MBL cases at higher risk of evolving into a clinically relevant disease do
exist. A detailed IG molecular analysis of individual MBL might then become a promising tool helping to identify those particular cases.
Paolo Ghia
BIOLOGY OF MULTIPLE MYELOMA
New insights into the anti-myeloma activity of proteasome inhibitors
Multiple Myeloma (MM) is a tumor of plasma cells (PC) growing almost exclusively within the Bone Marrow
(BM), which delivers pro-survival signals and confers chemo-resistance to neoplastic cells. BM angiogenesis also deeply contributes to MM development and progression. Despite the use of new therapeutic approaches, the
disease remains ultimately fatal. The proteasome inhibitor Bortezomib has been a major advance in the treatment of MM, but less than half of the patients achieve either a complete or a partial response. A better understanding of the mechanisms of action and of the cellular targets of proteasome inhibitors is therefore needed to
improve their therapeutic potential and to identify new combination strategies. We found that treatment with
Bortezomib induces redox perturbations in MM cell lines and PC from MM patients and that, conversely, sensitivity to the drug could be modulated by modifying redox homeostasis. This mechanism can be exploited to
potentiate the response to proteasome inhibitors. Bortezomib has also antiangiogenic properties. In particular,
we have demonstrated that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Quiescent EC are resistant to Bortezomib, while the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on sub-confluent,
spontaneously proliferating HUVEC. In addition, EC activation state deeply influences the death pathway
elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of sub-confluent EC is preceded by signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3
I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3Methyladenine prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC. Interfering with the autophagic response may potentiate
the antiangiogenic effect of the drug.
Marina Ferrarini
CELL ACTIVATION AND SIGNALLING
The principal aim of our Unit is to dissect the molecular events which regulate cell activation and signalling,
in particular focussing our attention on the B-cell receptor (BCR) and Toll-like receptors (TLR) signalling pathways in normal and malignant B lymphocytes. The investigation of these elements is leading to the identification of molecules and mechanisms that could be exploited as potential therapeutic targets.
Stimulation through the BCR is involved in the natural history of chronic lymphocytic leukemia (CLL). Some
cases respond to the in vitro cross-linking of surface immunoglobulin (sIg) with effective activation. In contrast,
the remaining cases do not respond to such stimulation, thereby resembling B cells anergized after antigen encounter in vivo. However the biochemical differences between the 2 groups were ill defined, and in humans the
term B-cell anergy lacks a molecular definition. We examined the expression and activation of key molecules in-
volved in signalling pathways originating from the BCR, and we report that a proportion of CLL patients a) expresses constitutively phosphorylated ERK in the absence of AKT activation; b) displays constitutive phosphorylation of MEK and increased NF-AT transactivation; and c) is characterized by cellular unresponsiveness to
sIg ligation. This molecular profile recapitulates the signalling pattern of anergic murine B cells. Our data indicate that MAPK cascade may be exploited as a novel therapeutic target in a selected group of pERK positive
CLL patients.
Mature B-cells can recognize microbial antigens via BCR in a specific way and via TLR in a costimulatory
manner. A wealth of information is gathering on the possible role of antigenic stimulation in the natural history
of CLL. However little is known regarding the repertoire and function of TLR in CLL cells. CLL cells were
found to express several functional pattern recognition receptors including TLR1, 2, 6, 10, NOD. Leukemic
cells, upon stimulation with TLR2 ligands, such as bacterial lipopeptides, activated the NF-kB signalling pathway, expressed activation molecules, and were protected from spontaneous apoptosis. These findings suggest a
potential role of TLR in modulating CLL cell response in the context of specific antigen recognition.
Marta Muzio
DYNAMIC FLUORESCENCE SPECTROSCOPY IN BIOMEDICINE
Spatial and temporal resolution of receptor signaling in cell-cell and cell-microenvironment cross-talk
The systems biology challenge is to understand the functional interplay and dynamic organization of complex
cellular protein machineries as they react to stimuli. In contrast to the static hard-wired diagrams, most proteins
interact dynamically and conditionally with biochemical modifications, giving rise to the mechanisms that cells
employ for rapid and accurate discrimination of signals in physiological and oncogenic conditions.
We aim at substituting the hard-wired diagrams of receptor interactomes (i.e. a schematic representations of
signaling pathways), with the real time dynamics of multi-protein complexes, as they assembly, translocate and
disassembly in living cells, governing the mechanisms of cellular adhesion and migration.
During last year, we have been pursuing two main goals. The first was to progress in the development of sensitive molecular imaging approaches that have the potential of following the dynamics of complex protein ensembles at real time, in live cells and with nanometric resolution. We have taken well-known fluorescence spectroscopy tools such as fluorescence lifetime and brightness, that for years have been applied only by a restricted
number of specialized laboratories in physics, and developed new algorithms for exporting them into the cell
biology world, transforming spectroscopy into microscopy [Digman, Caiolfa, et al., Bioph. J, 2008; Malengo,
Zamai et al., J Biomed. Opt, 2008].
The second goal was to unravel fundamental mechanisms of protein segregation and re-localization during
cell-to-cell adhesion and/or cell-to-ECM interaction. We have contributed to demonstrate for the first time the
existence of tetraspannin-based microdomains in the plasma membrane of primary endothelial cells. These are
the adhesive platforms (EAP) for leukocyte adhesion. We discovered by the new phasor-FLIM-FRET imaging
that EAP microdomains are present in the membrane prior to leukocyte adhesion, and contains tetraspanninspecific CAM receptors. We studied the dynamics of the individual EAP components and their specific interactions that result in the docking structures by which the leukocyte is trapped on the surface of the endothelium
[Barreio, Zamai et al., J Cell Biology 2008].
Valeria R. Caiolfa
LYMPHOID ORGAN DEVELOPMENT
The research in our laboratory is focussed on identifying the molecular and cellular mechanisms underlying
lymphoid organ development. We are interested to uncover the developmental programs responsible for specification and differentiation of stromal progenitors within lymphoid organs. Furthermore, we aim at identifying
how the stromal cell pool contribute to the formation and function of the lymphoid microenvironment and ultimately to understand how stromal cells support the function of normal lymphoid and leukaemia/lymphoma
cells. Concomitantly, we are translating our knowledge on how secondary lymphoid organs develop to construct functional artificial lymph nodes that could serve as a novel approach to enhance anti-tumor immunity.
1) Elucidating the roles of oncogenic transcription factors in secondary lymphoid organ development.
We have uncovered a genetic and transcriptional network underlying spleen development and demonstrated
the essential role for the oncogenic transcription factor Pbx1, Hox11 and Nkx2.5 during spleen organogenesis.
Specifically, by exploiting in vivo mouse models and well as cellular and biochemical approaches, we have identified the CDK inhibitor p15Ink4b as a target of the oncogenic transcription factor Pbx1 during organ development.
2) Uncovering the differentiation pathways of stromal progenitors during lymphoid tissue development.
By using a genetic approach to label in vivo mesenchymal cells we have traced spleen and lymph nodes stromal descendants during embryogenesis, and uncovered their differentiation pathways and their relationship
with lymphoid cells in adult organs.
3) Generating functional artificial lymphoid organs (aLOs).
By exploiting murine mesenchymal cells as a new source of stromal progenitors, we have succeeded in constructing aLOs with features similar to normal lymphoid organs such as presence of T- and B-cell compartments as well as a stromal-cell network. Our long term goal is to transplant aLOs loaded with tumor antigens
into tumor-bearing mice and seek to control tumor growth by inducing long lasting anti-tumor immunity.
Andrea Brendolan
PRECLINICAL MODELS OF CANCER
Role of angiogenesis in leukemogenesis
The main research focusis of our Unit has been to evaluate the role of pro-angiogenic factors in leukemogenesis by using mouse models.
Leukemia patients express high levels of pro-angiogenic factors such as VEGF and have increased angiogenesis in their bone marrow, suggesting that angiogenesis may foster leukemogenesis. However, the molecular
mechanisms leading to high VEGF production in leukemia are not known. We hypothesized that upregulation
of the transcription factor HIF-1a, the main positive regulator of VEGF expression in solid tumors, may cause
high VEGF expression also in some forms of leukemia.
In this past year:
1) we have optimized a transduction protocol, in the mouse, allowing to transduce hematopoietic stem cells
with oncogenic fusion proteins in order to establish acute myeloid leukemia and chronic myeloid leukemia
mouse models. These will be then utilized to measure the expression of HIF-1a and VEGF in preleukemic and
leukemic bone marrow in comparison with bone marrow angiogenesis and leukemia progression.
At the same time, in collaboration with the Unit of Pathology and the Hematology and Transplantation Unit
at our Institution, we have started to analyze bone marrow samples of human leukemia for HIF-1a and VEGF
expression. We have optimized an immunohistochemistry protocol on leukemic bone marrow smears and we
are currently collecting newly diagnosed leukemia samples that will be soon analyzed.
2) We have established lentiviral vectors to transduce mouse hematopoietic cells with HIF-1a and VEGF to
verify whether overexpression of pro-angiogenic factors accelerates leukemogenesis. We tested a series of vectors that allow tracking of the transduced mouse hematopoietic cells with GFP and we are currently setting up
co-infection protocols with leukemogenic fusion proteins.
3) We have begun to assess expression levels of HIF-1a and VEGF in normal hematopoiesis in the mouse.
Preliminary real-time PCR analysis results indicate that HIF-1a is not regulated during differentiation, while
VEGF expression decreases. Future experiments will better elucidate the relative expression of these genes in
hematopoietic stem cells compared to progenitors and committed cell.
Rosa Bernardi
TUMOR MICROENVIRONMENT
Set-up of a new 3-D approach in bioreactor for the study of Multiple Myeloma microenvironment
Multiple Myeloma (MM) is a tumor of fully differentiated plasma cells (PC), growing almost exclusively within the Bone Marrow (BM). The essential role of BM in disease maintenance and progression has been highlighted, with particular emphasis on angio-vasculo-genesis contribution. Indeed, direct and indirect interactions between PC and other cells and extracellular matrix (ECM) within the BM environment are key requirements for MM pathogenesis, MM cell growth, survival and drug resistance.
The generation of in vitro models able to recapitulate MM microenvironment is crucial to both the understanding of MM biology and the assessment of its vulnerability to drugs. To this purpose, we applied a 3-D culture innovative technology based on the use of the Rotatory Cell Culture System (RCCSTM) bioreactor.
The suitability of RCCSTM bioreactor for the 3-D culture of tissue samples was first assessed using skin biopsies that maintained intact architecture and viability. We then cultured in bioreactor samples obtained from two
bone marrow samples from MM patients, with opposite clinical histories and response to therapy. Histological
examinations performed on samples from the two patients up to 3 weeks, allowed to identify and characterize
MM plasma cells and vessel structures. Response to Bortezomib could also be assessed. Notably, supernatants
retrieved during 3-D cultures at different time intervals, showed increasing secretion and activity of MMP-2, at
variance from that obtained culturing rib fragments from healthy donors. This indicates that the system has the
potential to allow monitoring of metabolism and preserves viability, functionality and differentiation of tissue
samples. In parallel, we are exploiting the model in Bioreactor to assess the relative contribution of different
cellular components, in particular endothelial cells, to plasma cells survival/growth modalities. We are then
aiming at comparing this culture system with conventional 2-D cultures.
Elisabetta Ferrero
IMMUNO-BIOTHERAPY OF MELANOMA AND SOLID TUMORS UNIT
The main objective of our research Unit is the molecular characterization of new and more immunogenic tumor antigens (TA) recognized by T cells and their use in translational protocols of immunotherapy. We intend
to improve the knowledge of the relationship between tumor and host immune cells. This information will be
used to design new translational immunotherapy protocols for metastatic human solid tumors (melanoma;
glioblastoma - GBM - colon, prostate and pancreatic carcinomas).
The objectives of our research are:
1) molecular characterization of new TA recognized by T cells in HLA class I- e class II restriction, particularly those that may derive from tumor cell somatic mutations;
2) assessment of the role of NKT lymphocytes as anti-tumor effectors by the analysis of their NKG2D receptor and of its ligands expressed by melanoma and other human tumors;
3) immunologic antigen profiling and immunogenicity and/or immunsuppression function of cancer stem
cells (CSC) obtained from melanoma; GBM; pancreatic, colorectal tumors;
analysis of the role of regulatory T cells in patients undergoing immunotherapy.
In addition, translational clinical studies will be activated to enroll patients with metastatic melanoma or other tumors in protocols of immuno-biotherapy particularly in studies of combination of vaccines and other biological agents (e.g. anti-vascular compounds).
Results of 2008. In 2008 we have concluded the first part of the project on the immunologic analysis of human CSC of GBM in parallel with the tumor line from which CSC have been obtained. The CSC showed a
weak expression of class I and II MHC and of NKG2D ligands. However, in vitro treatment with IFN−α increased MHC and NKG2D ligand expression in CSC thus allowing CSC of GBM to be recognized and lysed
by autologous T and NKT cells in at least a fraction of patients. We have also shown that CSC and their GBM
line may express antigens like SOX-2, NY-ESO1, COA-1 that represent potentially specific targets for immunotherapy. In a different project, an analysis of expression of OX-40 and other T cell activation markers was
performed in more than 100 samples of human tumors to see whether a correlation may occur between expression of expression of these markers and tumor growth control.
Giorgio Parmiani
CANCER GENE THERAPY
Several pre-clinical and clinical studies have demonstrated that the immune system plays a key role in controlling tumor growth. That notwithstanding, the clinical exploitation of this discovery is far from being successful. Indeed, the results from the current cancer immunotherapy studies have been disappointing, leading to
a limited clinical efficacy. Several reasons can be responsible for that, such as the bias in selecting patients eligible for these treatments as well as the antigens and/or the strategies used. In this context, pathways perturbing
the tumor microenvironment have recently been demonstrated to condition the antitumor immune response allowing the tumor cells to escape immune surveillance. These pathways may act on the priming and/or on the effector phase of the antitumor immune response. In recent years, these mechanisms have been extensively investigated, leading to the identification of molecules and immune suppressive circuits responsible for the inhibition of the antitumor immune response.
The research of our group is focused on the investigation of the cellular mechanisms underlying immune responses to solid tumors, with the final goal to improve this response.
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. The clinical translation of this approach has led to the development of antitumor effectors correlating with a favorable clinical outcome in
melanoma patients. In addition, we have recently identified a novel mechanism of tumor immune escape that
dampens the spontaneous immune-mediated control of tumor growth by impairing the functional expression
of the lymphoid-organ homing receptor CCR7 on maturing dendritic cells.
Noteworthy, the use of drugs interfering with this pathway restores the spontaneous antitumor immune response and, as a consequence, the control of tumor growth in different murine tumor models.
Vincenzo Russo
FUNCTIONAL GENOMICS OF CANCER UNIT
Transcriptomic, genetic and epigenetic reprogramming of cancer cells
Our laboratory has been pursuing the following lines of research:
1. Role of histone methylation and demethylation in cancer development.
In the nuclei of eukaryotic cells, DNA is packed into chromatin. The basic constituent of chromatin, the nucleosome, is comprised of 147 bp of DNA wound around an octamer of core histone proteins. Post-translational modifications of the N-terminal tails of these core histone proteins, modulate chromatin configuration, resulting in changes in transcriptional regulation. These epigenetic modifications are controlled by complex enzymatic machinery that, when deregulated, disrupt normal transcriptional programs. Indeed, genomic alterations
of MLL, NSD1, CREBBP, WHSC1L1 and WHSC1, all encoding proteins involved in histone modification,
have been implicated in several cancer types.
Through genomic analysis and large-scale high-throughput sequencing, we have identified genetic lesions affecting histone methylases and demethylases and we are exploring the role of the genes implicated in these genomic rearrangements in the development of multiple myeloma, lung cancer and pancreatic adenocarcinoma.
2. Receptor tyrosine kinase receptors in the development of Multiple Myeloma.
The protein kinase is the most commonly represented Pfam domain encoded by cancer genes. Many carcinogenic tyrosine kinases are receptors, which are often overexpressed and/or mutated in a variety of tumors.
Therapeutic agents targeting this class of receptors have proven to be highly effective in the clinical setting.
Multiple Myeloma (MM) is the second most frequent hematological cancer and remains incurable. Several
RTKs are expressed in MM and there is mounting evidence of their pathogenetic importance in this disease.
We have conducted a genomic and proteomic survey of primary MM samples and identified two RTKs that
were overexpressed relative to levels present in plasma cells derived from normal donors. Strikingly, both RTKs
tap into developmental pathways that are highly relevant in cancer biology and demonstrated robust transforming activity.
We are now aiming at elucidating the nature of the signaling mediated by these RTKs in MM, both in vitro
and in vivo, with the final goal of identifying more effective drugs against MM.
Giovanni Tonon
MODEL GENETICS OF MEMBRANE TRAFFICKING UNIT
In the last few years, endocytosis has considerably expanded its action spectrum from a general tool to internalize plasma membrane and extracellular components to a specific mechanism for fine-tuning of a variety of
cellular functions, including cell signaling and neurotransmission.
Here we report the analyses of the function of two key endocytic adaptor families, namely the epsin and dynamin families, by a genetic approach in mice.
Epsin 1/2 KO mice. A manuscript addressing the first characterization of the epn1/2 DKOs is currently in
press on PNAS. Here, an outline of the results is reported. Epsins are endocytic adaptors with putative functions in general aspects of clathrin-mediated endocytosis. We have now tested the role of the ubiquitously expressed epsin genes, Epn1 and Epn2, by murine gene KO models. While either gene is dispensable for life,
their combined inactivation results in embryonic lethality at E9.5-E10, i.e. at the beginning of organogenesis.
Consistent with studies in Drosophila, where epsin endocytic function was linked to Notch activation, developmental defects observed in epsin 1/2 double knockout (DKO) embryos recapitulated those produced by a
global impairment of Notch signaling. Accordingly, expression of Notch primary target genes was severely reduced in DKO embryos. However, housekeeping forms of clathrin-mediated endocytosis were not impaired in
cells derived from these embryos. These findings support a role of epsin as a specialized endocytic adaptor, with
a critical role in the activation of Notch signaling in mammals.
Dynamin1 KO mice. Mutant mice for Dnm1, a GTPase implicated in the fission of synaptic vesicles, fail to
thrive and exhibit severe activity-dependent endocytic defects at their synapses. We used electron tomography
to investigate the accumulation of coated pits in a subset Dnm1 KO primary neuron cultures under conditions
of spontaneous network activity. We found that this increase occurs selectively at inhibitory synapses and, more
generally, that these latter synapses are uniquely sensitive to perturbation of endocytic proteins. Our findings
reveal a striking heterogeneity in the mode of presynaptic endocytosis in different synapses and functional
states.
Ottavio Cremona
MOLECULAR HISTOLOGY AND CELL GROWTH UNIT
Translational control in cancer cells
Translational control (regulation of protein synthesis) has acquired unexpected importance in cancer therapy.
Briefly, translation is controlled by initiation factors (eIF). The clearest example of an eukaryotic Initiation Factor (eIF) affecting cancer is eIF4E, as demonstrated by its ability to transform fibroblasts through overexpression. Tumorigenic properties of eIF4E are explained by the facts that it is rate-limiting in formation of the
eIF4F complex and that many mRNAs involved in cell cycle progression and tumorigenesis (c-my c,
VEGF)have a structured 5’UTR that requires eIF4F activity. Consequently, indirect inhibition of eIF4F formation by rapamycin analogues (mTORC1 blockers) is effective in cancer therapy. Other regulators of translation
have been suggested to play a role in cancer, though unfortunately no evidence of targetability has been so far
provided: eIF2-based control of hypoxia in tumors; IRES-based control of survival genes/oncogenes; miRNAs
in tumorigenesis and tumor dissemination. Are there other translational targets as good as eIF4F?
A new translation initiation factor that can be a target in cancer therapy is eIF6. The activity of eIF6 is essential for both the generation of 60S subunits, and for efficient translation. eIF6 is overexpressed in cancer cells
and is rate-limiting for growth, translation and transformation of cells. We have shown that a reduction of 50%
of eIF6 reduces tumorigenicity, of cells without affecting the viability of normal cells. The mechanism of action
of eIF6 may be dual: on one side, it may affect micro-RNA based translational repression; on the other, by impairing improper subunit joining, it is able, downstream of growth factor signaling, to increase translation in
conditions of high demand of growth. Notably, eIF6 is acting downstream of the growth factor cascade. We
have found that several signaling pathways may act on eIF6 activity. In this context, we have demonstrated that
in several tumors eIF6 is both overexpressed and yperphosphorylated.
The research activity in our Unit is now aiming at defining the tumors in which eIF6 activity is essential and
to develop blockers of eIF6 activity.
Stefano Biffo
TUMOR BIOLOGY AND VASCULAR TARGETING UNIT
Tumor necrosis factor-α and chromogranin A (CgA) in inflammation, angiogenesis and tumor
microenvironment biology
Our studies focus on the role of Tumor Necrosis Factor-α (TNF) and of other proteins containing NGR,
RGD and isoDGR motives (such as fibronectin and chromogranin A) in tumor vascular biology and angiogenesis. In addition, we are interested in developing new strategies for cancer therapy based on the manipulation of
the tumor microenvironment. We have found that circulating chromogranin A (CgA), an RGD-containing protein secreted by many neuroendocrine cells, is elevated in patients with cancer, heart failure, rheumatoid arthritis, and other inflammatory diseases, with important prognostic implications. In these patients we observed a
significant correlation between CgA and tumor necrosis factor-α (TNF), an inflammatory cytokine capable to
exert a variety of biological effects on tumor cells and microenvironment. In vitro and in vivo experiments have
shown that CgA can inhibit tumor growth, by affecting tumor microenvironment and vasculature, can affect fibroblast and endothelial cell adhesion, and can inhibit TNF-induced vascular leakage, suggesting that CgA
plays a role in tumor vascular physiology.
Another line of research is focused on the asparagine-glycine-arginine (NGR) motif, a sequence that is present in many molecules of the extracellular matrix. We have demonstrated that an NGR site of fibronectin, a
protein of the extracellular matrix (ECM), can undergo rapid deamidation reactions generating the isoAsp-GlyArg (isoDGR) sequence. Peptides and fibronectin fragments containing the isoDGR motif in turn can bind
αvβ3, an integrin expressed in angiogenic vasculature, can affect endothelial cell functions and can inhibit tumor growth. We have hypothesized that the NGR-to-isoDGR switching in fibronectin and in other proteins of
the ECM might work as a “molecular timer” for generating new binding sites for integrins. Finally, we have
found that peptides containing the NGR, isoDGR and RGD motives can be exploited for delivering TNF and
other cytokines to tumors vessels. One of these compounds, called NGR-TNF, can induce vascular damage and
can increase the penetration of various chemotherapeutic drugs in tumors. Because of these properties, NGRTNF is currently tested in Phase I and II clinical studies, alone and in combination with chemotherapy.
Angelo Corti
DIGESTIVE AND PANCREATICO-BILIARY ENDOSCOPY UNIT
The Unit is involved in the development and clinical application of advanced endoscopic imaging and endoluminal therapy for recognition and treatment of high-grade dysplasia and early cancer of the gastrointestinal
tract (G.I.) and pancreatico-biliary system.
Advanced endoscopic imaging. In the last years the research has been focused mainly on the use of Optical
Coeherence Tomography (OCT) for detecting and characterizing mucosal and submucosal lesions of the G.I.
tract and for differential diagnosis of structures of unknown aetiology of the main pancreatic and common bile
duct. OCT is an optical imaging modality that performs high-resolution, cross-sectional, subsurface tomographic imaging of the microstructure of the tissue. The physical principle of OCT is similar to that of B-mode
ultrasound imaging, except that it uses infrared light waves; the depth of penetration into the tissue is limited to
1-3 mm, so the technique is useful to investigate the mucosa and submucosal layers of the G.I. wall. OCT has
been previously used for investigating dysplasia and early neoplasia in Barrett’s esophagus and ulcerative colitis.
We first used OCT imaging to investigate the layers of the main pancreatic and common bile duct in ex-vivo
studies and in humans, by ERCP. Using this technique, we were able to characterize the intraductal tissue structure and differentiate between neoplastic and inflammatory strictures, as documented by recent publications.
At present, surface and contrast enhanced endoscopic imaging is used to investigate mucosal flat lesions (pre-
neoplastic and neoplastic); the technique appeared particularly useful in Barrett’s esophagus, gastric dysplasia,
and colonic flat adenomas. Confocal microscopy will be the next step in the endoscopic imaging.
Endoluminal therapy. Endoscopy is commonly used for treatment of superficial lesions of the G.I. tract, since
the technique permits to remove tissue by mucosal resection and submucosal dissection. The Unit is involved in
the development of new devices for tissue removal, including knife models and water jet probes for tissue lifting. By using these devices, dysplastic epithelium and early cancer within Barrett’s esophagus, as well as in the
stomach and colon, can be completely removed.
Pier Alberto Testoni
ENDOSONOGRAPHY: DIAGNOSTIC AND THERAPEUTIC
ENDOSCOPIC ULTRASOUND
The focus of the Endosonography Unit is to develop research programmes in diagnosis and treatment of premalignant and malignant pancreatic disorders. 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 premalignat lesions such as intraductal papillary mucinous neoplasms (IPMN) is necessary
to avoid that most patients have advanced disease at the time of diagnosis.
We are cooperating with Mayo Clinic Jacksonville for an international registry for multi-center collaboration
in 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.
The ability to perform EUS-guided fine needle aspiration (EUS-FNA) to acquire tissue samples allow us to
perform molecular analysis. We have demonstrated that RNA extraction from EUS-FNA of pancreatic lesions
is feasible and gives a sufficient quantity to analyze the pattern of expression of mucins. MUC expression profile can orientate the diagnosis and evolution of pancreatic lesions.
Patients with unresectable locally advanced pancreatic disease don’t have many chances and chemoradiation
confers them only a minimal symptomatic improvement. Radiofrequency ablation is a local thermal therapy
used for palliative treatment of solid tumours. We have developed a new flexible bipolar ablation probe combining radiofrequency and cryotechnology applied under EUS-guided and we have demonstrated the feasibility and efficacy of this new treatment, using it in a porcine model. We have also evaluated the efficacy of this
new hybrid cryotherm probe in destroying neoplastic tissue of explanted pancreas of patients with pancreatic
adenocarcinoma, analyzing both the tissue histological changes and relationship between application time and
long axis diameter of necrosis obtained. The application provokes selective necrosis in neoplastic tissue, and
there was a statistical significant correlation between necrosis diameter and application time.
Paolo Giorgio Arcidiacono
GASTROINTESTINAL SURGICAL ONCOLOGY UNIT
Translational research in gastrointestinal oncology
Our Unit’s research activity has been focussed on several different relevant topics in gastrointestinal oncology:
1) Role of the induction of innate and adaptive antitumor immunity in nonmetastatic rectal cancer patients
treated with neoadjuvant CT-RT and its relationship with pCR and survival. The aim is to verify whether innate
factors influence the outcome of antineoplastic treatment, and whether they may predict in selected patients the
clinical response and survival.
2) Evaluation of the clinical significance of CTCs in blood from patients with gastrointestinal cancers. The
aim is to determine and quantify CTCs in all patients with any stage of gastrointestinal malignancy, as well as
correlate its presence with clinical and pathological factors. Our second endopoint is testing the prognostic value regarding disease free overall survival.
3) Pharmacokinetics of intraperitoneal administration of antiblastic drugs. Aim of our study, conducted in
collaboration with Harvard University, was to test in a rat model the pharmacokinetics of intraperitoneal administration of new antiblastic drugs
4) HIPEC in the treatment of locally advanced gastric cancer following preoperative chemotherapy and curative surgery.
The purpose of the present protocol is to investigate the feasibility, morbidity, toxicity, mortality and oncological outcome of HIPEC in patients with locally advanced gastric cancer.
5) Cytoreductive surgery and HIPEC in the treatment of peritoneal carcinomatosis from colon cancer. The
purpose of the present pilot study is to investigate the feasibility, morbidity, toxicity, mortality and survival of
the cytoreductive surgery and HIPEC in colon cancer patients with primary/relapsing peritoneal carcinomatosis or at a high risk for peritoneal dissemination.
6) Sentinel node mapping during laparoscopic gastrectomy fro gastric cancer. Laparoscopic modified surgery
based on sentinel node status would be the goal of a minimally invasive approach for pathologically node negative early gastric cancer. The aim is to evaluate the feasibility in gastric cancer patients who underwent laparoscopic detection of sentinel node.
Carlo Staudacher
HEAD AND NECK ONCOLOGY UNIT
Our Unit’s main research focus is the investigation on functional problems and outcomes of advanced larynx
cancer bearers.
A new technique of subtotal laryngectomy has been performed, in cooperation with other Ear, Nose and
Throat (ENT) oncological departments, to preserve the voice in advanced larynx cancers, extended to the subglottis. Phonatory and deglutition results have been studied, together with the satisfaction degree. As far as total laryngectomy concerns satisfaction and quality of life after voice prosthesis rehabilitation have been investigated. New functional surgical techniques and psychooncological studies will be carried on in the next period
to guarantee the best social outcome in subjects undergoing organ sacrificing surgery for advanced larynx cancer.
A series of 214 cases of parotidectomies performed in 6 years has been investigated from a clinical and statistical point of view
Attention was paid to correlation between Fine Needle Aspiration Citology (FNAC) and definitive histological examination, to facial palsy, Frey’s syndrome and relapses; statistical analysis was performed on the grouped
data.
FNAC sensitivity was 81%, while specificity was 99%.
Frey’s syndrome complicated the clinical outcome in 35.04% of the cases. Temporary facial nerve palsy happened in 12% of the patients (18 to 65% of cases in the literature)
Multivariate analysis was performed to investigate if there were some prognostic factors causing relapses, that
we had in the 5.6% of the cases. Previous surgery was found the only predisposing factor.
Over past 20 years, high risk human papilloma virus (HPV) infections has been established as a risk factor for
developing head and neck squamous cell carcinoma, independent of tobacco and alcohol use. In our cases we
found HPV positivity in 17% of oropharyngeal cancer patients and in a small minority of oral cavity cancers (
5%). The most common high-risk subtypes are HPV-16 and 18; HPV-positive HSNCC has decreased expression of wild-type p53, additionally these tumours do not show p16 depletion. As it has been proved in the literature, we found an improved survival in oropharyngeal HPV tumors with overexpression of p16 level. Feasibility and efficacy of targeted HPV16 vaccination will be investigated in the future.
Mario Bussi
MULTIDISCIPLINARY GROUP FOR THORACIC SURGICAL ONCOLOGY
Multidisciplinary approach for patients affected by non-small cell lung cancer and colorectal and renal cancer
lung metastases
Surgery remains the best treatment for patients affected by non-small cell lung cancer (NSCLC). Advanced
age, cardiorespiratory comorbidities and pathological mediastinal lymph nodes represent some contraindication to surgical resection. To extend possibility of surgical treatment we undertook the following lines of research.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a potential alternative to mediastinoscopy to confirm or exclude lymph nodes metastases. Preliminary studies have
demonstrated that it may lead to improvement in the results of N-staging decreasing the morbidity correlated
to mediastinoscopy. The aim of this study is to assess the effectiveness and safety of EBUS-TBNA in staging
NSCLC patients.
Advanced emphysema is frequently associated with lung cancer and can impede surgical treatment. New
therapeutic strategies such as bronchoscopic lung volume reduction (BLVR) have been developed recently. The
goal of BLVR is to obtain a functional improvement by endoscopically-positioning one-way endobronchial
valves which divert ventilation from the emphysematous areas to more normal lung regions. The aim of this
study is to assess the results of BLVR in terms of post-treatment morbidity and improvement of respiratory
function aimed to perform surgery on patients affected by NSCLC.
Advanced age and associated cardiac and pulmonary diseases may however be a contraindication to surgical
treatment. The aim of the study is to assess the results of new treatment-strategies as percutaneous radiofrequency thermoablation and tomotherapy, a recently-developed radiotherapy technique, in patients with earlystage NSCLC with a contraindication to surgical treatment.
Surgical resection both for colorectal and renal cancer lung metastases are well-accepted treatment modalities. Identification of new tumor markers to supplement clinical and pathological staging may make possible to
identify those patients with lung metastases from colorectal and renal cancer at highest risk of recurrence following surgery. The aim of this study is to evaluate the use of immunohistochemical analysis to assess the prognostic value of some tumor markers (microsatellite instability and S100a4 protein) in colorectal and renal cancer metastases.
Piero Zannini
ONCOGENESIS IN LIVER NEOPLASMS UNIT
The Hepatobiliary Unit is a multidisciplinary clinical unit where the traditional gap between physicians and
surgeons has been overcome to reach the optimal standards of patient care. Indeed, the medical staff includes
hepatologists and hepatobiliary surgeons who share their specific competences to treat in an unique environment both “internal” and “surgical” patients. Clinical activities are mainly focused on hepatobiliary tumors and
chronic liver diseases, including primary (hepatocellular carcinoma and cholangiocarcinoma) and metastastic
liver tumors (mainly liver metastases from colorectal cancer), liver cirrhosis and related complications (portal
hypertension, ascites, esophageal varices), benign and malignant diseases of the biliary tract, acute and chronic
hepatitis.
As far as concern liver tumors, the research activities are mainly focused on the outcome (in term of overall
survival and disease-free survival) of patients affected by liver metastases from colorectal cancer and treated by
surgery and adjuvant/neoadjuvant chemotherapy. Studies regarding the prognostic factors of survival after surgery and the impact of locoregional chemotherapy on the outcome after surgery have been published (World J
Surg, Ann Surg Oncol).
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 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 Oncology Department is active in basic research, clinical research and routine patient care for acute leukemias, myelodisplasia, mieloproliferative disorders, and myelomas. One of our main goals is implementation of Investigator-Initiated clinical research. 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’s, a bone marrow transplantation unit
and a dedicated Day Hospital Unit. We participate and contribute to national and international disease networks (NILG, Gimema, Leukemianet). Clinical research is organized in Diseases Units. The clinical research
activity in ongoing clinical trials is organized in several disease-specific master trials: NILG-AML master trial of
the cooperative group NILG in AML at diagnosis; NILG-ALL 10/07 master trial of the cooperative group
NILG in ALL patients at diagnosis with a systematic application of an MRD-oriented strategy to post remission
therapies; salvage chemotherapy with clofarabine in relapsed AML; molecular bone marrow analysis at diagnosis to establish the predictive significance of disease persistence or relapse by MRD to tailor adoptive immunotherapy strategies post allogeneic bone marrow transplantation; MDS-WT1 trial with quantification of
WT1 in bone marrow and peripheral blood at diagnosis to establish the predictive significance of disease persistence or relapse (MRD) to tailor adoptive immunotherapy strategies post allogeneic bone marrow transplantation; a trial using lenalidomide in multiple myeloma at diagnosis. Several trials with new drugs (perixafor,
romiplostim, clofarabine, polo-like kinase inhibitor) are ongoing for advanced phase leukemias, myelomas and
MDS.
Fabio Ciceri
PANCREATIC CANCER UNIT: BIOLOGY AND NEW THERAPEUTIC
APPROACHES
The Unit of Pancreatic Surgery during 2008 performed 168 resections, a surgical volume among the highest
in Europe. These cases are a great source of data and material for every type of research in this field. Pancreatic
ductal adenocarcinoma was the cause of resection in 98 patients. Pancreatic cancer is the fourth leading cause
of cancer mortality in the Western world and, despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, little improvement in the outcome has been achieved. Complete surgical resection is considered the only therapy associated with a chance of cure, but 80 to 85% of patients have inoperable
disease at the time of initial diagnosis. Furthermore, even in the favourable prognostic group of patients undergoing resection, 5-year survival is around 15-20%. To improve discouraging present results, different new therapeutic strategies are under evaluation at our unit. The first one is a more effective adjuvant therapy: preliminary results of a prospective randomised trial comparing standard Gemcitabine with 4-drugs combination therapy showed a benefit in disease-free survival in favour of new combination therapy (1-year disease-free survival
65% versus 46%). Further, we analyzed the timing and the sites of recurrence after resection to better understand the natural course of recurrent cancer: 192 patients with pancreatic cancer treated by resection between
1997 and 2007, strictly followed-up by CT scan every 3-4 months were reviewed. Recurrence was observed in
81.9% of patients, and distant metastases were the most frequent site of failure (72.1%), whereas local recurrence occurred in 46.1%. There was no difference in the timing of failure between distant (11.5 months) and
local recurrence (12.2 months). These data suggest that:
1) pancreatic cancer is a systemic disease in most patients, even if it seems localized to the pancreas at preoperative imaging
2) the correct approach to adjuvant (or neoadjuvant) treatment is chemotherapy first, followed by radiotherapy.
In order to improve the cure rate of resection, we are now planning a prospective multicenter study on a
neoadjuvant approach to resectable/borderline pancreatic cancer.
Valerio Di Carlo
CLINICAL LYMPHOID MALIGNANCIES
The scientific activity of our Unit is focused on the study of distinct forms of extranodal lymphomas, in particular ocular adnexal MALT lymphomas (OAML), primary central nervous system lymphoma (PCNSL) and
intravascular large B-cell lymphoma (IVLBCL).
We demonstrated that Chlamydophiila psittaci (Cp) is associated with development of OAML; immunoistochemistry, immunofluorescence and laser-capture microdissection-assisted PCR showed that
monocytes/macrophages are carriers of this micro-orgainsm; electron microscopy showed the presence of intact Cp elementary bodies into these cells. Patients often presented a history of chronic conjunctivitis, resided
in rural areas and prolonged contact with household animals. In the clinical setting, Cp-eradicating antibiotic
therapy has been followed by lymphoma regression in a substantial proportion of OAML patients.
High-dose methotrexate (HD-MTX)-based chemotherapy is the conventional approach to primary CNS lymphomas (PCNSL). A benefit of adding high-dose cytarabine (araC) to MTX has been suggested by a metaanalysis and a large retrospective series. We conducted an international randomized phase II trial comparing
HD-MTX monochemotherapy versus HD-MTX plus HD-araC as primary chemotherapy in immunocompetent patients with PCNSL. This is the unique worldwide randomized trial in PCNSL patients with completed
accrual. The addition of HD-araC to HD-MTX resulted in significantly better outcome and acceptable toxicity,
thereby indicating MTX+araC as the standard chemotherapy approach to these patients.
IVLBCL is a rare, aggressive and disseminated neoplasm, characterized by the absence of lymphoadenophaty
and tumor masses and the localization of neoplastic cells within blood vessel. Each organ can be virtually involved by this malignancy. Using CHOP-based chemotherapy only 20% of patients are still alive at three years
of follow-up. In the context of an international cooperation, we demonstrated that the addition of Rituximab,
an anti-CD20 monoclonal antibody, to anthracycline-based chemotherapy improved the clinical outcome of
these patients, with a 3-year overall survival of >80%. CNS was the principal site of IVL failure: the addition of
drugs with a better CNS bioavailability is now under investigation.
Andres J. M. Ferreri
GYNECOLOGIC ONCOLOGY
In 2008 the gynecology oncology unit has been involved in endometrial ovarian and trophoblastic tumor research in order to improve the quality of clinical activity. We studied biologic and clinical prognostic factors
that may help the physician in decision making process.
Endometrial Cancer:
Definition of high risk stage I endometrial cancer and new prognostic factors as ploidy. The introduction of
DNA ploidy in clinical practice reduced of about 70% the adiuvant treatment.
We took part in a multicentric study which investigated the role of systematic lymphadenectomy in early stage
endometrial cancer. Although systemic pelvic lymphadenectomy improved surgical staging it did not improve
disease-free or overall survival.
Ovarian Cancer:
We took part in multicentric study (SOCRATES) which demonstrated that Mucinous ovarian carcinioma are
less sensitive to platinum based chemiotherapy.
We also work to improve quality of life of patients during chemotherapy treatment:
We introduced the ice therapy to prevent EPP syndrome in patients treated with Liposomal doxorubicin.
The use of ice packs around wrists and ankles is a simple and well tolerated prevention strategy.
Much effort has been invested in order to preserve fertility in young patients submitted to gynecology surgery.
Trophoblastic tumors were studied to evaluate the current clinical presentation that changed in the last 20
years. We introduced the intensive use of transvaginal ultrasound in the management of trophoblastic tumor.
We are now able to reduce follow up period in patients with a strong desire of pregnancy.
Giorgia Mangili
MEDICAL ONCOLOGY UNIT - CLINICAL TRIALS
The Unit is involved in clinical trials addressing the role of anti-neoplastic drugs and strategies in the therapeutic management of pancreatic, central nervous system (CNS), prostate, renal, colo-rectal, gastric, biliary
tract, and breast cancer. Scientific activity regards also translational research and studies aimed to identify new
prognostic and predictive biological markers. Regarding pancreatic cancer, scientific activity included: a) a single-institution phase II randomized trial comparing two different combination chemotherapy regimens as firstline treatment in advanced disease; b) a phase II trial randomizing patients with metastatic disease to receive
maintenance therapy with sunitinib or observation and exploring the role of potential surrogate biomarkers; c)
a study to individuate a proteomic profile predictive of the outcome of patients with advanced disease; d) a
pharmacogenetic trial to assess the impact on the outcome of the SNPs involved in the metabolism of antiblastic agents administered in advanced disease; e) a series of trials testing the activity of different chemotherapy
regimens as salvage therapy and contributing to identify prognostic variables; f) assessment of the role of radiotherapy (RT) after induction chemotherapy in stage III disease and of intra-operative RT in resected disease; g)
a randomized phase II trial comparing two different adjuvant chemotherapy regimens.
Regarding CNS tumors, ongoing trials are aimed at: a) identifying a proteomic profile able to predict the outcome of newly diagnosed glioblastoma multiforme treated by chemoRT (GBM); b) assessing the role of temozolomide associated to RT in newly diagnosed GBM in elderly patients; c) assesssing the role of cilengitide in
association with standard chemoRT in newly diagnosed GBM and methylated MGMT gene promoter; d) assessing the role of temozolomide concurrent to RT and adjuvant in non-1p/19q deleted anaplastic glioma; e)
analyzing the role of primary chemotherapy with temozolomide versus RT alone after stratification for 1p loss
in diffuse astrocytoma; f) exploring the role of salvage therapy with temozolomide in pituitary neoplasms; g) exploring the role of salvage therapy with hydroxyurea alone or in combination with imatinib in meningiomas.
Michele Reni
MEDICAL ONCOLOGY UNIT - PHASE I AND LUNG CANCER CLINICAL
TRIALS
The research activity of our Unit has been focussed focusing on improving understanding the molecular
mechanisms through which new and standard therapies are effective and induce specific toxicities and the
pathways involved in drug resistance, with the aim of defining more personalized therapies.
Phase I studies: Our experience with regards to Phase I studies started in 2003, with the new antiangiogenic
molecule, NGR-h-TNF, which has been designed and tested originally at the DIBIT at our institution and then
developed as first in man in clinical setting at our Department of Oncology. Since then, seven phase I studies
have been conducted. We are currently improving our knowledge in pre-clinical drug development in order to
potentiate and favor first in man studies.
The research activity of the Lung Cancer group is divided into two main areas: no profit and pharmaceutical
companies sponsored trials. Non profit trials are focussed on improving knowledge on molecular mechanisms
related to new and standard therapies, specific toxicities and pathways
of drug resistance for defining personalized therapies. Seven studies
have been conducted in 2008:
1. ECD-EGFR study is a single institution study, monitoring serum
extracellular EGFR domain during therapy with EGFR Tyrosin Kinase Inhibitors (TKIs) in NSCLC patients
2. A longitudinal proteomic single institution study is evaluating
VeristratTM algorithm created and validated in collaboration with
Vanderbilt University and University of Colorado Cancer Centre,
and Biodesix Company
Figure 1. Clinical benefit by plasma proteomic profile of patients
with NSCLC treated with EGFR-Tki
3. A proteomic profile evaluation was also conducted on 145 NSCLC patients treated with chemotherapy
4. Association between proteomic profile and clinical and known molecular features in NSCLC is ongoing
5. PROSE is a phase III multicentre Italian proteomic study created by our group and currently ongoing in
13 different Institutions. 76 out of 275 planned patients have already been enrolled in order to validate
protemic profile as predictive factor for personalizing treatment between chemotherapy and EGFR-Tkis
6. Identification of underlying specific proteins of NSCLC patients Veristrattm proteomic profile is ongoing.
Four out of 8 picks have been already identified.
Vanesa Gregorc
UROLOGICAL RESEARCH INSTITUTE (URI)
In 2008 the main research areas consisted of:
• Prostate cancer
• Kidney cancer
• Bladder cancer
• Infertility and andrology
• Female sexual medicine
• Benign prostatic hyperplasia
The clinical research relied on analyses of clinical, pathological and follow-up prospectively collected data regarding thousands of patients treated at San Raffaele Hospital. The records were collected within specific databases developed in the last years.
Currently, the prostate cancer dataset consists of more than 5000 patients treated with a radical prostatectomy since 1986. The database includes information about diagnosis, surgery technique, pathological outcome,
oncological follow up and quality of life. Such dataset represents one of the biggest and most accurate available
databases.
The kidney cancer database collects more than 1000 patients treated with either partial or radical nephrectomy for a kidney cancer.
The bladder cancer database was recently developed and today it includes prospectively collected data regarding 700 patients treated with radical cystectomy.
The Urogenital Research Institute holds unique opportunities within one single unit to address and investigate a variety of aspects of urogenital disorders (epidemiological, genetic, molecular, cellular, physiological,
pharmacological, clinical) of immediate relevance for the individual patient as well as the community healthcare system. Adaptive evidence-based and parallel investigative functions and objectives have been established
to study targets of disease, diagnosis, therapy, or prevention at multiple levels (genetic, proteonomic, cellular,
tissue, intact biological systems). The operational structure with several integrated methodological processes
“door-to-door” within one research unit not only optimizes the access to and utility of, but also improve cost
benefit ratio to function of the core facilities (expertise, technical platform) that belong to the Urogenital Research Institute. This structure is further aimed to produce an inspiring scientific environment that unifies clinical research and basic science in urology and urological pharmacology.
Francesco Montorsi
Pancreatic cancer Unit: biology and new therapeutic approaches
URI – Urological Research Institute
DIVISION OF NEUROSCIENCE - 23
DIVISION OF NEUROSCIENCE
Director: Gianvito Martino
Associate Director: Flavia Valtorta *
Research Units
Neuropsychopharmacology Unit
HEAD OF UNIT: Flavia Valtorta*
POST-DOCTORAL FELLOW: Francesca Botti
PHD STUDENTS: Serena Bellani**, Eugenio Fornasiero**
FELLOW: Laura Perlini
TECHNICIANS: Marta Monari, Giuseppina Sessa
Cell adhesion Unit
HEAD OF UNIT: Ivan De Curtis*
POST-DOCTORAL FELLOWS: Manuela Gavina, Roberta Pennucci
PHD STUDENTS: Claudia Asperti**, Antonio Totaro**
FELLOWS: Veronica Astro, Luisa Micheletti
TECHNICIANS: Sara Corbetta, Simona Paris
Cellular and molecular neurobiology Unit
HEAD OF UNIT: Jacopo Meldolesi*
RESEARCHER: Paola Podini
PHD STUDENT: Ilaria Prada**
FELLOW: Rosalba D’Alessandro
TECHNICIANS: Anna Lorusso, Gabriella Racchetti
HEAD OF UNIT: Fabio Grohovaz*
RESEARCHER: Daniele Zacchetti
PHD STUDENTS: Barbara Bettegazzi**, Romina Macco**, Ilaria Pelizzoni**
FELLOW: Alessandra Consonni**
TECHNICIAN: Franca Codazzi
Developmental neurogenetics Unit
HEAD OF UNIT: Gian Giacomo Consalez
POST-DOCTORAL FELLOW: Paola Zordan
PHD STUDENTS: Ilaria Albieri**, Valeria Barili**, Giovanna Calabrese, Giacomo Masserdotti
TECHNICIANS: Aurora Badaloni, Laura Croci
Neurobiology of learning Unit
HEAD OF UNIT: Antonio Malgaroli*
RESEARCHER: Vincenzo Zimarino
POST-DOCTORAL FELLOW: Maddalena Ripamonti
PHD STUDENT: Marcello Belfiore**
FELLOWS: Mattia Ferro, Laura Tambani
HEAD OF UNIT: Sonia Levi*
RESEARCHERS: Anna Cozzi, Paolo Santambrogio
PHD STUDENT: Alessandro Campanella**
FELLOW: Elisabetta Rovelli
Molecular genetics of mental retardation Unit (Dulbecco Telethon Institute)
GROUP LEADER: Patrizia D’Adamo
POST-DOCTORAL FELLOW: Maila Giannandrea
PHD STUDENT: Veronica Bianchi
Neural degeneration Unit (Dulbecco Telethon Institute)
GROUP LEADER: Manolis Fanto
PHD STUDENTS: Piera Calamita**, Ilaria Nisoli**, Simona Occhi
FELLOW: Francesco Napoletano
Stem cells and neurogenesis
GROUP LEADER: Vania Broccoli
RESEARCHER: Nicoletta Landsberger
PHD STUDENTS: Gaia Colasante**, Serena Giannelli**, Dionigio Prodi, Alessandro Sessa
FELLOWS: Bruno Di Stefano,Sara Lopalco, Sara Ricciardi, Federica Ungaro
Acute brain protection, Acute post-operative pain, Drugs and Central Nervous System Unit
HEAD OF UNIT: Luigi Beretta*
PHYSICIANS: Maria Rosa Calvi, Assunta De Vitis, Marco Gemma, Davide Poli
Eye repair Unit
HEAD OF UNIT: Paolo Rama
PHYSICIANS: Paolo Bettin, Stefania Bianchi Marzoli, Marco Codenotti, Ugo Introini, Rosangela Lattanzio, Gisella Maestranzi,
Giulio Modorati, Luisa Pierro
RESIDENTS: Umberto De Benedetto, Federico Di Matteo, Silvia Giatsidis, Laura Regali
CONSULTANTS: Carlo Ciampi, Annalisa Colucci, Marco Gagliardi, Maria Pia Manitto, Elena Mantovani, Lisa Melzi, Elisabetta
Miserocchi, Andrea Ramoni, Fabrizio Scotti, Marco Setaccioli, Alessandra Spinelli, Gemma Tremolada
TECHNICIANS: Giorgio Alto, Alessio Buzzotta
HEAD OF UNIT: Stefano F. Cappa*
RESEARCHERS: Jubin Abutalebi*, Andrea Moro*
PHYSICIANS: Maria Cristina Giusti, Sandro Iannaccone, Marco Lacerenza Alessandra Marcone, Michele Zamboni
POST-DOCTORAL FELLOWS: Pasquale Della Rosa, Nicola Canessa
PHD STUDENTS: Federica Alemanno**, Eleonora Catricalà, Monica Consonni**, Rosa Manenti
Experimental neurosurgery Unit
HEAD OF UNIT: Pietro Mortini*
PHYSICIANS: Lina Raffaella Barzaghi, Nicola Boari, Alberto Franzin, Marco Losa, Carlo Mandelli, Piero Picozzi
POST-DOCTORAL FELLOWS: Olga Passarin, Marco Riva
PHD STUDENT: Silvia Snider**
RESIDENTS: Luca Attuati, Paola Castellazzi, Filippo Gagliardi, Marzia Medone, Davide Milani, Alda Rocca, Carlo Serra
Functional neuroradiology Unit
HEAD OF UNIT: Andrea Falini
PHYSICIANS: Nicoletta Anzalone, Cristina Baldoli, Valeria Blasi, Silvia Pontesilli, Roberta Scotti, Paolo Vezzulli
PHD STUDENT: Monia Cabinio**
RESIDENTS: Antonella Castellano, Elisa Scola
TECHNICIAN: Antonella Iadanza**
In vivo Human molecular and structural neuroimaging Unit
HEAD OF UNIT: Daniela Perani*
RESEARCHERS: Chiara Agosta, Barbara Borroni, Assunta Carpinelli, Isabella Castiglioni, Mario Matarrese, Rosa Maria Moresco,
Alessandro Padovani, Paola Scifo, Marco Tettamanti
POST-DOCTORAL FELLOWS: Valentina Garibotto, Cristina Saccuman
FELLOWS: Paola Buffo, Danilo Spada
TECHNICIAN: Maria Grazia Minotti
Neuroothology Unit
PHYSICIAN: Lucia Oriella Piccioni
CONSULTANTS: Fabrizio Ferrario, Roberto Teggi
Psychiatry and clinical neurosciences Unit
HEAD OF UNIT: Francesco Benedetti
Psychiatry and clinical psychobiology
HEAD OF UNIT: Francesco Benedetti
RESEARCHERS: Sara Angelone, Cinzia Arancio, Barbara Barbini, Laura Bellodi*, Laura Bianchi, Marco Catalano,
Roberto Cavallaro, Maria Cristina Cavallini, Paolo Cavedini, Federica Cocchi, Cristina Colombo,
Stefano Erzegovesi, Linda Franchini, Marco Locatelli, Adelio Lucca, Giampaolo Perna, Ernestina Politi,
Laura Sforzini, Raffaella Zanardi
FELLOWS: Simona Anselmetti, Margherita Bechi, Alessandro Bernasconi, Sara Dallaspezia, Danilo Dotoli, Mara Cigala
Fulgosi, Cristina Lorenzi, Elena Marino, Adele Pirovano, Adriana Pontiggia
RESIDENTS: Marta Bosia, Eugenia Fauci, Laura Liperi, Alessia Malaguti, Fausto Panigada, Chiara Ruffini
Sleep medicine
CLINICAL GROUP LEADER Luigi Ferini-Strambi*
RESEARCHERS: Mauro Manconi, Alessandro Oldani, Marco Zucconi
Clinical psychology
CLINICAL GROUP LEADER: Cesare Maffei*
RESEARCHERS: Andrea Fossati*, Mariagrazia Movalli, Laura Vanzulli, Raffaele Visintini
PHD STUDENTS: Francesco Fresi, Sara Poletti
FELLOW: Serena Borroni
RESIDENTS: Roberta Alesiani, Ilaria Aina, Silvia Boccalon, Alessandra Bosaia, Naima Coppolino, Cinzia Facchi, Gianluca
Franciosi, Roberta Gallese, Laura Giarolli, Valeria Parlatini, Maria Monica Ratti,
Caterina Antonia Eloisa Rocco di Torrepadula, Erica Rossi, Martina Testa
HEAD OF UNIT: Alessandra Raschi
CLINICAL GROUP LEADER: Roberto Gatti
PHYSICAL THERAPIST: Andrea Tettamanti
INSPE, Institute of Experimental Neurology
Director: Giancarlo Comi*
Research Units
Experimental neurology Unit
HEAD OF UNIT: Giancarlo Comi*
Experimental neuropathology
GROUP LEADER: Angelo Quattrini
PHYSICIANS: Maurizio De Pellegrin, Marina Scarlato
PHD STUDENTS: Patrizia Dacci, Nilo Riva**
FELLOW: Daniela Triolo
RESIDENT: Federica Cerri
TECHNICIAN: Giorgia Dina
Experimental neurophysiology
GROUP LEADER: Letizia Leocani
BIOENGINEER: Marco Cursi
PHD STUDENTS: Ninfa Amato**, Marco Cambiaghi**, Alberto Inuggi, Kara Sinem, Svetla Velikova
FELLOW: Javier Gonzalez-Rosa
RESIDENTS: Mariangela Bianco, Raffaella Chieffo, Francesca Spagnolo, Laura Straffi
TECHNICIAN: Samantha Guzzoni
Molecular genetics of behaviour
GROUP LEADER: Riccardo Brambilla
PHD STUDENTS: Angela D’Antoni, Raffaele D’Isa**, Daniel Orellana**, Alessandro Papale**
FELLOW: Stefania Fasano
TECHNICIAN: Marzia Indrigo
Neuromuscular repair
GROUP LEADER: Stefano C. Previtali
POST-DOCTORAL FELLOW: Domi Teuta
PHD STUDENT: Emanuela Porrello**
RESIDENT: Ignazio Diego Lopez
TECHNICIAN: Isabella Lorenzetti
HEAD OF UNIT: Gianvito Martino
RESEARCHER: Luca Muzio
POST-DOCTORAL FELLOW: Erica Butti
PHD STUDENTS: Cecilia Laterza**, Cinzia Marinaro**, Annamaria Nigro**
TECHNICIANS: Andrea Bergamaschi, Alessandra Bergami, Elena Brambilla
Clinical neuroimmunology
GROUP LEADER: Roberto Furlan
PHD STUDENTS: Marianna Esposito, Chiara Maiorino
RESIDENT: Dacia Dalla Libera
TECHNICIANS: Francesca Ruffini
CNS repair
GROUP LEADER: Stefano Pluchino
PHD STUDENTS: Chiara Cossetti, Melania Cusimano, Elena Giusto, Lucia Zanotti
RESIDENTS: Marco Bacigaluppi, Luca Peruzzotti Jametti
TECHNICIAN: Giuliana Salani
Neuroimaging research Unit
HEAD OF UNIT: Massimo Filippi
BIOENGINEERS: Elisabetta Pagani, Paola Valsasina
RESIDENTS: Martina Absinta, Sebastiano Galantucci, Elisabetta Stefania Perego
FELLOWS: Federica Agosta**, Antonella Ceccarelli, Giulia Longoni, Michela Pievani**, Stefania Sala**
TECHNICIANS: Luca Dall’Occhio, Alessandro Meani, Melissa Petrolini, Roberto Vuotto
Neuroimaging of CNS white matter
GROUP LEADER: Maria Assunta Rocca
FELLOW: Valeria Barcella
PHD STUDENT: Gianna Riccitelli**
TECHNICIANS: Paolo Misci, Mauro Sibilia
Human inherited neuropathies Unit (Dulbecco Telethon Institute)
HEAD OF UNIT: Alessandra Bolino
PHD STUDENTS: Annalisa Bolis, Silvia Coviello, Ilaria Vaccari
FELLOWS: Enrico Fragasso, Lara Piantoni
TECHNICIAN: Patrizia Cassella
Axo-Glia interactions Unit (FISM)
GROUP LEADER: Carla Taveggia
POST-DOCTORAL FELLOWS: Amelia Trimarco
FELLOWS: Alberto Monti
TECHNICIANS: Rosa La Marca
Inflammatory CNS disorders Unit
HEAD OF UNIT: Vittorio Martinelli
RESEARCHERS: Filippo Martinelli-Boneschi, Lucia Moiola, Mariaemma Rodegher
PHYSICIAN: Paolo Rossi
PHD STUDENTS: Federica Esposito**, Marta Radaelli**
RESIDENTS: Sebastiano Bucello, Elda Judica
Cerebrovascular disorders
CLINICAL GROUP LEADER: Maria Sessa
RESEARCHER: Francesco Corea
PHYSICIANS: Silvia Mammi, Antonella Poggi, Luisa Roveri
PHD STUDENTS: Grazia Nuzzaco**, Maria Carmela Spinelli**
RESIDENTS: Chiara Ghidinelli, Sara La Gioia
Memory Disorders
CLINICAL GROUP LEADER: Giuseppe Magnani
RESIDENTS: Francesca Caso, Eliana Schiatti, Chiara Vismara
Movements disorders
CLINICAL GROUP LEADER: Ubaldo Del Carro
PHYSICIANS: Stefano Amadio, Roberta Guerriero, Stefania Medaglini, Maria Grazia Natali Sora, Maria Antonietta Volontè
RESIDENTS: Calogera Butera, Daniela Ceppi, Luisa De Toni Franceschini, Habtom Tesfaghebriel, Daniela Ungaro
Neuromuscular disorders
CLINICAL GROUP LEADER: Raffaella Fazio
PHD STUDENT: Daniela Privitera**
Paroxysmal events
CLINICAL GROUP LEADER: Fabio Minicucci
PHYSICIANS: Bruno Colombo, Giovanna Franca Fanelli, Fabio Formaglio, Paolo Marchettini
RESIDENTS: Beatrice Benedetti, Francesca Fumagalli, Giulia Pavan, Francesco Peschechera
The Division of Neuroscience is made up of 369 scientists – rostered in 21
basic research units and 17 clinical research groups – whose scientific endeavours are described under the sections dedicated to each Unit. The clinical research groups are affiliated to three clinical departments: the Dept. of Neurology, the Dept. of Clinical Neuroscience and the Dept. of Head and Neck,
whereas the units involved in translational medicine (11 basic research units
and 6 clinical research groups) form the Institute of Experimental Neurology
(INSPE).
Gianvito Martino
Members of the Division are part of the faculty of the Schools of Medicine,
Biotechnology, Psychology and Philosophy. In addition, the Division is actively involved in the training of graduate students, organizing Ph.D. Courses in Neuroscience, Experimental Neurology, Neurobiotechnology, Developmental Psychopathology, and taking part in the Ph.D.
Course in Cellular and Molecular Biology.
The scientific interests in the Division are wide, and range from the molecular analysis of brain development and function to the development and validation of novel therapeutic approaches for neurological
and psychiatric disorders. Since the beginning, the final aim of the Division has been the integration of
basic research with clinical applications. Given the diverse backgrounds of
the scientists affiliated to the Division, considerable effort has been dedicated
to the creation of a scientific community, by implementing divisional seminars and journal clubs and by organizing the research units into four thematic areas, i.e. development and plasticity, molecular and cellular neuroscience, neurobiology of diseases, and cognitive and systems neuroscience.
During the past year research has developed along a variety of lines, all
within the long-term goal of enhancing our comprehension of the normal
function of the brain and discovering cures for the nervous system ravaged
Flavia Valtorta
by disease. The following main themes can be identified:
(i) understand the healthy nervous system; (ii) understand neurological and psychiatric diseases; (iii)
enable early and routine diagnosis of neurological and psychiatric conditions; (iv) develop new therapeutic strategies; (v) accelerate the process of therapy development; (vi) develop new technologies for observing the nervous system; and, (vii) develop new strategies to probe neural functions.
Two interdivisional research programs which see the primary involvement of the Division of Neuroscience have been planned and designed and will be implemented in the next years:
BRAINMAP (HUMAN BRAIN IN-VIVO MAPPING WITH NEUROIMAGING)
BRAINMAP develops, in the field of basic technology research, and applies, in that of clinical research,
conventional as well as novel neuroimaging techniques for the evaluation of the physiological maturation and aging processes of the CNS and the assessment of the different pathological substrates of the
main neurological and psychiatric diseases.
BRIDGE (BRAIN REGENERATION USING MEDICAL DEVICES, GENE VECTORS, AND
STEM CELLS)
BRIDGE exploits premiere knowledge derived from state-of-the-art stem cell and gene therapy trials
to be conducted in our Institute for a number of inflammatory and neurodegenerative conditions. It also
combines 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.
Research Units
NEUROPSYCHOPHARMACOLOGY UNIT
Comprehensive goal of our research is the elucidation of the molecular mechanisms which underlie communication between cells of the brain, both in the adult and during development. The main form of communication between neurons is achieved through regulated secretion of neurotransmitter occurring at synapses. This
process is therefore of paramount importance for information processing in the central nervous system and is
known to be deranged in a number of pathological states.
Research in our group has focused on two main topics:
1) Diseases of synaptic origin
The main focus has been on the family of the synapsins and their link to epilepsy.
Synapsins are a family of brain phosphoproteins involved in neurotransmitter release through regulation of
synaptic vesicle availability. Synapsin KO mice develop an epileptic phenotype, and mutations in the human
synapsin I gene has been recently associated with epilepsy.
We have completed the study of the molecular mechanisms by which the reported mutation in the human
SYN1 gene leads to the development of an epileptic phenotype.
We have also found that networks formed by synapsin KO neurons are characterized by hyperexcitability,
which is due to both enhancement in excitatory transmission and impairment in inhibitory transmission. In addition, KO mice show cognitive impairment and behavioral abnormalities which worsen with age.
2) Membrane trafficking in neuronal development,
The process that leads from undifferentiated, round neuronal precursors to fully differentiated, highly polarized neurons is extremely complex. Among the various phenomena which drive this process, those associated
with membrane trafficking are of fundamental importance, but are as yet poorly characterized. We are interested in studying membrane trafficking in the very early steps of neuronal development. In this respect, we have
identified a process of developmentally-regulated, high-capacity endocytosis as one of the earliest marker of
neuronal polarity. In the next future, we will investigate the possible causative role of such process in driving
neuronal differentiation and its contribution to axonal navigation and pathfinding.
Flavia Valtorta
Figure 2. Axonal growth cone of a live embryonic
hippocampal neuron in culture showing intense endocytic
activity (red, uptake of the lipophilic dye FM4-64)
CELL ADHESION UNIT
Molecular networks for the regulation of cell motility
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. For this, we obtained 3 lines of mice with mutation in the Rac3 gene (Rac3 KO), conditional mutation of Rac1 in neurons (Rac1N), or mutation of both GTPases (Rac3 KO/Rac1N). Rac3KO and Rac1N mice develop normally, while double KO mice are heavily impaired neurologically (ataxic, uncoordinated, epileptic). Morphological analysis has revealed alterations in the
hippocampal organization, with lack of most hilar mossy cells, an important class of excitatory interneurons.
Dendrites, axons and synapses are strongly reduced in the dentate gyrus, suggesting that the alteration of hippocampal synaptic connectivity underlies the neurological defects observed. We have also compared synaptic
development in hippocampal cultures from wild-type, single, and double KO mice. Depletion of both Rac
genes strongly impaired synaptic formation by affecting the development of dendritic spines, while neurons
lacking either Rac were either normal or slightly affected. These results reinforce the notion that two Rac genes
are required for late neuronal development in mammals.
The multi-molecular GIT complexes are involved in the regulation of cell migration. These complexes are assembled by the multi-domain proteins GIT1 and GIT2, which functionally interacts with Arf and Rac GTPases. We found that GIT1 interacts also with Liprin-α’s, a family of adaptor proteins involved in the assembly of
neuronal synapses and in the organization of focal adhesions. We found that Liprin-α1 interacts with the carboxy-terminal portion of GIT1, and competes with paxillin for binding to GIT1. Expression of Liprin enhances cell spreading, while its downregulation prevents spreading and formation of lamellipodia. Analysis in
cell cultures including time-lapse imaging on living cells has shown that Liprin affects the dynamics of endogenous β1 integrins activation and focal adhesion formation at the cell edge, thus regulating cell motility. The
comprehensive molecular/cellular analysis performed by us has established Liprin-α as a novel essential regulator of cell motility and of invasion by tumor cell lines.
Ivan de Curtis
Figure 3. Liprin-α1 expression (green) induces
enhanced cell spreading on fibronectin and
the redistribution of activated β1 integrin
receptors (red)
CELLULAR AND MOLECULAR NEUROBIOLOGY UNIT
Membrane traffic and neurosecretion expression in nerve cells
Our research was developed along two main line. First, we have pursued the investigation of the enlargeosomes, the exocytic organelles discovered in the lab in 2002, working on the defective neurosecretory cell clone
PC12-27. In the meantime this organelle has been shown to be expressed by many, but not all types of cells,
neurosecretory and non-neurosecretory. The main step forward of this year has been the identification of
VAMP4 as the vSNARE specific for their exocytosis. This results is important because VAMP4 was believed to
be involved only in the membrane traffic in the Golgi-TGN area and in endocytosis. In contrast, it had never
been identified in exocytoses. Therefore enlargesomes appear as the only organelles employing VAMP4 for this
process. Based on this consideration we have already started to use VAMP4 as a marker of the involvement of
enlargeosomes in physiological processes such as neurite outgrowth. In addition, we have continued the study
of the specific plasma membrane patches that result from the exocytosis of enlargeosomes involved in the generation of small shedding vesicles released to the extracellular space upon cell stimulation. These vesicles, that
appear to play an essential role in the horizontal transfer of proteins and nucleic acids, are now recognized to
participate in physiological and pathological processes, incuding tumor spreading.
Our second line concerns the transcription repressor REST. We have shown that this factor controls neurosecretion. Neurons and wt neurosecretory cells, such as PC12, have low levels of REST. If the level is increased,
neurosecretion tends to disappear. Conversely, when the level was decreased in the defective clones PC12-27
and PC12-Trk, which are rich of the factor, neurosecretion was found to reappear.These results might be of
great importance in the study of diseases, such as type 2 diabetes, in which the activity of a neurosecretory cell
type is diminished, and in various tumors that are known to be sustained in their growth by a defect of REST.
We have also initiated the study of REST function showing that it depends not only on its level, but also on the
modulation of its activity by a protein participating in one of its effector complexes.
Jacopo Meldolesi
CELLULAR NEUROPHYSIOLOGY UNIT
Physiopathological mechanisms in neuroprotection and neurodegeneration
Neurodegenerative pathologies are a great and growing social problem, with Alzheimer’s disease representing
the most frequent form of degenerative dementia. Our research is aimed to understand the balance between
neuroprotection and neurodegeneration under physiological and pathological conditions. BACE1 is the β-secretase responsible for the production of the neurotoxic amyloid-β peptide that accumulates in the brain of patients affected by Alzheimer’s disease. We have investigated the complex mechanisms that control transcription
(effect of growth factors), translation (phosphorylation state of initiation factors) and activity (modulation of
amyloid-β production) of the endogenous BACE1 in brain and primary cultures from brain. We have also
found that astrocyte-derived amyloid-β is produced by the action of BACE2, the BACE1 homolog, and that
this production is modulated by the activation state of the astrocytes. We started a characterization of the molecular mechanisms of astrocyte activation by investigating: different protocols of stimulation leading to specific phenotypes; the underlying intracellular pathways; the upregulation of proteins and the release of molecules
in the extracellular milieu.
A parallel research line investigated in primary cultures of neurons and astrocytes, the neurotoxic role of iron
accumulation. We studied the pathways of iron entry, iron-mediated ROS accumulation, Ca2+ changes and cell
death. Our results indicate that iron can enter neurons through both Voltage Operated Calcium Channels
(VOCCs) and, during strong synaptic activity, NMDA receptors. Our results also indicate that mitochondria
are the main target of iron toxicity and that defense mechanisms are less efficient in primary cultures than in all
brain-derived cell lines analyzed. Interestingly, activation of astrocytes by exposure to proinflammatory cytokines, enhances the resistance to oxidative stress. We are currently studying the effects mutations in the ferritin light chain (inherited in the hereditary neuroferritinopathy disease) have in iron control and overall neuronal survival (in collaboration with the Proteomics of iron metabolism Unit).
Fabio Grohovaz
DEVELOPMENTAL NEUROGENETICS UNIT
From in vivo lineage analysis to neural stem cell manipulation
Our laboratory focuses on neurogenesis during embryonic development and is moving into the field of neural
regeneration. During embryonic development, neurogenesis requires a perfect balance between mechanisms
that support self-renewal of undifferentiated progenitors and others that push progenitors towards commit-
ment and post-mitotic differentiation. The mammalian cerebellum is a perfect example of this: in the mouse,
cerebellar neurogenesis starts on embryonic day 11 and is completed only around postnatal day 20, featuring
repeated events of self-renewal, cell fate determination, clonal expansion and neuronal migration.
Numerous spontaneous and induced mutations are providing precious information on the molecular mechanisms that regulate these phenomena, and on their links with human diseases of the cerebellum. Our group is
contributing to this knowledge with studies of cerebellar patterning (Masserdotti et al, submitted), cerebellar
cortical boundary formation (Croci et al., 2006, Chung et al, 2008), cerebellar GABAergic neurogenesis and
Purkinje cell specification (Zordan et al., 2008, Zordan et al., in progress), and of Purkinje cells survival (Croci
et al., submitted). Furthermore, we have contributed to the characterization of a novel type of neural stem cells
(Calabrese et al., submitted) to attempt to recapitulate in vitro the regulatory cascade that govern cerebellar
neurogenesis in vivo.
We are now planning to put our experience to task in order to assess the ability of in vitro implemented neural stem cells to integrate into the postnatal cerebellum of wild type mice and models of cerebellar ataxias.
Gian Giacomo Consalez
Figure 4. A Purkinje neuron (green) whose
progenitor was labeled indelibly during early
cerebellar development by activation of a genetic tag.
This approach makes it possible to uncover the
lineage relationships between early progenitors and
mature neurons, as well as between different
neuronal types. This information is a pre-requisite for
the rational manipulation of neural stem cells and for
the generation of specific mature neurons in vitro.
NEUROBIOLOGY OF LEARNING UNIT
A novel family of indicators to monitor synaptic activity in vivo
One of the most fascinating avenue in neuroscience is to find a more informative way to correlate behavior to
specific patterns of synaptic activity in subgroups of brain cells. As imaginable, besides addressing the functional wiring of the brain and understanding the basis of complex behaviors, this line of research would facilitate
the detection of several types of brain diseases in their early phases, when brain morphology is still fully intact
but somewhere in the brain an anomalous state of activity is already present. The most refined electrophysiological techniques available today can directly sample electrical activity with very high fidelity but their readout
is limited to one or just a few neuronal cells. Therefore most of our current knowledge about brain activity and
the functional wiring of behavior comes from certain modalities of recordings (functional brain imaging techniques) whose readout is more global, although, unfortunately, distantly related to the most important parameter i.e. neuronal and synaptic activity. In addition they do not provide the necessary spatial resolving power to
study small brain circuits which are made of neurons (10 -100 ?m) and their synapses (200 nm - 1 ?m). In line
with this idea our laboratory is currently developing a series of innovative genetically encoded indicators that
can be used to report synaptic trasmission both in vitro and in vivo. These new tools are based on the expression of engineered synaptic constructs which have been assembled starting from the moiety of the vesicular
protein VAMP2 with the insertion at the intraluminal ending of an aminoacidic cassette which contains a sequence recognized by a bait, a small peptide of ~ 4 KDa conjugated with a fluorophore. When these constructs
are expressed in neurons they are sorted to synaptic vesicles which are fusion competent and can take up in an
activity dependent manner the fluorescent bait from the extracellular environment. The specificity and the signal to noise ratio of these tools are both extremely high and synaptic activity can be visualized in cultured neurons but more importantly in brain slices and in the vivo brain. We believe that the confluence of advances in
these genetically encoded indicators with modern optical imaging will soon allow the in-vivo imaging of activity
in defined neuronal ensembles in the brain of freely behaving animals.
Antonio Malgaroli
PROTEOMICS OF IRON METABOLISM UNIT
The role of iron in neurodegenerative disorders
Neurodegenerative diseases with brain iron accumulation are a group of extrapyramidal disfuctions characterized by radiographic evidence of excessive brain iron content. We are investigating the patophysiological
mechanisms leading to two of these disorders: Neuroferritinopathies, which are dominant movement disorders
associated to mutations on the L-ferritin and the Pantothenate Kinase Associated Neurodegeneration (PKAN),
the disease with the highest brain iron accumulation, associated with several mutations in the Pantothenate Kinase 2 (Pank2) gene. We produced cellular HeLa stable clones and the lentiviral-transduced SH-SY5Y neuroblastoma cells expressing L-ferritin (Lwt) and variants causing neuroferritinopathies. The L-variants expression
caused a lower efficiency in ferritin iron incorporation, determining the cellular iron homeostasis alteration. In
HeLa cells the deregulation of iron homeostasis determined a modification of cellular oxidative status related
to cells apoptosis, while the SH-SY5Y appeared to be subjected to necrosis after treatment with iron. As occurs
in patients, the variants clones showed ferritin and iron aggregates and a strong decrease in proteasomal activity respect to the Lwt cells. The aggregates formation seemed not to be responsible for cells death while they appear an epiphenomenum of the increased oxidative stress. The L-ferritin pathogenic mutations act in a dominant-negative way on ferritin functionality, indicating that the disorder is linked to iron deregulation, rather
than being a protein conformational disease. To investigate the link between the PKAN defect and iron accumulation we analyzed skin fibroblasts from three PKAN patients compared with three healthy controls. Fibroblasts from three patients showed differences in iron manipulation during prolonged mild iron supplementation, with a reduced ferritins up-regulation and minor Transferrin Receptor 1 down-regulation. Defective
modulation of these proteins reflected abnormalities in the cytosolic Labile Iron Pool and consequent higher
ROS generation. Our data propose that all Pank2 mutations affect cellular iron homeostasis and that the severity of the defects probably relies on the specific mutations that differently influence activity and protein length.
Sonia Levi
MOLECULAR GENETICS OF MENTAL RETARDATION UNIT
Lack of aGDI causes a defect in synaptic vesicle recycling responsible for cognitive impairment and altered
social behaviour in Gdi1 knockout mice
Our research is focused on the understanding of the molecular causes leading to Retardation (MR), a common cause of inherited intellectual disability in the human population, with a reported prevalence of about 0,91,4/1000 males. Mutations in GDI1 are responsible for X-linked MR.
Gdi1 knock out (Gdi1 KO) mice were generated and they are viable and fertile and did not present visible
morphological or neuropathological alterations.
They are impaired in associative memory detected with two hippocampus dependent tests: the radial maze
and trace fear conditioning. They also showed inappropriate social behaviour, when tested in the resident-intruder paradigm, they lacked any sign of aggressive behaviour and they displayed signs of a friendly interaction
with the intruder.
The behavioural deficits showed that Gdi1 KO have specific and limited dysfunctions of hippocampal formation and amygdala.
αGDI is one of the proteins controlling the activity of small GTPases of the Rab family in intracellular trafficking. Gdi1 KO mice presented alterations in a specific set of few Rab whose amount and intracellular distribution appeared altered in KO brain extracts.
The functional impact of Gdi1 deletion on short-term plasticity at CA1 excitatory synapses of the hippocampus, showed that under a prolonged high-frequency stimulation of Shaffer collateral induces a stronger synaptic
facilitation in KO synapses, followed by a depressing phase. The subsequent recovery from depression was significantly slowed down in KO, suggesting an impairment in synaptic vesicles (SV) recruitment possibly related
to the marked reduction in the SV reserve pool.
Hippocampal Gdi1 KO SV pool was directly analyzed by electron microscopy on P10, P23, and P90 mice, to
monitor SV density during SV formation. A SV significant reduction was observed in all stages analyzed, regarding the reserve SV pool.
We are able to reverse the specific short-term memory deficit of Gdi1 KO mice by using a “spaced” instead to
“massed” training protocol in trace fear conditioning and radial maze tasks. The data suggest that lack of Gdi1
alters steps controlling the formation and maintenance of the SV pools possibly through changes in the Rab cycle and interfering with the efficiency of mental processing.
Patrizia D’Adamo
NEURAL DEGENERATION UNIT
Dentatorubropallidoluysian Atrophy (DRPLA) is a neurodegenerative disease caused by the expansion of a
polyglutamine tract in the Atrophin-1 gene. As for the other diseases of the polyglutamine family the precise
mechanisms through which neurodegeneration and the neurological manifestations arise are not clear. To address these issues we have generated several Drosophila models for DRPLA by expressing wt and mutated
forms of human Atrophin-1 and Drosophila Atro. It has been proposed that polyQ diseases are transcriptionopathies, in which toxicity first arises from large scale alterations of transcription due to the entrapment of
many transcription factors in polyQ inclusions. We have monitored by microarrays transcriptional alterations
due to polyQ Atrophin expression through an inducible system in the Drosophila retina, a dispensable part of
the fly nervous system widely used in polyQ modelling.
This analysis has shown that upon polyQ Atrophins expression retinal cells tend to de-differentiate and re-enter the cell cycle before degenerating. Degeneration is preceded by the upregulation of cdc25 and histones transcription and by the downregulation of the tumour suppressor and cell adhesion molecule Fat. We are currently verifying the functional significance of the transcriptional alterations for neurodegeneration and identifying
which genes are directly regulated by Atro.
In 2008 we have established that the fat tumour suppressor gene mediates neurodegeneration induced by the
polyglutamine protein Atrophin via deregulation of autophagy. Polyglutamine Atrophins induce autophagic
neurodegeneration with lysosomal blockage and repress fat transcription. Fat is known to interact with Atrophin to regulate planar cell polarity, however it protects from autophagic degeneration and Atrophin toxicity
through the Hippo tumour suppressor pathway. Our data thus provide a crucial insight into the specific mechanism of a polyglutamine disease and reveal an unexpected neuroprotective role of Fat and its growth control
pathway in the regulation of autophagy and cellular homeostasis, linking tumour suppression and neurodegeneration.
Manolis Fanto
STEM CELLS AND NEUROGENESIS
Functional analysis of Arx and Tbr2, two genes causing neurodevelopmental diseases in humans
The Arx transcription factor is expressed in the developing ventral telencephalon and subsets of its derivatives. Mutation of the human ARX ortholog causes neurological disorders including epilepsy, mental retardation and epilepsy. We investigated the nature, origin and evolution of these severe neurological alterations in
Arx mutant mice. In these animals we described a severe reduction in migration of cortical GABAergic neurons
from the basal ganglia to the developing cerebral cortex. Indeed, Arx mutant interneurons retained their differentiation potential but exhibited deficits in their migration ability in vitro. These findings and others imply that
cell-autonomous defects in neuronal migration are the main molecular cause of the neurological manifestations.
Altogether, these results highlight the critical functions of Arx in promoting neural migration and, thereby, regulating basal ganglia differentiation and supply of cortical interneurons, consistent with the phenotype exhibited by the patients.
Tbr2 gene silencing has been previously associated to microcephaly in humans. To clarify the mechanisms at
the foundation of this malformation, Tbr2 conditional mice were crossed with Emx1-cre transgenic mice in order to delete Tbr2 in the cerebral cortex. Tbr2 mutants displayed small cerebral cortices with hypoplastic olfactory bulbs, resembling the pathological phenotype observed in microcephalic patients. We confirmed that Tbr2
expression is selectively confined to the intermediate neuronal progenitors (INPs), a class of precursors which
constitutes the subventricular zone during corticogenesis. Interestingly, Tbr2 microcephalic phenotype is the
direct result of the loss of the majority of cortical INPs. We provided evidence that INPs are a crucial source of
cortical neurons contributing to the establishment of all the cortical layers and olfactory bulbs. To note, the in
vivo overexpression of Tbr2 is sufficient to revert radial glial cells into INPs. Thus, Tbr2 should be considered
the molecular determinant responsible for the fate switch between the two different types of cortical progenitors. Future studies will aim to unravel the Tbr2 dependent molecular pathway, which might lead to identify
candidate genes for other forms of inherited microcephaly.
Vania Broccoli
ACUTE BRAIN PROTECTION, ACUTE POST-OPERATIVE PAIN, DRUGS
AND CENTRAL NERVOUS SYSTEM UNIT
Neurosurgical Intensive Care
Diagnostic and prognostic value of Magnetic Resonance Imaging and CT scan in comatose patients with Diffuse Axonal Injury (DAI) after brain trauma.
DAI is frequently observed in the Intensive Care Unit since it is typically caused by the acceleration forces of
high speed impacts. Patients exhibit immediate severe impairment of consciousness but few CT scan alterations. An early evaluation of the prognostic factors associated with neuroradiological imaging may lead to
more correct treatment options and to an improvement of communication with the patients’ relatives.
CT perfusion study of the improvement of cerebral perfusion after cranioplasty in patients formerly submitted to osteodural decompression for intractable intracranial hypertension after acute brain injury.
Osteodural decompression may save the life of patients with intractable intracranial hypertension. As patients
recover from the acute phase of trauma, cranioplasty is performed for mechanical protection and on aesthetic
grounds. The observation of clinical neurological improvement after cranioplasty in these patients suggests a
possible improvement of cerebral perfusion after cranioplasty.
Neuroanesthesia
Evaluation of the impact of different sedative regimens on cortical activation during Functional Magnetic
Resonance (fMRI) in children of different ages.
Sedation is needed in children to warrant immobility during fMRI. Sedatives alter cerebral activation after
sensorial stimulation: an evaluation of their impact on fMRI may indicate which the best sedative in this setting.
Comparison of Total Intravenous Anesthesia and Sevoflurane anesthesia during elective neurosurgery (multicentre study).
The impact of these different anesthetic strategies in neurosurgery is a cool matter of debate. Recovery time,
neurovegetative activation, adverse events and costs are evaluated.
Evaluation of the miocardial effects of elective neurosurgery by echocardiography and perioperative evaluation of serum troponine and BNP.
Acute brain injury is a well known possible cause of miocardial impairment. This has been previously studied
in the setting of head trauma, subarachnoid hemorrhage, stroke, but not in patients submitted to major elective
neurosurgery.
Luigi Beretta
EYE REPAIR UNIT
Clinical and basic research in ophthalmology
Transplantation of cultivated corneal limbal epithelial stem cells:technique indicated for corneal surface reconstruction due to deficiency of limbal stem cells (burns).
Biophysical study of cornea and sclera: analysis of normal and pathological response to create a model of engineered cornea.
Transplant of oral mucous stem cells for treatment of limbal bilateral deficiency.
Retrospective evaluation of clinical management of patients affected by Acanthamoeba keratitis:a future
prospective trial will be conducted.
Randomized multicentric clinical trials for treatment of:
neovascular age-related macular degeneration: test safety and efficacy of new anti-VEGF drugs
retinal vein occlusion due to diabetes: test new therapies to avoid/treat macular edema and retinal ischemia.
Endothelial Progenitor Cells in Age Related Macular Degeneration: evaluate the behaviour of EPCs in relation to new onset CNV,anti-VEGF treatment and CNV response to anti-VEGF drugs; demonstrate that number of circulating EPCs is higher than normal at the time of CNV development and not reduced by intravitreally anti-VEGF drugs.
Genetic of DME: identify specific genetic markers in diabetic patients, affected by macular edema, leading to
high activity of poliol-pathway and damage of Muller cells.
Endothelial Progenitor Cells (EPCs) and retinopathy in type1 diabetes:investigate the role of bone marrowderived EPCs in the pathogenesis of diabetic retinopathy leading to new therapeutic approaches.
Combined Intravitreal Ranibizumab and Verteporfin Photodynamic Therapy for Choroidal Neovascularization in Angioid Streks: evaluation of double treatment of neovascular membranes in an uncommon
disease,charactirezed by unsuccessful responses to usual care.
Visual Impairment on Leber Hereditary Optic Neuropathy:from advanced diagnosis to rehabilitation: to
identify the clinical, morphological and genetic characteristics of patients affected by Leber and define visual
prognosis parameters; to identify morphofunctional alterations in asymptomatic subjects with genetic mutations to define the risks of manifested disease growth.
Analysis of neurogenic and regenerative potential of Muller Glial Cells in both healthy and diseased the mammalian retina: in collaboration with Dr Broccoli’s Unit; study of Muller Glia cells in-vitro and in-vivo.
Paolo Rama
COGNITIVE NEUROSCIENCE UNIT
This is a multi-disciplinary Unit, which combines expertises from different backgrounds (neurology, neuropsychology, linguistics, cognitive psychology, epistemology), with the general aim to investigate the neural
mechanisms of language and high-order cognition. The experimental approaches include behavioural studies in
normal subjects and in neurological patients, brain imaging using magnetic resonance techniques and positron
emission tomography, and neurophysiological investigations based on evoked responses and transcranial magnetic stimulation. The unit is involved in several research projects related to the investigation of the neural basis
of knowledge representation (semantic memory) for entities belonging to different categories; to the neurological mechanisms involved in syntax, in particular in relation to the question of its language specificity; to the representation of multiple languages in the polyglot brain and their impact on other cognitive functions; to the
brain foundations of social interaction, with a special emphasis on empathic phenomena; to the brain mechanisms responsible for decision making in uncertainty and their possible implications for economic choice and
managerial processes. These areas of basic cognitive neuroscience research are fully integrated with a clinical
research program, wich is based on the development and application of innovative neuropsychological tests
based on cognitive models to patients affected by cognitive disorders due to acquired focal and degenerative
brain damage. From this point of view an area of special interest is the investigation of patients affected by clinical conditions belonging to the fronto-temporal dementia spectrum. The main areas of dysfunction in these patients are language and social cognition; they thus provide an excellent pathological model for the cognitive areas investogated in normal subjects. The patients are studied with functional and structural imaging, in order to
investigate the correlation with neuropsychological findings. The same approach is also applied to Alzheimer
and Parkinson disese patients, which are providing important evidences about the neurological underpinnings
of semantic and syntactic processing, as well as to selected patients with focal brain damage.
Stefano F. Cappa
EXPERIMENTAL NEUROSURGERY UNIT
Developments in the investigation of hypothalamic-pituitary diseases
Research on pituitary diseases last year had as its principal focus the results of trans-sphenoidal surgery, analyzed in terms of efficacy and safety in patients with pituitary adenomas, operated in our center since 1990. In
more detail, we have published the data of 491 patients operated for a nonfunctioning pituitary adenoma, one
of the largest series in the world. The results confirmed the good efficacy and safety of pituitary surgery in this
disease and the value of adjuvant radiation therapy. Another paper reported the results in the group of patients
with “giant” adenomas, a very demanding and rare condition. We have also presented the data on the results of
gamma Knife radiosurgery as adjuvant treatment in acromegalic patients. The final report is under review. Our
continuing cooperation with other groups inside and outside our University led to a series of papers exploring
the mechanisms of GH action on osteoblastic function in vitro, the effect of ghrelin on ACTH secretion in cultured ACTH-secreting human adenomas and the metabolic profile of patients with Cushing’s disease as compared to subjects with the metabolic syndrome.
Pietro Mortini
FUNCTIONAL NEURORADIOLOGY UNIT
The Unit is composed by different groups that apply conventional and advanced MR techniques to investigate brain structure and functions in normal subjects, during physiological and pathological development, during normal and pathological aging, in neuro-oncology and neurovascular diseases. The neuropediatric group
has addressed its attention 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 Unit). 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 trying to characterize the selective involvement of different brain areas in different form of fronto-
temporal dementia patient group (in collaboration with Cognitive Neuroscience Unit). 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 able
to depict the main white matter tracts in vivo, in patients with gliomas. A second topic was the development of
new alghoritm based on tensorial diffusion, potentially useful to better characterize the different cellular and
extracellular components of brain tumors and adjacent normal structures.
Other topics like the study of inflammatory diseases or optic nerve degeneration have been performed in collaboration with other units of Neuroscience Division (Neuroimaging Research Unit, Neuroimaging of CNS
White Matter Unit, Eye Repair Unit).
Andrea Falini
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. In particular, 18F FDG is used for the evaluation
of glucose metabolism, 11C Raclopride and 11C Fe CIT for the dopaminergic system, 11C FMZ for the evaluation of the gabaergic system, and 11C MP4 for measuring the AchE activity. fMRI and MRI structural studies
were also used to address functional changes and morphometric changes (voxel-based-morphometry (VBM)
and diffusion tensor imaging (DTI) techniques) in neurological and psychiatric diseases.
The research protocols include Alzheimer and MCI, fronto-temporal dementia and its variants, early and late
onset of Parkinson’s disease, both sporadic and genetically determined, primary dystonia (genetic and sporadic), and rare conditions such as Fatal Familial Insomnia, an inherited prion disease. Among the psychiatric
disease, obsessive compulsive disorders (OCD) were studied with PET and 11C raclopride for the evaluation of
dopaminergic system, and 11C MDL for the evaluation of 5HT2 serotonin receptors. OCD selected cases were
also included in morphometric measurement of selected fiber tracts.
Depending on the pathological condition, PET and specific radiotracers reveal functional and neurotransmission changes which are also correlated with clinical symptoms and their severity.
MRI brain morphology and fiber tracts also showed brain anatomical changes related to the underlying neuropathological disease condition.
Using ad hoc experimental paradigms we also addressed functional changes (fMRI), morphometric changes
(VBM and DTI) in developmental dyslexia (sporadic, familial and in genetic association studies). The results
were also correlated to reading disabilities and neuropsychological deficits.
Daniela Perani
NEUROOTHOLOGY UNIT
Little is known regarding the cortical areas involved in human vocalization. The study aim is to investigate
larynx cortical area involved in phonation. A 3 Tesla Magnetic Functional Resonance is performed in 6 healthy
adults to evaluate voice production related brain activations, using 5 tasks involving laryngeal muscles motor
control. We analyzed cerebral network modifications caused by a damage to the laryngeal structures. The fMRI
is used to examine 12 patients underwent to laryngeal surgery from January 2007 to February 2008. The pts will
be evaluated with the same fMRI tasks used in the healthy population and the results obtained about the two
study groups (healthy and surgical group) will be compared in order to obtain informations about the neuronal
plasticity following the laryngeal surgery.
In a sample of 30 pts referring dizziness and migraine we found a higher prevalence of vestibular abnormalities than in a normal dizzy group. We found increased stabilometric parameters and visual dependence. We
compared the rate of vestibular anomalies and the presence of definite migrainous vertigo in a sample of 52 pts
with Panic Disorders and agoraphobia, 30 pts with Panic Disorders without agoraphobia and 20 pts with depression, all referring dizziness. Agoraphobic pts presented a higher rate of vestibular anomalies and definite
migrainous vertigo. Vestibular anomalies may play a role in the arise of agoraphobic symptoms. We demonstrated an increased body sway during non foveal visual stimulation in agoraphobic pts compared with normal
subjects. Establish a role of genetically determined alterations of ionic transporters in inner ear in predisposing
to develop Meniére Syndrome (MS). We demonstrated a higher rate of Adducin mutation in a sample of 30 pts
with definite MS than in 2 different normal control group. Pts with MS presented a lower serum levels of
ouabaine, an hormone controlling ionic transporters activity.
The results underline the possibility that an increased pump activity and a lack of feed-back mechanisms may
change osmolarity of endolymph. Establish the efficacy of low level laser therapy in tinnitus treatment. Our results on a sample of 30 pts with tinnitus did not demonstrate any therapeutic results.
Mario Bussi
PSYCHIATRY AND CLINICAL PSYCHOBIOLOGY
During the year 2008 we continued our research activities at the interface between neuroscience and behavioral disorders, with the aim of increasing scientific knowledge and developing effective diagnosis and treatment options in the broad field of Psychiatry and Clinical Psychobiology.
In the field of mood disorders, we discovered new influences of gene variants in the monoaminergic pathways
and in the biological clock on core feature of the illness and on response to treatments. In particular, we published the first reports on the influence of COMT variants on response to antidepressant drugs in naturalistic
settings, of 5-HT2A on response to chronotherapeutics, of PER3 and GSK3β on psychopatology, and discovered a method to overcome the detrimental influence of 5-HTTLPR short alleles by administering chronic lithium. Moreover, we created a new animal model of mania based on the manipulation of the sleep wake rhythm.
In the field of imaging genetics we produced the first report that CLOCK genes variants affect information
processing and neural correlates of moral decision making in bipolar depression, and that 5-HT2A and D2 are
dysfunctional in drug-naive obsessive-compulsive disorder.
In other psychiatric disorders, we discovered a new effect of transcranial magnetic stimulation in reducing cocaine craving in drug addicts; we produced the first normative data for the Italian population of the Brief Assessment of Cognition in Schizophrenia, to be used to assess rehabilitation outcome; and continued the characterization of comorbidities and psychopatological features of eating disorders.
All these findings were obtained in the context of research activities that had been ongoing since 1988 and
have continued thereon.
Francesco Benedetti
SLEEP MEDICINE
Sleep related movement disorders
Restless Legs Syndrome (RLS) is a motor sleep disorder characterized by disagreeable sensitive symptoms in
the lower limbs occurring at evening/night, at rest and improving with movement. RLS is often associated with
Periodic Limb Movements (PLMs) during sleep. A dysfunction in the dopaminergic nervous system seems to
play a significant role in the pathogenesis. Our group proved the efficacy of pramipexole (dopamine D3 receptor agonist) in suppress RLS symptoms and PLM since the first night of treatment and even at very low dosage.
Polysomnographic features of PLM and its specific response to dopamine agonists have been also studied,
founding that the periodicity of the motor events is the crucial aspect to predict the efficacy of the dopaminergic treatment. A reliable method of polysomnographic automatic detection and scoring of PLM has been validated by our group. Differences in term of the electromyographic time-structure between the PLM of restless
legs syndrome and those found in REM behaviour disorders and in narcolepsy have been enhanced by our
analysis, with the intent to improve the polysomnographic diagnosis of the sleep related movement disorders.
We demonstrated that PLM in RLS are associated with specific autonomic dysfunctions such as an increase of
the heart-rate variability. This finding may represent the reason of the increased risk for cardio-vascular diseases
in patients with RLS, recently relieved by large epidemiological surveys. We described the recovery of PLM and
its autonomic related dysfuncions by the dopamine agonists treatment, which might represent a promising extension of the well know beneficial effects of the drug, ranging from the RLS symptoms to the autonomic perturbations, with a potential protective effect on the cardiovascular system.
By three large and multicenter studies we demonstrated that multiple sclerosis is a significant risk factor for
RLS and, by unconventional MRI analysis, we showed that spinal cord lesions represent a specific risk for RLS.
Luigi Ferini-Strambi
CLINICAL PSYCHOLOGY
Mentalized affectivity, emotion instability, disorders of the Self, and aggression
The research project aimed at assessing the role of deficits in mentalization and emotion dysregulation in aggressive behaviors. A major result was that deficits mentalized affectivity significantly mediated the effects of attachment styles on impulsive aggressiveness, at least in nonclinical participants. A second major findigs was the
evidence of a dissociability of proactive aggression - from reactive aggression based on measures of emotional
instability. Interestingly, different manifestations of narcissistic personality were shown to have distinct patterns
of associations with reactive and proactive dimensions of aggression. Finally, over narcissistic personality features were shown to mediate the relation between the edonistic style of prosocial moral reasoning and proactive
aggression.
Cesare Maffei
MOTOR FUNCTION REHABILITATION
Analysis and rehabilitation of motor function
Research activities focuses on interactions between physiological aspects of motor control and motor performance in healthy subjects and subjects with motor impairments. Among the physiological variables involved
in the motor control, the studies concentrated on movement biomechanics and cortical brain activations, measured during the execution of motor tasks which are performed with different cognitive facilitations.
Biomechanical studies were carried out in the Lab of movement analysis of the School of physiotherapy,
measuring the gesture kinematics, the ground reaction forces, the surface electromyography and the muscular
torque. Topics were the gait analysis and the study of motor coordination. An example of gait analysis is the
biomechanical study of gait after knee replacement with different kinds of prosthesis. An example of study on
coordination regards the activation of agonist and stabilization muscles during the movement of lower limbs,
studied through surface electromyography in subjects with multiple sclerosis. Moreover, a collaboration with
the Functional Unit of Quantitative Neuroimaging of the San Raffaele Hospital, allowed to study the effect of
cognitive facilitations such as the execution of transitive versus intransitive task, the use of a video showing the
movement to be executed and the use of a mirror reflecting the movement of the contra lateral hand on brain
activation of healthy subjects.
Finally, we studied clinical applications of the facilitations analyzed with the fRMI. Examples are the observation training, the mirror therapy and the task-oriented movement. Observation training is a new approach
where patients watch videos showing an action and then are asked to perform it. In mirror facilitation patients
look at mirror that, reflecting movements of the sound side of the body, produces the illusion of movement of
the affected side. Task oriented exercises insert the motor impairment in a known and transitive gesture. A particular kind of task oriented exercise that we are studying is the application of the constraint induced movement therapy to the lower limbs of subjects affected by stroke. These subjects have to execute functional activities wearing devices like a knee brace and a skate on the sound lower limb.
Roberto Gatti
INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE)
Director: Giancarlo Comi*
The Institute of Experimental Neurology (INSPE) constitutes
one of the major European institutes primarily dedicated to
translational research in the neuroscience field. The overall ambition is to conjugate high level of basic research with the specific competences in pre-clinical and clinical research. This is
achievable considering that INSPE includes both research laboratories and the Neurological Department of the San Raffaele
Scientific Institute. Multiple sclerosis, stroke, traumatic injuries
of the central and peripheral nervous system, and neuromuscular diseases do represent the primary targets of the INSPE reGiancarlo Comi
search although research in neurodegenerative disorders is also
in the pipeline of the institute.
The primary goal is to better understand the molecular mechanisms that sustain inflammatory and degenerative pathogenic mechanisms underlying neurological disorders so to identify therapeutic targets,
validate in co-operation with third parties new treatments, develop new disease biomarkers for both
clinical trials and patients monitoring. The neurological department is deeply involved in the definition
of new treatment algorithms for stroke, inflammatory and neurodegenerative diseases. The molecular
and functional bases for central and peripheral nervous system recovery processes and the potential to
modulate them by cellular and gene therapy and by specific rehabilitation interventions are another area
of interest of INSPE.
The INSPE laboratories spans on three different levels in a newly established building within the DIBIT II. One floor is dedicated to neuropathlogy, experimental neurophysiology, neurogenetics of monogenic and complex diseases. Another floor is dedicated to basic and clinical neuroimmunology, neurobiology and neural stem cell research. The third floor is mainly focused on neuroimaging of neuro-inflammatory and neuro-degenerative disorders. Other laboratories involved in behavioral research and in signals
that regulate myelination and in clinical neurophysiology are also part of the Institute.
Research Units
EXPERIMENTAL NEUROPATHOLOGY
Implementation of new biomedical devices to promote nerve regeneration. Proposal and validation of new
histopathological criteria for early diagnosis of Motor Neuron Disease
Collagen-based scaffold for peripheral nerve regeneration: in vivo regeneration of human sural nerve. The
aim of the project is to evaluate the efficacy of collagen devices (MD) in order to facilitate the regeneration of
the PNS. Innovative is the use of a new biomaterial, which consists of a collagen tube in order to induce the regeneration of the nerve. The MD is based on the pattern of micropores acting as guides for regeneration
processes. We evaluated first the biocompatibility and the activity in nerve regeneration following implantation
of the MD. The functions of the MD are multiple: guidance regeneration; minimizing the infiltration of fibrous
tissue; possessing an adequate mechanical resistance and flexibility supporting the nerve regeneration; being
bio-compatible and bio-absorbable. The second objective of this study is to evaluate the regeneration of the
adult human sural nerve using this MD. A tube will be implanted into a 10-mm long gap in the sural nerve resulting from a biopsy taken for diagnosis of neuropathies. In case of positive result, the MD will be applied in
the neurosurgery field.
Early Diagnosis of Motor Neuropathy (MN) and Lower Motor Neuron Disease (LMND) by Motor Nerve
and Muscle Biopsy. Amyotrophic Lateral Sclerosis (ALS) is a severe degenerative disorder of the Central Nervous system CNS characterized by the destruction of upper motor neurons (UMNs) in the motor cortex and
lower motor neurons (LMNs) in the spinal cord and brainstem. The differential diagnosis is particularly important in the first stages of the disease as some forms of MN,are potentially treatable conditions with a normal life
expectancy,whereas ALS is an irreversible and fatal disease. We prospectively studied 21 consecutive patients
with a suspected diagnosis of MN or LMND. All patients were submitted to motor nerve biopsy of the obturator nerve and gracilis muscle. In 13 patients pathological findings suggested a suspected diagnosis of LMND. A
pathological diagnosis of suspected MN was made in 8 patients. At two years of follow-up we confirmed all the
diagnosis made on histopathological basis.We propose new histopathological diagnostic criteria to differentiate
these two different conditions.
Angelo Quattrini
EXPERIMENTAL NEUROPHYSIOLOGY
Our unit is involved in the non-invasive assessment of central nervous system function in physiological conditions and in diseases affecting the sensorimotor system, both in humans and in rodent models of neurological
diseases. We use electrophysiological methods (EEG, evoked potentials, transcranial magnetic stimulation),
alone or in combination with psychophysiological testing or functional-anatomical imaging techniques such as
magnetic resonance imaging.
In the past year, we investigated:
1) the reorganization of the motor system occurring with healthy aging, by mapping the motor representation
of the upper limb at rest using transcranial magnetic stimulation (evoking muscle responses) and by mapping
the spatiotemporal cortical activation during motor performance using high-resolution EEG. We found decreased selectivity and speed of muscle activation with aging, together with a reduced hemispheric dominance
in muscle cortical representation and segregation at TMS. We also investigated patients with stroke and Parkinson’s disease and are currently performing correlation between the pattern of cortical changes in the motor representation and the severity of neurological involvement.
2) functional cortical changes occurring in adults with Down syndrome using low-resolution tomography
(LORETA) of EEG rhythms at rest. Topographic abnormalities of EEG sources, analyzed in 34 patients, was
significantly correlated with the severity of cognitive involvement at neuropsychological testing, suggesting that
this EEG methodology may be applied in the investigation of cognitive functions in other neuropsychiatric conditions leading to cortical and subcortical dementia.
3) effects of neuromodulation to transcranial direct stimulation (tDCS) in mice. In a pilot study we investigating whether the effects of tDCS, which in humans has been been shown to enhance motor responses evoked by
TMS, could be replicated in mice on motor responses to transcranial electrical stimulation(TES). Similarly to
human findings, we found that anodal tDCS enhances muscle responses evoked by TES, while the opposite occurs with cathodal tDCS. This findingopens the way to further studies aimed at investigating specific
cortical/subcortical mechanisms on the effect of tDCS on the brain.
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 Ras-ERK intracellular signalling pathway that is
crucially involved in transducing signals from the neurotransmittter receptors to the nucleus, hence controlling
chromatin remodelling and gene expression, key steps involved in synaptic remodelling, long-term plasticity
and formation of long-term memory. Once receptors are activated, specific guanine exchange factors (GEFs)
are able to catalyse the exchange of GTP for GTP on Ras proteins, thus activating this class of small GTPases.
One of these GEFs is Ras-GRF1, which is exclusively expressed in the CNS. Conversely, GTPase Activating
Proteins do exactly the opposite and by removing a phosphate from GTP bound Ras inactivates the signalling.
Importantly, loss of function mutations in NF1 gene product neurofibromin, that preferentially activates the KRas isoform, lead to Neurofibromatosis type 1 disease. Activated Ras proteins then stimulate the core element
of the signalling pathway, the Ras-MEK-ERK protein kinase cascade.
Our laboratory is especially interested in investigating how the modulation of this pathway influences the
physiological response to different neurotransmitter systems and drugs of abuse. In that respect we have paid
particular attention to the striatum. This brain structure is a collection of several nuclei involved in a variety of
behaviours and brain diseases, including procedural and motor learning, drug addiction and Parkinson’s disease. We have recently completed the analysis of several mouse strains bearing mutations affecting striatum-dependent behavioural plasticity. For instance, mice deficient for Ras-GRF1 show major impairments in the
process of memory consolidation as revealed by several striatum-dependent learning tasks and also manifest
deficits in behavioural responses to drugs of abuse. Moreover, we showed that expression in the dorsal portion
of the striatum of a potent inhibitor of the CREB family of transcription factors in a reversible manner results in
significant alterations at the level of procedural memory and drug-dependent behaviour. Finally, we showed
that a conditional, forebrain specific gain of function mutation in K-Ras (K-RasG12V) largely recapitulates the
cognitive impairments found in NF1 mutant mice.
Riccardo Brambilla
NEUROMUSCULAR REPAIR
The role of adhesion in neuromuscular disorders
Progressive tissue degeneration and defective regeneration are responsible for disability in most chronic neuromuscular disorders, including hereditary neuropathies (HN) and muscular dystrophies. Although in many
cases the genetic causes and the clinical manifestations are well described, much remains unknown about the
pathogenetic mechanisms and in almost all the cases no reliable therapy is still available. The research field of
the unit is to investigate the pathogenetic role of adhesion in neuromuscular disorders, and its involvement in
tissue regeneration. Our main aims of studies are:
1) The efficacy of extracellular matrix (ECM) remodeling to promote regeneration in HN and congenital
muscular dystrophy (CMD). We are exploiting drug and cell therapy to interfere with ECM composition
in animal models of HN and CMD. For example, mesoangioblasts has been revealing as good carrier cells
to deliver in muscle and nerve cross-linker molecule to re-connect cells to the basement membrane in
CMD models. Preliminary studies showed amelioration of functional performances and muscle histology.
2) Role of the Schwann cell cytoskeleton in nerve development and regeneration. We are studying the consequences of the disruption of the Schwann cell cytoskeleton constituents, such as the intermediate filaments, on peripheral nerve development, function and regeneration. We observed that Vimentin deletion
in transgenic mice alters the Schwann cell-axon relationship and interfere with nerve regeneration.
3) The adhesion-derived intracellular signaling in nerve development and regeneration: the role of Jab-1.
We are investigating the role of the intracellular signaling molecule Jab-1 in nerve development and repair. Jab-1 is modulated by ECM and surface receptor signals, and is involved in the control of the cell cycle, protein degradation and gene transcription. Jab-1 is expressed by Schwann cells and modulated during myelination and nerve regeneration.
Stefano Carlo Previtali
NEUROIMMUNOLOGY UNIT
Neuroinflammation promotes damage and inhibits central nervous system repair in multiple sclerosis by
different molecular pathways
The role of inflammatory pathways in promoting vs. protecting from widespread damage in chronic inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS), is still far from being elucidated.
To dissect the inflammatory-mediated mechanisms leading to tissue damage vs. protection in MS, mice with experimental autoimmune encephalomyelitis (EAE) have been used as experimental tool. On one hand, we have
found that inflammation is capable to enhance glutamate transmission in the striatum, and to promote synaptic
degeneration and dendritic spine loss. These alterations occur early in the course of EAE, are independent of
demyelination, and are strongly associated with massive release of tumor necrosis factor (TNF) α from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced
synaptopathy subsided upon pharmacological blockade of AMPA receptors. On the other hand, we have found
pro-inflammatory cytokines (e.g. TNF-α, IFN-γ), inducing an increase of several cyclin-dependent kinase inhibitors (in particular of those inhibiting both M and S phase cell entry), induces morphological and functional
alterations of neural precursor/stem cell (NPCs) in the germinal niches. As a net effect, a reduced number of
type C (transit amplifying cells) and B (bona fide true stem cells) cells differentiating into type A (neuroblasts)
and type C cells is observed early after disease onset. To better understand the role of endogenous NPCs and
further explore the molecular mechanisms underlying the inflammatory-related impairment during EAE, we
have now generated a transgenic mouse line expressesing the ligand-dependent CRE/ERT2 gene under the
control of AspM regulatory regions and a second line in which the TK killing gene is under the control of the
nestin promoter. Our data indicate that neuroinflammation might promote damage and inhibit CNS repair in
MS by different, and only apparently distinct, pathways.
Gianvito Martino
CLINICAL NEUROIMMUNOLOGY
The Unit of Clinical Neuroimmunology is currently active in both experimental and clinical neuroimmunology with the aim to have a bi-directional transfer of scientific questions and experimental data between the two.
Active projects are:
• Gene therapy of experimental autoimmune encephalomyelitis (EAE). Our group established a CNS-targeted gene-delivery approach using non-replicative viral vectors injected in the cerebrospinal fluid (CSF)
circulation. We are using newly prepared IL-25 and IL-27-expressing lentiviral vectors to address the involvement of these molecules, part of a novel pathway in mice models and in human multiple sclerosis
(MS).
•
•
•
•
•
Role of Treg cells in the modulation of EAE. We are assessing the role of FoxP3+ Treg cells in the modulation of chronic and relapsing EAE, and their potential therapeutic potential both in a cell therapy setting and using drugs able to increase their number or recruitment.
The role of shed-vesicles of neural origin in EAE. Shed vesicles are newly described particles released by
several cell types through membrane budding whose physiological and patho-physiological role is unclear. We are currently investigating their production, content, and fate in EAE and MS.
The role of Treg cells in MS and related treatments. We are currently establishing, also on the basis of
what we have learned in mice, the best way to monitor Treg modulation in human MS patients. We are investigating their contribution in the different disease phases and clinical forms, and their modulation by
treatments, such as immunomodulatory drugs, or bone marrow transplantation.
Immunological markers in MS and psychiatric disorders. We use several different technological platforms, spanning from gene expression to microRNA, to multiparametric protein detection. We have ongoing investigations on MS patients, undergoing or not immunomodulatory or immunosuppressive treatments. We have recently extended our activity to patients affected by major psychoses such as schizophrenia, major depression, and bipolar disorder.
Identification of auto-antibodies in neurological disorders. We are screening sera from patients affected
by optic neuritis, retinitis, myelitis, and movement disorder to identify novel autoantibodies, and their
corresponding auto-antigen.
Roberto Furlan
CNS REPAIR
Somatic stem cell-based therapies of central nervous system (CNS) diseases
The development of cell-based therapies aimed to promote tissue repair in central nervous system (CNS) diseases, represents one of the most challenging areas of investigation in the field of regenerative medicine. Several cell-replacement strategies have been developed in the last few years. Recent evidence from our and other
labs indicates that undifferentiated neural stem/precursor cells (NPCs) might very efficiently protect the CNS
from chronic degeneration induced by inflammation both in small rodents as well as in primates (Nature 2003,
422: 688-694; Nature 2005, 436: 266-271; Stem Cells 2007, 5: 2583-2592; Ann Neurol, in the press). However,
before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions:
the ideal stem cell source for transplantation; the ideal route of cell administration; the differentiation and
persistence of stem cells into the targeted tissue and - last but not least - the functional and long-lasting integration of transplanted cells into the host tissue (Nat Rev Neurosci 2006, 7: 395-406).
Current projects in the laboratory have been further exploring the cellular and molecular mechanisms regulating the therapeutic plasticity of NPCs in inflammatory CNS diseases such as multiple sclerosis, ischemic
stroke and spinal cord injury, both in rodents as well as in non-human primates (Ann Neurol, in the press;
Brain, in the press; PLoS One, in the press).
Stefano Pluchino
Figure 5. Transmission electron microscopy (TEM)
images a large-size immunogold-labelled GFP+ NPC
within a cervical lymph node of a R-EAE mouse at 72
days after cell injection. These GFP+ cells display
morphological and ultrastructural features similar to
individual NPCs from neurospheres in vitro. The NPC
(pseudocolor green) takes contact with four individual
lymph node cells (pseudocolor orange). The NPC shows
an irregular and invaginated nucleus (n) with a single
nucleolus (nu), and its cytoplasm contains abundant
organelles (from Pluchino et al., PLoS One, in the press).
NEUROIMAGING RESEARCH UNIT
Assessment of Treatment Efficacy in MS Clinical Trials: treatment with glatiramer acetate (GA) of patients
with clinical isolated syndromes suggestive of MS reduces the conversion to clinically definite MS; in relapsingremitting (RR) MS, short-term combination of GA with IV Methylprednisolone may result in an early and sustained reduction of disease activity; Protiramer is safe and well tolerated in patients with RRMS.
In vivo Assessment of MS Pathophysiology by Quantitative MRI: grey matter (GM) volume loss follows different patterns of regional distribution according to the clinical MS phenotypes; over a one-year period, cortical lesions increase their number and size in a relevant proportion of MS patients; in benign MS the cortex is relatively spared, cognitive dysfunction is associated with the extent of corpus callosum damage, absence of cognitive
impairment and longer disease duration or lower disability identify patients with favorable disease evolution.
Functional MRI in MS: large multicenter fMRI studies of brain activations and effective connectivity in MS
are feasible; pediatric MS is associated with a preserved brain functional reserve (i.e., maintenance of selective
and strictly lateralized pattern of movement-associated activations and modulation of its functional connections); tactile-associated cervical cord overactivation is more prominent in relapse-onset MS patients with more
severe locomotor disability, and occurs also in primary progressive MS patients.
Structural and Functional MRI in Aging and Neurodegenerative Diseases: apoE4 is associated with a more
severe disease-specific pattern of brain atrophy in Alzheimer’s disease (AD) and frontotemporal dementia at
presentation; a widespread brain functional rewiring with increasing structural damage rather than a specific
response to cognitive network injury occurs in AD; semantic dementia is associated with anatomical damage to
the major temporal connections involved in semantic/lexical processes, with relative sparing of fronto-parietal
network; over less than 1 year, amyotrophic lateral sclerosis patients show cervical cord tissue loss and microstructural injury (which are independent of brain changes), and progression of GM atrophy in motor cortex
and basal ganglia.
Massimo Filippi
NEUROIMAGING OF CNS WHITE MATTER
In vivo assessment of pathophysiology of MS and other white matter diseases using MR-based techniques
Using functional magnetic resonance imaging (fMRI) and quantitative MR-based techniques, we found that: 1)
large multicenter fMRI studies of functional activations and effective connectivity changes in MS people are feasible
and can facilitate studies with sample sizes large enough for robust outcomes; 2) patients with pediatric MS maintain a selective and strictly lateralized pattern of movement-associated brain activations and functional connections,
suggesting a preserved functional reserve in these patients, which, in turn, might contribute to explain their favorable clinical evolution at short/medium term; 3) patients with relapsing-remitting MS with a normal level of function have an increased activation of regions which are part of the mirror neuron system, despite the presence of
widespread central nervous system damage, suggesting a possible adaptive role of these fMRI changes; 4) in patients
with benign (B) MS, abnormal activations of cognitive-related network as well as abnormal coefficients of connectivity inside this network occur during the performance of the Stroop task. The correlation found between measures
of abnormal functional connectivity and structural MRI metrics of tissue damage within intra- and inter-hemispheric cognitive related white matter (WM) fiber bundles suggest that functional cortical changes in BMS might represent an adaptive response driven by damage to specific WM structures; 5) in patients at presentation with clinically
isolated syndromes suggestive of MS, macroscopic focal lesions but not "diffuse" brain damage measured using
magnetization transfer MRI are associated to an increased risk of subsequent development of definite MS; 6) diffusion tensor tractography discloses optic radiation changes in patients with migraine with aura, which might represent a phenotypic biomarker of the disease given the lack of a correlation with clinical and structural MRI metrics.
Maria Assunta Rocca
HUMAN INHERITED NEUROPATHIES UNIT
MTMR2 phospholipid phosphatase as a regulator of membrane biogenesis during Schwann cell myelination
Myelin biogenesis is a major event during development of glial cells whose perturbation causes severe neurological disorders. Since myelin is a highly polarized structure, myelin biogenesis involves sorting and targeting
of selected lipids, proteins, and mRNAs to specific sub-domains, with a strong analogy to the polarized transport in epithelial cells and neuronal synapses.
However, the molecular machinery that directs the sorting and mediates polarized transport and targeting in
myelin-forming glial cells is largely unknown. Myotubularin-related (MTMR) 2 protein represents a ubiquitously expressed phospholipid phosphatase whose loss in human and mouse causes Charcot-Marie-Tooth type
4B1 neuropathy with myelin outfoldings, aberrant foldings of excessive membrane. We first generated a
Mtmr2-null mouse which reproduces the neuropathy. We also found that in Schwann cells Mtmr2 interacts
with Dlg1, a scaffold involved in cell polarity and membrane addition. As already demonstrated in differentiating oligodendrocytes and neuronal synapses, multidomain scaffolds play a role in membrane polarity and protein trafficking. We therefore exploited the Mtmr2-null mouse and myelin outfoldings as a model to assess
whether also in Schwann cells membrane addition/remodeling might be regulated by a multi-molecular complex organized by the Dlg1 scaffold. We provided evidence of the first machinery that in Schwann cells titrates
myelin formation during myelination.
Alessandra Bolino
AXO-GLIA INTERACTIONS UNIT
Role of secretases in type III Neuregulin-1 cleavage and myelination
Myelin is a highly specialized membrane which wraps around the axons in the peripheral (PNS) and central
nervous system (CNS) and is required to facilitate the efficient and rapid propagation of nerve impulses. Myelin
formation is tightly regulated and while the molecular events controlling the development of Schwann cells
(SC) and oligodendrocytes (OL) have been characterized, the axonal mechanisms directing its production have
been only recently identified. 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.
The development of OL and SC critically depends on axonal contact. Axons promote the proliferation, survival and differentiation of myelinating glia. Glial cells, in turn, promote neuronal survival and regulate the organization and maintain the integrity of axons. We have recently demonstrated that type III NRG1, a member
of the NRG1 family of growth factors, is the instructive signal for myelination in the PNS. Above a threshold
level of expression of type III NRG1, axons are myelinated and the amount of myelin is proportional to the levels of type III NRG1 present on the axons. We have also showed that in the CNS, type III NRG1 is not essential for OL myelination and the regulation of myelination in PNS and CNS is distinct.
In our laboratory we investigate the signals on the axon, and the downstream signaling pathways they activate
in myelinating glia, that regulate the formation of glial cells and maintenance of the myelin sheath. NRG1 are
proteolytically cleaved in their extra and intracellular domains, thus, we are examining the role of this cleavage
events in NRG1 cleavage and in myelination. Upon cleavage in the juxtamembrane region type III NRG1 remains tethered on the axonal surface and acts as a juxtacrine signal. We are now investigating the identity of the
secretases involved in NRG1 cleavage and their role in myelination. Our preliminary observations suggest the
ADAM 17 participates in type III NRG1 cleavage and, in vitro and in vivo studies, suggest that this cleavage
event controls myelination.
Carla Taveggia
INFLAMMATORY CNS DISORDERS UNIT
Our Clinical Unit was involved in many International RCTs (phase II, III or IV) to evaluate the safety and efficacy of newly-developed immunosuppressive or immunomodulatory drugs (Fingolimod, Laquinimod,
Cladribine, Teriflunomide, Firategrast Ocrelizumab and Alemtuzumab) or symptomatic therapies (Sativex and
Naltrexone) on MS patients. We coordinated a multicentre RCT on the long term benefits of a sequential therapy with Mitoxantrone (MTX) followed by Β-Interferon (IFN) on patients with bad prognostic factors in the
early phase of the disease. Moreover, we concluded 2 multicentre RCTs in patients with a first demyelinating
clinical event suggestive of MS; both RCTs demonstrated a significant beneficial effect of Glatiramer Acetate
(GA) (PRECISE) or IFN (BENEFIT) in delaying the conversion to MS.
We collected and analyzed, using a computerized database, clinical and laboratory data on more than 3000
MS patients, treated with immunomodulatory and immunosuppressive drugs, to identify possible predictors of
clinical efficacy or safety. In particular, we conducted a retrospective analysis on the efficacy of MTX treatment
in patients with RR and SP MS. Moreover we were the promoting centre of a national multicentre retrospective
study to evaluate the incidence of Acute Leukaemia in patients who had undergone MTX therapy.
We conducted a study with a whole-genome case-control approach using the Illumina platform, to identify allelic variants associated with the risk to develop MS and its variant “primary progressive”.
We planned a study to assess the efficacy of different aspects of intensive rehabilitation in MS patients with
and without fatigue. We conducted a study to evaluate the psychological correlates and the coping strategies
developed by patients with an early diagnosis of MS as well as the impact of MS diagnosis on the psychological
aspects of sexuality and maternity. We were also involved in an Italian co-operative study to explore both the affective and cognitive correlates of IFN and GA in adult and childhood-juvenile MS patients.
Finally, we evaluated the clinical, immunological, and MRI characteristics of “atypical” forms of MS, to define
an algorithm able to differentiate CNS demyelinating diseases from other primary CNS inflammatory diseases.
Vittorio Martinelli
CEREBROVASCULAR DISORDERS
The cerebrovascular patient: from bedside to bench and vice versa
The Stroke Team is involved in:
a) Optimization of the diagnostic workup and therapeutic management, in accordance with the requests of
the International Joint Commission for the recognition of the standard of excellence. We are the coordinator of a multicentric project aimed at the definition of outcomes of efficacy and efficiency in the management of the cerebrovascular patients.
b) International clinical trials evaluating therapeutic strategies in primary and secondary prevention.
c) Individuation and validation of diagnostic/prognostic markers.
• Biochemical markers – within a collaborative project funded by the Ministry of Health we are collecting
samples from patients undergoing thrombolysis in order to study the possible prognostic role of markers of haemostasis and inflammation.
• Cognitive markers - all consecutive patients admitted to the Stroke Unit are evaluated in the acute
phase and with repeated neuropsychological testings. Preliminary results indicate that executive dysfunctions are one of the most relevant consequences of stroke and TIA and that the Frontal Assessment
Battery represents a good measure of these dysfunctions and a good predictor of long-term cognitive
outcome (Arcari C et al).
d) Studies aimed to the identification of markers of instability of the carotid plaque. In collaboration with
the Cardiovascular Dept, we studied 32 patients with asymptomatic and symptomatic carotid stenosis
with Color or Power B-mode Ultrasonography (US) and histopathological analysis of the carotid plaque
(CP). Preliminary results show that US allow a detailed in vivo study of CP morphology and that CP unstable by US are more often characterized by intra-plaque thrombosis/ hemorrhage (Piscopiello M,
Spinelli M et al).
e) Studies aimed at the characterization of genetic determinants of ischemic stroke risk, with a whole
genome approach using a Bead Station 500® (Illumina®).
f) Studies aimed at the identification of the physiopathological role of patent forame ovale in patients with
migraine and/or stroke. 48 subjects were screened for the persistence of right-to-left shunt (RLS) with
transcranial Doppler and for the presence of white matter lesions (WMLs) using a 3.0 Tesla MRI. Preliminary results indicate that the presence of RLS does not increase WMLs.
Maria Sessa
MEMORY DISORDERS
The aim of our Unit is to identify early markers of disease to achieve the diagnosis in the early stage of
Alzheimer’s Disease (AD) and other dementias (non-AD dementia). The concept of the boundary between normal aging and very early or mild dementia has become an area of interest for theoretical and practical reasons.
Therefore, identification of early clinical AD has become an important public health priority as new treatments
have emerged. The main task of our unit is primarily the recruitment and proper diagnostic classification of patients with memory disorders and dementias respecting international diagnostic criteria: the correct identification of patients with dementia is the cornerstone of any type of study (neuroradiological, epidemiological, neurophysiological, genetics). Our Unit works in close collaboration with the Neuroimaging Research Unit (M. Filippi and F. Agosta) and Functional Neuroradiology Unit (A. Falini) to identify structural and functional MR
markers for the early diagnosis of the mild cognitive impairment (MCI), to define the structural and functional
CNS changes associated with the conversion of MCI to dementia and to characterize the structural and functional substrates of the non-AD dementia (i.e., frontotemporal dementia). Additional approaches in close collaboration with the Experimental Neurophysiology Unit (L. Leocani) have been based on studies on programming of voluntary movement and motor control in aged normal subjects, MCI and AD patients. Our interest is
also focused on the genetic components of AD. The Center is engaged in the collection of blood samples to create a clinical database and biological bank of subjects suffering from dementia with the aim to identify genetic
factors involved in the risk of developing dementia and in the individual response to drugs (F. MartinelliBoneschi; Laboratory of neurological complex disorders), for which a -genome-wide study has been recently
completed on 180 AD-treated patients. We are also involved in clinical pharmacological trials to provide to AD
patients innovative drugs.
Giuseppe Magnani
MOVEMENT DISORDERS
Our group is working on different fields of interest, in particular: 1)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) and identification of guidelines for the treatment with BT-A in MS patients with neurogenic bladder without urine retention. Moreover, it just started transcranial magnetic stimulation (TMS) study
of the exteroceptive suppression (“geste antagoniste”) in cervical dystonia. 2) 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. 3) the interoperating monitoring (IOM). In
the past year we perfected the protocol: ‘clinical and neurophysiological study of the efficacy and safety of the
repetitive transcranial magnetic stimulation (rTMS) in chronic neurogenic pain (CNP)’ and now almost all
question with ethic committee are clear up. We are also keeping on our animal neurophysiological studies in
several model of experimental peripheral neuropathy, like the nervous regeneration after crush, and verify
whether the association of classical neurophysiological tests and stimulated single fiber electromyography
(SFEMG) may contribute to better describe axonal and muscle fibers regeneration.
Ubaldo Del Carro
NEUROMUSCULAR DISORDERS
My group is working on two different topics Neuromuscular diseases and Clinical Neuroimmunology.
Neuromuscular diseases are a very heterogeneous group of neurological diseases including muscular diseases,
peripheral neuropathies and motor neuron diseases.
The pathogenic mechanisms underlying these diseases are heterogeneous too, including inflammation, au-
toimmunity, degenerative damage and genetic one.
The aims of our clinical studies is to give the best medical supports to our patient through new diagnostic
tools (i.e. detecting new markers, for example new antigens targets for autoimmune response against neuromuscular system, assessment of cutaneous biopsies in sensitive neuropathies), new therapeutic strategies (e.i.
FKT in ataxic patients ), new management of disability (i.e. timing of ventilations or PEG in ALS patients) new
drugs not only directed against the cause of the disease (immunomodulation in autoimmune peripheral neuropathies, talampanel and lithium in ALS patients) but also drugs inducing amelioration of the clinical symptoms (e.i. fatigue or pain in peripheral neuropathy) and signs in order to improve the life quality of our patients,
new modality for drugs intake (as subcutaneous immunoglobulins instead of ev immunoglobulins in dysimmune neuropathies). These clinical trials are organized in different experimental designs from controlled multi
centric trials to local observational and retrospective studies.
About clinical neuroimmunology we studied the presence of anti AQ4 antibodies in neuromyelitis optica
(Devic disease). We created an Italian multicentric web to collect sera from patients with Devic disease and we
analysed patient sera by tissue immunocytochemistry, immunofluorescence on stable cell line, and cell FACS
analysis in order to give an easy diagnostic tool for the detection of this inflammatory disease. We are evaluating
if these antibodies have a prognostic value in a prospective longitudinal study on relapsing myelitis.
Furthermore we are screening sera from patients affected by optic neuritis, retinitis, myelitis, and movement
disorders with the aim to identify new autoantibodies, and their corresponding auto-antigen.
Raffaella Fazio
PAROXYSMAL EVENTS
Our unit is principally involved in the evaluation of epileptic patterns during status epilepticus and single
seizures. Status epilecticus is a medical emergency and the times for its identification and treatment influence
the prognosis of the patient. The current limits are especially connected to the possibilities of access of instrumental diagnosis and to the lack of therapeutic protocols universally acknowledged. For a correct diagnosis of
non convulsive status epilepticus and to verify the effects of the therapies is essential the contribution of neurophysiological diagnostic and, in particular, the electroencephalographic one. Long term EEG monitoring
(LTM) is a well-established procedure in the evaluation of epilepsy patients. The analysis of EEG recordings is
necessary to determine the seizure onset zone. LTM is also particularly useful in the evaluation of critically ill
patients, in which seizures are frequently silent, and in the pre-surgical evaluation of patients with pharmacorefractory epilepsy. Main goal of our studies is related to the automatic analysis of seizures EEG pattern in order
to obtain a 24 hours of monitoring of patiens.
We are also involved in the neurophysiological evaluation of mechanisms mediating epileptogenesis in Tuberous Sclerosis Complex in mice and in the human evaluation of therapy with Rapamycin. This drugs has no documented properties as an anticonvulsant agent but it has strong efficacy for preventing epileptic encephalopathy in animal model of Tuberous Sclerosis.
Fabio Minicucci
Molecular genetics of mental retardation Unit
Clinical Neuroimmunology
CNS repair
DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES - 53
DIVISION OF METABOLIC
AND CARDIOVASCULAR SCIENCES
Research Units
Amino acid and stable isotopes Unit
HEAD OF UNIT: Livio Luzi
RESEARCHERS: Andrea Caumo, Stefano Benedini, Roberto Codella, Ileana Terruzzi
FELLOWS: Anna Montesano, Pamela Senesi
GROUP LEADER: Gianpaolo Zerbini
RESEARCHERS: Mara Lorenzi, Anna Maestroni
PHD STUDENT: Silvia Maestroni
CONSULTANT: Gemma Tremolada
TECHNICIAN: Daniela Gabellini
Obesity and metabolic related diseases
GROUP LEADER: Gianluca Perseghin
RESEARCHER: Guido Lattuada
TECHNICIAN: Francesca Ragogna
HEAD OF UNIT: Alessandro Rubinacci
RESEARCHER: Isabella Villa
POST-DOCTORAL FELLOW: Emanuela Mrak
CONSULTANTS: Giovanna Mignogna, Gianluigi Moro, Marcella Sirtori
TECHNICIAN: Ennio Leporati
Coagulation service & thrombosis research Unit
HEAD OF UNIT: Armando D’Angelo
RESEARCHERS: Luciano Crippa, Patrizia Della Valle, Annalisa Fattorini, Silvana Viganò
FELLOW: Giulia Pavani
TECHNICIAN: Francesca Sampietro
Cardiodiabetes & Core Lab
HEAD OF UNIT: Emanuele Bosi*
GROUP LEADER: Lucilla D. Monti
FELLOW: Elena Galluccio
TECHNICIANS: Sabrina Costa, Barbara Fontana
Pediatric endocrinology research
HEAD OF UNIT: Giuseppe Chiumello*
GROUP LEADER: Stefano Mora
FELLOWS: Silvia Carlucci, Annalisa Donini, Silvia Genovese, Ilaria Zamproni
TECHNICIAN: Maria Puzzovio
Diabetes and endocrinologyUnit
PHYSICIANS: Alberto Davalli, Gabriella Galimberti, Roberto Lanzi, Marco Federico Manzoni, Alessandro Saibene
RESIDENTS: Chiara Cappelletti, Valentina Crippa, Valentina Doria, Ilaria Formenti, Manuela Fortunato, Andrea Laurenzi,
Sara Madaschi, Elena Peretti, Francesca Perticone, Cecilia Piani, Maria Grazia Radaelli, Alessandro Rossini,
Annachiara Uccellatore, Valentina Villa
TECHNICIAN NUTRITIONIST: Monica Marchi
Cardiodiabetes and clinical trials
CLINICAL GROUP LEADER: Piermarco Piatti
FELLOWS: Emanuela Setola, Pietro Lucotti
Pediatrics Unit
Clinical pediatric endocrinology
CLINICAL GROUP LEADER: Giovanna Weber*
RESEARCHERS: Stefania Di Candia, Gabriella Pozzobon, Gianni Russo, Maria Cristina Vigone
Diabetes and metabolic diseases in children and adolescents
CLINICAL GROUP LEADER: Franco Meschi
RESEARCHERS: Karen Marenzi, Matteo Viscardi
Neonatology
CLINICAL GROUP LEADER: Graziano Barera
RESEARCHERS: Antonella Poloniato, Rosanna Rovelli
RESIDENT: Patrizia Corsin
Gynecology and Obstetrics Unit
Foetal-maternal medicine
CLINICAL GROUP LEADER: Maria Teresa Castiglioni
RESEARCHERS: Susanna Rosa, Maddalena Smid, Luca Valsecchi
PHD STUDENT: Paolo Cavoretto
FELLOWS: Federica Pasi, Serena Pirola, Audrey Serafini
Infertility
CLINICAL GROUP LEADER: Francesco Fusi
RESEARCHERS: Ilaria Cino, Lucia De Santis, Michela Molgora, Nicoletta Panacci, Enrico Papaleo, Simone Rofena
POST-DOCTORAL FELLOW: Elena Gismano
HEAD OF UNIT: Antonio Colombo
PHYSICIANS: Mauro Carlino, Alfredo Castelli, Alaide Chieffo, Iassen Michev, Matteo Montorfano
FELLOWS: Marta Bande, Cosmo Godino, Alfonso Ielasi, Azeem Mohamed Latib, Valeria Magni
RESIDENTS: Raffaele Lacquaniti, Marco Mussardo
TRIAL COORDINATOR: Angela Ferrari
Clinical cardiovascular biology Unit
HEAD OF UNIT: Domenico Cianflone*
PHYSICIANS: Enrico Ammirati, Stefano Coli, Nicole Cristell, Marco Magnoni
RESIDENT: Anna Chiara Vermi
POST-DOCTORAL FELLOWS: Dina Ianzano, Norma Maugeri
MD STUDENTS: Alessandro Durante, Alberto Monello
TECHNICIANS: Michela Banfi, Fabrizio Sioli
RESEARCH NURSE: Barbara Pontiroli
Ischaemic heart disease, heart failure and echocardiography Unit
HEAD OF UNIT: Alberto Margonato
PHYSICIANS: Eustachio Agricola, Alberto Capelletti, Andrea Conversano, Gabriele Fragasso, Stefano Gerosa, Andrea Macchi,
Michele Oppizzi
RESIDENTS: Michela Cera, Irene Franzoni, Chiara Gardini, Annalisa Pessina, Anna Salerno
POST-DOCTORAL FELLOWS: Fabio Buzzetti, Matteo Pisani
PHD STUDENTS: Francesco Maranta, Monica Mazzavillani, Claudio Montanaro, Isabella Rosa, Camilla Tarlasco
Organ protection in critically ill patients,
Advanced cardiac failure and mechanical supports Unit
HEAD OF UNIT: Alberto Zangrillo*
PHYSICIANS: Elena Bignami, Tiziana Bove, Luca Cabrini, Giuseppina Maria Casiraghi, Sergio Colombo, Remo Daniel Covello,
Giovanni Landoni, Giovanni Marino, Federico Pappalardo, Davide Salaris, Paolo Silvani
RESIDENTS: Giulia Maj, Anna Maria Mizzi, Giacomo Monti, Stefano Turi
POST-DOCTORAL FELLOWS: Ilaria Belloni, Laura Corno, Alberto Facchini, Reem Nassif, Laura Ruggeri
HEAD OF UNIT: Ottavio Alfieri*
PHYSICIANS: Stefano Benussi, Michele De Bonis, Francesco Maisano
FELLOWS: Flavia Bondardo, Andrea Guidotti, Valerio Zerbi
HEAD OF UNIT: Roberto Chiesa*
PHYSICIANS: Renata Clotilde Castellano, Efrem Civilini, Laura Dordoni, Gloria Esposito, Enrico Maria Marone, Massimiliano
Marrocco-Trischitta, Germano Melissano, Yamume Tshomba
RESIDENTS: Fabio Massimo Calliari, Giovanni Coppi, Andrea Kahlberg, Davide Logaldo, Daniele Psacharopulo, Sara Spelta
FELLOWS: Luca Bertoglio, Barbara Catenaccio
Center for arrhythmia research
HEAD OF UNIT: Carlo Pappone
CLINICAL GROUP LEADER: Vincenzo Santinelli
POST-DOCTORAL FELLOWS: Giuseppe Augello, Alessia Pappone, Simone Sala, Nicoleta Sora, Pasquale Vergara
RESIDENTS: Giuseppe Ciconte, Andrea Radinovic, Massimo Saviano
TECHNICIAN: Giorgio Maida
Introduction
Metabolic and cardiovascular diseases represent a major area of clinical care and research at San Raffaele Research Institute. Several leading groups of cardiologists, cardiac and vascular surgeons and diabetologists pioneered over the years the development and application of many innovative therapeutic approaches in patients with different types of cardiovascular and metabolic diseases. The scientific productivity of physicians and clinical scientists from the Division is remarkable, with internationally recognized areas of excellence in arrhythmology, cardiac valve and aortic surgery, coronary revascularization,
vascular inflammation, insulin resistance, diabetic macro- and microangiopathy, intermediary and energetic metabolism, bone pathophysiology. This excellent clinical research traditionally pursued by individual research groups has been reinforced by establishment of the Research Division of Metabolic and Cardiovascular Sciences where a strong basic research is going to be developed offering the opportunity for
close interaction between clinical investigators and basic scientists and the implementation of translational research projects..
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,
PPARã and leptin expression to evaluate the effect of deficiency in DNA methylation by polymorphisms on
cells myogenesis and adipogenesis promotion.
Metabolic outcome of islet transplantation: using clamp techniques combined with tracer infusions glucose,
lipid and amino acids metabolism are studied in type 1 diabetic individuals undergoing islet transplantation
Mathematical modelling of metabolic and endocrine systems. The simultaneous assessment of insulin sensitivity and insulin secretion is of paramount importance to evaluate the metabolic status of a subject at risk of
becoming diabetic or to monitor the effect of therapies. Aim of our research is to develop methods to perform
the simultaneous assessment of insulin secretion and insulin sensitivity. The increasing need to keep the experimental costs as low as possible has given remarkable impulse to the use of indices of derived from an oral glucose tolerance test (OGTT). We are developing a suitable mathematical model that will allow us to reliably estimate these parameters in different physiopathological states from a 3-sample OGTT.
Lastly, a nutraceutical line of research was undertaken to discover metabolic effects of plant-derived proteins.
Livio Luzi
COMPLICATIONS OF DIABETES
Prevention, cure and remission of the microvascular complications of diabetes
The clinical practice suggests that, despite increasing efforts, there is not yet a final cure for diabetes, whether
insulin-dependent or non-insulin-dependent. As a consequence of the above, diabetic complications remain
among the major causes of blindness and end stage renal disease in Western countries. The hypothesis we are
presently going after is that glucose toxicity represents a compelling challenge for progenitor cells of organs
such as the renal glomerulus or the retina known as the major targets of diabetes. To test this hypothesis we are
presently involved in two major projects:
a) Identification of glomerular progenitor cells.
Chronic nephropathies such as diabetic nephropathy are characterized by a progressive loss of proteins
through the glomerular filter due to the progressive death of podocytes, the cells responsible for the filtering
barrier. This process invariably leads to end stage renal failure.
Podocytes are terminally differentiated cells unable to divide, the identification of a podocyte progenitor cell
could allow to prevent the progressive loss of filtering capacity that accompanies the progression of diabetic
nephropathy but also, at least potentially, to reverse the natural hystory of this life-threatening complication.
b) Endothelial progenitor cells (EPCs) and vascular disease in type 1 diabetes.
The long-term goal of this study is to clarify whether EPCs can be used in subjects with type 1 diabetes as
markers of overall vascular status and occurrence of specific events in the retina. We previously observed that
patients with long duration of type 1 diabetes and good glycemic control manifest a reduced number and activity of circulating EPCs. The activity of EPCs is instead significantly increased in patients with proliferative
retinopathy. Altogether these findings suggest a possible active role of EPCs in the pathogenesis of the different
stages of diabetic retinopathy. To clarify this issue we are presently testing the impact on the number and activity EPCs of diabetes duration, insulin availability, glycemic control, susceptibility or resistance to retinopathy
and presence of proliferative retinopathy in patients affected by type 1 diabetes.
Gianpaolo Zerbini
OBESITY AND METABOLIC RELATED DISEASES
The western society is characterized by a large prevalence of obesity and of the metabolic syndrome (2530%). The metabolic syndrome is a cluster of dyslipidemia, diabetes, hypertension, steatohepatitis, and pro inflammatory state but visceral obesity is the major criteria for the diagnosis. The metabolic syndrome is an independent risk factor of cardiovascular disease, and insulin resistance represents its pathogenic process. The onset of insulin resistance in humans is a common adaptive/maladaptive response due to the excess of nutrients in
the diet. Under this view we hypothesize that the metabolic syndrome may be secondary to an impaired insulin
action at the level of fatty acids metabolism. Insulin in fact is not only able to modulate glucose metabolism but
is also involved into the regulation of fatty acids biosynthesis and release at the level of the liver, skeletal muscle,
adipose tissue and heart. The understanding of the pathogenic events leading to insulin resistance 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 function 3) increased fat delivery to
peripheral tissues due to higher energy intake constitutes a detrimental factor predisposing to the onset of insulin resistance. We were among the first to demonstrate that in humans increased fat accumulation within the
skeletal muscle and the liver has systemic deleterious metabolic effects and that increased epicardial fat and intracardiac fat accumulation is a major factor involved in diabetes-induced heart alterations. Therefore, identification of the targets to be treated to reduce fat-induced insulin resistance is of paramount importance. The
methodological approach we developed to address this issue is based on in vivo Magnetic Resonance Spectroscopy techniques to study non invasively the alteration of energy metabolism in single organs and tissues and
to assess their impact on the whole body system. In particular application of the 31P-MRS at the cardiac and
hepatic sites are novel tools to identify targets for potential treatments.
Gianluca Perseghin
BONE METABOLISM UNIT
Aging bone: gene expression and endocrine mileu
The three major findings in aging bone, i.e decreased osteoblastogenesis, increased adipogenesis and increased osteoclastogenesis, could be related to altered canonical Wnt signaling. Wnt signaling is emerging as a
key regulatory pathway in osteoblast differentiation, bone mass accrual and bone loss. We have therefore studied Wnt signaling in a cohort of aged population of postmenopausal women To this purpose the expression
profile of a panel of genes relevant for Wnt signaling have been analyzed by real time PCR. The gene expression
analysis was done on trabecular bone samples derived from postmenopausal women divided into two groups, a
younger and an older one, according to the donors’ age. Preliminary results showed an increase in the expression of PPAR-γ, β-catenin and DKK1 in the older group while Runx2 was not differently expressed between
the two groups. In the older group the expression of RANKL was higher than in the younger one, while that of
OPG didn’t show a striking change in expression due to age, although it displayed a trend to decrease. The results suggest that in the older group there is a decrease of Wnt signaling, as a consequence of an upregulation of
Dkk1, that might lead to reduced osteoblastogenesis whereas the induction of PPAR-γ expression would drive
cell differentiation towards adipogenesis. This shift towards adipogenesis is accompanied by RANKL expression enhancement, which, on the other hand, induces osteoclastogenesis. The gene expression profile here observed is consistent with the major features of aging bone.
Collaboratives efforts are also underway to characterize the bone phenotypes of mice models of ADA deficiency, experimental diabetes and MPS as well as bone metabolism in adult GH-deficiency, HIV/HAART, genetic clusters, coronary calcification, ovariectomy and Paget disease. The results of all these studies will lead to
improvement of osteoporosis treatment strategies and allow to identify new pharmacological targets.
Alessandro Rubinacci
COAGULATION SERVICE & THROMBOSIS RESEARCH UNIT
Our research unit is since a long time interested in the mechanisms whereby natural anticoagulant systems influence the inflammatory response. We have reviewed the anti-inflammatory activity of vitamin K-dependent
protein S, and as an introduction to an animal model of severe sepsis (acute lung injury in rats), we have investigated cytokine release, small airway injury, and parenchimal damage during various types of mechanical ventilation (zero end-expiratory pressure, ZEEP; ZEEP plus administration of dioctylsodiumsuccinate, ZEEP-DOSS;
negative EEP, NEEP; large tidal volume, LTV) in normal open-chest rats. The control group was ventilated at
low tidal volume with PEEP and displayed no change in lung mechanics. Airway resistance and quasi-static
elastance increased to different extents in the other groups of rats, which exhibited histologic signs of bronchiolar injury, with parenchymal and vascular injury occurring in the ZEEP-DOSS and LTV groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the control and ZEEP
group, but increased in all other groups, and higher in the ZEEP-DOSS and LTV groups. Cytokine levels were
correlated with vascular-alveolar damage, suggesting a relationship with stress-related perturbation of endothelial-alveolar cells. Interestingly however, the mechanisms involved in the fall of exhaled nitric oxide (NOe) concentration were independent of TNF-α, and pro-inflamamtory prostaglandins, but they were associated with
bronchiolar epithelial damage caused by the abnormal stresses related to cyclic opening and closing of small
airways.
Our group is also actively involved in the conduct of international multicenter studies on new anticoagulant
drugs.We took part in a randomized, open-label non-inferiority trial comparing idraparinux, a long-acting factor Xa inhibitor, with vitamin K antagonists in patients with atrial fibrillation at risk for thromboembolism. The
trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux) and a mean follow-up period of less than 1 year because of excess relevant bleeding with idraparinux (19.7 vs 11.3 per 100 pt-yrs;
p<0.0001), with higher occurrence of in intracranial bleeding (1.1 vs 0.4 per 100 pt-yrs, p=0.014).
Armando D’Angelo
CARDIODIABETES & CORE LAB
NO produced by eNOS is the key regulator of vascular homeostasis and represents a major second messenger
for a plethora of physiological processes. NO from the endothelium is considered an important atheroprotective mediator, and acquired defects in NO generation associated with cardiovascular risk factors cause endothelial dysfunction and may contribute to the development of atherosclerosis. Central to all these physiological
functions is the proper eNOS expression and adequate eNOS enzyme activity. Our previous clinical experience
demonstrated a specific phenotype characterized by increased fasting nitric oxide levels but reduced response
after an insulin stimulus in patients with cardiovascular disease and in type 2 diabetic patients and their first degree relatives. At genetic level we found a strong association between eNOS gene variants and type 2 diabetes
and intra-stent restenosis. The polymorphism in intron 18 of eNOS gene affects the physiological mRNA splicing, with skipping of exons 19 and 20. As a result, the alternative transcript does not encode an enzymatically
active protein and, when co-expressed, it inhibits enzymatic activity of the full-length, thus acting as dominant
negative regulators of nitric oxide synthesis. This suggests that truncated NOS polypeptides have diminished
enzymatic activity and it will explain the presence of dramatically increased presence of early restenosis in patients carrying the eNOS SNP in intron 18. Our project is aimed to evaluate eNOS gene function and the
mechanisms of gene expression and regulation in the presence of gene variants and the impact at cellular and
tissue levels both in an animal model and in arterial or platelet cells of patients carrying the polymorphism. The
importance of metabolic factors, i.e. the presence of alterations of glucose or lipid metabolism will be taken into account. Other fields of research are the evaluation of new candidate genes, the definition of the molecular
mechanisms involved in early endothelial activation and inflammation in isolated endothelial cells and the evaluation of genes expression for inflammation and oxidative stress in endothelial progenitors cells and the search
of new serological indices involved in the pathogenesis of CARDIO-DIABETES.
Lucilla D. Monti
PEDIATRIC ENDOCRINOLOGY RESEARCH
Bone health in childhood and adolescence
The interest in children’s bone health has been expanding over the last decade, following the evidence for a
role of bone accrual in the determination of fracture susceptibility in adult life. In particular, bone mass gain
during childhood and adolescence is regarded as a key factor for the development of senile osteoporosis. Bone
mass accrual is determined by the concerted action of bone-forming cells (osteoblasts), and bone-resorbing
cells (osteoclasts). The physiologic changes of bone metabolism during growth are still largely unknown. Our
group is investigating such changes in healthy children and adolescents. Moreover, we have assessed the possibility of using different kinds of bone densitometers in the bone mass measurement in children.
Numerous pediatric disorders are complicated by impaired bone mineral accrual and altered bone metabolism. Our group is investigating skeletal health in young patients with gastrointestinal, endocrine, and chronic
infective diseases. We reported alteration of bone metabolism leading to reduced bone mass in celiac children.
We are currently exploring the hypothesis of autoimmunity involvement in the genesis of bone mass impairment in celiac patients. The use of antiretroviral drug increased the survival of HIV-infected patients, but they
also show important side effects. Among others, low bone density has been described in children. We are currently following a large number of HIV-infected youths, in collaboration with Alessandra Viganò at Sacco Hospital, Milan, to assess the long-term impact of treatment on bone health.
Stefano Mora
DIABETES AND ENDOCRINOLOGY UNIT
The research of our unit in the field of type 1 and type 2 diabetes is focused on relevant clinical questions,
such as self-monitoring of blood glucose, lifestyle changes (diet and physical activity), disabling diabetic neuropathy:
Self-monitoring of blood glucose for the management of patients with type 2 diabetes is a controversial issue.
We are conducting a large, Nationwide multicenter randomized clinical trial to study the impact of a program
of lifestyle changes based on self-monitoring of blood glucose in patients with type 2 diabetes treated with diet
alone or oral agents. The trial will recruit 1000 participants in over 30 diabetes outpatient clinics throughout
Italy.
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.
Patients with type 1 diabetes need to adjust their pre-meal insulin bolus according to the expected carbohydrate content of their meal. The method of carbohydrate counting has become very popular in Northern America and more recently in Europe. We are conducting a randomized clinical trial to study the impact of carbohydrate counting on glucose control in patients with type 1 diabetes treated with continuous subcutaneous insulin
infusion using an external insulin pump.
Peripheral neuropathy is a frequent and disabling microvascular complication of both type 1 and type 2 diabetes. Pharmacological treatment of diabetic neuropathy is purely symptomatic and largely unsatisfactory. As a
novel and original non pharmacological treatment, a Frequency modulated Electro-Magnetic neural Stimulation (FREMS) method, characterized by sequences of modulated electrical stimuli which vary automatically in
pulse frequency, duration and voltage amplitude, has recently been developed by our group. In a pilot trial
FREMS proved to be safe and efficacious in the treatment of painful diabetic neuropathy, with the evidence of
associated enhancement of local tissue microcirculation. An International Multicenter trial is currently ongoing
to validate FREMS as an effective treatment of diabetic neuropathy.
Emanuele Bosi
CARDIODIABETES AND CLINICAL TRIALS
The main hypothesis of CARDIO-DIABETES Project is that type 2 diabetes mellitus (DM2) and ischemic
cardiomyopathy (CAD) are the same disease. Furthermore, in our opinion, the heart is not only a passive player being affected by the negative effects of DM2 but is also an active player acting as an endocrine-metabolic organ able to induce DM2. The project will help to recognize new pathogenetic mechanisms and innovative therapies with the final goal to prevent endothelial dysfunction (ED), insulin resistance (IR), DM2 and CAD. To
screen populations at higher risk to develop DM2, we initiated the characterization of the metabolic and endothelial differences between coronary and carotid atherosclerosis. Preliminary data in a small group of patients suggested that coronary atherosclerosis is characterized by decreased adiponectin levels, insulin resistence and a more proatherogenetic profile than carotid atherosclerosis. Conversely, an increased prothrombotic state and higher platelet activation seem to be present in patients with carotid vasculopathy, suggesting
the presence of a marked heterogeneity of coronary and carotid atherosclerosis. In patients with heart valve disease we demonstrated a high prevalence of DM2 associated with increased ANP and FFA levels. In the attempt
to evaluate the role of inflammation on insulin resistance, we demonstrated that in first degree relatives normal
glucose tolerant women, fasting hyperinsulinemia, independently of the presence of Metabolic Syndrome, is associated with elevated IL-6 and leptin levels, suggesting an increased cardiovascular risk. In the light to evaluate
innovative treatments to revert IR and ED, as part of the Cardio-Metabolic and Clinical trials Unit, two intervention studies with L-arginine are ongoing in CAD and IR. In patients with CAD, we showed that chronic oral
L-arginine therapy ameliorated insulin sensitivity, glucose tolerance and inflammation. The second study, in patients with glucose intolerance and metabolic syndrome, is ongoing and will enlight the role of L-arginine in the
prevention of DM2. The group is also involved in the largest and major world-wide sponsored Clinical Trials
for the prevention and cure of DM2 and CAD.
Piermarco Piatti
CLINICAL PEDIATRIC ENDOCRINOLOGY
The incidence of congenital hypothyroidism (CH) has significantly increased in the last few years, also due to
the lower TSH cut-off for the recall at newborn screening.
We have observed a increase in CH cases with gland in situ. A percentage of these forms can be related to iodine organification defect or mutations in rTSH gene. We continued molecular studies on CH with gland in
situ and dyshormonogenesis, in collaboration with the University of Milano. We focused our attention on gene
involved in iodide organification: DUOX2 and DUOXA2 and published the first mutation in DUOXA2 in a
mild form of permanent CH with gland in situ.
Congenital hyperinsulinism of infancy (CHI) is a yet unresolved problem for paediatric endocrinologists. Several genes have been found to be responsible for CHI (ABCC8, KCNJ11, GLUD1, GCK, HADH, PCSK1,
phosphomannose isomerase). The patients are screened for mutations in ABCC8 and KCNJ11 by direct sequencing in collaboration with University of Milan.
Small for gestational age (SGA) children are at risk for obesity and Metabolic Syndrome (MetS). We hypothesized that overweight SGA children presented more components of the MetS than overweight children born
appropriate for gestational age (AGA).The intrahepatic fat (IHF) was measured using localized hepatic 1HMRS. IHF content, whole body energy homeostasis, insulin sensitivity, and body composition were measured in
SGA and AGA adolescents.
Giovanna Weber
DIABETES AND METABOLIC DISEASES IN CHILDREN AND
ADOLESCENTS
Heterozygous, gain-of-function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood. The aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies.: We reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified
seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies. We sequenced the INS gene in these seven patients. In two patients whose diabetes onset had been at 2 years 10
months of age and at 6 years 8 months of age, respectively, we identified the mutation G(B8)S and a novel mutation in the preproinsulin signal peptide (A(Signal23)S). Insulin gene mutations are rare in absolute terms in
patients classified as type 1 diabetic (0.6%) but can be identified after a thorough screening of type 1 diabetes
autoantibodies.
The study was in conducted in collaboration with Fabrizio Barbetti (Laboratory of Molecular Endocrinology,
Bambino Gesù Pediatric Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Laboratory of Molecular
Endocrinology and Metabolism, San Raffaele Biomedical Park Foundation, Department of Internal Medicine,
University of Rome–Tor Vergata, Rome, Italy).
Franco Meschi
NEONATOLOGY
Central nervous system in newborn
The study of nervous system maturation is one of the most important research area of our group.
We collaborate with Neuroradiology Unit to study CNS maturation in term and preterm newborn.
From 2006 a longitudinal study is in progress to evaluate myelinitation and maturation of brain by serial MRI
scan in preterm with gestational age inferior to 34 weeks at birth: different imaging tecniques like diffusion tecnique imaging (DTI) and functional MRI are performed with high field MRI. Clinical and psychomotor followup evaluations will be correlated to post-natal clinical
datas.
Another collaboration with Neuroradiology Unit
and Neuroscience Department has studied neuronal
processes understanding melodic and language processing in the first week of life.
At last a multicentric study on life quality of “wellbeing” preterm infants is in progress with other Italian
Neonatology Units: the aim of this study is to evaluate
quality of care and its perception till seven years of life.
Graziano Barera
Figure 6. Preterm infants care
FOETAL-MATERNAL MEDICINE
Study of new predictors of pregnancy outcomes in women with high risk pregnancies
1. Study of markers of vascular injury
Pregnant women with type 1 diabetes have an increased incidence of preeclampsia. Furthermore, among
these patients diagnosing preeclampsia may be challenging since microalbuminuria, proteinuria and/or hypertension may be present before pregnancy. We reported that pentraxin 3 (PTX3), a marker of vascular injury, in-
creases in the plasma of pregnant women several weeks before the clinical onset of preeclampsia. Recent evidences suggest that hyperglycaemia damages the trophoblastic tissue playing a role in the development of
eclampsia. We will measure PTX3 during the first trimester to monitor placental development in diabetic pregnancies and to study whether early changes in PTX3 levels may be predictive of preeclamsia in pregnant patients with type 1 diabetes.
2. Study of early morphological markers of abnormal fetal development
Despite optimal pre-natal care pregnant patients with type 1 diabetes have an increased risk of macrosomia
and fetal distress compared to women without diabetes. Furthermore, the growth pattern of fetuses of diabetic
mothers and the timing of growth changes are poorly understood. Recent evidences are highlighting the relevance of first trimester of pregnancy for the development of complications in the last phases of pregnancies. By
means of conventional and 3D ultrasound we are studying fetal and placental volumes to document fetal and
trophoblastic development during the first trimester and correlating these measurements with pregnancy outcomes in women with type 1 diabetes and women with high risk pregnancies.
3. Study of feto-placentar nucleic acids in maternal plasma
During the past year we collaborated with the Genomic Unit for Diagnosis of Human Pathologies to develop
a new method for non-invasive pre-natal diagnosis of β-thalassemia based on the study of the fetal DNA present in maternal blood. We are now planning to study transcripts of fetal genes that are found in maternal blood
and that are potentially involved in the pathogenesis of preeclampsia and fetal growth restriction. The identification of early markers of these diseases will be important for early diagnosis and prevention.
Maria Teresa Castiglioni
INFERTILITY
Our Group for Research in Infertulity care was involved in several clinical and basic researches.
For clinical studies we worked on:
a) A phase 3 study for the evaluation of efficacy of LH addition in the ovulation induction for poor responders.
b) A study for the evaluation of the efficacy of administration of progesterone in aqueous phase instead than
oleous phase in the luteal part of the cycle
c) A study for the evaluation of the role of Cabergoline in the prevention and treatment of severe hyperstimulation.
For laboratory studies our unit has been involved in two important studies supported by the Istituto superiore di sanità and the Regione Lombardia.
1) The first study is on oocyte cryopreservation. Several experimental designs were performed to understand the best way of freezing human oocytes.
2) The second study is in the right choice of gametes for insemination. Experiments are done to assess the
oocyte competency with the study of first polar body, and the sperm morphology using high magnification microscope.
Francesco Fusi
CARDIOVASCULAR INTERVENTIONS UNIT
Complex Coronary Lesions: We have conducted different retrospective multicentre registries in order to
evaluate the safety and efficacy of drug-eluting stent (DES) implantation in unprotected left main lesions showing encouraging results. Two randomized trials are also conducted in order to assess the optimal revascularization therapy (CABG vs. DES) in diabetics with multivessel disease (FREEDOM) and 3 vessel disease and/or
left main lesions (SYNTAX).
The stenting strategy in true bifurcation lesions has been evaluated in the multicenter randomized CACTUS
trial (crush vs. provisional stenting technique).
A novel dedicated bifurcation stent was indeed evaluated in the Sideguard 2 registry.
New Stents: A novel nano-structured titanium nitride stent is currently under investigation in a multicenter
randomized trial (MARTIN).
Imaging/ Intravascular Ultrasound (IVUS): New criteria for optimal DES deployment were tested in the multicenter randomized “Angiography vs. IVUS Optimisation” (AVIO) study.
Adjunctive therapy:In the prospective randomized study (NAPLES II) a single, high loading dose of atorvastatin is evaluated in preventing periprocedural MI. In the SATURN trial the effect on percent atheroma volume
of high dosages of atorvastatin vs. rosuvastatin is assessed.
Neoangiogenesis: is currently 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: A multidisciplinary program for transcatheter aortic
and mitral valve therapy has been developed. Our experience since the beginning of the aortic valve program
(November 2007) showed encouraging results.Two devices received CE-mark approval in 2007 and are currently used in our aortic valve program: the balloon-expandable Edwards-Sapien valve, and the self-expanding
CoreValve ReValving System.
Antonio Colombo
CLINICAL CARDIOVASCULAR BIOLOGY UNIT
Acute Coronary Syndromes: from bedside to bench
Targeted biological strategies to prevent Acute Coronary Syndromes (ACS) are limited despite effective and
expensive therapies. Animal models do not incur in ACS thus making necessary the study on patients (pts) to:
1) foster the understanding of the immuno-inflammatory response in the pathogenesis and complications of
atherosclerosis; 2) translate novel molecular approaches into the development of innovative diagnostic, preventive, and therapeutic strategies.
The key attitude of our Unit is the attempt to create a link between basic multidisciplinary biomedical research and the clinical field making possible a translational medicine.
Bedside researches:
1. Active collaboration in phase II and III International Clinical Trials to test newer anti-thrombotic drugs
(TIMI-50)
2. As coordinating center, we closed the enrollment of cases and controls in the multi-ethnic First Acute
Myocardial Infarction (FAMI) for the study of inflammatory and genetic components that trigger ACS.
Initial results were presented (Am.Coll.Cardiology)
3. In-vivo bioimaging of active carotid plaques by echocontrast (JACC - with Roberto Chiesa)
Bench researches on:
1. The synergic role of B and T cells and the cytokine milieu in pts with ACS. We documented the presence
of an antigen-driven B cell maturation within human coronary lesion (J.Immunol. – with Microbiology
Unit, M. Clementi). We defined a specific proatherogenic T-cell subset (TCRz dim) that we found increased during ACS (Arteriosclerosis, Thrombosis and Vascular Biology) by polychromatic flow cytometry (with Flow Cytometry - A. Palini) and analysis are performed exploiting machine learning algorithms
on multi-parameter data obtained (with University of California - T. Ravasi). We described a selective cytokine signature in a fraction of pts with ACS, identified by high levels of circulating IL-6 not secondary
to myocardial damage.
2. The interaction of circulating neutrophils and platelets occurs during ACS. We have observed and we are
characterizing a P-selectin mediated pathway of reciprocal activation of circulating platelets and leukocytes (Blood - with Clinical Immunology Unit, A. Manfredi) to curb artherial thrombosis.
3. Genetic factors that predispose to ACS on the FAMI samples. Analysis are ongoing (with M. Ferrari and
G. Casari).
Domenico Cianflone
ISCHAEMIC HEART DISEASE, HEART FAILURE AND
ECHOCARDIOGRAPHY UNIT
Heart failure
1) ACITRIM: to assess myocardial function and metabolism after acute metabolic modulation.
2) TRIMCAL: to assess myocardial function, after inhibition of FFA oxidation.
3) METNIC: to assess the effetcs of metformin on myocardial function and metabolism, insuline sensivity,
effort tolerance, insuline resistance.
4) BEM: to evaluate the expression of mytocondrial ferritin in myocardial biopsies.
5) CREMONO: to evaluate membrane diffusion and CO exhaled.
6) HODIC: to evaluate the effectiveness of heparin anticoagulation therapy in atrial fibrillation.
7) AA/CHF: to evaluate the therapeutic effect of a mix of essential aminoacids.
8) SHIFT: to evaluate the effect of ivabradine on morbility and mortality
9) VILDAGLIPTIN: to evaluate the effect on cardiac function of Vildagliptin, an oral antidiabetic drug.
10) RENO DEFEND-1: to evaluate the safety and efficacy of SLV320 on renal function, in patients with
acute heart failure and renal dysfunction.
11) ATMOSPHERE: to evaluate the effect of aliskiren on cardiovascular morbidity and mortality.
Ischaemic heart disease
1) Sindrome X: perfusional, metabolic and neuro-endocrinal characteristics in patients with microvascular
angina.
2) CAD 1: to evaluate the role of osteoprotegerin in the evolution of coronary lesions.
3) CAD 2: to evaluate the correlation between major risk factors and the severity of coronary disease in Pts
with CAD
4) CAD 3: to assess the role of a new test(Loxin test to evaluate LDLC oxidation)to predict events in patients with CAD
5) CAD 4: to evaluate the protective effect of a combination treatment against contrast induced nephropathy.
Echocardiography
EchoLab of Division of Cardiology was actively involved in 2 research fields:
• Translational Research in 3D Echo;
• Mitral Valve Disease; Diastolic Heart Failure.
In particular, in the field of 3DE we tested:
1) The potential application and the added value of Real-Time 3D Transesophageal Echo in the common
clinical scenario;
2) The added value of 3DE in the anatomic and functional delineation of MVD and ASD.
Alberto Margonato
ORGAN PROTECTION IN CRITICALLY ILL PATIENTS, ADVANCED
CARDIAC FAILURE AND MECHANICAL SUPPORTS UNIT
Perioperative organ failure is associated to high morbidity and mortality. We are coordinating large multicentre randomized controlled studies at the Italian level on numerous topics. These studies are supported by the
two largest and most influential Italian scientific societies in the field of anesthesia and intensive care (SIAARTI
and ITACTA). All the studies have been approved by the Ethical committee of San Raffaele Hospital, have
been published on www.clinicaltrials.gov and include:
•
•
prevention of dialysis dependent acute renal failure after cardiac surgery is studied with a 20 centres,
1000 patients study (fenoldopam vs placebo)
optimization of perioperative cardiac protection (esmolol vs placebo and volatile agents versus total intravenous anesthesia) is studied. Volatile anesthetics, commonly used for general anesthesia during surgery
•
•
•
•
to induce and maintain hypnosis, analgesia, and amnesia seems to reduce myocardial infarction and improve postischemic recovery at the cellular level. We are studying preventive measures (pharmacological
preconditioning with halogenates) that could be transferred to all ischemic patients undergoing procedures that could trigger ischemia and myocardial damage.
early treatment of low cardiac output syndrome with pharmacological (levosimendan vs placebo) or mechanical supports (ECMO, VAD) is one of our main topics of interest. We also have a scientific collaboration with the Berlin Hertz Centrum.
safety and efficacy or recombinant activated factor VII, of desmopressin, factor XIII, protein C zymogen
and protein C activated in patients experiencing excessive bleeding after surgery in large multicentre randomized studies or in patients with severe sepsis admitted in the intensive care unit.
anesthesiological challenges of the unfit patients, ideal candidate to transfemoral artery aortic valve implantation.
non-invasive ventilation outside intensive care unit and the role of the Medical Emergency Team for a
timely treatment of critically ill patients in the hospital ward.
We have also published numerous original papers and systematic review of the literature on the above described topics. With 23 papers published in international indexed journals in 2008 we’re the most prolific Italian group publishing in anesthesia and intensive care journals. We are also publishing a new journal “HSR proceedings in Intensive Care and Cardiovascular Anesthesia”, freely available on www.itacta.org
Alberto Zangrillo
STRUCTURAL HEART DISEASE UNIT
Treatment of structural heart disease
Heart failure
Surgical strategies to treat patients with heart failure due to ischemic or idiopathic cardiomyopathies are investigated. Original procedures to correct secondary mitral and tricuspid regurgitation have been developed
and extensively applied with a rigorous long-term follow-up.
A multidisciplinary protocol for mechanical circulation assistance has been prepared and selection intense
have been established.
Cell therapy (myoblast) has been used in patients with post infarction left ventricular dysfunction, in the contest of a multicenter prospective monitorized placebo controlled study (MAGIC study).
Heart valve disease
Innovative techniques to repair mitral and aortic valve are systematically evaluated. New imaging modalities
are applied and correlated to the operative findings.
In repair the tricuspid valve, a new prosthetic ring has been developed and tested on the bench
Ischemic heart disease
Active contribution has been given to the SYNTAX study and the FREEDOM study, both comparing PCI
and CABG in multivessel disease
Atrial fibrillation
New surgical methods to increase the effectiveness of the atrial fibrillation ablation procedures, during open
heart surgery, have been developed. A program for the treatment of lone atrial fibrillation via a minimally invasive approach has been initiated, and new technologies have been introduced and meticulously tested. The left
atrial remodeling has been studied non only structurally but also at molecular and biochemical level.
Transcatheter valve therapy
A multidisciplinary program for transcatheter aortic and mitral valve therapy has been developed using a
wide spectrum of techniques and technologies. Guidelines have been prepared and extensive investigation in
this new area are ongoing.
Ottavio Alfieri
STUDY AND TREATMENT OF AORTIC DISEASE UNIT
Our group is conducting several clinical research studies regarding the treatment of abdominal, thoracic, and
thoracoabdominal aortic disease.
ABDOMINAL AORTA: We are reviewing the early and late results of endovascular infrarenal aortic
aneurysm repair with different endograft devices, and particularly in patients at high risk for conventional open
repair. We also analysed the outcome of pararenal aortic aneurysms and pseudoaneurysms repair, evaluating the
impact of different therapeutic strategies, including open, endovascular, and hybrid (open + endovascular)
techniques. In particular, we focused on perioperative determinants of post-operative glomerular filtration rate.
Finally, we retrospectively reviewed a large series of patients affected with aortoiliac occlusive disease and treated by bifurcated longitudinally extensible expanded polytetrafluoroethylene bypass grafting.
THORACIC AORTA: Endovascular repair has emerged as an extremely valuable alternative modality for the
treatment of thoracic aortic diseases due to its reduced invasiveness as compared to open repair. We are studying technical and clinical outcomes recorded in the different anatomical zones especially focusing on the offpump hybrid repair of aortic arch aneurysms.
We are also focusing on anatomic and pathophysiological determinants of postoperative spinal cord ischemia,
including the preoperative detection of the Adamkiewicz artery by multidetector computed tomography, to develop new prevention strategies. We are also evaluating the perioperative and late results of new devices specifically designed for endovascular repair of type B dissection.
In addition, we are reviewing early and long-term results of endovascular repair of
traumatic thoracic aortic rupture, and conducted a National survey on endovascular
repair of aorto-oesophageal and aorto-bronchial fistulas.
THORACOABDOMINAL AORTA: As a Nation referral Center, we are reviewing our large experience of open and hybrid repair of thoracoabdominal aortic
aneurysms and dissections with the use of the more innovative technique of extracorporeal circulation, intraoperative hypothermic renal perfusion, and specific graft
material. A manuscript on our experience of thoracoabdominal aortic aneurysm hybrid repair (see figure), that represents the largest worldwide single-center series to
date, has been also recently published.
Roberto Chiesa
Figure 7. Picture shows an example of sequential treatment of type B aortic dissection. After TEVAR, a type IA endoleak was discovered on follow-up and
required further treatment with proximal extension in zone 1 (revascularization
of supra aortic vessels via carotid-carotid-subclavian bypass). Later type IB was
discovered. this condition required hybrid treatment with revascularization of
the common hepatic artery, superior mesenteric artery, right and left renal artery
by a custom made four-branched graft anastomized to the infrarenal aorta and
subsequently deployment of a third stentgraft.
CENTER FOR ARRHYTHMIA RESEARCH
The research activity of the Arrhythmology group of San Raffaele University-Hospital is focused on atrial fibrillation ablation, particularly on remote ablation using tip-irrigated magnetic catheters in 2008. In our center
catheter ablation of atrial fibrillation is safely performed in many patients with and without comorbidities. We
are conducting a large study in the elderly to assess both efficacy and safety in this patient population. Another
area of research is the pathophysiology of atrial fibrillation investigating the natural history of the arrhythmia
with its progression from the first symptomatic episode. We are also assessing the effect of catheter ablation on
atrial fibrillation progression by the APAF2 study which is a 3-year extension study of the previous 1-year
APAF trial. It was designated to compare the long-term outcome of catheter ablation versus conventional antiarrhythmic drug therapy in a large number of patients randomized to both strategies. At 3 years (2008) the results demonstrate a striking superiority of catheter ablation over antiarrhythmic drugs in terms of efficacy, arrhythmia progression and late complications. The identification of asymptomatic subjects at risk of sudden
death with either latent Brugada syndrome or Wolff-Parkinson-White syndrome represents another important
area of research in our center. Finally, the last area of research is the development of new technologies for
catheter design and 3D anatomical reconstruction of cardiac chambers for atrial fibrillation ablation.
Vincenzo Santinelli
Figure 8. Clinical Research: Light and Hope
DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY - 71
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
HEAD OF UNIT: Giulio Cossu
RESEARCHER: Graziella Messina
POST-DOCTORAL Fellows: Arianna Dellavalle, Jordie Diaz, Hoshia Hidetoshi, Anna Pistocchi, Gonzalo Ugarte
PHD STUDENTS: Sara Benedetti, Ornella Cappellari, Saverio Tedesco
TECHNICIANS: Diego Covarello, Anna Innocenzi, Stefania Monteverde, Laura Perani, Rossana Tonlorenzi
GROUP LEADER: Silvia Brunelli
POST-DOCTORAL FELLOWS: Stephanie François, Thierry Touvier
PHD STUDENTS: Emanuele Azzoni, Patrizia Pessina
FELLOWS: Valentina Conti, Stefania De Cesare
Gene expression and muscular dystrophy Unit (Dulbecco Telethon Institute)
GROUP LEADER: Davide Gabellini
POST-DOCTORAL FELLOWS: Sergia Bortolanza, Cristina Godio, Paola Picozzi, Mariaelena Pistoni
PHD STUDENT: Daphne Cabianca
Molecular and functional immunogenetics
GROUP LEADER: Katharina Fleischhauer
POST-DOCTORAL FELLOW: Federico Sizzano
PHD STUDENT: Pietro Crivello
FELLOW: Giandomenico Turchiano
TECHNICIAN: Laura Zito
GROUP LEADER: Rossella Galli
PHD STUDENTS: Daniela Corno**, Laura Magri**, Stefania Mazzoleni**
FELLOW: Mauro Pala
TECHNICIAN: Vivian Deidda Vigoriti
Autoimmunity & vascular inflammation Unit
HEAD OF UNIT: Angelo A. Manfredi*
PHD STUDENTS: Lidia Bosurgi**, Lucia Cottone
FELLOW: Norma Maugeri
TECHNICIANS: Annalisa Capobianco, Antonella Monno
Innate immunity and tissue remodelling
GROUP LEADER: Patrizia Rovere-Querini
POST-DOCTORAL FELLOW: Gianfranca Corna
PHD STUDENTS: Lara Campana, Alessandra Castiglioni, Michela Vezzoli
Cellular pharmacology Unit
HEAD OF UNIT: Emilio Clementi
POST-DOCTORAL FELLOWS: Clara De Palma, Sestina Falcone, Cristiana Perrotta
PHD STUDENTS: Laura Bizzozero, Roberta Buono, Serena Pisoni
FELLOW: Sara Baldelli
TECHNICIAN: Clara Sciorati
HEAD OF UNIT: Chiara Bonini
RESEARCHER: Attilio Bondanza
POST-DOCTORAL FELLOW: Luca Vago
PHD STUDENTS: Monica Casucci, Elena Provasi
FELLOW: Maddalena Noviello
RESIDENT: Sara Mastaglio
TECHNICIANS: Zulma Magnani, Veronica Valtolina
Angiogenesis and tumor targeting
HEAD OF UNIT: Luigi Naldini*
GROUP LEADER: Michele De Palma
POST-DOCTORAL FELLOWS: Roberta Mazzieri, Mary Anna Venneri
PHD STUDENTS: Francesco Boccalatte**, Ferdinando Pucci**, Mario Squadrito**, Erika Zonari
FELLOW: Daniela Biziato
Hematology and hematopoietic stem cell transplantation Unit
PHYSICIANS: Andrea Assanelli, Jacopo Peccatori
RESIDENTS: Valeri Calbi, Daniela Clerici, Raffaella Greco
POST-DOCTORAL FELLOWS: Maria Teresa Lupo Stanghellini, Annalisa Ruggeri
TECHNICIAN: Roberta Mattarucchi
Immunohematology and transfusion medicine Unit
HEAD OF UNIT: Silvano Rossini
RESEARCHER: Laura Bellio
FELLOW: Alessandra Venditti
PSIEP-Strategic Program of Pediatric Immunohematology
HEAD OF UNIT: Maria Grazia Roncarolo*
PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Barbara Cappelli, Robert Chiesa, Sarah Marktel
RESIDENT: Erika Biral
The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET)
Director: Luigi Naldini*
Research Units
Gene transfer technologies and new gene therapy strategies Unit
HEAD OF UNIT: Luigi Naldini*
POST-DOCTORAL FELLOWS: Mario Amendola, Bernhard Gentner
PHD STUDENTS: Alessio Cantore**, Angelo Lombardo**
FELLOW: Pietro Genovese**
TECHNICIANS: Giulia Schira, Lucia Sergi Sergi
Gene/Neural stem cell therapy for lysosomal storage diseases
GROUP LEADER: Angela Gritti
PHD STUDENTS: Chiara Cavazzin, Margherita Neri, Sara Santambrogio
FELLOW: Annalisa Lattanzi
TECHNICIAN: Claudio Maderna
Hematopoietic stem cell gene therapy for lysosomal storage disorders
GROUP LEADER: Alessandra Biffi
PHD STUDENTS: Alessia Capotondo**, Martina Cesani**, Ilaria Visigalli**
FELLOWS: Stefania Delai, Silvia Ungari
Safety of gene therapy and insertional mutagenesis
GROUP LEADER: Eugenio Montini
PHD STUDENTS: Daniela Cesana**, Marco Ranzani**
TECHNICIAN: Fabrizio Benedicenti
HEAD OF UNIT: Giuliana Ferrari*
RESEARCHERS: Maria Rosa Lidonnici, Emanuela Anna Roselli
POST-DOCTORAL FELLOW: Rossella Ierardi
TECHNICIANS: Giacomo Mandelli, Claudia Rossi, Francesca Tiboni
Immunological tolerance Unit
POST-DOCTORAL FELLOWS: Andrea Annoni, Laura Strauss
PHD STUDENT: Maura Rossetti
TECHNICIANS: Grazia Andolfi, Claudia Sartirana, Eleonora Tresoldi
From FOXP3 mutation to IPEX syndrome
GROUP LEADER: Rosa Bacchetta
PHD STUDENTS: Sara Di Nunzio, Laura Passerini, Giorgia Serafini
FELLOW: Giada Alberigo
GROUP LEADER: Silvia Gregori
PHD STUDENT: Chiara Magnani
TECHNICIAN: Daniela Tomasoni
Pathogenesis and therapy of ADA-SCID Unit
HEAD OF UNIT: Alessandro Aiuti
POST-DOCTORAL FELLOW: Silvia Selleri
PHD STUDENTS: Luca Biasco, Immacolata Brigida, Aisha Sauer
TECHNICIANS: Raisa Jofra Hernandez, Anna Ripamonti
Gene therapy for WASP/Omenn
GROUP LEADER: Anna Villa
POST-DOCTORAL FELLOWS: Marita Bosticardo, Francesco Marangoni, Samantha Scaramuzza
PHD STUDENTS: Marco Catucci, Michela Locci, Veronica Marrella
TECHNICIAN: Elena Draghici
Clinical research Groups
Pediatric clinical research Unit
COORDINATOR: Alessandro Aiuti
PROJECT LEADERS: Alessandro Aiuti (ADA-SCID), Maria Grazia Roncarolo* (WAS), Maria Sessa (MLD)
PHYSICIAN: Alessandra Biffi
RESIDENT: Francesca Fumagalli
QUALITY ASSURANCE AND REGULATORY AFFAIRS: Valentina Bergamante
FELLOWS: Francesca Ferrua
PHD STUDENT: Martina Cesani
TECHNICIAN: Tiziana Plati
RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi
Giulio Cossu
The Division of Regenerative Medicine was created at the end of year
2008, by joining the Telethon Institute of Gene Therapy (TIGET), that remains an independent institute directed by Luigi Naldini, with former
Stem Cell Research Institute and also includes researchers with expertise in
developmental and stem cell biology, inflammation, immunology, tissue regeneration as well as clinicians actively involved in clinical trials, mainly in
hematology. TIGET contributes its expertise and international leadership
in gene therapy, including the development of new pre-clinical protocols,
vector design and new clinical trials, in addition to the one currently running of congenital immune deficiency do to a mutation in the Adenosine
Deaminase gene.
The Division currently comprises 10 Principal Investigators/Heads of Unit,
10 Group leaders, and approximately 200 researchers, clinicians, post and predoctoral fellows, undergraduate students and technicians.
Projects focus on stem cell biology and physiopathology of the hematopoietic
system, skeletal muscle and of the nervous system aiming at elucidating the
pathogenesis of certain diseases of these tissues (congenital immune deficiencies, thalassemias, hemophilias, leukemias, muscular dystrophies and tesauris- Fabio Ciceri
mosis), at developing pre-clinical models and clinical protocols of gene and cell
therapy. Several clinical trials for onco-hematologic pathologies are currently running.
Research Units
SKELETAL MUSCLE DEVELOPMENT AND THERAPY UNIT
1. Control of skeletal muscle development
We have shown that the myogenic bHLH MRF4 is able to replace Myf5 and MyoD during Zebrafish myogenesis, much as it happens during mouse myogenesis. This does not happen when both Myf5 and MyoD are silenced because the natural expression of this gene is late in the fish (Schnapp et al. 2009). We have also shown
that the NFI-X transcription factor regulates the transcriptional shift between embryonic and fetal muscle, by
repressing embryonic genes and activating fetal ones either alone or forming a ternary complex with MEF2A
and PKC theta (Messina et al. submitted).
2. Origin and fate of mesoangioblats
Mesoangioblasts, vessel-associated mesoderm progenitors, can be induced to differentiate in several types of
solid mesoderm. We have shown that skeletal myogenesis of mesoangioblasts requires Pax3 (Messina et la.
2009).
Currently we aim to identify the signaling molecules that commit vessel-associated progenitors to a skeletal
myogenic fate. Moreover, by means of Cre-lox lineage marking using an inducible Cre driven by a pericyte specific promoter, we have preliminary evidence that pericytes contribute to muscle fiber formation during unperturbed development of the tissue.
3. Pre-clinical models of cell therapy for muscular dystrophies
We are developing new protocols with autogous cells, either reversibly immortalized by floxed lentiviral vectors expressing human telomerase and Bm-1, or with iPS induced to a mesoangioblast fate. Gene correction
will be carried out either by lentiviral vectors expressing mini-dystrophin or α sarcoglycan or, alternatively, with
a human artificial chromosome containing the whole dystrophin locus. These strategies will be tested in immune deficient, dystrophic mice.
4. A clinical protocol for allo-transplantation of donor mesoangioblasts from an HLA-identical healthy sibling in three patients affected by Duchenne Muscular Dystrophy (DMD).
This protocol is the result of pre-clinical studies in dystrophic dogs and mice.
Mesoangioblasts will be grown under GMP conditions and transplanted folowing a three-step protocol (intra-muscular; intra femoral artery; multi-district intra-arterial) at escalating doses of cells. A preliminary protocol to validate outcome measures in ongoing.
Giulio Cossu
FUNCTIONAL GENETICS OF MUSCLE REGENERATION
Molecular mechanisms of endogenous stem cells mediated muscle regeneration
Regeneration of muscle fibers, lost during pathological muscle degeneration or after injuries, is sustained by
generation of new myofibers. Necdin (Ndn) is a MAGE protein expressed in satellite cells derived myogenic
precursors during perinatal growth. Following muscle injury necdin null mice showed a significant defect in
muscle healing while mice over-expressing necdin showed significantly increased myofiber regeneration. We
elucidated the role of necdin in muscle showing that it increases expression of myogenin, by cooperating with
MyoD in the transcription of Myogenin promoter and accelerates differentiation (Deponti et al. JBC, 2007). We
have also shown that necdin is selectively expressed in the atrophic muscles of cachectic mice (tumor induced
cachexia) and proved that its expression is causally linked to a protective response of the tissue against tumor-
induced wasting, inhibition of myogenic differentiation and fiber regeneration. Necdin plays this role mainly
via interference with TNFα signaling, including regulation of expression of TNFRI, of p53 and of the activity
of caspase 3 and 9 (Sciorati et al., JCS, 2009). Furthermore we were able to isolate a novel protein that interacts
with Necdin, CCAR1/CARP1: the complex Necdin/CCAR1/ p53 appears to mediates the anti-apoptotic action
of Necdin in myoblast precursor cells.
These data prompted us to investigate whether Necdin could be exploited also to enhance myogenic differentiation and inhibit cell death of other types of stem cells, such as mesoangioblasts (MABs). Overexpression of
Ndn in vitro increases the differentiation ability of MABs, and inhibit cell death. In addition muscles of αSarcoglycan dystrophic mice injected with Ndn-MABs showed a greater reconstitution of stem cell derived fibers respect to wt MABs.
To investigate in vivo the role of endothelial derived myogenesis, we have generated a transgenic mouse expressing an inducible Cre recombinase (CRE-ERT2) under the control of an endothelial specific promoter
(Vascular Endothelial Cadherin). Lineage tracing experiments using ROSAfloxed mice show that endothelial
progenitors can give rise to cells of the skeletal muscle lineage at fetal and perinatal stages and contribute to
muscle regeneration following acute damage in the adult.
Silvia Brunelli
GENE EXPRESSION AND MUSCULAR DYSTROPHY UNIT
A ncRNA regulates the epigenetic switch at the basis of facioscapulohumeral muscular dystrophy (FSHD)
Our group is interested in elucidating the regulatory pathways controlling muscle-specific gene expression
and delineate how they become subverted in muscular dystrophy using facioscapulohumeral muscular dystrophy (FSHD) as a paradigm. FSHD is the third most common hereditary disease of muscle. FSHD is an autosomal dominant disorder that is not due to a mutation within a protein-coding gene. Instead, FSHD patients carry deletions of 3.3 kilobase repeat units, termed D4Z4, located at chromosome 4q35. FSHD results form a
complex epigenetic cascade activated by deletion of a 3.3 kb repeat (D4Z4) located on chromosome 4q35.
D4Z4 appears to regulate chromatin structure and its partial deletion causes over-expression of the 4q45 FRG1
gene. Importantly, transgenic mice over-expressing FRG1 display an FSHD phenotype and are the first animal
model of the disease.
Figure 9. Current model for the role of the ncRNA in regulating 4q35 gene expression
The number of D4Z4 repeats is a critical determinant of the age of onset and clinical severity of FSHD. In
general, fewer repeats are associated with a more severe phenotype that presents in childhood. Paradoxically,
individuals completely devoid of D4Z4 are normal. This suggests that at least one copy of D4Z4 is required to
cause FSHD, possibly through a gain-of-function mechanism.
Our preliminary results indicate that a chromatin-bound ncRNA is generated starting from upstream of
D4Z4 uniquely in FSHD patients. Notably, shRNA knockdown of this transcript causes a significant reduction
of 4q35 gene expression. Hence, it is tempting to speculate that production of this ncRNA activates the epigenetic cascade culminating with 4q35 gene de-repression in FSHD. An attractive hypothesis would be that transcription of the region proximal to D4Z4 may play a role in de-condensation of the 4q35 genomic region, setting the stage for activation of 4q35 genes and, most importantly, preventing re-repression of the region.
We are characterizing the ncRNA to determine how it regulates 4q35 gene expression. These studies will provide a critical nexus for revealing the basis of ncRNAs in FSHD etiology and their possible use as therapeutic
targets.
Our analysis will generate novel insights into the biological role of RNAs in regulating chromatin structure in
higher eukaryotes.
Davide Gabellini
MOLECULAR AND FUNCTIONAL IMMUNOGENETICS
Molecular and functional immunogenetics of hematopoietic stem cell transplantation
The research activity of the group is focused on the role human leukocyte antigen (HLA) and other polymorphic immune-related molecules in promoting graft versus leukemia (GvL) activity versus adverse clinical effects
(graft versus host disease, interference with engraftment, rejection) in the context of hematopoietic stem cell
transplantation (HSCT) from partially HLA-mismatched unrelated or haploidentical donors, for the cure of
high risk hematopoietic malignancies.
In the year 2008, the following main results were obtained:
1. Non-Permissive HLA-DPB1 T cell epitope disparities associated with clinical outcome of unrelated HSCT
Summary: In a collaborative study with the 15th International Histocompatibility Workshop, we showed that
non-permissive HLA-DPB1 disparity defined according to an algorithm based on T cell alloreactivity patterns,
was associated with significantly increased hazards of transplant related mortality, acute graft versus host disease grades 2-4 and 3-4, and overall mortality, in over 5838 unrelated transplants matched for 10/10 of the other HLA alleles.
2. Natural Killer Cell Alloreactivity and Chimerism Monitoring after haploidentical HSCT
Summary: In 56 patients receiving haploidentical HSCT for high-risk hematologic malignancies, we could
not detect a beneficial effect of natural killer (NK) cell alloreactivity, according to mismatch for killer immunoglobulin like receptor (KIR) ligands, on clinical outcome, consistent with phenotypic and functional immaturity of these cells arising early after transplantation. Post-transplant follow-up of patients transplanted
from HLA mismatched donors by HLA typing was introduced and validated as being highly sensitive for detection of disease relapse.
Katharina Fleischhauer
NEURAL STEM CELL BIOLOGY
Glioblastoma multiforme (GBM) is characterized by enhanced tumor cell dispersal into the brain parenchyma. Most of de novo GBMs express the epidermal growth factor receptor (EGFR) unevenly, thus suggesting
that it might specifically label subsets of GBM cells that could behave as tumor-initiating cells (TICs). To test
this hypothesis, we purified different cell fractions from GBM patient’s specimens by fluorescence activated cell
sorting (FACS), based on their relative expression of EGFR and of the putative TIC marker CD133. Remarkably, all these subpopulations were endowed with tumorigenic potential, although to different extent. The pivotal role of EGFR in gliomagenesis was also confirmed by the functional modulation of EGFR expression in
CSCs by means of lentiviral-mediated over-expression and silencing.
Medulloblastoma (MB) is the most common brain tumor in childhood. MB is thought to derive from
stem/progenitor cells of the cerebellum (CB) that undergo malignant transformation. In the last year, we isolated several cancer stem cell (CSC) lines from mouse MBs, aiming at the identification of CSC-specific genes by
molecular comparison with normal neural stem cells (NSCs). As expected, transcriptome analysis suggested
that MB CSCs share many more molecular determinants with cerebellar NSCs than with the subventricular
zone (SVZ) NSCs. We are now validating some of the top-ranking genes differentially expressed between CSCs
and NSCs, by semi-quantitative RT-PCR and real-time qPCR.
Finally, in order to generate a highly representative pre-clinical model of Tuberous Sclerosis Complex (TSC),
given the putative correlation between the occurrence of TSC mutations in embryonic ventricular and adult
SVZ progenitors and the temporally-regulated onset of TSC-associated brain lesions, we selectively targeted
Tsc1 deletion to NSCs and progenitors. During the last year, we have generated and preliminarily characterized
Tsc1 mutant mice that display: i) shortened life span; ii) neuropathological features such as alteration in cortical
lamination; and iii) spontaneous epileptic seizures. We also provided evidence that, in mutant mice, the adult
NSC compartment is severely affected.
Rossella Galli
AUTOIMMUNITY & VASCULAR INFLAMMATION UNIT
Innate and acquired immune response to cell death in autoimmune and rheumatologic diseases
Inflammation is a key homeostatic process elicited by microbial components and by tissue damage. Increasing evidence indicates that the outcomes, either tissue repair or persistent inflammatory damage and degeneration, tightly depend on the pattern of cell death in situ and on the features of infiltrating leukocytes and antigen
presenting cells that actually dispose of cell death remnants. Defects in the initiation and execution steps of
programmed cell death such as in the clearance of cell debris are indeed critical for the pathogenesis of systemic
autoimmune diseases, in which the deregulated response to cell death behaves both as an initiator and an amplifying circuit, leading to the specific features of each disease. In particular, during vascular inflammation a
self-sustaining circuit attracts and activates inflammatory leukocytes in the wall of vessels of various size and
anatomical characteristics. Vascular inflammation fulfils homeostatic roles and the activation of circulating
leukocytes, platelets and endothelial cells is under the control of humoral innate immunity. We are directly addressing the molecular mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue
injury, with specific attention to the role of injury-associated signals (Damage-Associated Molecular Patterns,
DAMPS, or Alarmins) and of acute phase proteins.
Angelo A. Manfredi
Figure 10. EM imaging of the phagocytic
clearance of an activated platelet
INNATE IMMUNITY AND TISSUE REMODELLING
Macrophages play a dual role in damaged tissues: they enhance local injury through their effectors functions
or they favour repair. Two macrophage populations exist, polarized type I (classically activated) and type II (alternatively activated) macrophages. The characteristics of infiltrating macrophages determine whether they increase the healing process or exacerbate tissue damage in response to sustained noxae. The main goal of the research team directed by Dr. Patrizia Rovere-Querini is to molecularly dissect the role of infiltrating polarized
macrophages in in vivo models of acute (toxic) and chronic injury of skeletal muscle (muscular dystrophies and
inflammatory myopathies) and of the peritoneum, as a consequence of benign (endometriosis) and malign
(ovary carcinoma) ectopic cellular growth.
Patrizia Rovere Querini
Figure 11. Cross-talk between polarized
macrophages and vessel-associated stem cells
CELLULAR PHARMACOLOGY UNIT
Mitochondrial dynamics in myogenesis: endogenous nitric oxide stimulates myogenic differentiation by
inhibiting mitochondrial fission
Mitochondrial fission and fusion processes participate to cellular adaptation to changing metabolic needs
contributing to tissues development and function. Their functional roles in skeletal muscle function are unknown. We found that inhibition of mitochondrial fission with formation of elongated mitochondria is required
for myogenesis to occur and that this event depends on endogenous generation of nitric oxide (NO) by the differentiating myogenic cells. Blockade of NO synthesis enhanced activity, translocation and docking to mitochondria of the pro-fission GTPase dynamin related protein 1 (Drp1), inhibiting mitochondrial elongation and
myogenic differentiation. A dominant-negative Drp1 reversed the effects due to NO synthesis blockade on fission and myogenesis, establishing a causal relationship between these processes. Under NO synthesis blockade,
myogenic precursors displayed a latent mitochondrial dysfunction, compensated under basal conditions but
that rendered cells more sensitive to apoptotic clearance. This indicates the existence of a quality control check
for myogenesis, dependent on generation of NO and correct mitochondrial morphofunctional status. The effects of NO on mitochondrial fission and myogenesis depended on generation of its physiological messenger
cyclic GMP. Thus, NO is a central mediator of myogenesis, exerting a quality control check of the process via
regulation of mitochondrial fission and bioenergetics.
Emilio Clementi
EXPERIMENTAL HEMATOLOGY UNIT
T-cell Based gene therapy to treat hematologic malignancies
Cellular adoptive immunotherapy is a powerful approach to treat cancer; nevertheless limitations still need to
be overcome to fully endorse this treatment modality. In the context of allogeneic hemopoietic stem cell transplantation (HSCT) donor lymphocytes are highly effective against leukemia but mediate the detrimental graftversus-host disease (GvHD). Conversely, the adoptive transfer of autologous tumor specific T lymphocytes has
an optimal toxicity profile, but is limited by the difficulty in isolating and expanding rare, high-avidity tumorspecific cells. Our lab exploits gene transfer technologies to overcome these limitations. In the context of
HSCT, we showed that the transfer of a suicide gene into donor lymphocytes, prior to infusion to transplanted
patients, allows selective and complete control of GvHD, while promoting rapid and effective immune reconstitution after HSCT from HLA-identical and haploidentical donors. To further increase the efficacy of adoptive immune-gene therapy, we developed protocols to expand and gene-modify central memory (TCM) T lymphocytes, long-lived cells able, upon antigen re-encounter, to expand extensively, self-renew and differentiate
into a progeny of effectors, thus mediating long-term protective immunity. By applying this protocol we observed that:
1.T cell activation with leukemic dendritic cells, obtained upon in vitro differentiation of leukemic blasts, induce the expansion of TCM cells from SCT donors, highly reactive against the original leukemia in vitro and in
vivo.
2.T cell activation with co-stimulation and culture with IL7/IL15 promotes retro and lentiviral-mediated
transduction of functional TCM cells. By using lentiviral vectors with bidirectional promoters encoding for an
optimized TCR specific for the oncogenic WT1 antigen, we generated tumor-specific TCM lymphocytes able to
expand, recognize and kill primary leukemic blasts. To reduce variability in transgene expression, and further
improve the quality of gene-modified lymphocytes, we exploited the ZFN technology, and developed a protocol for integration of a desired transgene in CCR5, a safe genetic harbor for TCM cells. Efficient and targeted
integration of genes in TCM lymphocytes might overcome all major hurdles of adoptive cancer T cell therapy.
Chiara Bonini
ANGIOGENESIS AND TUMOR TARGETING
Tie2-expressing monocytes (TEMs): targets and vehicles of anticancer therapy
Increasing data indicate that tumor-infiltrating myeloid cells promote tumor angiogenesis. We contributed to
this concept by describing a novel myeloid cell type, the Tie2-expressing monocyte (TEM), which is implicated
in this process. Indeed, the specific elimination of TEMs inhibits tumor angiogenesis and growth in several
mouse models (De Palma et al., Nat Med 2003; Cancer Cell 2005). Yet, little is known of the biological bases of
TEMs’ activity in tumors. By comparing the gene expression profile of TEMs with that of classic tumor-associated macrophages (TAMs), we found that the two macrophage subsets were highly related. However, several
genes were differentially expressed, highlighting a TEM gene signature consistent with enhanced proangiogenic/tissue-remodeling activity and lower proinflammatory activity. Interestingly, resident monocytes and
TEMs on one hand, and inflammatory monocytes and TAMs on the other hand, expressed coordinated gene
expression profiles, suggesting that the two blood monocyte subsets are committed to distinct extravascular
fates in the tumor microenvironment (Pucci et al., Blood 2009). Ongoing studies are aimed at identifying the
signals that govern the lineage determination of TEMs and their recruitment to sites of active tissue morphogenesis. To achieve this goal, we are developing a lentiviral vector (LV)-based platform to knock selected genes
down specifically in TEMs using a BM transplantation approach.
We also exploited the tumor-homing ability of TEMs to target biotherapeutics to tumors. The toxicity of
high-dose, systemic interferon-α (IFN-α) in cancer therapy provided the rationale for exploring the benefits of
targeted gene delivery. By transplanting hematopoietic progenitors transduced with a Tie2p-Ifna1 LV, we efficiently targeted the IFN response to orthotopic human gliomas and spontaneous mouse mammary carcinomas
and obtained substantial antitumor responses. TEM-mediated IFN delivery inhibited tumor angiogenesis and
activated innate and adaptive immune cells, but did not impair myelopoiesis and wound healing detectably (De
Palma et al., Cancer Cell 2008). Thus, TEMs may represent both targets of anticancer therapies and ideal vehicles for the targeted delivery of cancer biotherapeutics.
Michele De Palma
HEMATOLOGY AND HEMATOPOIETIC STEM CELL
TRANSPLANTATION UNIT
Since 1991 at the San Raffaele Scientific Institute is active an Hematology and Bone Marrow Transplantation
(BMT) Unit. The staff is build on 3 MD consultants, 6 junior physicians and 12 fellows in hematology. The Unit
is site of the school in Hematology of the San Raffaele University.
The stem cell transplantation activity is integrated with the Blood Bank Unit (Director Silvano Rossini) in a
Stem Cell transplantation Program as member of European Group for Blood and Marrow Tranplantation,
EBMT (www.ebmt.org), in the file for Jacie-EBMT accreditation. Overall, the Unit is the largest Italian Unit for
allogeneic HSC transplantation, performing since 2006 around 100 allogeneic tranplants/year. The Unit has
long-lasting experience in transplantation from family mis-matched haploidentical donors, with programs of
cell therapy with suicide-gene modified donor T lymphocytes and cell therapy with IL-10 induced T-regulatory
cells for the control of Graft-versus-Host disease in this context. The Unit has a wide-range activity on all hematological malignancies and non-malignant hematological disorders. In particular programs are ongoing for
acute leukemias (NILG, www.leukemianet.org ), multiple myeloma, lymphomas, with more than 20 ongoing investigator-sponsored trials (IST). Our aim is to develop new modalities for hematopoietic stem cells transplantation (HSCT) both in autologous and allogeneic setting to reduce transplant related toxicity, testing new conditioning regimens based on reduced-toxicity drugs (i.e. treosulfan, clofarabine) and new anti-infective drugs
(i.e. posaconazole, anidulafungin, maribavir) for patients with leukemia, lymphoma, myelosisplasia, myeloma,
bone marrow failure syndromes and inherited disorders such as hemoglobinopaties and immunodeficiencies
Several phase II trials with these drugs are ongoing.
Fabio Ciceri
IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE UNIT
The Unit of Immunohematology and Transfusion Medicine is responsible for the collection and testing of
blood to be transfused into patients at San Raffaele Hospital (traditional “”blood banking””). This Laboratory
is responsible for ensuring that only the highest quality and safest blood products are given to the patients. New
technologies such as genetic red blood cell typing are being investigated. An RFID project is underway with the
goal of increasing safety by implementing radiofrequency identification technology in the daily management of
transfusions and transfusion products. This system is a model for process traceability from donor to patient, for
automation in the identification of patients, blood units and/or cellular products.
The 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 transplantations, and offers a Stem Cell Cryo Banking service for autologous and allogeneic bone marrow products. Our
objective is to provide clinical grade human cells for therapeutic use and translational trials. This unit also performs therapeutic apheresis procedures to treat patients with neurologic and blood diseases.
Silvano Rossini
PSIEP - STRATEGIC PROGRAM OF PEDIATRIC
IMMUNOHEMATOLOGY
The Strategic Program of Pediatric Immunohematology is a pediatric Unit dedicated to translational and
clinical research in children with immunological, hematological 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.
From 2005 in partnership with the Mediterranean Institute of Hematology, our Unit has developed a program for research, diagnosis and cure of blood disorders in patients from the Middle East. This partnership allowed children affected by β thalassemia from Syria, Lebanon, Palestine, Iraq, Jordan and Egypt to receive
bone marrow transplantation (BMT) at HSR. During 2007 and 2008 the Unit has conducted a project aimed at
transferring the BMT technology to Syria. This has involved the training of 22 Syrian professionals (physicians,
nurses, lab technician and transfusion biologists). The first BMT was performed in Damascus in September
2008 and the Syrian BMT Unit is running autonomously at present. In 2008 the Strategic Program of Pediatric
Immunohematology has performed 17 allogeneic bone marrow transplantations for β thalassemia and 2 gene
therapy procedures for ADA-SCID. The clinical performance of the Unit in 2008 was very high as demonstrated by an engraftment rate of 95% and a treatment related mortality of 5%.
The Program is collaborating with HSR-TIGET on the study of pathogenesis and therapy for genetic diseases, with particular regards to primary immunodeficiencies and autoimmune diseases with known or unknown genetic defect. In synergy with the Pediatric clinical research Unit of HSR TIGET, clinical studies for
gene therapy of pediatric genetic diseases are ongoing (ADA-SCID) or in preparation (Wiskott-Aldrich Syndrome, Metachromatic Leukodystrophy, thalassemia). Finally, the Program is implementing a cell therapy clinical study for Duchenne muscular dystrophy (project leader Prof Cossu).
Figure 12. A drawing by one of the children cured at the PSIEP
THE SAN RAFFAELE TELETHON INSTITUTE FOR GENE
THERAPY (HSR-TIGET)
Director: Luigi Naldini*
The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) was
created in 1995 as a joint-venture between the San Raffaele Scientific Institute and the Telethon Foundation for the implementation of basic and clinical research for genetic diseases. The mission of the Institute is to perform
cutting edge science in the field of gene and cellular therapy and to promote
the translation of basic discoveries into therapeutic advances.
The research projects span from basic studies aiming to:
• identify the genetic bases of inherited diseases;
• develop new gene transfer technologies for more efficient and safe genetic modification of target cells;
• establish procedures for isolation, gene transfer and and transplantation
of stem cells;
Luigi Naldini
• modulate immune response to gene and cell products to improve efficacy
and stability of the therapy, to pre-clinical studies testing the experimental therapeutic strategies in disease models and eventually to the establishment of clinical trials of the new therapies in human patients.
The genetic diseases, which are presently under investigation (from those in advanced clinical experimentation to those in early pre-clinical development) include primary immunodeficiencies and some autoimmune disease, leukodystrophies and other lysosomal storage disorders, thalassemias, type I diabetes,
hemophilia. Furthermore, we have established a Pediatric Clinical Research Unit that focuses on the diagnosis, treatment and follow up of patients with primary immunodeficiencies, hematologic and metabolic disorders, including those enrolled in the gene therapy trials. The TIGET clinical trial for a severe
form of primary immunodeficiency (ADA-SCID) has provided the most successful demonstration today
that gene transfer into human hematopoietic stem cells can result in long-term correction of disease with
an excellent safety record.
Research Units
GENE TRANSFER TECHNOLOGIES AND NEW GENE THERAPY
STRATEGIES UNIT
Our laboratory has long been at the forefront of the development of experimental gene transfer and has exploited the new technologies to gain novel insights into fundamental biological processes of high relevance for
molecular medicine, such as stem cell activity and angiogenesis. Recently, we pioneered two new strategies to
improve gene transfer: regulating transgene expression by exploiting cellular microRNAs and targeting integration by designer Zinc finger nucleases. The application of microRNA regulation to vector design has provided a
new experimental strategy in which transgene expression can be made specifically responsive to the cell lineage
and differentiation stage of the target cell. By using this approach, we could overcome the immunological barriers to stable gene transfer, a major hurdle to successful gene therapy, and establish long-term correction of hemophilia in mouse models. We have also recently extended these studies to develop a platform for knockingdown microRNA activity in vivo and investigating their function.
We have also demonstrated the use of engineered Zinc-finger nucleases to target vector integration and edit
the human genome. This proof-of-principle study has opened the way to correct, rather than replace genes.
We are now investigating the microRNA network regulating hematopoiesis and exploiting the new knowledge to develop vectors with stringently controlled expression throughout the hematopoietic lineages. We are
developing Zinc finger nuclease-based vectors that insert the transgene with high efficiency and specificity either downstream to its own endogenous promoter or into a safe genomic harbor that allows for robust expression without interference on the neighboring genes. By combining these strategies we will provide radically improved gene transfer platforms.
Furthermore, we will exploit these technologies for the generation and genetic correction of induced pluripotent stem cells, providing a potentially unlimited source of patient-derived vector free gene corrected multipotent stem cells for future applications of regenerative medicine.
Luigi Naldini
GENE/NEURAL STEM CELL THERAPY FOR LYSOSOMAL STORAGE
DISEASES
Our main goal is to develop novel combined gene- and neural stem cell (NSC)-based approaches to treat
Leukodystrophies and GM2-gangliosidosis, a group of lysosomal storage disorders (LSD) with CNS involvement. In order to exploit the therapeutic potentials of NSCs we want to study their biology in both physiological and pathological conditions. Our research activity can be divided as follows:
• Functional characterization of NSCs in LSD animal models. On NSC cell lines derived from disease animal models and from the WT counterpart we investigate: i) the impact of the genetic defect on stem cell
functional parameters; ii) the efficiency of lentiviral-mediated gene-correction; iii) the potential toxicity
due to metabolite accumulation and/or protein over-expression. We established optimal conditions for
successful reconstitution of enzyme activity in NSCs and their progeny while preserving their biological
features. We have also described a disease-dependent proliferation defect in the precursor cell population
residing in the CNS neurogenic niches.
• Gene/NSC-based therapy. We use WT or enzyme-deficient LV-gene corrected NSCs for heterologous or
autologous transplantation, respectively, in different experimental settings.
We are currently optimizing transplantation protocols trying to clarify to which extent exogenous NSCs
may contribute to delay/prevent/arrest the progressive and widespread demyelination/neurodegeneration typical of these diseases, also giving information on the potential advantage of genetically-modified
NSCs on their wt counterpart.
•
Lentiviral (LV)-mediated multiple gene delivery strategy. Our goal is to combine intracranial and systemic
LV delivery performed in neonatal mice to achieve sustained production and widespread distribution of
the deficient enzymes in the CNS, PNS and viscera starting from the early days after birth. This gene delivery approach might be coupled to an anti-inflammatory treatment able to modulate the progressive
neuroinflammation that concurs to the progression of pathology. We are evaluating the safety and the efficacy of the procedures, also assessing whether their combination might have additive or synergistic effects, eventually resulting in improved pathology and function as well as in prolonged lifespan.
Angela Gritti
HEMATOPOIETIC STEM CELL BASED GENE THERAPY FOR THE
TREATMENT OF LYSOSOMAL STORAGE DISORDERS
In most Lysosomal Storage Disorders (LSD) hematopoietic stem cell (HSC) transplantation is not or poorly
effective. HSC gene therapy could ameliorate the outcome of allogeneic transplant and thus provide an expectation of efficacious treatment for these LSD. HSC can be genetically modified to express supra-normal levels
of the therapeutic enzyme, and become a quantitatively more effective source of functional enzyme than normal
donor’s cells. Moreover, autologous HSC are immediately available, thus saving precious time in rapidly progressing forms, and, when employed in a transplant setting, significantly reduce transplant-related morbidity
and mortality. We are thus implementing an innovative approach based on the transplantation of autologous,
gene corrected HSC for the treatment of severe LSD lacking efficacious and safe therapeutic opportunities. To
this goal, we exploit the unique features of lentiviral vectors (LV), which are prime candidates for HSC gene
transfer. By using LV for HSC gene correction, we proved the therapeutic potential of HSC gene therapy in the
murine model of metachromatic leukodystrophy (MLD), a severe dysmyelinating LSD. Based on the results obtained in the preclinical model and on an extensive safety study, HSC gene therapy for MLD is now entering
clinical testing. The same approach has been applied with success to the murine model of type 1 Mucopolysaccharidosis (MPS1), a LSD characterized by visceral organ, skeleton and nervous system involvement. Thus,
MPS1 may become a second target for translating this approach into clinical testing. In the case of globoid cell
leukodystrophy (GLD) or Krabbe disease, we recently demonstrated that the disease-causing enzyme (GALC)
could not be over-expressed in HSC since it causes an unbalance in the content of bioactive sphingolipids tightly controlling HSC survival. Interestingly, when using a LV in which GALC expression is regulated by an HSCspecific 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 the treatment of GLD.
Alessandra Biffi
SAFETY OF GENE THERAPY AND INSERTIONAL MUTAGENESIS
Our group is focused on 2 main research areas: A) studying and improving the safety of vector integration B)
vector-based oncogene tagging for the discovery of cancer genes in hematopoietic and solid tissues.
A)We dissected the contribution of vector design and viral Integration Site Selection (ISS) to oncogenesis using an in vivo genotoxicity assay based on transplantation of vector-treated tumor prone Cdkn2a-/- mouse
Hematopoietic Stem/Progenitor Cells (HSPCs). By swapping genetic elements between γ-Retroviral Vectors (
γ-RV) and Lentiviral Vectors (LV), we demonstrated that transcriptionally active Long Terminal Repeats (LTRs)
are crucial determinants of genotoxicity even when reconstituted in LV, and that self-inactivating (SIN) LTRs
enhance the safety of γ-RV. The ISS and the position of enhancer/promoter elements within the vector modulate vector genotoxicity to a previously unappreciated extent. Because LV has a safer ISS and a SIN LTR design,
it may represent the first choice among currently available integrative vectors. These data have been recently
published in Journal of Clinical Investigation (Montini, Cesana et al., JCI. 2009 Apr;119(4):964-75). We will
test additional genetic elements to improve the safety of gene therapy vectors in alternative in vivo models to assay residual vector genotoxicity.
B) We used a new LV with LTRs carrying enhancers capable to activate neighboring genes upon integration
and exploited its broader tissue tropism and high in vivo transduction efficiency to mutagenize the murine liver.
We tested this genotoxic LV (gLV) on mouse models of Cdkn2a or Pten deficiency, whose mutations are relevant in human hepatocellular carcinoma (HCC), and wild type mice. This gLV was able to induce HCCs in the
different mouse models while none was found in untreated controls. Vector integrations studies on the HCCs
led to the identification of novel liver cancer genes. This project could open new avenues in unraveling synergistic interactions between cancer genes and in the discovery of early diagnostic markers and pharmacological
targets for the effective diagnosis and treatment of HCC and solid tumors in general. The data obtained are
now being submitted to a high ranking journal.
Eugenio Montini
GENE TRANSFER INTO STEM CELLS UNIT
Gene therapy for β-thalassemia
Thalassemias are globally the most common monogenic disorders, affecting thousands of newborn annually.
Patients affected by the most severe form of β-thalassemia is characterized by a profound anemia that leads to
death unless treated with regular blood transfusions. So far, allogeneic bone marrow transplantation from HLAmatched donors represents the only curative treatment, although limited to patients with compatible donors.
For patients lacking a donor, autologous transplantation of genetically corrected HSCs offers the promise of a
definitive cure. Therefore, a relevant issue is to demonstrate feasibility, safety and therapeutic efficacy of gene
transfer in pre-clinical models and patients’ cells. We developed a β-globin-expressing lentiviral vector
(GLOBE) able to sustain long-term correction of thalassemia in the murine preclinical model (Miccio et al.
PNAS, 2008). To move forward with clinical translation, the therapeutic efficacy of GLOBE was tested in the
context of human cells. From the collaboration with PSIEP the availability of samples from a large population of
patients allowed us to perform analyses with statistically significant numbers. No difference in the yield and
clonogenic potential of CD34+ cells was found between normal and thalassemic samples (n=29). We transduced
BM-derived CD34+ cells (n=16) at high efficiency (37-95%, mean: 62%), leading to normal levels of HbA in
culture and BFU-Es. Following pre-activation by cytokines, we monitored changes in committed progenitors
and global gene expression profile. To assess the risk of integration in potentially dangerous genes, we sequenced and mapped the GLOBE integration sites in the genome of thalassemic CD34+ cells. Analysis of integration events showed preference for intragenic regions, without hot spots in protoncogenes, tumor-supressor or
cell cycle related genes. Cross-annotating the expression category for flanking host genes revealed that GLOBE
preferentially lays into proximity of expressed genes. The genotoxic potential of LCR-containing globin vectors
in perturbing the expression of hit genes or flanking the integration site will be tested in human erythroid cells.
Overall, these results provide evidence of efficacy and safety for the use of GLOBE in a clinical setting.
Giuliana Ferrari
IMMUNOLOGICAL TOLERANCE UNIT
The induction of immunological tolerance in allogeneic hematopoietic stem cell (HSC) or solid organ transplantation, autoimmune diseases, and gene therapy remains an important yet elusive goal for immunologists.
We focused our studies on CD4+ regulatory T (Tr) cells, which actively control immune responses. CD4+ Tr
cells have been classified based on their ontogenesis: nTr (CD4+CD25+FOXP3+) cells generated in the thymus,
and Tr1 cells induced in the periphery upon chronic antigen (Ag) stimulation in the presence of IL-10. nTr suppress effector T cells via a yet to be clarified mechanism which requires cell-cell contact whereas Tr1 cells (IL10++, TGF-β+, IFN-γlow, IL-2-, IL-17-, IL-4-, IL-5+) suppress through a cytokine dependent mechanism. We are
exploring and developing different strategies to promote and maintain tolerance via Tr cells: a) the in vivo induction of Tr cells using novel therapeutic approaches, b) adoptive cell therapy with in vitro expansion/induc-
tion of Tr cells, and c) adoptive cell therapy with effector T cells converted into Tr cells by gene transfer with
FOXP3 or IL-10.
In a model of pancreatic islet transplantation, we demonstrated that treatment with an IL-10-based protocol
efficiently promoted tolerance in vivo via the induction of both nTr and Tr1 cells. Furthermore, adoptive transfer of allo-Ag specific but not polyclonal Tr1 cells endorsed long term tolerance, indicating that therapeutic efficacy of Tr1 cells is highly dependent on their Ag-specificity. In a model of gene therapy, we showed that incorporation of target sequences for the hematopoietic-specific micro-RNA, miR-142, into an antigen-encoding
transgene (Tg), avoids Tg expression from APC, and promotes Tg-specific tolerance via the induction of Agspecific Tr cells.
To generate Tr cells in vitro suitable for cell therapy, we developed protocols for both selective expansion of
CD4+CD25+FOXP3+ T cells using rapamycin and induction of allo-specific Tr1 cells using either exogenous
IL-10 or a population of tolerogenic DC, called DC-10. In patients with mixed chimerism after allogeneic
hematopoietic stem cells we demonstrated that tolerance correlated with a high frequencies of alloantigen specific Tr1 cells. Based on all these data, we are conducting a clinical trial in patients receiving haplo-identical
HSC-transplant using allo-specific Tr cells induced in vitro with exogenous IL-10, with the aim to demonstrate
that cellular therapy with Tr cells is safe, can provide immune-reconstitution, and decreases graft versus host
disease severity.
These novel approaches represent the first step towards the definition of new therapeutic protocols for suppressing pathology and restoring peripheral tolerance in immune-mediated diseases.
FROM FOXP3 MUTATION TO IPEX SYNDROME
IPEX syndrome as a paradigm of monogenic autoimmune disease: genotype/phenotype correlation, immune
pathogenic mechanisms and novel therapeutic options
Immune dysregulation, Polyendocrinopathy, Enteropathy, X?linked (IPEX) syndrome is due to mutations of
FOXP3 gene, the transcription factor driving the differentiation and function of regulatory T (Treg) cells. The
disease is characterized by early onset refractory and life threatening enteropathy, eczema, elevated IgE levels
and Type I diabetes. Within the Italian Study Group of IPEX (www.ipexconsortium.org), to date the disease
has been carefully analysed in 14 unrelated affected males with different mutations. We observed that similar
genotypes did not always result in similar phenotypes in terms of disease presentation and severity; in addition,
FOXP3 expression did not correlate with disease severity. Genetic analysis of FOXP3 mutations should always
be performed to ensure an accurate diagnosis and FOXP3 protein expression analysis should not be the only
diagnostic tool for IPEX.
Since IPEX patients have both impaired suppressive function by nTreg and defective Th1 cytokine production by effector T (Teff) cells, studies aimed at understanding the respective contribution of nTreg and Teff cells
in the pathogenesis of IPEX are currently ongoing. We have recently demonstrated that in carrier mothers of
FOXP3 mutations only the nTreg cells bearing the active wt allele of FOXP3 are selected to give rise to a normal Treg cell population, suggesting that the active mutFOXP3 allele might not interfere with an overall normal
Teff cell differentiation.
At present, immunosuppressive drugs can only partially control the clinical manifestations and haematopoietic stem cell transplantation (HSCT) is the only definitive cure, but it is accessible for a limited number of patients. Results of FOXP3 gene transfer into conventional Teff cells demonstrated that suppressive capacity is
conferred to human T cells upon high and stable lentiviral mediated FOXP3 expression even in the presence of
FOXP3 mutations. Therefore, gene transfer might represent an alternative strategy to restore tolerance in
IPEX patients.
Results obtained from this study will provide new insights into the biology of immune regulation, and will
pave the way for expert diagnosis and more rationale therapeutic approaches not only for IPEX but also for
other autoimmune pathologies.
Rosa Bacchetta
TOLEROGENIC DENDRITIC CELLS
Further characterization of the mechanisms of adaptive type 1 regulatory T (Tr1) cell induction via
tolerogenic dendritic cells and function
Type 1 regulatory T cells (Tr1) are a subset of regulatory T cells that is induced in the periphery in the presence of IL-10, produces high levels of interleukin-10 (IL-10) and suppresses effector T cells via a cytokine-dependent mechanism. IL-10 is essential not only for suppression mediated by Tr1 cells, but also for their differentiation in vitro and in vivo. However, little is known on the molecular mechanisms underneath the IL-10-mediated induction of Tr1 cells. We characterize a novel subset of human DC, termed DC-10, present in vivo and
inducible in vitro in the presence of IL-10. DC-10 secrete high levels of IL-10 and IL-6, but low IL-12 and
TNF-α, are CD14brightCD16+CD11c+CD11b+HLA-DR+CD83+CD1a-CD1c-, express CD40, CD80, and CD86,
but not CD68 and M-DC8. DC-10 express high levels of the tolerogenic molecules immunoglobulin-like transcript(ILT)2, ILT3, ILT4, and HLA-G1. DC-10 are potent inducers of allo-specific IL-10-producing Tr1 cells in
vitro.DC-10 promote induction of Tr1 cells through the IL-10-dependent ILT4/HLA-G pathway. Therefore,
DC-10 represent a newly identified subset of human tolerogenic DC with unique cytokine production profile
characterized by a high ratio of IL-10/IL-12 production, that express ILT4 and HLA-G1, and induce Tr1 cells
via the IL-10-dependent ILT4/HLA-G1 interaction. Recently perforin and granzyme B have been involved in
the immunosuppressive mechanism of Tr1-like cells generated by activation of naive CD4+ T cells with
CD3/CD46 cross-linking. To exploit whether bone fide Tr1 cells utilize granzyme B to suppress immune responses, we examined expression, release, and function of granzyme B in Tr1 cell lines and clones. Tr1 cell lines
were differentiated in the presence of IL-10 and IFN-α with a system of artificial APC and Tr1 cell clones were
isolated from peripheral blood of normal donors. Tr1 cell lines and clones express and secrete high level of
granzyme B and specifically lyse antigen-presenting cells. Our findings demonstrate that granzyme B together
with perforin plays an important role in the modulation of immune-responses mediated by Tr1 cells.
Overall, these studies further advance our knowledge on induction of tolerance by Tr1 cells via tolerogenic
DC.
Silvia Gregori
PATHOGENESIS AND THERAPY OF ADA-SCID UNIT
Pathogenesis of ADA-SCID and its correction by gene therapy
Adenosine (ADA)-deficient SCID is a primary immunodeficiency characterized by an altered purine metabolism leading to impaired immune function and organ alterations. Our studies are aimed at investigating the molecular and cellular mechanisms linking the purine metabolism disorder to the immune and non immune alterations of the disease and to assess their correction by gene therapy. We found that both intracellular and extracellular adenosine-mediated signalling cooperate in inducing the severe T-cell dysfunction of ADA-SCID patients. Two lines of research are currently ongoing in ADA-KO mice and humans to study the mechanisms
causing immune dysregulation in ADA deficiency. Our preliminary results showed an altered thymic structure
in untreated mice and the development of autoimmune manifestations in mice treated with enzyme replacement therapy.
Since bone and hematopoietic defects are commonly observed in ADA-SCID, we have studied the effects of
the altered ADA metabolism on bone and stromal cells. We found that ADA-KO mice show a specific bone
phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced RANKL/OPG axis, causing decreased osteoclastogenesis,
and of a low bone formation rate due to deficient osteoblast function. Furthermore, the bone marrow microenvironment of ADA-KO mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-KO neonatal mice with lentiviral-mediated gene therapy resulted in full recovery of the altered
bone parameters, similarly to bone marrow transplant. Thus, ADA metabolism represents a crucial modulatory
factor of bone cell activities and remodeling.
Studies on vector integrations are providing crucial information on vector biology, the dynamics of genetically modified cells, and the safety of gene therapy. Specifically, gene expression studies at bulk and clonal level
have confirmed that integration of retroviral vectors induce minor changes in the transcriptional activity of T
cells from ADA-SCID patients treated with gene therapy.
Our findings are providing new insights into the pathogenesis of the ADA-SCID and will contribute to the
design of better therapeutic approaches.
Alessandro Aiuti
GENE THERAPY FOR WASP/OMENN
Characterization of hematopoietic and immune defects & gene therapy preclinical studies
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by severe hemorrhages, recurrent infections, increased lymphomas and autoimmune manifestations. As an alternative treatment to allogeneic HSC transplantation, we have developed a gene therapy (GT) approach based on lentiviral
vector containing the WAS promoter/cDNA sequences. We demonstrated that this vector allows WASP expression to physiological levels in T cells and led to correction of cytokine production and proliferation. In the
WAS-/- mouse model, infusion of in vitro HSC transduced led to WASP expression in multiple hematopoietic
lineages, including T cells, B cells and platelets. During this last year, we have completed the preclinical evaluation of efficacy and safety of in vitro GT with HSC in was-/- mice, by the generation of a large cohort of GT
treated mice using low (10-20) and high MOI (200). We took advantage of CD45.1-CD45.2 mismatched transplantation to determine donor engraftment by means of FACS analysis. Treated mice were followed for 12
months. Levels of engraftment in the low MOI group were >90% in total bone marrow (BM) cells and in T
cells purified from the spleen, while those in control groups lin—wt and lin—was-/- were >80%. In the high
MOI group, the average T cell engraftment was 86% and 69% in the lin—was-/- group. In the other cell types
tested, full donor engraftment was observed. Efficacy of GT was evaluated by assessing the persistence of engraftment of WASP-expressing cells, and the long-term correction of T cell function. In the low MOI group,
BM cells contained a median of 1 VCN, while splenic T cells had a median value of 2.2. As expected, total BM
and T cells of mice belonging to the high MOI group contained a higher VCN: 2.5 and 4, respectively. Taken
together, these data demonstrated that engraftment of lentiviral-vector transduced lin- cells persisted for 12
months, and suggested that a selective growth advantage was taking place in T cells. Importantly, no tumours
derived from donor origin were observed in GT treated mice.In parallel, we have characterized iNKT cell defect in the absence of WASp. We demonstrated that was-/- iNKT cells are functionally impaired contributing to
the pathogenesis of WAS.
Anna Villa
PEDIATRIC CLINICAL RESEARCH UNIT - GENE THERAPY FOR
WISKOTT-ALDRICH SYNDROME
Clinical trial of gene therapy for Wiskott-Aldrich Syndrome
Wiskott-Aldrich Syndrome (WAS) is a rare genetic disease characterized by multiple haematopoietic cellular
defects, including thrombocytopenia, decreased capacity to control infections, autoimmune manifestations, and
susceptibility to develop cancer. Transplantation of haematopoietic stem cell (HSC) from HLA-identical
donors provides a complete cure for this disease but is not available for all patients and is still associated with
risks of complications. For this reason, gene therapy with autologous HSC could represent a valid alternative
approach, potentially applicable to all patients.
We have developed and tested a lentiviral vector containing the WAS cDNA/promoter sequences (w1.6W).
GMP grade, highly purified vector lots have been produced in large scale for clinical use. We have completed
the preclinical studies showing that the GMP grade vector can efficiently transduce CD34+ HSC from normal
donors and patients leading to restoration of WASP expression in the absence of toxicity. Transplant of transduced CD34+ cells into the Rag2-/-/ γ-chain-/ murine model showed that HSC were able to normally differentiate in various haematopoietic lineages, containing the normal WASp gene. These data, combined with the results form the preclinical studies in the mouse model demonstrating the long-term safety and efficacy in vivo,
provide the necessary preclinical basis for the implementation of a gene therapy trial.
We are now implementing a phase I/II clinical trial based on infusion of CD34+ HSC transduced with the
w1.6W vector, combined to a reduced intensity conditioning. The regimen is designed to allow a competitive
advantage to gene corrected HSC and mature lymphocytes and deplete potentially autoreactive cells, while providing less toxicity than current preparatory schemes used in HSC transplant. The clinical trial is aimed at investigating: 1) the safety of the procedure and of the use of lentiviral vectors; 2) the in vivo long-term engraftment and expression of vector-derived WASP; 3) the ability of gene corrected cells to restore immune functions
and increase platelet counts. If successful this study will provide key results on the safety and efficacy of gene
therapy for WAS.
PEDIATRIC CLINICAL RESEARCH UNIT - ADA GENE TRANSFER INTO
HEMATOPOIETIC STEM CELLS FOR THE TREATMENT OF ADA-SCID
SCID due to adenosine deaminase (ADA)-deficiency is a fatal congenital disorder of the immune system associated with systemic toxicity. In the absence of an HLA-matched sibling donor, hematopoietic stem cell
(HSC) transplant from alternative donors is still affected by high morbidity and mortality, while enzyme replacement therapy (PEG-ADA) fails often to sustain adequate immune reconstitution. Our approach is based
on gene transfer into bone marrow CD34+ HSC combined to a nonmyeloablative chemotherapy prior to cell
reinfusion. Fifteen ADA-SCID children hae been treated according to this experimental protocol, enrolled in 3
different clinical trials. No toxicity or adverse events related to gene transfer have been observed after gene
therapy. The reduced dose of busulfan induced a transient myelosuppression, which was sufficient to achieve
long-term engraftment of gene corrected HSC, differentiating into myeloid and lymphoid cells. The dose of
CD34+ cells infused and the efficiency of gene transfer were shown to be critical factors in determining a higher proportion of gene corrected myeloid cells engrafting in patient. Molecular analysis revealed a polyclonal
profile of vector integrations, reflecting the preference for retroviral vector at the time of transduction in
CD34+ cells, and without in vivo bias for potentially dangerous genes. ADA expression persisted long-term, resulting in efficient systemic detoxification. Immunological studies showed a progressive recovery in T-cell count
and normalization of immune functions; in the 6 patients in whom IVIg replacement was discontinued, antigen-specific antibody responses were demonstrated after exposure to vaccine or viral antigens. Effective protection from infections and improvement in patients’ physical development led to a normal life style. All patients are alive and 13 remain off PEG-ADA, with the longest follow up at >8 years after gene therapy. In conclusion, these studies have provided evidence that HSC
gene transfer is a safe and efficacious therapy for ADASCID, resulting in correction of both the immunological
and metabolic defects. These results have opened a new
perspective for the cure of other life-threatening diseases
using gene therapy combined to a conditioning regimen.
Alessandro Aiuti
Figure 13. Schema of ADA-SCID gene therapy
PEDIATRIC CLINICAL RESEARCH UNIT - CLINICAL TRIAL OF GENE
THERAPY IN METACHROMATIC LEUKODYSTROPHY
A natural history study for defining clinical trial design in hematopoietic stem cell gene therapy for
metachromatic leukodystrophy
Metachromatic Leukodystrophy (MLD) is a rare demyelinating lysosomal storage disease caused by deficiency in arylsulfatase A (ARSA) activity. It is characterized by signs and symptoms of involvement of central and
peripheral nervous systems (CNS and PNS) with variable onset and severe prognosis in the majority of cases.
Since no effective treatment is currently available, we are developing a gene therapy approach with hematopoietic stem cells (HSC) engineered to over-express the ARSA gene.
In the last six years we have studied the natural history of MLD on a cohort of 27 patients, to collect information for the clinical translation of the gene therapy approach. We demonstrated a precise genotype-phenotype
correlation, confirming that patients carrying at least one severe mutation of the ARSA gene have an early disease onset (late infantile and early juvenile) and a rapid and homogenous clinical progression, while patients
with two mild mutations have a late onset (late juvenile and adult) and are characterized by stability of the disease and significant heterogeneity in their clinical presentation. According to these findings, early onset patients
represent the best candidates for our novel treatment having a favourable risk-benefit ratio, given their severe
disease, and being more informative due to their homogenous phenotype and evolution. Indeed, in late onset
patients, it would be difficult discriminating between the potential clinical benefit and the natural benign
course of the disease. Moreover, this study allowed us to validate clinical (Gross Motor Function Measure,
GMFM) and instrumental (brain Magnetic Resonance, MR; ElectroNeuroGraphic recordings, ENG) tests to
monitor disease progression. Based on this information, we defined as efficacy end-points for the upcoming trial the stability or reduced progression of the motor impairment, as assessed by the GMFM scoring, and of demyelination in the CNS and PNS, assessed by brain MR and ENG, respectively, in comparison to control untreated subjects. GMP-grade lentiviral vectors encoding the therapeutic ARSA gene were produced and are
currently being validated for clinical use. We foresee to start recruiting patients fro the trial at the beginning of
2010.
Maria Sessa
Gene expression and muscular dystrophy Unit
PSIEP - Strategic Program of Pediatric Immunohematology
DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES - 95
DIVISION OF IMMUNOLOGY,
TRANSPLANTATION, AND INFECTIOUS DISEASES
Director: Ruggero Pardi*
Associate Director: Adriano Lazzarin*
Research Units
HEAD OF UNIT: Ruggero Pardi*
RESEARCHER: Monica Fabbri
POST-DOCTORAL FELLOWS: Lorenzo Bombardelli, Raffaella Molteni, Martina Panattoni**
PHD STUDENTS: Antonella Giammarresi**, Carolina Lage Crespo**, Anna Lukacs**, Michela Palmisano, Michol Savio**
TECHNICIAN: Barbara Clissi
Cellular and molecular allergology
GROUP LEADER: Samuele E. Burastero
PHD STUDENT: Mona-Rita Yacoub**
TECHNICIAN: Daniela Breda
Human virology
GROUP LEADER: Mauro S. Malnati
RESEARCHER: Silvia Heltai
PHD STUDENT: Lia Vassena**
FELLOWS: Giulia Cassina, Emanuela De Martino
TECHNICIAN: Francesca Sironi
Infection and cystic fibrosis
GROUP LEADER: Alessandra Bragonzi
POST-DOCTORAL FELLOW: Cristina Cigana
PHD STUDENTS: Irene Bianconi, Nicola Ivan Lorè, Moira Paroni
GROUP LEADER: Luca Vangelista
POST-DOCTORAL FELLOW: Massimiliano Secchi
γδ T cells in innate and adaptive immunity
RESEARCHER: Maria Raffaella Zocchi
Infectious diseases Unit
HEAD OF UNIT: Adriano Lazzarin*
Immunobiology of HIV
GROUP LEADER: Lucia Lopalco
PHD STUDENTS: Lorenzo Diomede, Maria Luisa Visciano**
FELLOW: Valentina Merati
TECHNICIAN: Claudia Pastori
Immunological diagnostics of tuberculosis
GROUP LEADER: Claudio Fortis
FELLOW: Manuela Ratti
HEAD OF UNIT: Guido Poli*
RESEARCHER: Massimo Alfano
PHD STUDENTS: Luca Cassetta, Giulia Della Chiara, Samanta Mariani
TECHNICIAN: Chiara Rizzi
HEAD OF UNIT: Massimo Degano
POST-DOCTORAL FELLOWS: Beatrice Alfieri, Fabrizio Gangemi
PHD STUDENTS: Claudia Minici, Stefano Vavassori**
FELLOW: Francesca Giannese
TECHNICIAN: Paola Tornaghi
Cellular immunology Unit
HEAD OF UNIT: Matteo Bellone
PHD STUDENTS: Elena Jachetti**, Alessia Ricupito**, Nicolò Rigamonti**
TECHNICIAN: Matteo Grioni
HEAD OF UNIT: Daniela Maria Cirillo
PHD STUDENT: Paolo Miotto
FELLOWS: Rossella Baldan, Emanuele Borroni, Antonella Tuscano, Diego Zallocco
Experimental immunology Unit
HEAD OF UNIT: Paolo Dellabona
RESEARCHERS: Giulia Casorati, Claudia De Lalla
PHD STUDENTS: Virginia Cecconi**, Maya Fedeli**, Marco Lepore, Anna Napoletano, Elena Tonti
FELLOW: Sara Del Mare
TECHNICIANS: Marta Delogu, Claudio Garavaglia
Immunopathology Unit
HEAD OF UNIT: Luca G. Guidotti
RESEARCHER: Giovanni Sitia
POST-DOCTORAL FELLOW: Lara Ravanetti
PHD STUDENT: Matteo Iannacone
TECHNICIAN: Marta Mainetti
HEAD OF UNIT: Anna Mondino
POST-DOCTORAL FELLOWS: Chaitanya Ekkirala, Rodrigo Hess Michelini
PHD STUDENTS: Teresa Manzo**, Romana Tomasoni**
TECHNICIAN: Veronica Basso
Tumor immunology Unit
HEAD OF UNIT: Maria Pia Protti
RESEARCHER: Lucia De Monte
POST-DOCTORAL FELLOW: Giulia Di Lullo
PHD STUDENTS: Samantha Seresini, Elena Tassi
FELLOW: Donato Calabrese
TECHNICIAN: Giuseppe Consogno
HEAD OF UNIT: Gabriella Scarlatti
POST-DOCTORAL FELLOW: Mariangela Cavarelli
PHD STUDENTS: Miriam Baroni, Stefania Dispinseri, Lara Mainetti
FELLOWS: Priscilla Biswas, Chiara Foglieni, Stefania Sala
TECHNICIAN: Angela Pastore
HEAD OF UNIT: Elisa Vicenzi
POST-DOCTORAL FELLOW: Anna Kajaste-Rudnitski
PHD STUDENT: Tiziana Coradin
FELLOW: Cinzia Pultrone
TECHNICIAN: Silvia Ghezzi
Infectious diseases Unit
Management and antiretroviral treatment of HIV infection
CLINICAL GROUP LEADER: Antonella Castagna
PHYSICIAN: Nicola Gianotti
FELLOWS: Francesca Cossarini, Vincenzo Spagnuolo
STATISTICIAN: Laura Galli
TECHNICIAN: Andrea Galli
Neurovirology
CLINICAL GROUP LEADER: Paola Cinque
PHYSICIANS: Simona Bossolasco, Annamaria Pazzi
POST-DOCTORAL FELLOWS: Roberta Formicola, Anna Granata, Manuela Testa
TECHNICIAN: Arabella Bestetti
Study and treatment of hepatotropic viruses related diseases
CLINICAL GROUP LEADER: Caterina Uberti Foppa
RESEARCHER: Giulia Morsica
POST-DOCTORAL FELLOWS: Sabrina Bagaglio, Giulia Gallotta, Hamid Ibrahim Hasson
FELLOW: Lucy Porrino
Vaccine and immunotherapy
CLINICAL GROUP LEADER: Giuseppe Tambussi
PHYSICIANS: Silvia Nozza, Cecilia Pizzocolo
FELLOW: Manuela Pogliaghi
TECHNICIAN: Andrea Galli
Clinical immunopathology and advanced medical therapeutics Unit
HEAD OF UNIT: Maria Grazia Sabbadini*
PHYSICIANS: Elena Baldissera, Enrica P. Bozzolo, Giselda Colombo, Lorenzo Dagna, Massimo Memoli, Luisa Praderio,
Moreno Tresoldi
POST-DOCTORAL FELLOWS: Patrizia Tanina Aiello, Stefano Franchini
FELLOWS: Fulvio Salvo, Mirta Tiraboschi
Clinical transplant Unit
HEAD OF UNIT: Antonio Secchi*
PHYSICIANS: Rossana Caldara, Francesca De Taddeo, Chiara Gremizzi, Rosa Pedale
POST-DOCTORAL FELLOWS: Alessandra Petrelli, Andrea Vergani
Gynecological cancers immunology
CLINICAL GROUP LEADER: Massimo Origoni*
PHYSICIAN: Luigi Caputo
RESIDENTS: Francesca Occhi, Chiara Stefani
Immunology in liver neoplasms
CLINICAL GROUP LEADER: Luca Aldrighetti
PHYSICIANS: Marco Catena, Renato Finazzi
RESIDENT: Carlo Pulitanò
Obesity
RESEARCHER: Michele Paganelli
Pancreatic tumors: immunotherapy and β-cell function substitution
CLINICAL GROUP LEADER: Alessandro Zerbi
PHYSICIANS: Marco Braga*, Marco Stella
RESIDENTS: Vanessa Capitanio, Giovanni Capretti, Federica Merlini
Gastroenterology Unit
Head of Unit: Pier Alberto Testoni*
Clinical hepato-gastroenterology
RESEARCHER: Mario Guslandi
Digestive pathophysiology
RESEARCHER: Sandro Passaretti
Transplant surgery
RESEARCHER: Carlo Socci
DRI, Diabetes Research Institute
Director: Luca G. Guidotti
Associate Director: Emanuele Bosi*
Research Units
Immune tolerance
GROUP LEADER: Manuela Battaglia
PHD STUDENTS: Alessandra Ferraro, Nicola Gagliani
FELLOW: Andrea Valle
TECHNICIANS: Tatiana Jofra, Angela Stabilini
GROUP LEADER: Marika Falcone
POST-DOCTORAL FELLOW: Ester Badami
PHD STUDENT: Simone Caielli
FELLOWS: Caterina Di Pietro, Carlo Ruberto
TECHNICIAN: Alessandra Caputo
β cell biology
GROUP LEADER: Lorenzo Piemonti
POST-DOCTORAL FELLOW: Leda Racanicchi
PHD STUDENT: Valeria Sordi
FELLOWS: Elisa Cantarelli, Erica Dugani
Cell imaging
HEAD OF UNIT: Alessandro Del Maschio*
GROUP LEADER: Maria Luisa Malosio
FELLOW: Cristina Brigatti
Islet transplantation
CLINICAL GROUP LEADER: Paola Maffi
BIOLOGIST: Paola Magistretti
Prevention in Type 1 diabetes
CLINICAL GROUP LEADER: Luca Falqui
PHYSICIANS: Matteo Rocco Pastore, Sabina Martinenghi
RESIDENT: Laura Molteni
RESEARCH NURSE: Pauline Grogan
Epidemiology & data management
RESEARCHER: Marina Scavini
Childhood diabetes
RESEARCHER: Riccardo Bonfanti
SUPERVISOR: Lorenzo Piemonti
RESEARCHER: Rita Nano
FELLOWS: Raffaella Melzi, Alessia Mercalli
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
constituting 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 pathoRuggero Pardi
genesis of the above conditions is highly diversified, 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 will foster research efforts and development of new technologies aimed at dissecting the
Adriano Lazzarin
mechanisms underlying the immune response to infectious agents,
cancer- and transplantation-associated antigens, as well as the dysregulation of the mechanisms involved in 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 has structured 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 Immuno-biotherapy 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 soon to be launched 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.
Research Units
LEUKOCYTE BIOLOGY UNIT
Adhesion receptor signaling and dynamics in leukocyte migration, proliferation and survival
Most somatic cells require adhesion to substrate for progression through the cell cycle and the onset of DNA
replication in response to growth factors. This phenomenon is known as “anchorage-dependence” (AD), and is
thought to be largely dependent on active signaling by surface integrins. AD is lost at an early stage in neoplastic transformation. We have identified a multimolecular protein complex, the COP9 signalosome (CSN), which
appears to act as a point of convergence of signals originated from adhesion receptors and conveyed to the nucleus via post-translational modifications of selected transcription factors involved in cell proliferation, differentiation and the adaptive response to stress. We are investigating this novel signaling axis within the context of
normal developmental processes (e.g. liver regeneration, see Figure) and in neoplastic transformation. To this
aim we have generated conditional knockout mice in which the catalytic subunit of the CSN has been genetically inactivated in various tissues (T cells, macrophages, hepatocytes). We also investigate adhesion receptor
dynamics in cell migration: in primary neutrophils, we have shown that unengaged αL/β2 integrin (LFA-1) is
internalized and rapidly recycled upon chemoattractant stimulation via a clathrin-independent, cholesterol-sensitive pathway involving dynamic partitioning into detergent-resistant membranes (DRMs). DRM-associated
endocytosis allows efficient retrieval of integrins, as they detach from their ligands, followed by polarized recycling to areas of the plasma membrane, such as lamellipodia, where they establish new adhesive interactions
and promote outside-in signaling events. More recently, we unveiled a novel role of β-arrestins in regulating the
activation of signaling pathways underlying discrete integrin-mediated steps in CXCR2-driven leukocyte extravasation. By combining in vivo approaches in β-arrestin knockout mice with in vitro studies in engineered
cellular models we show that membrane-recruited β-arrestin-2 is required for the onset and maintenance of
shear stress-resistant leukocyte adhesion mediated by both β-1 and β-2 integrins.
Ruggero Pardi
Figure 14. CSN5 expressing clones of
hepatocytes emerge in conditionally
deleted CN5 knock-out regenerating liver
parenchyma
CELLULAR AND MOLECULAR ALLERGOLOGY
Recombinant allergens are entering clinical practice as highly performing diagnostic tools and demonstrated
efficacy and safety in controlled clinical trials. Recombinant allergens can be mutated to reduce their allergenicity, i.e., IgE binding, while fully maintaining T-cell stimulatory potential, which is mandatory for the success of
immunotherapy. Modified, allergens with reduced allergenicity are referred to as “allergoids”.
Conventional strategies to generate allergoids include extended deletions of B-cell epitopes and multiple mutations of the allergen. Alternatively, we are investigating the possibility to destroy crucial B cell epitopes with a
single mutation approach.
We propose to verify whether structurally-guided point mutations represent a successful strategy in the design of modified allergens for immunotherapy, as opposed to standard approaches implying more radical molecular modifications.
We have been working in the last year on the model of the Mus m 1 major mouse allergen, belonging to the
lipocalin protein family. We found that Tyr120 is particularly important for the overall stability of this protein.
Mutations at the level of this residue appear primarily responsible for alterations in the H-bonds network that
stabilizes this molecule and provide striking conformational modifications of the global protein architecture, as
assessed by NMR.
We will investigate whether and to what extent this approach is capable of significantly impairing allergen
recognition by IgE from mouse-allergic patients, and its impact on T-cell epitopes.
We are also interested to verify whether this strategy can be applied to recombinant panallergens. Panallergens, such as profilins, are promising tools to vaccinate a relevant proportion of allergic subjects who are
presently orphans of a specific immunotherapy. We demonstrated that profilins play a crucial role in the epitope spreading of the immune response in polysensitized individuals, who represent approximately one third of
allergic individuals. A specific vaccination with immunogens clinically “easy to handle” due to low allergenicity
could bring about a favorable interference in this process for a large proportion of allergic individuals.
Samuele E. Burastero
HUMAN VIROLOGY
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 in two projects focussed 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 HIV1 Envelope protein gp120 aiming to individuate key structural modifications to render the gp120 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 gp120 scaffolds of two selected HIV-1 strains: the CCR5 dependent strain BaL and the R5X4 strain US077.
Main results obtained in 2008
A strong polyepitopic response against the HIV-1 encoded antigen Tat is the hallmark of EC individuals
showing, in addition a peculiar restriction towards particular regions of the protein that are never or rarely seen
by patients belonging to other cohorts of HIV-1 infected individuals. On the contrary, in LTNP the major feature of the T-cell mediated immune response is represented by a distinctive population of TEMRA CD8 cells
secreting Mip-1â representing a specific immunological marker of natural protection from HIV-1 disease progression.Regarding the second project the functional analysis of the gp160 proteins expressed in vaccinia virus
vectors demonstrates that the deletion of the V1 region is well tolerated by both gp160 scaffolds with preserved
function. On the contrary deletion of the V2 region reduced fusion and modify the recognition of mAbs directed against CD4 induced epitopes.
Mauro S. Malnati
INFECTION AND CYSTIC FIBROSIS
Pseudomonas aeruginosa-host interactions in Cystic Fibrosis: implications for pathogenesis and therapy
Persistent bacterial infections involving Pseudomonas aeruginosa pose serious problems for human health including Cystic Fibrosis (CF) patients. After causing an initial acute disease state, which is kept in check by an
adaptive immune response, Pseudomonas aeruginosa establishes persistent infection and colonize the host by
evading immune surveillance. The goal of our program is to elucidate cellular and molecular mechanisms that
are involved in the host-pathogen interactions during persistent infection with the aim of devising new therapeutic approaches to treat respiratory infections.
•
•
Cellular and molecular mechanisms involved in P. aeruginosa-host pathogen interactions. We selected
strains from CF patients, which carried the same clonal lineage from the onset of colonization over many
years. Genotypic analysis showed genome rearrangements, uptake or loss of genomic islands and acquisition of pathoadaptive mutations. Virulence of early and late CF isolates was assessed by monitoring acute
mortality versus survival, and P. aeruginosa persistence versus clearance in mice of different genetic backgrounds, including CF. We found that chronic infection is established with pathogenic variants distinguished by initially acquired strains and attenuated in causing acute mortality. Of particular interest is the
finding that P. aeruginosa virulence factors are modified or selected against during chronic infection. In
particular, changes in P. aeruginosa PAMPs lead to escape host innate immune system and endorse pathogenesis. Our findings emphasize studies to define novel virulence determinants in adapted P. aeruginosa
population and to identify novel targets which may lead to improved antimicrobial therapy strategies.
Evaluation of novel molecules for treating respiratory infection and inflammation. Our group has established and characterized a mouse model for airway chronic infection with opportunistic P. aeruginosa and
collected unique reagents such as highly virulent CF-related pathogens. Based on this expertise, we have
established the Cystic Fibrosis Animal Core Facility (CFaCore) to support investigations on candidate
therapeutic molecules and to favor the translation of basic research projects into pre-clinical applications.
Alessandra Bragonzi
PROTEIN ENGINEERING AND THERAPEUTICS
Research in our laboratory focuses on molding protein design, engineering and expression strategies into
novel therapeutic interventions. Two major fields are being exploited. The chemokine-chemokine receptor axis
is one of them. Main efforts are devoted to HIV-1 entry inhibitors based on engineered derivatives of RANTES
and other CCR5-binding chemokines, in an attempt to create CCR5 antagonists with potent anti-HIV-1 activity. Both full-length RANTES mutants and short peptides are presently being developed as CCR5-antagonist anti-HIV-1 mucosal microbicides. In perspective, AIDS prevention by microbicides represents an alternative as
well as a complement to an HIV-1 vaccine. The ‘live microbicides’ field is a particularly promising and innovative approach based on the engineering of human commensal bacteria, such as lactobacilli, to produce antiHIV-1 protein therapeutics, a field in which we are involved and committed. A further aspect of HIV-1 entry
inhibitor development consists in the possible combination of different lead compounds. Both full-length and
short peptide RANTES derivatives presented full additivity or even slight synergism when tested in vitro in
combination with different HIV-1 inhibitors. In a second research area, 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 codirected 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 IgE anti-tumor effect. We are now evolving this
system by recruiting also membrane-bound IgE variants and safe recombinant viral vectors. We engineered a
recombinant MVA (modified vaccinia virus Ankara) to express a truncated version of human membrane IgE
capable to bind and activate human Fc ε RI. This system, that includes the use of transgenic mice expressing
the human receptor, has the advantage of being safe and close to the clinics.
Luca Vangelista
Figure 15. The “live
microbicide” concept represented by an engineered
lactobacillus secreting
RANTES that diffuses
and blocks cellular CCR5
at mucosal sites
γδ T CELLS IN INNATE AND ADAPTIVE IMMUNITY
Involvement of γδ T cells in host defense against infections and lymphomas
Circulating Vδ2 T lymphocytes are involved in the response to mycobacterial infections and EBV, while Vδ1
T cells, resident in mucosal-associated lymphoid tissues, contribute to the immunity against L. monocytogenes
and CMV. Vδ2 T lymphocytes recognize non-peptidic phosphorylated metabolites of isoprenoid biosynthesis,
expressed by mycobacteria, while Vδ1 T cells interact with stress-induced MHC-related antigens (MIC-A,
MIC-B) and with the UL-16 binding proteins (ULBPs), receptors for the UL-16 protein produced by CMV-infected cells. Vδ1 T lymphocytes are increased in HIV-1 infected patients and we showed that this is related to
chemokine receptor expression and chemokine response. In these patients ex-vivo isolated Vδ1 T cells express
cytoplasmic interferon (IFN)-γ and interleukin (IL)-17. These cells proliferate and produce IFN-γ and IL-17 in
response to C. albicans, while Vδ2 T cells respond to mycobacterial or phosphate antigens. The IFN-γ/IL-17
double producer γδ T cells express the Th17 RORC and the Th1 TXB21 transcription factors, bear the CD27
memory T cell marker, the CCR7 homing receptor, the chemokine receptors CCR4+ and CCR6+ and the
CD161 molecule, that mediates transendothelial migration and marker of Th17 cells (Blood 2009, in press). We
also found that circulating Vδ1 T lymphocytes are increased in patients with CLL and non Hodgkin NHL,
where they can proliferate, produce TNF-α or IFN-γ in response to autologous cells, provided they express
MIC-A or ULBPs, and in NHL also IL-4 (Blood 2007, 109:2078-2085). These ligands can be up-regulated both
in vitro and in vivo by the use of all-trans-retinoic acid or sodium valproate (Leukemia 2009, 23:642-648). Of
note, the number of circulating Vδ1 T cells in CLL and of IL-4 producing Vδ1 T lymphocytes infiltrating the
lymph nodes in NHL correlates with disease stage and progression. Thus, specifically equipped circulating
memory γδ T cell populations seem to be expanded in different pathological conditions, being preferentially
Th1/Th17 or Th2, probably depending on the antigen(s) encountered in the microenvironment of lymphoid
tissues undergoing infections, chronic inflammation, or lymphoid malignant transformation.
Maria Raffaella Zocchi
IMMUNOBIOLOGY OF HIV
HIV-specific mucosal immunty involved in HIV exposure/infection
Since HIV-1 is sexually transmitted, the genital mucosa represents the main site for initial host-virus contact,
although the role of oral mucosa is not jet clarified. We studied the humoral immune responses at both genital,
oral and systemic levels of HIV-exposed but uninfected individuals (ESN) adults and in samples from seronegative babies born from Subtype C infected mothers, which represents a relevant issue in order to better understand
biological mechanisms involved in natural resistance to HIV infection. We also determined whether oral HIV-1
exposure incites a persistent systemic anti-HIV-1 response in ESN of discordant couples of men who have sex
with men (MSM), and whether this response correlates with exposure to HIV as measured by viral load in the
HIV-positive partners. Orally exposed uninfected MSM can mount neutralizing anti HIV-1 activity in plasma,
mediated primarily by IgA1. This activity correlates with the viral load in HIV-positive partners. Moreover, we
found IgA1 to CCR5 in a subset of HIV seropositive subjects who did not progress toward disease. In this
study we will focus on immuno and virologic characterization of such HIV blocking antibodies. We also analyzed cord blood from 37 seronegative babies born from HIV-seronegative mothers and plasma from the mothers.
We found high titers of IgG directed against one region within the HR1 portion of gp41 but not against MPER (region recognized by 2F5 and 4E10 which are two broad neautralizing antibodies) in seropositive mothers, although
high levels of IgG antibodies against both of these two regions of gp41 were found in their neonates. A
specific neutralizing activity was found in a large number of exposed but uninfected babies and in their mothers.
Preliminary data indicate a positive correlation between neutralizing antibodies and two regions of gp41 such as a
domain within the α helic region and a second domain overlapping with 2F5 epitope but not with 4E10 epitope.
The characterization of mucosal immune system in HIV infection could give us a key to better understand the
mechanisms of viral transmission. Our findings may be relevant in the design of an HIV vaccine able to protect
from HIV-1 Subtype C strains.
Lucia Lopalco
IMMUNOLOGICAL DIAGNOSTICS OF TUBERCULOSIS
A flow cytometric assay for discriminating active from latent Mycobacterium tuberculosis infection
The WHO estimated that one-third of the world’s population harbours Mycobacterium tuberculosis (Mtb) in
an asymptomatic, latent form but retains a lifelong risk of future disease.
We have recently validated an in-house ELISpot-IFN-γ assay based on a restricted pool of highly selected
peptides derived from MTb-specific proteins (here defined MTP). The test resulted highly specific (87%) and
sensitive (93%) for detecting MTb infection. However, actually no tests are able to discriminate active from LTBI.
The possibility to identify specific T cell subsets and different patterns of T cell memory responses by means
of a selected panel of surface and intracellular markers makes flow cytometry an invaluable tool for discriminating active from LTBI as recently suggested by several animal models of infection characterised by a rapid clearance or persistence of the pathogen.
We have conducted a preliminary flow cytometric analysis on active Mtb-infected and LTBI subjects (all with
a positive ELISpot-IFN-γ MTP-specific response) using a panel of 4 mAbs against surface (CD4 and CD45RA)
and intracytoplasmic (IFN-γ and IL-2) markers. Cryopreserved PBMC were stimulated 6h with the pool of
MTP plus a costimulatory signal (anti-CD28/-CD49d mAbs); after 1h Brefeldin A was added. As negative control unstimulated cells, and as positive control cells stimulated with PMA/Ionomycin were used. The analysis
was performed first gating on CD4+ T lymphocytes then on either CD45RA+ or CD45RA- subsets. Within
each subset, the frequency of single positive (IFN-γ+ or IL-2+) or double positive (IFN-γ+/IL-2+) cells was determined and the ratio MTP-stimulated/unstimulated (S/US) cells calculated. While CD4+CD45RA- single or
double positive T cells were present in both active and LTBI subjects, a significant increase of CD4+CD45RA+
double positive cells in LTBI vs. active MTb-infected subjects was observed. We calculated the Area Under the
Curve (AUC)=0.7 (CI 95% 0.503-0.897) and the best cut off point to discriminate active from LTBI. When the
cut off S/US cells <1.5, sensitivity= 87% and specificity= 50%. Two observation could be extrapolated from
these results: first, when the cut off >1.5 is highly probable that the subject have a LTBI; second two subgroups
of LTBI subjects are recognized, and probably only those with the higher cut off could harbour replicating mycobacteria so representing real latently MTb-infected persons.
Claudio Fortis
AIDS IMMUNOPATHOGENESIS UNIT
Immunopathogenesis of HIV infection
Central theme of our Unit is the regulation of HIV replication by exogenous host factors, primarily of immunological nature. In this scenario, we have been focusing our research primarily on the 4 topics listed below.
I. Molecular pathogenesis of HIV infection, with specific regard to the role of the JAK/STAT signaling pathway, and of STAT5 in particular, in HIV replication. This project is the development of our paper published in
2007 (A. Crotti et al. Blood) in which we demonstrate a direct and functional binding of STAT5 and of its naturally C-terminus truncated variant STAT5∆ to the HIV-1 LTR. In addition, we are pursuing the characterization of a transcriptome derived from primary CD4+ T cells infected with either a CCR5-using (R5) vs. a CXCR4-dependent (X4) HIV infection.
II. Role of macrophage polarization in HIV infection. This project explores the potential role of M1 vs. M2
polarization of monocyte-derived macrophages (MDM) infected in vitro with R5 HIV-1 in terms of virus replication. We have observed that both M1 and M2 polarized MDM support less efficiently virus multiplication, although with differences in terms of potency (M1>M2), duration (M2>M1) of the effect and mechanism of action (M1: pre-integration; M2: post-integration).
III. Role of cell adhesion in controlling HIV replication. Based on our published papers on the inhibitory effect of urokinase-type plasminogen activator (uPA), we are addressing the role of static adhesion and of integrin-dependent signaling in impeding the release of mature virions from intra-cellular compartments from infected MDM and related cell lines.
IV. Genetic studies in HIV long-term nonprogressors (LTNP). Within a EC-funded consortium
(“GISHEAL”), headed by Guido Poli, we are performing genome-wide association studies (GWAS) using an
ILLUMINA platform to identify candidate alleles associated with the LTNP condition. The preliminary analysis encourages this approach.
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 three-dimensional 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 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
CELLULAR IMMUNOLOGY UNIT
Our major goal is to achieve a deeper understanding of the molecular events regulating the interactions
among transformed cells, their surrounding stroma and the immune system during the different phases of tumor development and progression. This knowledge is then implemented to identify means whereby induce in
vivo a therapeutic tumor-specific immune response.
These tasks require investigation into reliable animal models that truthfully reflect the human pathology.
Monitoring the immune response against the tumor associated antigen Tag in the transgenic adenocarcinoma of
the mouse prostate (TRAMP) mice, a primary model of prostate cancer (PC), we have found that spontaneous
tumor development and progression associates with the induction of a progressive state of selective immune
tolerance to Tag. Indeed, tumor-bearing mice still harbor Tag-specific T lymphocytes that no longer respond to
a specific vaccination. So far, none of the best-characterized mechanisms of tumor escape [i.e. regulatory T cells
(Treg), myeloid derived suppressor cells (MDSC), and inhibitory enzymes] although existing in tumor-bearing
TRAMP mice, appeared to be relevant for the induction of Tag-tolerance. Indeed, neither depletion/impairment of Treg by monoclonal antibodies or cyclophosphamyde, inhibition of MDSC function by arginase and
iNOS inhibitors, nor inhibition of IDO allowed rescue of Tag-specific T cells and/or delay in tumor progression.
In parallel, we are investigating an original therapeutic approach that combines chemotherapy and immunotherapy with molecules able to affect tumor vessels. This approach aims at improving penetration of conventional doses of chemotherapeutic drugs in tumors, favoring their local anti-tumor and immune adjuvant effects. However, it can also be exploited to reduce the dose of chemotherapeutic drugs and their toxicity, including that against cells of the immune system, with potential additive and synergistic effects. We recently
showed that pre-treatment with NGR-TNF-α, a TNF-α derivative able to target tumor vessels and alter vessel
permeability, increases the penetration and the efficacy of doxorubicin in pre-clinical models of PC.
Matteo Bellone
EMERGING BACTERIAL PATHOGENS UNIT
Pathogenesis and epidemiological control of drug resistant bacterial pathogens of community and
nosocomial origin
1) Tuberculosis (TB): from public health to basic and applied research.
We target some of the research priority areas in the TB field: new diagnostics tools for accurate and rapid
DRTB diagnosis and markers of virulence for a potential vaccine strategy.
We established a European consortium with extensive experience in basic and clinical research relating to
MDR-TB, TB control and epidemiology. TBPAN-NET and TM-REST FP7grants sustain this project. Part of
this activity is integrated with the activities of our HSR-WHO TB Supranational laboratory.
We used our MDR-TB strains collection for the development of an automated innovative platform for MDRTB diagnosis.
An efficient innate immune response is crucial in the natural resistance against MTB. We established an in vitro model for MTB infection in human macrophages for studying the gene regulatory events associated with
host-pathogen interaction by the analysis of small RNAs induced in both macrophages and bacteria. We used a
bioinformatics approach to identify one hundred putative sRNAs candidates in M.tuberculosis. sRNA fraction
from the pathogenic M. tuberculosis H37Rv and the avirulent strain M.bovis BCG were sequenced.
2) Molecular epidemiology and virulence factors characterization of nosocomial multidrug resistant microorganisms.
Global epidemiology of S.aureus methicillin-resistant (MRSA) is constantly evolving and the community-acquired (CA) highly virulent US300-ST8 MRSA clone is the predominant MRSA clone in the US. In Europe several clones CA-MRSA are emerging. Studying 350 MRSA strains since 2005 we have identified: 1) a significant
shift over the years from clones bearing the scc mecI to clones with scc mec IV; 2) two predominant clones,
ST22 (EMRSA15) and HSR1 (Italian); 3) toxigenic US300 related strains causing severe infections. We are investigating the expression of virulence determinants in the identified clones.
C.difficile associated-colitis is increasing in nosocomial settings and highly virulent strains are spreading
worldwide. We characterized 130 C.difficile strains positive for tcdA/tcdB, 40/130 harbouring cdtA/B as additional virulence factor. We are now investigating the presence of mutations in the tcdC gene, coding for the negative regulator of toxinA/B.
Daniela Maria Cirillo
EXPERIMENTAL IMMUNOLOGY UNIT
Investigating the T cell response specific for tumor-specific peptide or lipid antigens
1. Investigating the development and function of T cells that recognize self-lipid antigens presented by CD1
molecules.
We study two types of CD1-restricted T cells. First, the invariant (i)NKT cells, which are a distinct lineage of
T lymphocytes with innate effector functions, whose development relies on a unique genetic program. Our data support a critical role of miRNAs in the physiology of iNKT cells. Furthermore, we have found that iNKT
cells sustain antibody response to vaccine models by licensing APCs and facilitating the induction of Th cells.
Finally, we have obtained evidence both in man and mouse that the presence of iNKT cells plays a protective
role against cancer.
We are interested also in a second type of CD1 restricted T cells, which recognise self-lipid antigens presented by CD1a, b, c. We are testing the hypothesis that lipids synthesised by malignant cells may stimulate this
CD1-restricted T cell response. We have identified a set of self-lipids extracted from leukemia cells that stimulate CD1-restricted T cells.
2. Discovery of unique tumor antigens and characterization of the specific T cell responses.
We are testing the hypothesis that somatic mutations in selected colon cancer genes (CAN-genes) generate
strongly immunogenic antigens and specific immune responses in patients. We have started the identification of
the somatic mutations in 40 CAN-genes by massive parallel sequencing from several CRC specimens. Furthermore, we have shown that it is possible to substantially improve HLA-DR tetramer technology to help identifying tumor antigen-specific T cells by optimizing peptide binding registers
Paolo Dellabona
IMMUNOPATHOLOGY UNIT
Host-Virus interactions in the pathogenesis of viral hepatitis and viral hemorrhagic fevers
The hepatitis B virus (HBV) and hepatitis C virus (HCV) are noncytopathic viruses causing acute and chronic hepatitis of variable duration and severity. Over 700 million people worldwide are chronically infected by
these viruses and about 2 million of them die each year from the complications (i.e. cirrhosis and hepatocellular
carcinoma, HCC) of these infections. The main objective of our research is to define the cellular and molecular
mechanisms responsible for viral clearance and disease pathogenesis during HBV or HCV infection with the
expectation that our results will help to devise new therapeutic approaches to prevent and cure these diseases.
Our hepatitis program takes advantage of infected patients, unique mouse models of infection and new technological advances in the field of live imaging, tackling a number of unresolved issues that comprise the means by
which virus-specific T cells traffic and recognize viral antigens within the liver and how such processes are affected by the anatomical and hemodynamical changes that characterize the complications of chronic HBV infection. Having recently described a novel role for platelets in the pathogenesis of viral hepatitis (i.e. activated
platelets contribute promote the recruitment of virus-specific T cells into the liver), we are also currently dissecting the molecular basis of platelet/CTL interactions and the impact that pharmacologic inhibition of
platelet activation may have on the severity of immune-mediated chronic liver injury and HCC development. In
related studies aimed at testing the role of platelets in the pathogenesis of viral hemorrhagic fevers, we found
that mice infected with different isolates of hemorrhagic arenaviruses develop a mild hemorrhagic anemia,
which becomes severe and eventually lethal in animals depleted of platelets or lacking integrin β-3. Lethal hemorrhagic anemia is mediated by virus-induced interferon (IFN)- α/β that causes platelet dysfunction, mucocutaneous blood loss and suppression of erythropoiesis. Further, platelet-depleted mice fail to mount an efficient
T cell response and do not clear the virus. These studies indicate that IFN- α/β is required and sufficient to
cause the platelet dysfunction and the mechanism of this action is currently under investigation.
Luca G. Guidotti
LYMPHOCYTE ACTIVATION UNIT
Understanding the cellular and molecular events underlying T-cell dependent immunity and tolerance
Our research activity is centered on the characterization of the cellular and molecular events underlying protective immunity and tolerance. In particular we are interested in defining CD4+ T lymphocytes activation,
proliferation, and differentiation as these cells orchestrate immune responses against pathogens and tumors.
To characterize the relative contribution of TCR/CD28 and cytokine-mediated events to T helper cell clonal
expansion and differentiation, we are studying antigen- induced responses in primary T cells by biochemical
and molecular biology assays coupled to single cell flow cytometry analysis. At present we are focusing on
mTOR-mediated signaling controlling cell growth and transcription of cytokine genes important for cell polarization. The in vitro studies are coupled to the in vivo analysis of antigen-specific T cells. We have developed a
number of mouse models where to track antigen-specific CD4+ and CD8+ T cells in lymphoid and non-lymphoid tissues by flow cytometry and immunohistochemestry. These models allowed the study of the dynamic
interaction between developing tumors and adaptive immune responses and the definition of active and adoptive immunotherapy strategies able to overcome mechanism of central and peripheral tolerance. In collaboration with the group of M. Bellone we are also investigating the contribution of minor histocompatibility antigen-restricted T cells to protective anti-tumor immunity in the context of allotransplantation. Finally, in collaboration with I. De Curtis and M. L. Feltri we are also studying the impact of a dysfunctional nervous system development on the acquisition and maintenance of immunocompetence.
Future challenges will involve the definition of in vitro strategies able to modulate T cell function and allowing the generation of defined lymphocyte population capable of transferring protective immunity of tolerance
upon in vivo infusion.
Anna Mondino
TUMOR IMMUNOLOGY UNIT
Role of tumor antigen specific CD4+ T cells in tumor regression and promotion
Animal models have shown that CD4+ T cells play a role in anti-tumor immunity by licensing dendritic cells
to fully activate CD8+ T cells in the lymphnodes and indirectly by cytokines release at the tumor site. To address the role of tumor antigen specific CD4+ T cells in the human system we first set a strategy to identify tumor peptides recognized by CD4+ T cells and second we used those peptides to study the quantity and quality
of the spontaneous tumor specific CD4+ T cell immunity in neoplastic patients. The models used are cervical
and pancreatic cancer.
Cervical lesions are associated with infection by HPV, mostly genotypes 16 and 18. Development of different
grade HPV-16+ cervical intraepithelial neoplasia (CIN) to cervical cancer has been associated with impaired
CD4+ T cell immunity against early antigens. We focus on HPV-18 and in patients with high-grade CIN undergoing conization. We found that HPV-18 E6 and E7 specific CD4+ T cells are present in 50% of patients, irrespective of the presence of HPV-18 in their lesions. Importantly, a robust Th1/Th2 immune response against
E7 but not E6 was associated with the HPV-18- status. On the contrary, when the patients were divided based
on their clinical outcome after surgery, a robust Th1/Th2 immune response against E6 but not against E7 correlated with lack of relapse. Our data demonstrate that, at difference with HPV-16, HPV-18 is immunogenic
and suggest different roles for anti-E6 and E7 CD4+ T cells in anti-viral and anti-tumor immunity.
Pancreatic cancer (PC) is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which favors rapid tumor progression. We evaluated the extent of cancer immune-surveillance and immune-suppression in PC patients by comparing the anti-tumor (antiCEA) and anti-viral CD4+ T cell immunity. We found that PC patients have a Th2 skew in the anti-CEA but
not in the anti-viral CD4+ T cell immunity, demonstrating that Th2 immune-deviation in PC is not generalized
but tumor related and possibly due to factor(s) present at the tumor site. In agreement, immunohistochemical
analysis showed the presence of a predominant GATA-3+ tumor lymphoid infiltrate, supporting a Th2 skew also at the tumor site.
Maria Pia Protti
VIRAL EVOLUTION AND TRANSMISSION UNIT
Antigenic and phenotypic characterisation of HIV-1 variants in transmission and disease progression as
target for vaccine development
Production of an broad neutralizing antibody (Nab) against multiple HIV-1 variants is a desired characteristic for HIV vaccines. Some HIV-1 variants are able to elicit a strong humoral virus-specific, broad Nab response, providing fundamental proof-of-principle that such a response can be elicited in vivo, and thus these
same variants may elicit a potent response again if formulated into an appropriate vaccine. We showed that
viruses with a more flexible use of the CCR5 as coreceptor (called R5broad) and a high resistance to the natural
ligand RANTES, are predictive of immunological failure in the infected newborn. Progression of disease is accompanied with an evolution of the virus to a more complex and flexible CCR5 usage. However, individuals
who do control the disease progression (Long-term non progressors) and/or control naturally the virus (Elite
controllers) have particularly slow replicating viruses which retain the specificity for the wild-type coreceptor
only (R5narrow). These data demonstrate the high degree of variability within R5 viruses, and the need to confine R5 evolution to prevent disease progression.
The development of a Nab response against the transmitted virus can appear as early as 6 months post-infection in adults and children, and persist throughout the disease progression. A Nab response is detectable in
slow but not rapid progressing children. Nab against virus variants newly arising during disease are characteristic of immune escape. The specificity of binding of these antibodies as well as the genetic patterns of immune
escape are ongoing research.
In this regard we are also investigating the role of the intestinal mucosa, the main portal of entry of HIV-1 via
all routes of transmission, and the site of major immune subversion early after infection, which can give us important information on which B and T cell responses HIV-1 is targeting. Our results support the hypothesis
that dendritic cells mediate HIV-1 transmission from the lumen through the intestinal mucosa with a process
similar to bacterial sampling via a virus envelope-mediated mechanism. Understanding the cellular cross-talk
and the type of immune responses promoted, will provide useful information on how to achieve an efficient anti-HIV immune responses in vivo.
Gabriella Scarlatti
VIRAL PATHOGENS AND BIOSAFETY UNIT
Human Immunodeficiency Virus (HIV): virus-host interactions, SARS coronavirus (SARS-CoV)
pathogenesis and Influenza viruses
HIV. We have been studying HIV-infected individuals who naturally control HIV-1 infection maintaining a
healthy clinical state without the use of antiretroviral drugs (defined as LTNP). Among the nine HIV genes, the
integrity, variability and function of nef and vif accessory genes have been analyzed in LTNP. Since in vitro studies have shown that these two and 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 in vitro infection. We have identified a model of U937 cell
subclones in which TRIM22 endogenous expression correlates with poor HIV replication. Current studies are
ongoing to define the precise mechanism of TRIM22 restriction.
SARS-CoV is the etiological agent of the Severe Acute Respiratory Syndrome (SARS). Although the virus primarily infects the lungs, however, SARS-CoV causes a systemic infection since the virus has been found in
blood, urine and stool. We have been particularly interested in the kidney tropism of the virus and identified
human kidney cell lines that support SARS-CoV persistent infection. Such an infection leads to viral adaptation
sustained by the emergence of a single point mutation in the viral membrane glycoprotein that increases SARSCoV replication in vitro and contributes to enhance its cytopathicity in a mouse model of SARS-CoV infection.
Influenza viruses. A currently believed dogma assesses that avian influenza viruses of H5, H7 and H9 subtypes have the potential to be passed from animals, whether domesticated or wild, to humans. In contrast, H1
and H3 subtypes are devoid of such danger since the human population is endowed with cross-neutralizing antibodies raised during seasonal infection and/or vaccination. By screening a panel of sera obtained from health
care workers who have responded to the seasonal influenza vaccine, we have demonstrated that humans do not
have cross-reacting antibodies against contemporary avian viruses raising concerns on future pandemic influenza.
Elisa Vicenzi
NEUROVIROLOGY
Viral infections of the Central Nervous System (CNS): HIV infection of the CNS and Progressive Multifocal
Leukoencephalopathy (PML)
The importance of HIV CNS infection in the current era of suppressive antiretroviral treatment is related to
the role of the CNS as virus reservoir and the concern that its chronic infection may cause cognitive problems
over a time frame of years that need be distiguished from other forms of cognitive impairment not related to
HIV. Within an international 4-part ‘cerebospinal fluid (CSF) consortium’, which collects and studies biomarkers of HIV CNS infection, we have recently identified and validated the neurofilament light chain (NFL) and
the soluble amyloid precursor proteins (sAPPa, sAPPb) as sensitive and specific markers of HIV-associated dementia (HAD) that differentiate this form from other forms of dementia. Also, we have investigated the role of
the urokinase system in HAD and found that the soluble urokinase receptor (suPAR) is overexpressed in CSF
and brain tissue of patients with HAD and that its CSF expression is highly correlated to intrathecal HIV replication, immune activation, and the above markers of neuronal damage, suggesting that suPAR might also play a
role in mediating HIV-induced neurotoxicity.
PML is a progressive demyelinating disease caused by JCV infection of oligodendrocytes. It is not known
why, when and where JCV reactivates in certain patients with compromised immunity causing PML. We have
sequenced the JCV non coding control region (NCCR), which enabled to identify identically highly ‘rearranged’ sequences in CSF and plasma pairs, but not in urine, from the majority of PML patients, suggesting
that JCV might either reactivate in the CNS or in peripheral sites. By sequencing the viral capsid protein-1 (VP1) coding gene we identified point mutations in both CSF and plasma, but not in urine, of PML patients, 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 associated with increased neurotropism. Preliminary results by the IFN-γ Elispot assay also showed that some of these PML-specific substitutions also involve epitopes specifically recognised by JCV-specific T-cells.
Paola Cinque
VACCINE AND IMMUNOTHERAPY
Immunotherapy of HIV infection
HIV infection is characterized by depletion of CD4 T cells and altered immune function, leading to severe
immune deficiency. Mechanisms leading to this T-cell depletion are not completely understood. Potent antiretroviral therapy restores T-cell counts and improves prognosis.
For many years, the use of recombinant interleukin-2 (IL-2) in HIV-infected individuals has been explored.
The results of the two large clinical endpoint studies of IL-2 (SILCAAT and ESPRIT) the results of SILCAAT
and ESPRIT indicate that IL-2 offers no clinical benefit compared to ART alone. Whether these findings are
relevant to other immunotherapies, such as IL-7, is uncertain. The precise role of the immune system in the
pathogenesis of HIV infection may benefit from a re-evaluation as a consequence of these results. These data
indicate that all CD4+ subsets may not be equal with respect to host defence and suggests that refinements in
CD4+ measurements might improve the prognostic and/or surrogate marker value of T cell subset determinations.
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.
Numerous recent findings highlight the importance of IL-7 pathway impairment in the pathogenesis of HIV
infection. Notably, IL-7 levels increased with advancing CD4 T-cell lymphopenia, whereas IL-77 receptor expression is downregulated mainly on CD8 T cells.
The clinical research activity of Vaccine and Immunotherapy Research Center is currently focused on the
conduction of multicentric, internantional phase I clinical trials employing IL-7 as immunotherapy on HIV
positive patients with poor CD4 recovery under conventional antiretroviral therapy.
GiuseppeTambussi
CLINICAL IMMUNOPATHOLOGY AND ADVANCED MEDICAL
THERAPEUTICS UNIT
The main interest of our group is the study of the immunological features of systemic inflammatory diseases.
In particular we focus on the identification of new diagnostic and predictive markers of disease and disease activity, and on the understanding of the pathogenic mechanisms underlying such diseases, also in order to find
more effective and less toxic therapeutic strategies. We are specifically interested in:
• the pathogenesis of the prototypic systemic autoimmune disease, Systemic Lupus Erythematosus, with
particular regards to the processes leading to kidney damage and pregnancy complications;
• the role of neuroendocrine mediators in vessel inflammation. In particular, we are carrying out a rather
comprehensive analysis of the factors underlying the enhanced cardiovascular risk of patients with sustained systemic inflammation;
• the immunopathogenesis of scleroderma and possible novel therapies for it;
• 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).
The research work is carried out in tight collaboration with the activities of the Unit of Internal Medicine and
Clinical Immunology, which encompasses a clinical ward with 43 beds for inpatients, a Center for Allergy, dedicated outpatient clinics for Rheumatology, Clinical Immunology, Autoimmunity and Pregnancy, and Medical
Hepatology. The staff comprises 18 staff physicians and 7 fellows from the Residency Programs in Allergy and
Clinical Immunology and in Emergency Medicine of the Vita-Salute San Raffaele University.
Maria Grazia Sabbadini
CLINICAL TRANSPLANT UNIT
Impact of Pancreas transplantation on diabetic nephropathy
Diabetic nephropathy in its early stage is frequently observed in type 1 diabetic patient undergoing pancreas
transplantation alone. The beneficial effect of tight blood glucose control achieved with pancreas transplantation can be counterbalanced by the use of nephrotoxic agents, such as Calcineurin inhibitor.
The aim of the study is to compare the impact of isolated pancreas transplantation on patient survival and diabetic nephropathy compared to an optimized exogenous insulin therapeutic regimen in type-1 diabetic patients with fragile metabolic control
Metabolic impact of portal venous drainage in pancreas transplantation
The veins of a transplanted pancreas are usually anastomozed to the external iliac vein of the recipient, leading to peripheral insulin secretion, while in physiological setting insulin is secreted within the portal system.
This leads to peripheral hyperinsulinization, a condition that was reported to be atherogenic. Pancreas transplantation can be performed with portal venous drainage, but requires a more complicated surgical procedure.
Furthermore portal drainage of the transplanted pancreas was considered less immunogenic than systemic
drainage.
The aim of this study is to evaluate the endocrine-metabolic impact and rate of rejection of portal venous
drainage in patients undergoing pancreas transplantation, compared to systemic venous drainage.
Open-label single center study comparing the efficacy and safety of tacrolimus vs cyclosporin in simultaneous
kidney-pancras transplantation.
The aim of the study is to evaluate the impact on patient survival, graft survival, rate of rejection, rate of complications and metabolic control of Cyclosporin vs Tacrolimus in kidney-pancreas transplantation.
All patients receive concomitant rATG induction therapy, MMF and short-term corticosteroids.
Neurophysiological study of the impact of pancreatic islet transplantation on diabetic neuropathy in uremic
type 1 diabetic kidney transplanted patients
The aim is to evaluate whether pancreas transplantation may help stabilising polyneuropathy in type 1 diabetic patients undergoing kidney transplantation, and to assess reliability of nerve conduction tests for longitudinal
monitoring of neuropathy.
Antonio Secchi
GYNECOLOGICAL CANCERS IMMUNOLOGY
Cervical cancer is the second most common cancer among women worldwide, accounting for 11.7% of the
total cancer burden. There is indisputable evidence that cervical cancer is related to persistent infection of Human Papillomavirus (HPV). Using sensitive Polymerase Chain Reaction (PCR) techniques, HPV-DNA is detected in almost 100% of invasive cervical cancers.
Actually HPV is the most prevalent sexually transmitted disease; approximately 80% of sexually active
women have been in contact with genital HPVs.
Human Papillomaviruses consist of over 100 identified genotypes showing different tissue tropism and association with specific disease manifestations. Of the 15 types of High-Risk (HR) HPVs, the most predominant
are HPV-16 and HPV-18, which are found in 40-60% and 10-20% of uterine cervix invasive cancers, respectively.
The highest prevalence of HPV-induced cervical pre-neoplastic changes occurs in the third decade, while the
mean age of invasive carcinoma occurs in the middle of the sixth decade, suggesting a prolonged latent phase of
genital infection before the onset of malignant disease.
Cancers caused by a viral agent are unique in that they are related to the host immunity. In the immunocompetent host, it has been demonstrated that HPV infection is usually transient, with a median duration of 8
months. Seventy percent (70%) of women clear a new HPV infection within 12 months and 91% clear it within 24 months, leading to frequent spontaneous resolution of early dysplastic changes. Immunocompromised
patients present some problems to clear HPV infections, presumably due to an impaired ability to clear virus.
We previously reported that anti-HPV-18 E6 CD4+ T cells are present, although at variable extent, in 100%
of patients with high-grade HPV-18 expressing cervical lesions but also in 50% of patients, independently of
the HPV type carried. These results indicated that HPV-18 E6 is very immunogenic and suggested that all responsive patients, irrespective of the HPV expressed, had encountered the HPV-18 and cleared the infection.
We found that, although E7 specific CD4+ T cells were present in all women, a robust Th1/Th2 type response
was associated with the HPV-18 negative status, suggesting that indeed these patients might have cleared the
virus. In agreement with this hypothesis, we found a strong anti-E7 CD4+ T cell immunity also in 20% of normal donors without evidence of disease. On the contrary, anti-E6 CD4+ T cell immunity did not discriminate
between HPV-18 positive and negative patients. When the patients, independently of the genotype carried,
were divided based on their clinical outcome after surgery, a robust Th1/Th2 type response against E6 but not
against E7 correlated with lack of relapse. Collectively, our data strongly suggest a different role for anti-HPV18 E6 and -E7 CD4+ T cells in anti-viral immunity.
Massimo Origoni
IMMUNOLOGY IN LIVER NEOPLASMS
Evaluation of stress response in laparoscopic liver surgery: a prospective study of inflammatory profile,
coagulation, homeostasis, and clinical outcome
The aim of this prospective study is to perform a case-matched analysis to investigate the short term outcome
in patients undergoing laparoscopic and open liver resections, in particular in terms of clinical outcome, inflammatory profile and coagulation homeostasis. Thirty-two (=32) patients undergoing elective hepatic resections have been enrolled in the study. Sixteen (=16) patients were non randomly assigned to the laparoscopic
approach (LPS group), while the further 16 to the traditional open procedure (LPT group). The two groups
were matched for the extent of resection, and then for further parameters such as age, gender, preoperative liver function, tumor histology and size, and ASA score. We collected information about several indicators of
postoperative clinical outcome, such as operating time, intraoperative blood losses and blood transfusions, tumor exposure at the transection surface and minimal surgical margin, hospital stay and overall morbidity rate,
postoperative analgesic therapy, mobilization recovery time and fasting duration.. We obtained plasmatic samples (collected preoperatively, in 1st, 2nd and 5th postoperative day) for the liver function assessment, measuring the Aspartate Aminotranspherase (AST), Alanina Aminotranspherase (ALT) and Total Bilirubin (BIL) levels. Moreover, we determined the serum levels of white blood cells count (WBC), C-reactive protein (CRP), Interleukin-6 (IL-6) and Tumor Necrosis Factor (TNF) as markers of the inflammatory surgical stress response.
Finally, we evaluated the coagulation homeostasis measuring the serum levels of several parameters, such as
prothrombin time (PT ratio), platelets count (PLT), fibrinogen (FG), antithrombin III (ATIII) and fibrin Ddimer (XDP).Postoperative plasma levels of AST, ALT, WBC, CRP, IL-6, PT and XDP, along with blood losses, blood transfusions rate, analgesic therapy amount, fasting duration, mobilization recovery time and overall
morbidity showed a lower rise in LPS group compared to LPT group. The decrease of PLT, ATIII and FG levels was lower in LPS group than in LPT group. The laparoscopic technique for hepatic resections results in improved clinical outcome, lower inflammatory stress response and lower coagulation alterations.
Luca Aldrighetti
OBESITY
Laparoscopic gastric banding for morbid obesity
Laparoscopic adjustable gastric banding (LAGB) is performed in case of primary obesity with Body Mass Index (BMI) >40 or BMI >35 with concomitant serious medical obesity-related conditions, unresponsive to dietary treatment. Preoperative evaluation included screening for endocrine disease, endoscopic and radiological
study of the upper digestive tract and ultrasound study of the upper abdomen.
Between June 1996 and December 2008, 336 patients (58 males/278 females, ranging 18-65 years) received
LAGB. Mean body weight was 116.1 ± 18.7 Kg (range 90-195 Kg), with a BMI ranging between 35 and 65.7
(mean 43.2 ± 5.9). The laparoscopic procedure was completed in 327 patients (97.3 %). Eight cases (2.4%) had
to be converted to the laparotomic procedure either because of hepatomegaly (1 case) or because of gastric lesion during the laparoscopic approach (7 cases). In one patient the procedure was performed with open technique together with ventral hernia repair.
Michele Paganelli
PANCREATIC TUMORS: IMMUNOTHERAPY AND β CELL FUNCTION
SUBSTITUTION
The Unit of Pancreatic and Endocrine Surgery during 2008 has focused its clinical research on pancreatic tumors. Surgical procedures performed by the Unit represent the source of data and material necessary for every
type of investigation and research. During 2008, 168 pancreatic resections have been performed, represented in
details by: 94 pancreatoduodenectomy, 60 distal pancreatectomy, 9 enucleation, 5 total pancreatectomy. In 162
cases (96.4%) resection was performed for a tumor: histology was ductal carcinoma in 98 cases, endocrine tumor in 23 cases, cystic tumor in 16, ampullary tumor in 13, distal bile duct in 8, metastasis in 4 (in 3 cases from
a renal cancer, in 1 case from a melanoma).
In cooperation with the group of tumor immunology, we recruited 26 patients with pancreatic ductal carcinoma undergoing resection, in which a peripheral blood sample (about 60 ml) was obtained before surgery, to isolate T cells (CD4) and to assess their reaction to antigenic peptides. In these patents specimens of tumor tissue
and lymph nodes were also obtained, to test the ability of activated lymphocytes to recognize specific tumor
antigens.
The main clinical research evaluated different techniques to manage pancreatic stump after pancreatoduodenectomy. Among the 94 pancreatoduodenectomy performed, in 20 cases the pancreatic stump was at highrisk for fistula, i.e. with soft parenchyma and/or non-dilated duct (1-3 mm). In these patients two techniques
were applied: A. standard reconstruction (pancreatic, biliary and duodenal anastomosis on the same loop) (8
patients); B. pancreatico-jejunostomy on a separate Roux-en-Y loop with external Wirsung stenting (12 patients). Pancreatic fistula rate was 62.5% in group A, 66.6% in group B (p=0.3). The severity of fistula was
measured by the fistula-related mortality and relaparotomy rates: they were 0% and 25% in group A; 8.3% and
8.3% in group B (not significant reduction, due to the poor number of cases). The Roux-en-Y anastomosis with
external Wirsung stenting may then reduce, but not avoid, the dramatic sequelae of an anastomotic leak. We
are planning a study to prospectively compare this type of reconstruction with pancreatic stump removal (i.e.
total pancreatectomy) combined with islets autotransplantation.
Alessandro Zerbi
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.
Either non-adsorbable antibiotics such as rifaximin or probiotics can represent a safer alternative.
Probiotics have been tested in the treatment of ulcerative colitis and Crohn’s disease (both in the acute phase
and in the maintenance of remission) with variable but promising results.
The choice of the specific probiotic agent to is a critical point because the mechanism of action of the various
Lactobacillus strains, Bifidobacteria or yeasts such as Saccharomyces boulardii is quite different.
To further our previous published experience in this area, we are currently evaluating the precise role of single probiotic agents, probiotic mixtures and rifaximin in the acute and chronic treatment of chronic intestinal
disorders both of overt inflammatory nature (ulcerative colitis and Crohn’s disease) and where microscopic inflammation has a recognized pathogenetic role (microscopic colitis, irritable bowel syndrome).
Moreover, in co-operation with the recently established Probiotic Club ( a multidisciplinary national society
including gastroenterologists, paediatricians and microbiologists) we are endeavouring to identify and develop
proper study protocols in order to evaluate the efficacy of probiotic agents in clinical trials carried out according to a correct methodology able to generate sound evidence-based data.
Mario Guslandi
DIGESTIVE PATHOPHYSIOLOGY
1) Evaluation of new approaches for endoscopic fundoplication in patients with gastro-esophageal reflux
evaluating symptoms, quality of life and gastroesophageal refluxes, measured by manometry and esophageal
pH-impedence.
2) Evaluation of new techniques for the study of esophageal motility such as high resolution manometry
(HRM) and their application in a clinical setting.
3) Surgical operation proposed for haemorrhoids induces a reduction of rectal distensibility that could be responsible
for symptoms of rectal urgency referred by some patients. We are investigating the effect on rectal physiology
(rectal motor and sensory response to distension) of the surgery for haemorrhoids.
4) Previous studies have demonstrated that patients subjected to rectal resection for neoplasia developed
symptoms of rectal urgency reducing their quality of life. We are evaluating symptoms, quality of life, and rectal
sensory and motor function, as measured by electronic barostat, before and after surgical operation with or
without radiotherapy.
Sandro Passaretti
TRANSPLANT SURGERY
The Area of Transplant Surgery focused its clinical research on Simultaneous Pancreas and Kidney Transplantation and Pancreas Alone Transplantation in IDDM patients regarding the following three fields: a) effect
of pancreatic transplantation with portal delivery of insulin secretion; b) effect of immunosuppressive protocols
on pancreas alone transplantation; c) efficacy of pancreas from pediatric donors tu cure diabetes.
a)
25 patients underwent to pancreas transplantation with portal delivery of insulin secretion. Survival
b)
c)
of the pancreas was 82% and 63% at 1 and 5 years, respectively. Homa B% values which represent
insulin delivery and insulin sensitivity recipients was no significantly differente between patients with
portal drainage transplant and normal individuals.
From 2004 38 Pancreas transplantation alone have been performed; All of them received the whole
organ with enteric diversion of exocrine secretion, 8 with portal-venous and 20 with systemic-venous
graft drainage.
Two regimens of immunosuppressive therapywere used: in 2004 it was prednisone, mycophenolate
mofetil, ATG (Anti-thymocyte globulin) and cyclosporine A, while from 2005 to 2009 was prednisone, mycophenolate mofetil, ATG and tacrolimus. Cyclosporine A group included nine patients
while tacrolimus group included nineteen.
1 year graft survival was 55% in the cyclosporine A group while it was 80,7% in the tacrolimus group
(p 0.12); after 5 years, graft survival was 33% in the cyclosporine A group and 72,7% in the
tacrolimus group (p 0.062).
Pediatric donors could represent a novel source available for pancreas transplantation. From 2006 13
IDDM patients received pancreas transplants from pediatric donors (age between 12 and 17 years).
After 1 year, patients survival rate is 92%, while pancreas graft survival is 61,5%, 40% for portal and
75% for systemic drainage. 2 patients with portal drainage developed graft thrombosis and one interrupted immunosuppressive therapy because of the onset of Moskowitz syndrome. 1 year after the
operation mean HgbA1 was 4,9 (range 4,6 to 5,4) %; during OGTT mean basal glucose was
81,9mg/dl and mean basal insulin was 9,1 µU/ml, at 120 minutes mean glucose was 88,3mg/dl and
mean insulin was 42,4 µU/ml.
Carlo Socci
DIABETES RESEARCH INSTITUTE (DRI)
Director: Luca G. Guidotti
Associate Director: Emanuele Bosi*
Type 1 diabetes (T1D) is the most frequent chronic disease of childhood and
adolescence in developed countries and its incidence is steadily increasing.
T1D results from the body’s inability to produce insulin, a hormone that is
needed to convert glucose into energy and regulate metabolism. The cause of
insulin deficiency is the immune-mediated destruction of insulin producing
β-cells located within the islets of the pancreas. The cellular and molecular
determinants mediating this autoimmune process are still largely unknown.
Luca G. Guidotti
Over the last 3 decades T1D has been one of the most relevant single areas
of interest for patient care and research at the San Raffaele Scientific Institute. With the objective of reinforcing and expanding its commitment on diabetes research and care, in late 2007 a specialized and independent Research
Institute entirely devoted to T1D, denominated Diabetes Research Institute (HSRDRI), was launched at San Raffaele.
HSR-DRI is part of the International DRI federation (DRI-NET), which includes 12 other DRI’s around the world. HSR-DRI has an Executive Committee
(Maria Grazia Roncarolo, Emanuele Bosi, Luca G. Guidotti, Alessandro Del Maschio, Antonio Secchi) and a Scientific Advisory Board (Guido Pozza, Camillo Ricordi, Giuseppe Chiumello, Massimo Trucco) and is composed of five Units of Basic
Research and four Groups of Clinical Research.
Emanuele Bosi
The Institute collaborates with nine groups of Basic Research (E. Bonifacio, Uni-Dresden; M. Von
Herrath, Uni-San Diego; M. Atkinson, Uni-Gainesville; P. Fiorina, Harvard; S. Gregori, Tiget; R. Bacchetta, Tiget; G. Zerbini, M. Lorenzi, V. Lampasona, HSR), six external Units of Clinical Research (C.
Ricordi, Miami; A. Ziegler, Uni-Munchen; F. Bertuzzi, Niguarda, Milan; PM. Piatti, G. Perseghin; M.
Venturini HSR) and three external Cores (L. Monti, HSR; E. Bazzigaluppi, Laboraf; A. Sanna, LaboRaf), which closely interact with HSR-DRI scientists and actively contribute to the scientific progress of
the Institute.
The overall objective of HSR-DRI is to prevent and cure T1D.
To achieve this objective, two specific programs are pursued, both of which take advantage of patients
and animal models:
Prediction and prevention of T1D: this program aims to define mechanisms of induction and perpetuation of autoimmunity and at developing strategies for halting/reverting the progression to T1D.
β cell replacement and cell therapy in T1D: this program aims to develop novel immune tolerance-inducing, immunosuppression-lightening and islet-regeneration therapies to prolong the survival of native
and/or transplanted β cells.
Research Units
IMMUNE TOLERANCE
Immunological tolerance in autoimmune type 1 diabetes: from problems toward solutions
Aims: Type-1 diabetes (T1D) is a chronic disorder mediated by self reactive cells that invade the pancreas and
destroy the insulin-producing cells. Peripheral tolerance results from a fine tuned balance between autoreactive
T cells and regulatory T cells (Tregs). Our goals are to: (i) characterize the immune responses occurring in the
target organ of T1D patients; (ii) define new clinical grade protocols for the expansion of human Tregs; and (iii)
identify new therapies for establishing tolerance in pre-clinical animal models of T1D.
Achievements: (i) Pancreatic lymph nodes (PLN) were collected from T1D patients who underwent pancreas
transplantation. These samples were characterized phenotypically by flow cytometry and functionally by in vitro cultures. Phenotypical analysis revealed that, on the contrary to what observed in the periphery, Tregs are significantly reduced in PLN of T1D patients as compared to that of controls. In addition, increased memory T
and B cells in PLN of T1D patients were observed as compared to those of controls. (ii) We previously demonstrated that rapamycin selectively spares Tregs while impedes the expansion of effector T cells. New studies
have now delineated a good manufacturing practice (GMP) protocol for rapamycin-based human Tregs expan-
sion. Finally, (iii) we took advantage of the NOD mouse, a preclinical model for T1D, to test whether rapamycin, which prevent T1D in NOD mice, could increase the therapeutic effectiveness of anti-CD3 in T1D
treatment. To evaluate this possibility, anti-CD3 was administered to diabetic NOD mice alone or together with
rapamycin. Surprisingly, the addition of rapamycin to anti-CD3 blocked its ability to effectively reverse disease
in NOD mice.
Conclusions: (i) The target organ of T1D patients has an altered balance between effector and regulatory T
cells which might be the cause for autoimmune disease development. (ii) The definition of a GMP grade protocol for Treg expansion opens new interesting therapeutic possibilities for the treatment of T-cell mediated diseases. (iii) The unexpected role of rapamycin on anti-CD3 therapy poses caution in combinational therapies but
can also shed light onto the mechanisms by which anti-CD3 affords its therapeutic benefit.
Manuela Battaglia
EXPERIMENTAL DIABETES
Innate immune regulation in Type 1 Diabetes
Autoimmune disease results from the interplay between environmental and genetic factors. Inherited susceptibility to autoimmune disease such as Type 1 Diabetes (T1D) is related to defects of immune regulatory pathways whose function is to avoid or limit the activation of self-reactive T lymphocytes. It recently emerged that
innate immune cells such as dendritic cells, mast cells and natural killer T cells play a central role for self/nonself discrimination and for prevention of autoimmunity. During infections they recognize “danger” and contribute to the immune responses for the clearance of pathogens. In the steady state those innate cells are crucial
to maintain peripheral tolerance and prevent autoimmune diseases such as T1D. Our objective is to determine
whether a defect of those innate immune cells underlies the pathogenesis of autoimmune diabetes in mice and
humans and to restore those immune regulatory pathways for prevention of T1D.
We demonstrated that those cells play an important immune regulatory role in the pathogenesis of autoimmune diabetes and that their functional defects are found in mice and humans affected by autoimmune diabetes. Specifically, we found that dendritic cells of diabetic NOD mice or patients affected by T1D lacked their
capacity to induce the differentiation of regulatory T cells including invariant NKT cells (Baev D.V. et al. J Immun 2008) and peripheral differentiation of FoxP3+CD25+CD4+ Treg cells in the gut (Badami E. et al. manuscript in preparation). In addition, we found that mast cells of NOD mice fail to acquire a tolerogenic IL-10-secreting phenotype and contribute to the pathogenesis of autoimmune diabetes with an overly inflammatory
phenotype (Gri G. et al. manuscript in preparation). Our future goal is to develop molecular and cellular to restore the immune regulatory function of innate cells and to restore immune tolerance against islet antigens in
pre-clinical models of T1D. On the other hand, we aim to assess whether those defects of immune regulation
are present in T1D patients and their “at risk” relatives. Our final goal is to demonstrate that functional impairment of innate immune regulation is involved in the pathogenesis of human T1D and can be corrected to prevent and/or cure autoimmune diabetes.
Marika Falcone
β CELL BIOLOGY
β cell replacing in diabetes
Background and unsolved issues.
In principle, treatment for type-1 diabetes and many cases of type-2 diabetes, lies in the possibility of finding
a β cell mass replacement capable of performing two essential functions: assessing blood sugar levels and secreting appropriate levels of insulin in the vascular bed. Our project focuses on creating conditions that favour
β cell expansion and survival in transplanted and native environments Currently, the only available clinical therapy capable of restoring β cell mass in diabetic patients is the allogeneic/autologous transplantation of β cells.
Despite advances in recent years the somatic cell therapy is still problematic
Starting hypothesis and main results.
The somatic cell therapy for T1D is a great platform to address mechanistic questions regarding type-1 diabetes. In the last years we were able to study the impact of β cell challenge to the immune status of the patient
and the efficacy of immunotherapeutics and their ability to control allogeneic and autoimmune responses. The
results of these studies demonstrate (i) that survival of both syngeneic and allogeneic islet grafts in the liver is
sub-optimal, (ii) that inflammatory reaction play a relevant role for the survival and function of islets after transplantation, (iii) 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: (I) study bone marrow
as site for islet transplantation, (II) develop novel islet survival strategies by modulating inflammation specifically inhibiting pathways involving CCL2 or IL-8, (III) Improve islet transplantation outcome by cotransplantation of islets and feeder cells using mesenchymal stem cells, (IV) determine mechanisms of islet autoantigen immunization and destruction (V) to identify a renewable source of cells to be used to increase the transplantable
β cell mass.
Lorenzo Piemonti
Figure 16. Histological appearance (10x) of C57BL/6 mouse femur 12
month after intra bone islet syngeneic transplantation. Upper panel:
Hematoxylin & Eosin staining: B= bone, BM= bone marrow. Lower
panel: immunoistochemistry image shows insulin staining (red). Scale bar
100 µm
CELL IMAGING
Improving the procedure for detection of intrahepatic transplanted islets by Magnetic Resonance Imaging
Background and unresolved issues
Islet transplantation is an effective therapy for restoring normoglycemia in type-1 diabetes, but long-term islet
graft function is achieved only in a minority of cases. Developing a reliable, non-invasive imaging modality to
trace over time the fate of islets transplanted within the liver would help the interpretation of functional parameters monitored in the periphery.
Starting hypothesis and main results
Non-invasive magnetic resonance imaging of pancreatic islets is an attractive option for the “real-time” monitoring of graft evolution. So far, previous studies have been performed in the absence of a standardized labeling
procedure and, besides a human feasibility study in patients, the effectiveness and safety of various labeling approaches were tested only with high field small bore magnets (4.7T). We have now addressed: a.) standardization and reproducibility of a procedure for the labeling of human islets with the clinically-approved contrast
agent Endorem®, b.) safety aspects of labeling related to inflammation, c.) quality of imaging both at 7T and
1.5T. We have highlighted that the ratio of Endorem®/islet is crucial for reproducible labeling and demonstrated that labeled islets are neither inflamed nor more susceptible to inflammatory insults than unlabeled ones. We
also successfully compared, at 1.5T and 7.0T magnetic fields, transplanted animals up to 143 days after intrahepatic infusion (Figure 17; Malosio et al. 2009 AJT, in press).
Conclusions and future plans
The results of this work have been important for the development of a standardized clinical protocol allowing
non-invasive imaging of transplanted islets in humans, that has been recently approved by the ethical committee. Future plans will include to perform the clinical protocol and to understand the quantitative potential of
MRI in islet transplantation. Furthermore our wish is to develop novel imaging approaches for monitoring the
endogenous islet mass and the inflammatory processes taking place in diabetes.
Maria Luisa Malosio
A
B
C
D
st.
s.c.
E
F
K
600
Labeled
Unlabeled
500
mg/dl
400
300
200
100
0
0
20
40
60
80
100
120
Days after transplant
G
s.c.
H
I
J
st.
Figure 17. In vivo magnetic resonance imaging of transplanted islets at
1.5 and 7.0 T Magnetic resonance transverse sections of liver regions
(7.0T, panels A-E; 1.5T, panels F-J) of mice transplanted with either
unlabeled islets (E, F) or labeled islets (A-D; G-J) at 48 h (A), 9 days
(G), 20 days (B), 35 days (H), 57 days (C), 65 days (I), 105 days (D)
and 142 days (J). Images in panels A-D and G-J at different time
points were obtained from the same subject analyzed both at 1.5 and
7.0 T. Red circles and arrows highlight hypointense regions associated
with the presence of Endorem®-labeled islets; st = stomach, s.c. =
spinal cord. Panel K: non-fasting blood glycemia of animals transplanted with labeled or unlabeled islets measured weekly after transplantation (n=4).
ISLET TRANSPLANTATION
The clinical Islet Transplantation Program included the following lines of research:
1) study of the effect of exenatide on the transplanted islet dysfunction. Three patients, who previously received islet transplant alone achieving long lasting insulin independence, were enrolled when early signs of
islet dysfunction arose: they received exenatide, they were evaluated monthly for metabolic control, every
3 months for insulin response to stimuli (i.v arginine; oral glucose). The scheduled duration of treatment is
1 year. One patient dropped out because of exenatide side effects; two patients are still in follow-up.
2) pilot clinical trial, started in 2007, based on the development of new immunosuppressive regimen accomodating T regulatory cells expansion, avoiding daclizumab and calcineurin inhibitors. This study is part
of a multicenter trial in collaboration with the European Consortium for Islet Transplantation (ECIT). 5
infusions were performed in three patients with type 1 diabetes in agreement with the inclusion criteria;
after completion of transplants one patient became insulin independent and one patient had partial function; one patient, not completed, had early failure, probably because of acute rejection.
3) study of the effect of islet transplantation alone in patients with type 1 diabetes on long-term diabetes
complications: early retinopathy (ophthalmologist assessment, doppler ultrasound of the retinal vein and
retinal central artery, OCT); neuropathy (measurement of nerve conduction velocity); carotid artery disease (Doppler ultrasound of the carotid arteries). These parameters have been evaluated yearly; data will
be processed after 5 years follow-up.
4) prospective study of kidney function and incidence of cancer in patients with type 1 diabetes who received islet transplant alone.
5) commitment in the Collaborative Islet Transplant Registry, supported by USA National Institute of
Health and JDRF.
6) evaluation of the safety and efficacy of pancreatic islet autotransplantation with completion pancreatectomy in the management of patients with high risk for pancreaticojejunostomy after Whipple Resection.
One patient received islet autotransplant, with normalization of metabolic control in presence of few
units of exogenous insulin.
Paola Maffi
PREVENTION IN TYPE 1 DIABETES
This research program encompasses all studies aiming at the definition of pathogenetic mechanisms of induction and perpetuation of autoimmunity in humans and the identification of strategies for halting or reverting
the progression to clinically overt type 1 diabetes. In 2002, with the support of the Juvenile Diabetes Research
Foundation (JDRF), a Clinical Center infrastructure has been created at San Raffaele to host a TrialNet Center.
TrialNet is a NIH-supported network of clinical centres, investigators and core support facilities in the US and
Canada, United Kingdom, Italy, Germany, Finland and Australia. The goals of TrialNet programs are to: further define epidemiology, natural history and risk factors of type 1 diabetes; support the development and implementation of clinical trials of agents to slow the progression of type 1 diabetes in new-onset patients, and delaying or preventing the emergence of type 1 diabetes in individuals found to be at risk of the disease. Recently
completed studies at the San Raffaele Centre include: the metabolic assessment of residual insulin secretion in
patients with type 1 diabetes and the Mycophenolate/Daclizumab clinical trial in recent onset patients; ongoing
studies include: the natural history of development of type 1 diabetes; studies under implementation include:
Oral Insulin for the prevention of diabetes in relatives at risk. An additional focus of the Clinical centre is the
creation and expansion of a wide network of affiliate and satellite centres throughout Italy to support the enrolment into all the TrialNet studies. Based on the same JDRF-funded infrastructure, other clinical trials, in addition to those performed within TrialNet, are expected to be developed in the future, possibly including also
phase I/proof-of-concept studies.
Emanuele Bosi
EPIDEMIOLOGY & DATA MANAGEMENT
The mission of the Epidemiology and Data Management Core is to provide methodological support to investigator-initiated clinical research projects within the Department of Immunology, Transplantation and Infectious Diseases with special regards to those within the Diabetes Research Institute (DRI). Priority of this core
are the translational research projects developed within the San Raffaele Scientific Institute.
The Epidemiology and Data Management Core is currently providing support to four major projects within
the Diabetes Research Institute, all conducted within the Islet Transplant Program:
a) a clinical trial testing safety, feasibility and efficacy of an immunesuppressive regimen that is compatible
with the use of T regulatory cells to induce immune tolerance. This study is part of a multicenter trial in
collaboration with the European Consortium for Islet Transplantation (ECIT);
b) a pilot trial testing feasibility, safety and efficacy of the bone marrow as an alternative site for islet cell
transplant in patients with type 1 diabetes following the encouraging experience in animal models;
c) 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 <3 mm). This project is conducted in collaboration with the University of Pisa;
d) a longitudinal study to identify and characterize the organ donor “inflammatory signature” and the potential for this “inflammatory signature” to predict graft outcome. The study is conducted in collaboration with the Nord Italian Transplant program (NITp) and will involve over 1000 cadaveric organ donors
and 2000 organ recipients over the area served by NITp.
Marina Scavini
CHILDHOOD DIABETES
The aim of the unit is to do clinical research in children with type 1 diabetes. We follow in our out-patients
unit more than 700 children and we have 80-100 new cases of disease each year.
We have two main lines of research:
1) Study of etiopathogenesis of new cases of insulin dependent diabetes in childhood. We try to define using
immunology and genetics all new cases of diabetes. In this way we define type 1 a in 96% of patients (at
least 1 of 5 antibodies for diabetes). We were able to identify 2 cases of genetic diabetes due to a mutation
of insulin gene. We published our results in Diabetes Care 2009,32;123-125 and Diabetic Medicine
2009,26;660-661.
2) Studies of intervention in patients at onset of disease. At the moment we are part of a study of phase 3 using vaccination with GAD-alum in order to reduce the β cell distruction after the clinical diagnosis, sponsored by Dyamid. We screened 4 patients and we started the treatment in 2 patients.
Moreover we are part of a study who planned to use Metformine in diabetes at onset in order to reduce immune destruction of β cells and we collaborate to a study of primary prevention in children with high genetic
risk of diabetes (Prepoint) and we submit as soon as possible to IRB of HSR.
We actively participate to the Diabetes in Children group of SIEDP/ISPED and we collaborated in different
multicenter studies: Twins study, Vipkids, etc
Riccardo Bonfanti
ISLET PROCESSING ACTIVITY
Islet Processing Facility (IPF) of San Raffaele Scientific Institute was established as the Unit devoted to islet
of Langerhans isolation from human pancreas. IPF mission is to provide isolated human islets for transplantation in type 1 diabetic patients as stated on the Italian organ and tissues transplant regulation. Islets available
for transplantation means that they have been determined to meet all release specifications and to be suitable
for utilization. At this purpose, IPF organized management with the target of ensuring that human islets have
the quality required for transplantation in humans. Human islet preparations not suitable for transplant in patients can be used as a mean to drive the isolation procedures improvement, engraftment and its outcome, according to the local ethical committee decisions. Moreover the Milan Centre belongs to an European Consortium (ECIT) supported by JDRF, that distribute final islet preparation not suitable for transplant, with the aim
to improve the research activities in diabetes. Together with the human islet transplantation program, the center has developed all the in vivo and in vitro experimental models for islet studies:
1) production of islet from mice, rats and pig
2) islet transplantation in mouse and rat (liver, kidney capsule) including metabolic follow up (ie IVGTT,
OGTT) and morphologic study (i.e. immunohistochemistry, immunofluorescence, confocal microscopy)
3) islet culture in vitro
4) islet function in vitro (stimulation in static incubation or dynamic perfusion).
Different studies are currently in progress with the aim to increase the effectiveness in times of the transplant,
to achieve the immunological tolerance, define the best culture condition in terms of recovery before the transplant, and improve the islet transplant program with the stem cell base therapy.
Rita Nano
Figure 18. Human Islet after isolation before infusion in man
Human virology
Immune tolerance
Neurovirology
Cell imaging
β cell biology
DIVISION OF GENETICS AND CELL BIOLOGY - 127
DIVISION OF GENETICS AND CELL BIOLOGY
Director: Roberto Sitia*
Associate Director: Marco E. Bianchi*
Research Units
HEAD OF UNIT: Roberto Sitia*
RESEARCHERS: Tiziana Anelli, Ester Zito
POST-DOCTORAL FELLOWS: Jose Garcia-Manteiga, Eva Margittai**
PHD STUDENT: Margherita Cortini**
FELLOWS: Milena Bertolotti, Giada Bianchi, Riccardo Ronzoni
TECHNICIANS: Claudio Fagioli, Elena Pasqualetto
GROUP LEADER: Simone Cenci
PHD STUDENTS: Elisa Benasciutti, Laura Oliva**
FELLOW: Niccolò Pengo**
TECHNICIAN: Elisabetta Mariani
GROUP LEADER: Antonio Siccardi
FELLOWS: Rita Nunzia Fucci, Elisa Nigro
TECHNICIAN: Elisa Soprana
HEAD OF UNIT: Marco E. Bianchi*
POST-DOCTORAL FELLOWS: Roberta Palumbo, Angela Raucci
PHD STUDENTS: Antonella Antonelli, Barbara Lanfranchi**, Jaron Liu, Tobias Pusterla
FELLOWS: Lisa Trisciuoglio, Luca Sessa
TECHNICIANS: Francesco De Marchis, Alessandro Catucci
In vivo Chromatin and transcription
GROUP LEADER: Alessandra Agresti
PHD STUDENT: Barbara Celona
HEAD OF UNIT: Lawrence Wrabetz
POST-DOCTORAL FELLOWS: Maurizio D’Antonio, Pietro Fratta
PHD STUDENTS: Nicolò Musner**, Francesca Ornaghi**, Elisa Tinelli**, Domenica Vizzuso**
TECHNICIANS: Cinzia Ferri, Paola Saveri
Biomolecular mass spectrometry Unit
HEAD OF UNIT: Angela Bachi
POST-DOCTORAL FELLOWS: Alfonsina D’Amato, Vittoria Matafora, Federico Torta
PHD STUDENTS: Umberto Restuccia, Vera Usuelli
FELLOW: Santosh Anand
TECHNICIAN: Angela Cattaneo
Gene expression Unit
HEAD OF UNIT: Fulvio Mavilio
RESEARCHERS: Maria Pannese, Alessandra Recchia
POST-DOCTORAL FELLOW: Claudia Cattoglio
PHD STUDENT: Valentina Poletti**
FELLOWS: Alessandro Bertolo, Simona Capossela
TECHNICIAN: Serenella Sartori
Genetics of common disorder Unit
HEAD OF UNIT: Daniela Toniolo
RESEARCHER: Silvia Bione
POST-DOCTORAL FELLOW: Giorgio Pistis
PHD STUDENT: Tanguy Corre**
FELLOWS: Ivan Buetti, Salvatore Carrabino, Corrado Masciullo, Alessandra Sirri
TECHNICIANS: Cinzia Sala, Fiammetta Viganò
Molecular basis of polycystic kidney disease Unit (Dulbecco Telethon Institute)
HEAD OF UNIT: Alessandra Boletta
POST-DOCTORAL FELLOWS: Isaline Rowe, Claas Wodarczyk
PHD STUDENT: Maddalena Castelli**
FELLOW: Monika Pema
TECHNICIANS: Marco Chiaravalli, Gianfranco Distefano
Molecular genetics Unit
HEAD OF UNIT: Francesco Blasi*
RESEARCHER: Daniela Talarico
POST-DOCTORAL FELLOW: Silvia D’Alessio
PHD STUDENTS: Patrizia Marzorati, Silvia Mori
FELLOWS: Ambra Crippa, Laura Gerasi
TECHNICIAN: Massimo Resnati
Molecular dynamics of the nucleus
GROUP LEADER: Massimo Crippa
POST-DOCTORAL FELLOWS: Carmelo Ferrai, Nicola Micali
PHD STUDENT: Monika Wozinska**
FELLOWS: Matteo Marinelli, Andrea Boni
NeuroGlia Unit
HEAD OF UNIT: Maria Laura Feltri
POST-DOCTORAL FELLOWS: Silvia Bogni, Ernesto Pavoni
PHD STUDENTS: Cristina Colombelli, Marta Pellegatta**
FELLOW: Monica Ghidinelli
TECHNICIANS: Stefania Saccucci, Desirée Zambroni
HEAD OF UNIT: Clara Camaschella*
POST-DOCTORAL FELLOW: Laura Silvestri
PHD STUDENTS: Antonella Nai, Alessia Pagani
RESIDENT: Erika Poggiali
Molecular genetics of renal disorders Unit (Dulbecco Telethon Institute)
GROUP LEADER: Luca Rampoldi
POST-DOCTORAL FELLOW: Céline Schaeffer
PHD STUDENT: Ilenia Bernascone**
FELLOWS: Simone Perucca, Elisa Zanella
Dento-facial histopathology Unit
HEAD OF UNIT: Enrico Gherlone*
PHYSICIANS: Paolo Capparé, Carlo Alberto Cortella, Roberto Crespi, Massimo Pasi, Raffaele Vinci
Genomics of renal diseases and hypertension Unit
HEAD OF UNIT: Paolo Manunta*
CLINICAL GROUP LEADER: Donatella Spotti
RESEARCHER: Laura Zagato
PHYSICIANS: Teresa Arcidiacono, Chiara Lanzani, Luisa Persichini, Maria Teresa Sciarrone Alibrandi, Giuseppe Vezzoli
RESIDENTS: Giovanna Bonavida, Lino Merlino, Marialuisa Querques, Francesco Rainone, Marco Simonini
FELLOWS: Lorena Citterio, Simona Delli Carpini, Elisabetta Messaggio
TECHNICIAN: Nunzia Casamassima
HEAD OF UNIT: Gianfranco Fraschini*
CLINICAL GROUP LEADER: Giuseppe M. Peretti
PHYSICIAN: Corrado Sosio
RESIDENTS: Laura Mangiavini, Alessandro Pozzi, Celeste Scotti
POST-DOCTORAL FELLOW: Daniela Deponti
FELLOW: Rosa Ballis
The Division of Genetics and Cell Biology (DGCB) consists of 14 basic
and 3 clinical research groups, totaling over 140 staff. It occupies laboratory space in Dibit 1 and 2 buildings.
Mission - DGCB aims at the mechanistic comprehension of biological
phenomena to acquire basic knowledge and fuel translational and clinical
research with novel concepts, tools and protocols. Understanding Physiology and Pathology in cellular and molecular terms is fundamental to cure
disease and create novel bio-technologies. Scientific training is another
DGCB priority.
Roberto Sitia
Organization - Scientists are free to engage
in competitive research projects: they are encouraged to join forces, data and equipment so as to foster synergies. Areas of
particular strength include bone and cartilage physiopathology, the physiopathology of stress responses and conformational diseases, chromatin dynamics and epigenetics, cell polarity, and the genetics of complex disorders.
DGCB staff are engaged in inter-Divisional Research Programs and Institutional Facilities.
Goals - Biology is becoming more and more a hard science. Surprising disMarco E. Bianchi
coveries are still made of course, but there is little doubt that quantitative aspects are now essential. This is especially true for an Institute like ours, which
expects basic and clinical research to synergistically flourish. In strict collaboration with the Center of
Genomics, BioInformatics and BioStatistics, DGCB develops state of the art technological platforms for
the scientific community.
DGCB aims at providing clinical sciences with novel concepts and protocols and develops robust cellular and animal models for their testing. As important is reverse translation, where the detailed analysis of
cohorts of patients can unravel physiological mechanisms. Identifying mutational hotspots in patients, for
instance, sheds light on the structure and function of the normal product. The iterative process of translation is a key asset for DGCB.
Training opportunities - DGCB hosts both PhD and PostDoctoral training programs, where positions
are offered on a competitive basis for a minimum of 3 and 2 years, respectively.
Research Units
PROTEIN TRANSPORT AND SECRETION UNIT
Our Unit is exploring the processes of oxidative folding, quality control and degradation of proteins - antibodies in particular - in the early secretory compartment. Solving the structure of ERp44 revealed a novel
mechanism that regulates the binding and release of this chaperone to its client proteins (Wang et al., 2008;
Fraldi et al., 2008). ERp44 interacts also with ERGIC-53, and Ero1 and plays a key role in IgM polymerization.
With Ero1, it also regulates IP3R1 channels (Bergamelli et al., submitted), thus integrating redox and calcium
homeostasis/signaling (Anelli & Sitia, 2008). By manipulating the expression of these molecules we were able to
modulate the rate and extent of intracellular protein aggregation (Ronzoni et al., unpublished). These results
have profound implications in the pathogenesis of ER storage disorders and other protein conformational diseases.
The lab analyses also the mechanisms that orchestrate the architectural (de novo biogenesis of the secretory
apparatus) and functional (onset of Ig secretion and eventually apoptosis) changes during B lymphocyte-plasma
cell differentiation. Our observation that proteasomal capacity declines in parallel to the massive increase in antibody production explains in part the exquisite sensitivity of normal and malignant plasma cells to proteasome
inhibitors (Nerini et al., 2008; Cascio et al., 2008). Indeed, the proteasomal load vs capacity ratio correlates with
drug sensitivity and can hence provide a useful clinical indicator (Bianchi et al., 2009). The possibility of modulating ER proteostasis and stress could offer new therapeutic strategies not only in ER storage and conformational diseases, but also in myeloma and other types of cancer.
Roberto Sitia
AGE RELATED DISEASES
We explore the basic cell biology of normal and malignant plasma cells, with implications for Ab responses
and Multiple Myeloma (MM, 2% of all cancer deaths).
Our discovery that differentiating plasma cells decrease proteasome activity and suffer from proteotoxic
stress (Cenci et al, 2006) provided us with a unique biological model linking protein synthesis to death, with
key immune and oncological implications, like the potential exploitation of proteasome inhibitors (PI) as humoral immunosuppressants in vivo (Cascio et al, 2008). Hence, our research activity aims at: understanding
how plasma cells cope with stress and proteasomal overload, investigating the mysterious mechanisms regulating mammalian proteasome biogenesis; exploiting proteotoxicity to identify novel targets against plasma cell
cancers.
Along these lines, we found that plasma cells deploy autophagy with potent regulatory effects on lifespan and
Ig secretion (Pengo et al, manuscript in preparation). In MM, proteasome expression and functional workload
are key determinants of apoptotic sensitivity to PI, providing potential molecular targets and prognostic indicators (Bianchi et al, 2009). Moreover, we are demonstrating an adaptive role for autophagy in MM (Fontana et
al, unpublished).
Parallel in vivo studies on the molecular mechanisms driving the differentiation of osteoclasts, unique boneresorbing cells, are unveiling novel links between adaptive immunity and bone biology, of potential therapeutic
interest against bone-wasting conditions (Cenci et al, 2003; Benasciutti et al, manuscript in preparation). Given
the vicious connection between MM and bone cells, this model will be of use to better understand the MM environment.
Simone Cenci
MOLECULAR IMMUNOLOGY
Two main projects are pursued.
1) Construction of recombinant poxviruses.
We developed novel methods that allow an extremely rapid production of recombinant poxviruses (MVA
and FPV). An interesting side product was the description of the sequence of homologous recombination
events that lead to the formation of markerless recombinants (Di Lullo et al., 2009a; Di Lullo et al., 2009b, submitted). Moreover, the parallel construction of MVA and FPV recombinants (that are not immunologically
cross-reactive) allows an efficient prime/boost strategy. 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).
2) Exploiting the adjuvant role of membrane IgE in cell vaccines.
Owing to interactions between membrane IgE with specific receptors located on effector cells in a form of intercellular synapsis (Vangelista et al., 2005), tumor cells bearing membrane IgE are better vaccines than control
cells (Reali et al., 2001). The adjuvanticity is dependent upon the interaction with Fc-epsilion RI receptor bearing cell (as demonstrated in knock-out mice). The adjuvant effect of human membrane IgE is demostrable also
in mice which express only the human receptor (Nigro et al., 2009, submitted). Double-recombinant MVA expressing membrane IgE and any other antigen have allowed to extend the adjuvant effect to all sorts of vaccines.
Antonio Siccardi
CHROMATIN DYNAMICS UNIT
Our group studies chromatin organization and function, and in particular the role of one protein, High Mobility Group Box 1 (HMGB1). The state of chromatin determines how specific genes are expressed by different
cells in the same organism (that contain the same genome). Moreover, differentiated cells maintain their identity over time, and stem cells maintain their plasticity. When they fail in this, they can become tumors, or simply
start performing erratically (degenerative diseases of various kinds).
We are also very interested in a remarkable property of HMGB1. This nuclear protein can be leaked out of
necrotic cells and signal traumatic tissue damage, triggering inflammation, cell proliferation and migration, innate and adaptive immune responses, angiogenesis and eventually tissue repair. The connection between chromatin status in apoptosis and tissue repair is a particular focus of our group.
During 2008 we investigated the role of HMGB1 in muscle and skin repair, and during ischemia-reperfusion
in the heart. We have also continued to investigate the signalling pathway of extracellular HMGB1: we showed
that the RAGE receptor is expressed at extremely low level in most cells, in part because it is constitutively
cleaved by the membrane-associated protease ADAM10.
We also found that HMGB1 that remains tightly attached to nucleosomes originating from apoptotic cells
can trigger inflammation and dendritic cell activation by interacting with the TLR2 receptor. As a consequence,
autoantibodies are produced against histones and DNA, which is a hallmark of autoimmune diseases. In fact,
HMGB1-nucleosome complexes have been found in the blood of patients with systemic lupus erythematosus
(SLE), where they can play a role in the pathogenesis.
The Group led by Alessandra Agresti has built and tested a computational model of the activation of NF-κB,
the transcription factor responsible for most inflammatory responses. They have also shown that the systems oscillates in living cells, and that the oscillations are required for specific gene expression programs.
Marco E. Bianchi
Figure 19. Real time monitoring of GFP-p65 using GFP
knock-in MEF and live cell
microscopy allows accurate
quantification of single cell
dynamics of endogenous p65.
(A) The population average
time course of nuclear NF-kB
(red) can show strongly
damped oscillation even when
the individual cells (black, 20
out of 1000 shown) have sustained oscillatory dynamics.
Thousand hypothetical sine
waves were generated to have a period slightly varying from 2 hours (15% S.D. in cycle frequency) and linearly decreasing amplitude. The late peaks become unsynchronized, making the average profile appear constant. (B) The knock-in mice have the endogenous p65 locus replaced by GFP-p65 and have wild-type phenotype. (C) A typical time series of a single living cell treated with 10 ng/ml TNF-a and imaged overnight.
The low GFP level required special image acquisition setup. The quantification of the GFP intensity data is
shown in the time course plot in (D). (D) The time lapse image analysis procedure is shown schematically.
The nuclear:total ratio of GFP-p65 plotted is for the cell in (C), where the labeled arrows correspond to the
images. The ratio was obtained as the mean nuclear intensity divided by mean cellular intensity. The periodogram on right has a single sharp peak and indicates that the estimated period is ~ 1.5 hours for this cell.
IN VIVO CHROMATIN AND TRANSCRIPTION
Sustained oscillations in NF-κB produce differential gene regulation
Inducible transcription factors, like the inflammatory NF-κB family, activate the expression of genes that provide feedback loops upon their own signalling pathways. These feedback loops also create the potential for NFκB to oscillate between cytoplasm and nucleus over hours. However, oscillations of endogenous NF-κB have
not been clearly described in living cells and the functional significance of such oscillations is unknown. Are
they a mere side effect of the pathway settling back to the basal state, or are periodic cycles required for proper
gene expression programs?
We used an NF-κB/p65-GFP knock-in system and time-lapse microscopy in living cells to demonstrate that
oscillations of p65 were sustained, with several cycles of transient nuclear translocation after TNF-α stimulation. NF-κB ability to interact with the genome in vivo remained functional, from early to late cycles.
Mathematical modeling and computational simulations predicted that two different system perturbations
would abolish oscillations, constrain p65 in the nucleus and result in opposite functional consequences of p65
activity.
In vivo experiments confirmed model predictions: both perturbations abolished oscillations, but had opposite effects on p65 genome-scanning activities.
Consistent with the hypothesis that dynamic patterns in the oscillations of NF-κB activity encode specific cellular signaling information, we found that expression of NF-κB target genes is either inhibited or profoundly
enhanced when NF-κB oscillations are manipulated. Moreover, some genes are transcribed only after the second cycle of NF-κB activation, indicating that NF-κB activates transcription according to the persistence of the
inflammatory signal.
We propose that “classical negative feedback” in the NF-κB pathway does not simply function to terminate
signaling, but enables repeated sampling of the environment thanks the oscillatory dynamics it creates. In this
way, NF-κB signaling can orchestrate optimal transcriptional responses, some of which are immediate whereas
others are tuned to occur only after prolonged stimulation.
Alessandra Agresti
BIOLOGY OF MYELIN UNIT
Genesis and maintenance of myelin
We have a long-standing interest in myelin, the sheath that enwraps larger axons in both the central (CNS)
and peripheral nervous system (PNS) 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.
More 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 a congenital hypomyelination; mice expressing P0 with a myc-epitope tag at the amino terminus unexpectedly model two more severe subtypes of CMT1B neuropathy; and mice expressing P0 with any of five known human
MPZ mutations model CMT1B or Congenital Hypomyelination Neuropathy. We validated these preclinical
models (Figure shows onion bulbs and demyelination in peripheral nerve of MPZS63del mice), confirmed that
the mutations operate through gain of function, and showed that the mutant proteins have their ‘toxic’ effect
from various locations in the Schwann cell, many times away from myelin itself. For example, in MpzS63del
mice, we have identified endoplasmic reticulum retention of the mutant P0 and activation of protein quality
control pathways in myelinating Schwann cells of peripheral nerve. Our recent data suggest that protein quality
control unintentionally alters translation of myelin proteins or impairs proteasome degradation of myelin proteins, thereby impairing myelin stability in CMT nerves.
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 20. Onion bulbs and demyelination in peripheral
nerve of MPZS63del mice
BIOMOLECULAR MASS SPECTROMETRY UNIT
Our group is mainly interested in the development and application of sensitive and specific methods for protein identification and microcharacterization. We are developing novel approaches that can be applied to the
proteome analysis of cells under physiological and pathological states.
During 2008 we investigated different protein post-translational modifications. In particular, to gain insights
into the interconnection of the SUMO and the ubiquitin-proteasome pathway, we have studied, by a SILAC
based quantitative approach, the effect of proteasome inhibition on SUMO-conjugated proteins. 193 potential
SUMO-1 substrates were identified, 78 of which are upregulated upon proteasome inhibition. Among these,
Histone H1, Histone H3 and p160 myb binding protein 1A have been further characterized as novel SUMO-1
substrates. The analysis of the nature of the SUMO-1 targets identified strongly indicates that sumoylation regulates the maintenance of nucleolar integrity acting in coordination with the ubiquitin-proteasome system.
As part of the study of phosphorylation in cells and as a methodological approach to improve the selective enrichment of phosphorylated peptides, a new MALDI target was built, called T-plate, produced by exploiting
pulsed laser deposition (PLD) of a nanostructured titanium dioxide thin film onto a standard stainless steel
plate (in collaboration with Dr. Casari at Politecnico di Milano). This new active surface is able to bind and enrich phosphopeptides from complex mixtures and make them detectable for a standard MALDI-MS or
MS/MS analysis. The compatibility with a MALDI-TOF/TOF instrument could open the perspective of using
it for the identification of phosphosites in complex biological samples while its ability to retain also other kind
of phosphorylated biomolecules could open a new way of studying phospholipids.
Another PTM that we tried to characterize is S-nitrosylation which is induced by Nitric oxide (NO) on specific cysteine residues. This route is dynamically regulated and is known to be part of the redox signaling pathway. We have developed a specific MS-based method for the characterization of S-nitrosylated residues and applied it to several cellular and animal models.
Angela Bachi
Figure 21. MS/MS
spectrum acquired on a
LTQ-Orbitrap
GENE EXPRESSION UNIT
The molecular basis of the interactions between retroviruses and mammalian genomes is poorly understood.
We investigate the genetic and viral determinants of target site selection of MLV- and HIV-derived retroviral
vectors in human hematopoietic cells. Retroviral integrations are mapped on the human genome, comparatively analyzed, and correlated with the activity of genes located around insertion sites. The genetic and epigenetic
features of the chromatin regions preferentially targeted by retroviruses are determined in different cell types.
By a combination of genomic, bioinformatic and biochemical techniques, we study the role of transcriptional
regulatory elements and transcriptional complexes in targeting viral pre-integration complexes to specific chromatin regions. We showed that MLV, but not HIV vectors integrate in genomic regions enriched in cell-type
specific subsets of transcription factor binding sites. The MLV integrase and LTR enhancer are the viral determinants of this selection. This study suggests that transcription factors binding the LTR enhancer may synergize
with the integrase in tethering retroviral pre-integration complexes to transcriptionally active regulatory regions. These data indicate that γ-retroviruses and lentiviruses have evolved different strategies to interact with
the host cell chromatin, with important implications for the biosafety of viral vectors in clinical applications.
Control of translation plays a critical role in development, growth, and differentiation. In eukaryotes this
process is mainly regulated at the level of the initiation step. Wbscr1 encodes for eIF4H, a positive regulator of
protein synthesis at the initiation level. The human homolog is on chromosome 7, in a region commonly deleted in patients affected by Williams-Beuren Syndrome. We have generated mutant mice for Wbscr1. The null
mice are characterized by dwarfism, reduced fertility and an impairment of sensorimotor coordination, as in
WBS patients. To identify genes regulated at translational level by Wbscr1 we are performing microarray profiling on total and polysomal mRNAs from MEF and liver of wild type and null mice. These data will be a starting
point to clarify the functions of this gene in physiology and pathology
Fulvio Mavilio
GENETICS OF COMMON DISORDERS UNIT
Genetics of complex disorders
One of the projects of the Unit is the study of the genetics Premature Ovarian Failure (POF) and of age of
menopause, complex traits that have become relevant due to the postponement of first child bearing occurring
in most countries and the consequent infertility problems. The research involves the study of genetic association of DNA variants in candidate genes identified by us as well as genome wide association studies in a large
cohort of women presenting POF collected over the years with the collaboration of clinicians and patients associations in Italy. Two genes have been recently identified and replication of the associations as well as functional studies are ongoing to confirm their involvement in ovarian function, to elucidate their role and to identify
the causative variants.
The study also involves the analysis of a genetically isolated population living in a geographically isolated valley in the Apennine, Val Borbera, whose inhabitants live in 7 villages. We have collected clinical and family data of 1800 people representing about 60% of the resident population and a large genealogical tree has been
constructed to establish all the family relationships going back to the 1600. Epidemiological and genetic data
analysis is ongoing on fertility traits as well on many other traits representing risk factors for complex disorders.
From the data collected we have the possibility to study hematological, endocrinological, cardiovascular traits,
food preferences and cognitive functions by studying the whole set of variation as well as by selecting peopled
presenting extreme values. Such phenotypes may be caused by rare variants present in the general populations,
but that could be identified more easily or exclusively in such special populations.
Daniela Toniolo
MOLECULAR BASIS OF POLYCYSTIC KIDNEY DISEASE UNIT
Unraveling the function of Polycystin-1, the protein most commonly altered in Polycystic Kidney Diseases
The nephron is the filtering unit of the kidney and is formed by the glomerulus and the renal tubule. The diameter of the tubule needs to be tightly controlled for its proper function. Polycystic Kidney Diseases (PKD)
are a class of pathologies characterized by abnormally enlarged tubules, eventually causing renal failure. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of PKD and a very frequent
genetic disease affecting 1:1000.
ADPKD is caused by mutations in either the PKD1 (in 85% of cases) or the PKD2 genes (in 15%) encoding
for Polycystin-1 (PC-1), a large plasma membrane receptor, and Polycystin-2 (PC-2), a calcium channel, respectively. Our major interest is on studying the normal function of PC-1.
In the past we had found that PC-1 is a multi-tasking receptor involved in regulating several signaling cascades. PC-1 induces cell-cycle arrest in the G0/G1 phase of the cell cycle and concomitantly resistance to apoptosis. More recently, using a series of loss and gain of function in vitro models we have shown that PC-1 controls
cell growth (size) in addition to and independently of its action on proliferation. PC-1 achieves this effect by inhibiting the mTORC1 pathway by cross-talking with Tsc2 and controlling its ERKs-dependent phosphorylation. Next, we have generated a conditional Pkd1 line and crossed it with a kidney- specific Cre line, resulting
in massive renal cystogenesis. Biochemical analysis confirmed upregulation of the mTORC1 cascade in polycystic kidneys through an ERKs-dependent, Akt-independent mechanism. Our data show that PC-1 inhibits the
mTORC1 pathway and that lack of PC-1 results in upregulation of the cascade in PKD via an unusual mechanism. We are currently investigating further the molecular details of this and the significance of PC-1/Tsc2
cross-talk in vivo using a series of animal models.
Alessandra Boletta
MOLECULAR GENETICS UNIT
Prep1 Structure and Function.
Prep1 is an homeodomain transcription factor essential for mouse development. We have studied its function
in thymus demonstrating its role in the early T cells differentiation (Penkov et al, PLOS One, 2008) and in the
musckle, demonstrating that it is required for regulating insulin sensitivity (Oriente et al, Mol Cell Biol, 2008).
At the molecular level, we ha investigated the mechanism through which the lack of Prep1 induces apoptosis.
Prep1 is a direct regulator of Bcl-xL. In the absence of Prep1, Bcl-xL mRNA and protein is reduced and this induced mitochondrial potential anomalies and apoptosis (Micali et al, Mol Cell Biol, 2009). Moreover we have
identified a nover cytoplasmic role of Prep1. In fact, by interacting with 4EHP ribosomal protein, Prep1 inhibits the translation of the HoxB4 mRNA which results in major anomalies in the structure and function of the
mouse oocytes. Finally, we have demonstrated that actin polymerization is required for transcription of the
HoxB genes, through an interaction with Prep1 (Ferrai et al, Mol Biol Cell, 2009, in press).
Urokinase receptor (uPAR) structure and function.
We have analyzed the lipid composition of the membrane microdomains that contain uPAR and shown that
this is dependent on the binding of its ligand, uPA (Cortese et al., PLOS One, 2008). At the functional level, we
have studied the uPAR Ko mkice and demonstrated that they have a defective would healing. This is due to to
the abdence of activation of the EGF receptor and to the inability to deposit laminin (D’Alessio et al., J Cell Sci,
2009). Finally, we have examined the role of uPAR in quiescent and mobilized hematopoietic stem cells. We
find that uPAR is essential in both stem cells maintenance and homeostasis. This appears to be due to an interaction between uPAR and the integrin α4β1, that together constitute a retaining signal for hematopoietic stem
cells (Tjwa et al, J Clin Inv, 2009).
Francesco Blasi
MOLECULAR DYNAMICS OF THE NUCLEUS
In 2008 laboratory activities focused on two major topics: 1) the role of the TALE transcription factor Prep1
in development and pathology and 2) the relationship between the genomic component (DNA) of the cell nucleus and non-genomic (protein) components from
the structural and functional standpoint.
1) By using hypomorphic Prep1i/i mutant mice we have shown that the homeobox-containing transcription
factor Prep1 is involved in apoptosis by directly modulating mitochondrial homeostasis through the transcriptional control of the endogenous levels of the antiapoptotic Bcl-XL mRNA and protein, providing a possible explanation for the general organ hypoplasia and the small size of Prep1i/i embryos and mice (collaboration with
Prof. F. Blasi, Università Vita-Salute S. Raffaele).
We also nearly completed studies on the role of Prep1 in Down Syndrome. We find that overexpression of
Prep1 (located on human chromosome 21, in the region relevant for DS) in fibroblasts from DS patients alters
their homeostasis and it may be a relevant therapeutic target for DS-associated diseases.
2) Our studies on the molecular dynamics of the nucleus allowing transcription to take place led us to identify novel nuclear structures associated with yet untranscribed genes. They oscillate between an inactive and an
active state through small modification of their protein component, allowing a rapid and efficient transcriptional response of the genes associated with them.
We have also contributed to establish a major role for actin in the transcriptional activation of the Hox-B
gene cluster in mouse cells (collaboration with Prof. F. Blasi).
We investigated the role of unconventional Myosin VI in the onset and development of prostate cancer. We
find that the depletion of myosin VI by RNA interference in an androgen-insensitive, prostate cancer cell line
(PC3) affects their growth and invasiveness. This, in turn, affects the onset and development of tumors in mice
subcutaneously injected with these cells.
We continued our investigation on the nuclear role of myosin VI by studying the nucleo-cytoplasmic shuttling of the protein by live cell microscopy and by exploring myosin VI-associated nuclear and cytoplasmic protein complexes by proteomics.
Massimo Crippa
NEUROGLIA UNIT
Laminin receptors in nerve development and hereditary diseases
Schwann cells myelinate peripheral nerves, and contribute to neuronal development, differentiation, integrity
and regeneration. Laminins and their receptors are required for many of these functions, and mutations in
genes coding for laminins or components of laminin receptor complexes cause hereditary neuropathies
(Merosin Deficient Congenital Muscular Dystrophy 1A, CMD1A and Charcot-Marie-Tooth 4F).
One of the processes affected in the absence of laminins in CMD1A is axonal sorting, the process by which
large axons to be myelinated are segregated by a single Schwann cell. We have used the Cre/LoxP system to
identify laminins and a β1 integrin as the receptors that allow Schwann cells to sort axons. This year we have
determined that another receptor, dystroglycan, is required, and β1 integrin pair with two different α integrins
to mediate sorting. All these are laminin receptors, so experiments are underway to determine if they bind to
different laminins present in the Schwann cell basal lamina, and if they activate different signaling pathways.
One signaling pathways that we had identified is the small RhoGTPase Rac1. We are using primary co-coltures
of sensory neurons and Schwann cells to identify Rac1 effectors relevant to myelination.
It is known that neuropathies due to laminin deficiency also have abnormal folding of myelin and short myelin
segments (internodes). This in turn leads to myelin instability and reduced nerve conduction velocity. We have
shown that this is due to lack of adhesion to α6β4 integrin and dystroglycan, as mice lacking both of these receptors develop myelin instability causing an age-dependent acute demyelination. Also, we showed that short internodes correlate with lack of proper compartmentalization of the myelin fiber, caused by abnormal linkage between laminin 211, dystroglycan, dystrophin-related-protein2, and periaxin (mutated in Charcot-Marie-Tooth
4F). We also showed that glycosylation of dystroglycan is required for this linkage to form (Court et al. J. Neuroscience 2009). Similar abnormalities are found in CMD1A patients. Thus, laminin receptors have important and
diverse function in peripheral nerves, which are relevant to the pathogenesis of neuromuscular diseases.
Maria Laura Feltri
Figure 22. Compartments in the outer cytoplasm of myelinated
peripheral nerve fibers are stained for f-actin (red), tubulin (blue)
and dystrophin-related-protein 2 (DRP2, green). Wild type mice
show fibers (top four) with small Cajal-bands containing tubulin
and f-actin separated by large DRP2 apposition, in contrast in the
absence of dystroglycan this cytoskeletal organization is disrupted
(bottom four fibers).
REGULATION OF IRON METABOLISM UNIT
The aim of our research is to investigate how the liver peptide hepcidin regulates systemic iron availability, as
a background to understand the molecular pathogenesis of genetic iron disorders leading to both iron deficiency and overload. Hepcidin is upregulated in iron overload by a bone morphogenetic protein (BMP) - SMAD
dependent pathway that uses the hemochromatosis protein hemojuvelin as coreceptor. Hepcidin expression is
also increased in inflammation by an IL-6-STAT3-dependent pathway. Hepcidin expression is suppressed in
iron deficiency/hypoxia by several partially unexplored mechanisms. Recent genetic evidence indicates that the
liver serine protease matriptase-2, encoded by TMPRSS6, is a powerful hepcidin inhibitor, since TMPRSS6 inactivation leads to low iron absorption and iron deficiency due to high hepcidin levels in both mice and humans. However, the protease substrate and the molecular mechanism of hepcidin downregulation remained unknown. We have shown that matriptase-2 cleaves hemojuvelin through its proteolytic processing on plasma
membrane and that this cleavage is suppressed in TMPRSS6 mutants lacking or mutated in the serine protease
domain. Matriptase-2 knock down by morpholino oligos causes anemia with high hepcidin levels in zebrafish
embryos, whereas the expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and indirectly its interaction with hemojuvelin. Matriptase-2 lacking the protease
domain is still able to interact with hemojuvelin strengthening that the interaction occurs through its
ectodomain. Our findings indicate that suppression of the BMP stimulatory pathway is essential for hepcidin
inhibition and suggest that this pathway requiring hemojuvelin as coreceptor is the main iron-dependent pathway of hepcidin regulation. These results are of relevance to understand the molecular pathogenesis and to implement innovative treatments for the two opposite disorders of iron metabolism: hemochromatosis and iron
refractory iron deficiency anemia (IRIDA).
Clara Camaschella
Figure 23. Control of iron homeostasis by hepcidin
in mammals (Camaschella C., Nat Genet 2009)
MOLECULAR GENETICS OF RENAL DISORDERS UNIT
Cellular and animal models for the identification of the pathogenetic mechanisms in uromodulin-associated
renal cystic disorders
Medullary cystic kidney disease/familial juvenile hyperuricemic nephropathy (MCKD/FJHN) are autosomal
dominant kidney diseases characterized by alteration of urinary concentrating ability, frequent hyperuricemia,
tubulo-interstitial fibrosis, cysts at the cortico-medullary junction and renal failure. MCKD/FJHN are caused
by mutations in the uromodulin gene, UMOD (Hart et al., 2002).
Uromodulin is exclusively expressed by epithelial cells of the thick ascending limb of the loop of Henle and
by distal convoluted tubules and it is released in the urine through a conserved proteolytic cleavage (Santam-
brogio et al., 2008). Its biological function is still not fully understood. Studies on umod knock-out mice
demonstrated that it has a protective role against urinary tract infections (Bates et al., 2004) and calcium oxalate
crystals-induced urothelial damage (Mo et al., 2004). To date, more than 50 UMOD mutations have been reported in MCKD/FJHN patients. All but three (in-frame deletions) are missense changes likely leading to protein misfolding. Indeed, the presence of uromodulin aggregates within the cytoplasm of tubular cells has been
reported in kidney biopsies of MCKD/FJHN patients (Dahan et al., 2003; Rampoldi et al., 2003).
Our research interest is to understand the mechanisms of pathogenesis in MCKD/FJHN and to gain insights
into uromodulin biology. Through studies in transfected cells we demonstrated that mutations in uromodulin
lead to ER retention of mutant protein (Rampoldi et al., 2003; Bernascone et al., 2006). We are currently investigating both in in vitro and in vivo models the molecular pathways that are activated upon uromodulin intracellular retention and aggregation. We also focused our studies on the molecular mechanisms that regulate uromodulin polymerization. We recently identified two motifs whose mutations lead to premature intracellular
polymerisation of a soluble uromodulin isoform demonstrating the inhibitory role of these sequences for protein assembly. Proteolytic cleavage separating one of the two motifs from the mature monomer is necessary to
release the inhibitory function and allow protein polymerisation (Schaeffer et al., 2009).
Luca Rampoldi
DENTO-FACIAL HISTOPATHOLOGY UNIT
We assessed the biological features and clinical applications of bone substitutes in grafting procedures and
dental devices to allow implant-proshtodontics oral rehabilitations in edentulous patients.
Firstly, we analyzed magnesium-enriched hydroxyapatite (MHA) and calcium sulfate (CS) in clinical studies
by radiological, histological and histomorphometric examinations (percentages of mean vital bone, connective
tissue and residual grafting material). In 45 postextractions sockets, radiographic examination revealed a
greater reduction of alveolar ridge in the CS group then MHA one, histologic examination showed more bone
formation and faster resorption in CS group and more residual implant material in MHA group (see figure).
Both biomaterials, in particular MHA, demonstrated bone regeneration features to allow predictable implant
positioning and oral rehabilitations. Thus, we applied these findings in testing ‘platform switching’ dental implants, reporting high-predictable results in 45 patients.
Furthermore, MHA is widely used in preimplant oral surgery as a bone substitute because of its osteoconductive ability. So far, evaluation of clinical outcome and histomorphometrical parameters are the only ways to
demonstrate successful engraftment, but a pre-clinical indicator of successful bone regeneration would be precious for both clinical and biotechnological purposes (e.g. biomaterial validation). So, we developed an alternative technological platform based on ex vivo osteoblast expansion and highly sensitive gene expression profiling
by real-time reverse transcriptase polymerase chain reaction (RT-PCR). In 25 bone specimens obtained from 15
patients, we demonstrated that gene expression profiling of an array of osteoblast specific genes is effective in
certifying osteoblast identity and function in the bone tissue regenerated by the engrafted MHA. These findings
provide the framework to develop a strategy to test the osteoinductive capacity of a given biomaterial at the biomolecular level.
Enrico Gherlone
Figure 24. Histological section from bone obtained 3 months postgrafting, with presence of osteons and numerous connective tissue
spaces (CT) and vital bone (VB) in contact with MHA particles (GM)
GENOMICS OF RENAL DISEASES AND HYPERTENSION UNIT
Genomics and pharmacogenomics of complex renal diseases
Calcium kidney stone disease is a complex disorder due to nutritional and genetic alterations. Calcium sensing receptor rs7652589 and rs1501899 polymorphisms were associated with stones in patients with primary hyperparathyroidism (n=296), a finding previously observed in idiopathic stone formers. The nutritional analysis
in stone formers identified high sodium and fructose intake as a risk factor for the stone production.
A GWA study carried out on salt-sensitivity of never treated hypertensive patients allowed to discover: i. 76
intragenic and 154 flanking “top” SNPs (p≤10-4) detecting loci related to cytoskeleton rearrangement
(DAAM2, RHOC), ion transport (SLC24A3, KCNMB4) and vasoconstriction (BDKRB2, PRKG1); ii. “candidate” SNPs (p≤10-3) located in SLC8A1, SLC12A3, PKD2, UMOD and ADRB2 genes. Analysis of genetic
profile would predict sodium-sensitive hypertension susceptibility.
Response to ?-blocker therapy is variable among hypertensive patients. A number of sympathetic nervous system genes have been explored for this variability such as ?1-adrenergic receptor gene (ADR?1). We investigated the relationship between dipping and non-dipping nocturnal pattern. Patients undergone a 24-h ambulatory
BP monitoring and the acute salt load test, received ?-blocker (Atenolol or Nebivolol) for 2 months. Carriers of
wild-type Arg389Gly ADRB1 genotype resulted dipper, salt-resistant and responsive to ?-blockers. Salt sensitivity test together with ADR?1 genotype can predict the best responders to ?-blocker therapy.
In the OASIS trial (Ouabain Adducin Specific Intervention with Sodium in hypertension), we analyzed the
response to PST2238 drug (rostafuroxin) according to candidate genes involved in Adducin-Ouabain pathway.
The end point was the difference in SBP office after five weeks of therapy. No difference between placebo and
2238 effect was found. However a greater response to 2238 has been showed in patients carrying a LSS2 mutation. In patients carrying specific genotypic combinations the relative risk to be responder to rostafuroxin was
18.84 (p model <0.001). PST2238 is an effective anti-hypertensive drug only in selected patients that can be
identified by genotyping for candidate genes.
Paolo Manunta
TISSUE ENGINEERING AND BIOMATERIALS
Tissue engineering and analysis for cartilage, meniscus and tendon tissue
One of the goals of our research is the development of an engineered osteochondral composite for the repair
of the cartilage lesion. In our studies, we focused on engineering in vitro a biphasic composite made of cellular
fibrin glue and an osteo-bio-compatible scaffold. Our studies have demonstrated a gross a stable integration between the two components and a cartilage-like quality of the newly formed matrix. In collaboration with other
laboratories, we are also testing different biomaterials as scaffold for the reparative cells.
We are also started a series of experiments with the attempt of characterizing the meniscal cells having the ultimate goal of developing an engineered meniscal substitute. We have demonstrated the presence of at least
three cell lines within the meniscus tissue.
We have recently started a series of experiments with the goal of create a tissue engineered tendon. Tendons
do not repair spontaneously in the acute or chronic ruptures. We believe that a tendon engineered in vitro with
a biological scaffold seeded with autologous fibroblasts could represent an important solution. As possible cell
source we have tested tendon, ligament, and derma. We have also started a series of tests for the creation a lesion model in the rabbit patellar tendon. This would allow to test in vivo the efficacy of the engineered tendon
for repairing lesion defect in vivo.
In collaboration with the Politecnico di Milano, we have started a series of studies on the analysis of the biomechanical properties of normal and osteoarthritic articular cartilage, including the permeability, which is a
crucial property for the functionality of this tissue. Recently we have started a series of studies on cartilage at
the early stage of osteoarthrosis. This would allow understanding the correlation between the macroscopic appearance of the degenerative process in articular cartilage and the decrease of biomechanical properties of the
tissue.
Giuseppe M. Peretti
Genetics of common disorder Unit
NeuroGlia Unit
Molecular genetics of renal disorders Unit
Molecular basis of polycystic kidney disease Unit
CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS - 145
CENTER FOR GENOMICS, BIOINFORMATICS
AND BIOSTATISTICS
Director: Giorgio Casari *
Research Units
Neurogenomics Unit
HEAD OF UNIT: Giorgio Casari*
RESEARCHER: Giovanni Lavorgna
POST-DOCTORAL FELLOW: Francesca Maltecca, Riccardo Vago
PHD STUDENTS: Laura Cassina, Loredana Leo**, Michela Riba
FELLOWS: Laura Corti, Sara Cottonaro
TECHNICIANS: Maurizio De Fusco, Celia Pardini
Theoretical Biology
GROUP LEADER: Riccardo Fesce
Biogenesis and motility of secretory organelles Unit
HEAD OF UNIT: Maria Vittoria Schiaffino
POST-DOCTORAL FELLOWS: Rosa Lucia D’Ambrosio, Tiziana Daniele, Ilaria Palmisano
PHD STUDENT: Angela Palmigiano**
Genomic Unit for the diagnosis of human pathologies
HEAD OF UNIT: Maurizio Ferrari*
RESEARCHERS: Annapaola Andolfo, Sara Benedetti, Paola Carrera, Laura Cremonesi, Isabella Fermo, Vito Lampasona
FELLOWS: Stefania Battistella, Sara Bonalumi, Viviana Bornaghi, Angela Brisci**, Francesca Bruno, Emanuela Castiglioni,
Vincenza Causarano, Chiara Di Resta, Alessandra Foglio, Silvia Galbiati, Cristina Montrasio, Elena Sommariva,
Stefania Stenirri, Chiara Redaelli, Daniele Zeni
Proteome biochemistry Unit
HEAD OF UNIT: Massimo Alessio
POST-DOCTORAL FELLOWS: Barbara Comuzzi, Valeria Corti
PHD STUDENTS: Carlo Vittorio Cannistraci, Stefano Olivieri**
FELLOW: Sara D’Annibale
TECHNICIAN: Antonio Conti
Biomolecular NMR laboratory (Dulbecco Telethon Institute)
GROUP LEADER: Giovanna Musco
POST-DOCTORAL FELLOWS: Massimiliano Gaetani, Michela Ghitti, Silvia Mari, Luca Mollica, Andrea Spitaleri
PHD STUDENTS: Francesca Chignola, Dmitrios Spiliotoupulos, Chiara Zucchelli
FELLOW: Valeria Mannella
After the completion of the human genome sequence, and as well many
other model organism genomes, we entered a sort of new deal in life sciences
taking advantage of innovative powerful technologies, such as deep sequencing, total gene expression, protein mass spectrometry and molecular
NMR and of recently discovered or rediscovered phenomena, such as microRNAs, epigenetic regulation, abundant untranslated transcripts, posttranslational modifications. All these cooked together with powerful algorithms aimed at detecting functional relations among genes, proteins, pathways, disease conditions. The Center for Genomics, Bioinformatics and Biostatistics originates as an institutional initiative and follows this track.
Giorgio Casari
The CGBB actually bases on two components: research groups with established biological expertise already present in the institute and computational
and system biology scientists, who are partly to be recruited. We reckon to complete this phase within the
next few months. Notwithstanding, we are setting up platforms for Gene expression, Genetic analysis,
Deep sequencing, Computational biology thanks to internal and external collaborations. A proteomics
service is also being activated for the institute community.
The Center is being located in the core of Dibit2, the “Basilica” central building on a 1500 sq.m. area
and includes, at present, 52 researchers.
Research Units
NEUROGENOMICS UNIT
A single protein complex for two diseases. The case of the mitochondrial metalloprotease m-AAA
Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric
paraplegin/AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named
m-AAA proteases. These complexes exert protein quality control on mitochondrial proteins and are players in
the regulation of mitochondrial fusion and fission. When mutated, both proteins cause diseases: paraplegin mutations are responsible for hereditary spastic paraplegia (HSP), while AFG3L2 mutations are associated to
spinocerebellar ataxia type 28 (SCA28). At present, the study of murine mutants are opening the way for the
comprehension of the pathogenetic mechanisms leading to these degenerative forms, which substantially differ
for the neuronal targets, such as the motoneuron (HSP) and Purkinje cell (SCA28).
PINK1, the mitochondrial kinase associated to Parkinson’s disease
Although familiar forms of PD are rare, the identification of genes responsible for Mendelian forms of PD
has contributed crucial information on the molecular mechanism of the disease. Mutations of PINK1, a serthreo mitochondrial kinase, are responsible for a juvenile recessive form of PD. We demonstrated that mutant
variants display a reduced autophosphorylation activity, which is regulated by the carboxy-terminus moiety of
the protein. At present, the project is focusing on the physiologic role of PINK1 and on the identification of
natural substrate and interactors, which associate PINK1 to autophagy.
Na,K ATPase and hemiplegic migraine
Migraine is a common chronic recurrent disease characterized by disabling headache attacks, which can be
associated to additional symptoms, such as aura. We demonstrated that familiar hemiplegic migraine type 2
(FHM2) is due to ATP1A2 gene mutations. In vitro models suggest a loss of function effect of the mutants
showing a reduced resting potential and increased excitability, associated to cortical spreading depression, the
neuronal correlate of aura. The project focuses on the molecular mechanism at the basis of the facilitated cortical spreading depression in FHM knockin and conditional knockout murine models.
Giorgio Casari
Figure 25. Fusion and fission dance
THEORETICAL BIOLOGY
Research activity is aimed at developing original approaches to data analysis, simulation and modelling. Such
approaches are to be applied in particular to the study of synaptic function.
During the last year two projects have undergone significant progress:
1) We have almost completed the set up of a system for simultaneous acquisition of extracellular electrophysiological signals from a microelectrode array (MEA), with the associated procedures of data/signal analysis, to
study the connectivity and plasticity (short term recruitment and fatigue, long-term potentiation, LTP and de-
pression, LTD) in cultured hippocampal neurons or in hippocampus slices from adult animals.
The cultures are used to characterise the role of specific proteins in synaptic function (the first target will be
synapsin I, a protein involved in synaptic vesicle availability for transmitter release), by comparing cultures
from wild-type and knock-out animals (collaboration with prof. Valtorta’s lab – San Raffaele Scientific Institute).
As tissue slices make it possible to study hippocampal connectivity and plasticity at late postnatal developmental stages, this second approach will be employed to study the acute and chronic action of psychoactive
drugs on hippocampal function, and its possible residual alterations in adults exposed to psychoactive drugs
during adolescence (collaboration with prof. Parolaro’s lab, Insubria University).
2) Our competence in signal/data analysis and mathematical modeling has been exploited in a collaborative
effort with the groups of prof. Sacchi and prof. Rossi in Ferrara University:
• we have studied the bioelectrical properties of the orthosympathetic neuron in the rat superior cervical
ganglion and observed the contribution of a little known chloride conductance to underthreshold behavior of the neuron, to its excitability properties and to the ionic selectivity of the nicotinic acetylcholine receptor channel.
• an original signal analysis software has been developed to quantify synaptic activity at the cytoneural junction of frog labyrinth, and has been employed to study the effects of exposure to simulated micro-gravity
conditions on labyrinthine function; quantal release and spike generation were observed to be markedly
compromised.
Riccardo Fesce
BIOGENESIS AND MOTILITY OF SECRETORY ORGANELLES UNIT
The ocular albinism type 1 protein (OA1), an intracellular G protein-coupled receptor, regulates organelle
biogenesis and motility in pigment cells
We are focused into the study of secretory organelle biogenesis and transport in mammalian cells as alteration
of these processes represents an important cause of human disease. Our experimental model is ocular albinism
type 1, an X-linked disorder characterized by severe reduction of visual acuity, nystagmus, strabismus, photophobia, retinal hypopigmentation, foveal hypoplasia and misrouting of the optic tracts. The protein product of
the ocular albinism gene, named OA1, is a pigment cell-specific membrane glycoprotein, displaying structural
and functional features of G protein-coupled receptors (GPCRs), yet exclusively localized to intracellular organelles, i. e. lysosomes and melanosomes. Although the precise signaling pathway activated by OA1 remains
unknown, the presence of giant melanosomes (macromelanosomes) in the skin and eyes of patients with ocular
albinism suggests that this receptor is implicated in the biogenesis of melanosomes. In order to unravel the
downstream pathway of OA1, we generated melanocyte cultures from an Oa1-KO mouse model. We found
that, in addition to a reduced number of melanosomes and to the presence of giant melanosomes, Oa1-KO
melanocytes display an abnormal distribution of the organelles toward the cell periphery. The same phenotype
was observed in the retina, at developmental stages relevant for the development of the optic system, yet preceding the formation of macromelanosomes. Time-lapse video microscopy and organelle tracking analyses
showed that Oa1-KO melanosomes display a defective motility along microtubules, but only in the presence of
an intact actin cytoskeleton. Thus, OA1 appears to facilitate melanosome motility along tubulin versus actin filaments and could co-ordinate the maturation of melanosomes with their transport toward the cell periphery.
These findings imply a novel interpretation of the role of OA1 in pigment cells and suggest that ocular albinism
results from a different pathogenetic mechanism than previously thought, based on the disruption of an organelle-autonomous signaling pathway implicated in the regulation of both membrane traffic and transport.
Maria Vittoria Schiaffino
GENOMIC UNIT FOR THE DIAGNOSIS OF HUMAN PATHOLOGIES
The Genomic group applied advanced methodologies to molecular analysis of genes involved in several
pathologies, including neurologic and neuromuscular disorders, arhythmogenic disorders, pediatric surfactant
deficiency, macular degeneration, neurodegeneration, iron metabolism disorders, polycystic kidney disease, and
myeloproliferative disorders. This led to the identification of a variety of known and new sequence variations
and made possible a genotype-phenotype correlation with particular respect in the field of both monogenic and
multifactorial traits. In addition, we performed case-control association and pharmaco-genetic studies to correlate genome variation to disease predisposition and drug response.
We also developed new genotyping devices and methodologies, such as GS-FLX parallel pyrosequencing on
amplicon pools, high throughput SNP analysis, automation of genotyping process, microchip electrophoresis
with dual color single-photon avalanche diodes, ligation detection reaction on copolymer-coated glass slides,
PNA-mediated enriched PCR for noninvasive prenatal diagnosis of beta-thalassemia, and new microarray substrates for high sensitive genotyping of minority mutated alleles.
In the frame of the International Human Variome Project (HVP) and the Human Genome Variation Society
(HGVS) we are involved in creation and maintenance of Locus Specific Data Bases and Clinical-Molecular Data Bases aimed to realize an accurate documentation of genome variants related to disease.
Our Clinical Proteomics group is working out strategies for biomarker discovery in different pathologies:
prostate cancer, laminopathies, type-1 diabetes-related nephropathy. Our approach consists of identification of
differentially expressed proteins by means of 2D-electrophoresis, image analysis and mass spectrometry, in order to clarify molecular mechanisms of pathogenesis, indicate diagnostic tools or therapeutic targets to develop.
Diagnostics of autoimmunity is largely based on measurements of disease associated circulating autoantibodies. In our immunoassay development laboratory novel assays were introduced based on recombinant autoantigens including those for autoantibodies to the type 1 diabetes autoantigen ZnT8 and to the neuromyelitis optica autoantigen AQP4.
Maurizio Ferrari
PROTEOME BIOCHEMISTRY UNIT
Differential proteomics profile analysis
ONCO-PROTEOMICS
Serological Proteome Analysis (SERPA) of colorectal carcinoma:
Immunologic tolerance to self-components is broken in pathologic conditions such as cancer. In this project
we performed a screening of the colorectal tumor proteoma by exploiting auto-antibodies contained in the sera
of patients to identify colon specific tumoral antigens. Tumour-specific immunoreactive proteins have been
found, the analysis demonstrated a modification in antigen recognition by patients B cells as a function of colon
cancer progression.
Characterization of Mena breast carcinoma antigen:
Human Mena, is an antigen overexpressed in breast cancer playing a role in the control of cell motility and
adhesion regulating the actin cytoskeleton. By 2D-electrophoresis we identified different Mena isoforms generated by alternative splicing and/or by different protein post translational modifications. Mena phosphorylation
has been detected as consequence of EGF treatment of breast carcinoma cell lines and both its overexpression
and phosphorylation lead to increase p42/44 MAPK activation and cell proliferation.
NEURO-PROTEOMICS
Protein pattern changes in cerebrospinal fluid (CSF) of neurodegenerative diseases:
CSF being in contact with the brain contains proteins released directly from the central nervous system following pathological conditions, thus CSF analysis is very important to understand the pathological processes
and for diagnostic purpose. We successfully applied differential expression proteomics analysis to CSF of patients with Amyotrophic Lateral Sclerosis compared to healthy subjects finding that ceruloplasmin protein is
expression was increased in ALS patients and that in particular an asialo-ceruloplasmin isoforms was increased.
We are currently working on CSF from patients affected by and Parkinson’s Disease. Proteins involved in the
regulation of redox balance that might be a target of oxidative stress damage have been found differentially expressed showing also different post-translational modifications. We also developed computational tools based
on linear and non-linear dimensional reduction approaches followed by automatic clustering evaluation for the
analysis of 2DE imagines aimed at the patients clustering and classification.
Massimo Alessio
BIOMOLECULAR NMR LABORATORY
We study the structure and dynamics of biomolecular complexes in solution by NMR spectroscopy in combination with a wide range of biochemical, biophysical and computational techniques.Our activity is focused on
two main projects: 1) Structural characterization of the interaction of small drugs with extracellular cellular receptors; and 2) Structural and dynamic characterization of novel chromatin-interacting modules.
1. Integrin aVb3 is involved in many biological processes such as angiogenesis, inflammation, and cancer.
aVb3 exerts its role interacting with proteins containing an RGD motif. Recent drug design research has therefore focused on the development of RGD-containing ligands for medical applications. A. Corti has recently
shown that the isoDGR motif can compete with RGD in the binding to aVb3. By means of docking approaches
and molecular simulations we have characterized the interaction isoDGR-aVb3. Using ligand-based NMR techniques we are characterizing the interactions of a small library of RGD derived ligands with surface receptors
localized on living cells (in collaboration with Molmed)
2. Methylation of lysine residues on histone H3 tails regulates transcription. A recent addition to the list of
known methylated histone binding modules is the PHD finger. AIRE protein contains two PHD fingers and
mutations in AIRE gene cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells where it promotes the expression of tissue-specific antigens. The
mechanism by which AIRE controls gene expression is currently unknown and the function of its domains, in
particular of its PHD fingers is still elusive. We have characterized the three-dimensional structure of AIREPDH1 in complex with H3Keme0 (in collaboration with P-Peterson,T artu- University) providing a new link
between the status of histone modifications and the regulation of tissue-specific antigen expression in thymus.
The group collaborates to other projects aiming to characterize at molecular levels a) the interactions of the
protein HMGB1 with CpG rich oligonucleotides (M.Bianchi) and b) the interaction between PKD1 and
NPHP1, two protein involved in renal genetic diseases (A. Boletta)
Giovanna Musco
Figure 26. Solution structure of AIREPHD1 in complex with H3K4me0.
Surface plot of the lowest energy complex
structure. Cyan-dashed lines represent
intermolecular hydrogen bonds. Colour
coding: pink, AIRE-PHD1; blue,
H3K4me0; orange, protein residues
forming specific polar contacts with
H3K4me0; green, protein residues
forming hydrophobic contacts with
H3K3me0
Neurogenomics Unit
Neurogenomics UnitProteome biochemistry Unit
Biomolecular NMR laboratory
CENTER FOR IMAGING - 153
CENTER FOR IMAGING
Clinical and experimental radiology Unit
HEAD OF UNIT: Alessandro Del Maschio*
PHYSICIANS: Francesco De Cobelli, Pietro Panizza, Massimo Venturini
CONSULTANTS: Antonio Esposito, Claudio Losio
TECHNICIAN: Tamara Canu
High technology in radiation therapy Unit
HEAD OF UNIT: Nadia Di Muzio
PHYSICIANS: Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Italo Dell’Oca, Andrei Fodor, Micaela Motta, Marcella Pasetti,
Paolo Passoni, Lara Rigoni, Stefano Schipani
RESIDENTS: Mariangela Caimi, Aniko Maria Deli, Najla Slim
TECHNICIANS: Laura Longoni, Simone Selli.
Molecular imaging Unit
HEAD OF UNIT: Luigi Gianolli
PHYSICIANS: Elena Busnardo, Carla Canevari, Federico Fallanca, Claudio Landoni, Patrizia Magnani, Maria Cristina Messa,
Andrea Panzacchi, Maria Picchio, Ana Maria Samanes Gajate, Pietro Spagnolo, Paola Todeschini
RESEARCHERS: Sara Belloli, Valentino Bettinardi, Assunta Carpinelli, Isabella Castiglioni, Maria Carla Gilardi, Mario Matarrese,
Maria Grazia Minotti, Rosa Maria Moresco, Marco Rigamonti, Paola Scifo, Sergio Todde
POST-DOCTORAL FELLOWS: Ioana Florea, Manuela Giglio, Valeria Masiello
PHD STUDENTS: Francesca Gallivanone, Cristina Monterisi, Eugenio Rapisarda
TECHNICIANS: Antonia Compierchio, Andrea Fabro, Paola Lanzoni, Carlo Pizzamiglio, Pasquale Simonelli, Stefano Stucchi,
Francesco Sudati, Elia Anna Turolla, Mauro Vaghi
Neuroradiology research group
HEAD OF UNIT: Giuseppe Scotti*
CLINICAL GROUP LEADER: Letterio Salvatore Politi
PHYSICIANS: Simonetta Gerevini, Claudio Righi, Franco Simionato, Francesco Scomazzoni
FELLOW: Sara Pizzi
Introduction
Clinical Imaging including Radiology (Conventional Radiology / CR, Ultrasound / US, Computed
Tomography / CT, Magnetic Resonance Imaging, / MRI, Diagnostic and Interventional Angiography /
DSA), Neuroradiology (as above), Nuclear Medicine (Conventional Scintigraphy, Single Photon Emission Tomography / SPECT, Positron Emission Tomography / PET) is probably the most complete and reliable method to explore the human body in order to establish disease prediction/prevention and/or diagnosis. Clinical Imaging is closely related to clinical, biochemical and histopathological data.
Clinical Imaging provides morphological, structural and metabolic information to confirm clinical assumptions and to solve differential diagnoses. Moreover, Clinical Imaging is highly relevant to validate
results from clinical trials and it is often considered the standard of reference for phase I-II-III-IV clinical trials.
Today it is possible to apply these technologies to pre-clinical animal studies and indeed Experimental
Imaging is becoming instrumental for translational research.
The Imaging Center is comprehensive of a complete set of Clinical Imaging and Experimental Imaging techniques.
The Experimental Imaging Center includes:
• MR imaging / spectroscopy, 7 Tesla, small bore, for animal studies (mouse, rat, rabbit)
• Micro CT
• Micro PET
• Optical Imaging / O.I. (infrared waves / fluorescence)
• Microscopic Ultrasound Imaging
• In vivo microscopy: Single photon, double-photon
These technologies have been applied to the following research fields: Macroscopic imaging (organs &
tissues), Cell imaging (aggregations of cells and single cells), Molecular Imaging and Spectroscopy imaging (characterization of molecular metabolic processes).
In addition, the Imaging Center is dedicating resources to the technological progress and development
of original models.
CLINICAL AND EXPERIMENTAL RADIOLOGY UNIT
The main research projects of the Clinical and Experimental Radiology Unit encompass:
1) Cardiac magnetic resonance (CMR) Imaging and Spectroscopy and cardiac Computed Tomography (CT).
We are developing different lines of research: the first is on characterization of different causes of cardiomyopathy using the gadolinium delayed-enhanced CMR technique; the second line is on evaluation of
ventricular function and energy metabolism in different conditions such as different type of exercise training, obesity and fatty liver or insulin-resistance; the third line consists in the evaluation of the accuracy of
CT in excluding the disease in patients with suspected CAD.
2) Diffusion-weighted Magnetic Resonance Imaging. Non-invasive differential diagnosis of pancreatic disease
and breast lesions is a major challenge. We demonstrated that DWI provides quantitative and qualitative
evaluation of pancreatic and breast focal lesions, helping to differentiate between malignant and non-malignant lesions; moreover, DWI allows early information about patient’s response to chemotherapy.
3) Development of clinical trials with new contrast agents. In the last year clinical trials mainly on different
contrast media have been conducted in evaluation of breast lesions, cardiac diseases, coronary disease and
Takayasu’s arteritis.
4) Cellular and molecular imaging. 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. A similar approach
for cells labeling and imaging was also used to follow the pancreatic islets fate, after their transplantation in
mouse model of type 1 diabetes.
5) Pancreatic cancer’s imaging. In the last year we focused our research on the evaluation of endocrine tumors
and periampullary tumors performing a prospective study using Color-Doppler Ultrasound, Endoscopicultrasonography and MDCT in evaluation of vascular invasion.
6) Implementation of radiotherapy planning by new imaging-techniques. Our aim has been to use different
techniques such as MRI and 4D-CT to improve target volume definition in prostate cancer and in pancreatic ductal adenocarcinoma.
Alessandro Del Maschio
HIGH TECHNOLOGY IN RADIATION THERAPY UNIT
Our scientific activity in 2008 was focused mainly on the following areas: prostate, rectal, pancreatic, lung,
head and neck and central nervous system neoplasms.
Prostate cancer:
1) Phase I-II study comparing a short course adjuvant tomotherapy (1 month) VS conventional radiation
therapy (2 months) in terms of acute and late genito urinary (GU) and gastrointestinal (GI) toxicity and
biochemical control.
2) Phase I-II study of radical hypofractionated RT with tomotherapy assessing acute and late GU and GI
toxicity and biochemical control.
3) Investigation of the role of dose in post-operative setting, leading to the first mono institutional analysis
indicating a clinical benefit from doses ≥ 70 Gy in the early adjuvant setting.
4) Study of dose escalation on dominant intraprostatic lesion individuated by means of MRI in order to definitively eradicate prostate cancer.
Rectal and Pancreatic Cancer:
1) A dosimetric study of comparison between 4D-CT vs standard technique and between tomotherapy vs
3D-CRT.
2) A Phase I study of tomotherapy in combination with capecitabine.
Rectal cancer:
A Phase II study of preoperative tomotherapy in combination with oxaliplatin and 5-FU in rectal cancer.
Lung:
Hypofractionated tomotherapy treatments in early and advanced stage NSCLC with various radiation dose
delivery regimens utilizing PET/CT for planning and CT/SPECT for evaluation of lung perfusion in order to
reduce radiation toxicity to the lung.
Head and Neck:
Study of moderate hypofractionation radiation therapy in adjuvant and radical treatment by means of simoultaneous integrated boost technique utilizing MRI and PET/CT for improved definition of tumors, organs at
risk and more radioresistent tumor subvolumes on which to implement dose escalation.
CNS:
1) study of hypofractionated tomotherapy treatment vs. γ knife radiosurgery for benign neoplasms (meningioma; pituitary adenoma).
2) EORTC trial on low grade gliomas standard radiotherapy alone vs. chemiotherapy alone.
3) Study of tomotherapy treatment for large skull base meningiomas not suitable for γ knife or surgery in
terms of acute a subacute side effects and disease control.
Nadia Di Muzio
MOLECULAR IMAGING UNIT
Main research activities are focused on: 1) Radiochemistry, 2) Technological developments, 3) Preclinical
Imaging, 4) Clinical Imaging in Oncology, 5) Clinical Imaging in Neuropharmacology, and 6) Clinical Imaging
in Cardiovascular Disease.
1) Radiolabeling of ligands for in vivo PET imaging:
a) an activated microglia linked Translocator Protein ligand: 19F-VC701;
b) a β amyloid complex ligand: 11C-PIB and
c) a marker for cardiac sympathetic nervous system: 11C-HED.
d) In addition, the development of new tools for in vivo detection of angiogenesis and hypoxia and of an automatic system for the production of radiolabeled metals, such as 64/60 Cupper and 110 Indium are still
ongoing.
2) Development of novel methods of image acquisition, processing and analysis:
a) respiratory gating technique (4D PET/CT) to improve PET image quality and to optimize RT target volume definition, by accounting for respiratory movements;
b) a web service based on GRID technology for statistical analysis of PET and SPECT neurological studies,
to support the diagnostic confidence level.
3) Preclinical imaging activities for:
a) pharmacological evaluation of ligands for in vivo hypoxia detection in rodent models of cancer,
b) potential use of 18F-FDG for imaging inflammation in a mouse model of lung injury and
c) biological characterization of models of neurodegenerative and neoplastic diseases.
4) Evaluation of PET/CT in staging and re-staging different neoplastic diseases, by using 18F-FDG and 11CCholine. In particular, it has been established that PSA serum levels and anti-androgenic therapy are, respectively, positive and negative predictors of prostate 11C-Choline uptake.
5) Clinical Imaging in Neuropharmacology was dedicated to the development of methods for the in vivo
quantification of brain inflammation and to the study of the neurobiology of human behaviour, and in particular of the involvement of mu opiate receptors in the hedonic component of obesity.
6) Clinical Imaging in cardiovascular disease was dedicated to cardiac fusion imaging (SPECT and 64-MDCT): clinical feasibility in patients risk stratification, and to the validation of a new MDCT acquisition protocol
with a dramatic reduction of radiation exposure without compromising image quality.
Luigi Gianolli
NEURORADIOLOGY RESEARCH GROUP
The research activity of the Neuroradiology Research Unit is focused on 2 main areas:
1) Preclinical studies: using a human-grade 3 Tesla Magnetic Resonance Imaging (MRI) apparatus equipped
with a mouse-dedicated coil we evaluated and quantified structural changes in the brains of murine models of
several neurological pathologies, such as inherited or acquired demyelinating disorders and brain tumors. Further, with the aim of tracking somatic stem cells (SC) upon transplantation or within gene therapy applications,
we explored several cell labelling strategies based on superparamagnetic iron oxides particles and on different
MR reporter genes, allowing iron accumulation within cells. Lentiviral vectors (LV) carrying the cDNA of the
human tyrosinase, intracellular H-ferritin, L-ferritin and a mutated form of the latter were produced and employed for transducing cell lines, neural and hematopoietic SC (HSC), and for in vivo gene expression studies.
Interestingly, when transduced HSC were trasplanted into recipient mice after bone marrow ablation, a signal
change was observed in repopulated tissues. LV were also directly injected in the hippocampus of mice that underwent serial MRI examinations. Signal change due to gene expression was detectable in vivo in the relevant
areas from 2 to 15 weeks from the time of injection. Overall these data indicate that expression of tyrosinase
and ferritin enables efficient cellular marking for MR localization studies and represent a promising strategy for
in vivo long term monitoring of the fate of SC and their progeny.
2) Clinical studies: conventional and advanced MRI studies were performed on patients carrying, orbital lesions, such as orbital adnexal lymphomas of thyroid associated orbitopathy, progressive multifocal leukoencephalopathy or HIV- positive patients affected by central nervous system immuno-reconstitution inflammatory syndrome. Diffusion weighted imaging, proton MR spectroscopy and diffusion tensor imaging techniques
were employed and their clinical usefulness in suggesting correct diagnosis and assessing response to therapy
was determined. Further, we investigated the potential of MRI in depicting and quantifying peripheral nervous
system inflammatory and post-traumatic lesions.
Letterio Salvatore Politi
FACILITIES - 159
FACILITIES
ALEMBIC , Advanced Light and Electron Microscopy BioImaging Center
HEAD OF UNIT: Fabio Grohovaz*
RESEARCHER: Maria Carla Panzeri
FELLOW: Miriam Ascagni
TECHNICIANS: Cesare Covino, Andrea Menegon
CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis
HEAD OF UNIT: Marco E. Bianchi*
FELLOWS: Elisa Allievi, Ivana Benzoni, Rosanna Rinaldi
TECHNICIANS: Maria Luisa Pintonello, Lorenza Ronfani
FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications
Laboratory
HEAD OF UNIT: Alessio Palini
BIOLOGIST: Chiara Villa
TECHNICIAN: Emanuele Canonico
CERMAC, Centre of Excellence of High Field Magnetic Resonance
PHYSICIAN: Valeria Blasi
RESIDENTS: Antonella Castellano, Elisa Scola
POST-DOCTORAL FELLOWS: Monia Cabinio, Sara Cirillo, Roberta Longaretti, Silvia Polverigiani
PHD STUDENT: Paolo Vezzulli
FELLOW: Paola Scifo
TECHNICIAN: Antonella Iadanza
Mouse histopathology
HEAD OF UNIT: Claudio Doglioni*
GROUP LEADER: Francesca Sanvito
TECHNICIAN: Martina Rocchi
ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center
Alembic is a resource for the scientific community by providing both access to sophisticated imaging techniques and innovation through the efforts of a small staff. The facility is designed to accommodate researchers
by providing instrumentation and instructing them in the most effective use of it, so that they may perform experiments independently. This is particularly true for access to optical microscopes for which those interested
are required to attend a course taught by the Alembic staff before being authorized to use the instrumentation.
The research activity of the staff also promotes technical updates on a regular basis to keep the local facility on
the forefront of available technology. In the course of the years, several new technologies have been integrated
into Alembic and new ones are being developed.
There is also an area in which the staff develops new methodologies and conducts research on techniques
with significant potential to enhance bioimaging research. These activities converge within two main directions:
• Use of voltage sensitive dyes - 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 (in collaboration with Optotec);
• Imaging of luminescence signals - set up of conditions for the in vitro and in vivo imaging (in collaboration with San Raffaele Units and Axxam); evaluation of new photon counting detectors (SPAD, in collaboration with Politecnico di Milano).
Main instrumentations 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
• ∆Vision 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 2008 are: 561 registered users (292 active), 95 persons attending theorical/practical courses;
about 6000 hours of independent microscopes use.
Web: www.sanraffaele.org/research/alembic
Fabio Grohovaz
Transgenic and knock-out mice are widely used in the research because of their high impact in the understanding of the proteins functional role and because constitute models to study
genetic diseases.
The San Raffaele-Telethon Core Facility for Conditional Mutagenesis (CFCM) is operative from 1999. During this time CFCM provided to the Scientific Community more than 280 murine models.
CFCM performs pronuclear injections and lentiviral infections to generate transgenic mice, offers the electroporation of Embryonic Stem 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.
From 1999 to now the number of services offered by CFCM duplicate.
FACILITIES - 161
In the last year CFCM introduced two services: 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.
More information can be found at the site http://www.sanraffaele.org/CFCMn.html
Marco E. Bianchi
FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications
Laboratory
The Flow cytometry Resource and Analytical Cytology Technical Applications Laboratory is a core facility
that offers state-of-the-art instrumentation and analysis techniques to the scientific community. Flow cytometry
is an evolving field; it is continually being re-discovered by young scientists who approach this technology to
answer a multitude of questions in their discovery work. Cytometrists continue to find and develop new applications. So wide ranging is the applicability of this technology that practitioners may include, in addition to biologists, physicians, microbiologists, marine biologists, veterinarians and research chemists to name a few. Verifiable results can easily be obtained for such applications as Immunophenotyping, Cell division and Apoptosis,
Cell activation, Intracellular pH shifts, Phagocytosis, Oxidative burst and many more. In addition to the analytical capabilities of this technique, the core facility offers assisted cell Sorting services for characterizing, separating and purifying populations of particles as diverse as beads, bacteria, micro-particles, cells and chromosomes.
In 2008 the facility supported over 350 Researchers, performed more than 1400 cell sorts and logged over 9000
hours of analytical instrument time.
Alessio Palini
CERMAC, Centre of Excellence of High Field Magnetic Resonance
CERMAC is a Centre of Excellence financed by an original grant of the ministry of Education and Ministry
of health.
Different research groups have access to the centre and perform studies independently financed.
The core facility available is a 3Tesla magnet with post processing hardware and software facilities for advanced morphological and functional studies of the Central Nervous System.
The following research groups have access and develop their projects within the centre: Neuroradiology, Nuclear Medicine, Neurology, Psychiatry, Radiology, Cognitive neurosciences.
In 2008, 20 papers have been published in indexed journals.
The main fields of research are devoted to:
• Development and validation of MR advanced techniques and dedicated post-processing programs
• Application of conventional and advanced techniques in the study of the normal brain:
• Brain maturation in premature and terms neonates
• Aging
• Brain functions in paediatric and adult population (perception of music and sounds, language, memory
and other cognitive functions)
• Motor system function including mirror neurons system
• Application of conventional and advanced techniques in the study of the diseased brain:
• Brain inflammatory diseases, with a special focus on Multiple Sclerosis
• Mood disorders and other psychiatric diseases like schizophrenia
•
•
•
Neuro-oncology (diffusion tensor imaging and tractography in brain tumors)
Vascular diseases
Degenerative diseases
Giuseppe Scotti
MOUSE HISTOPATHOLOGY
The principal aim of the Rodent Histopathology Unit is to support, complement and favour the advancement
of scientific projects, by providing conventional morphological analysis and immunophenotyping.
The facility is located in the Department of Pathology and offers the technical and the interpretative 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:
A) macroscopic examination including perfusion and necroscopy
B) 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
C) image analysis
The role of pathology in the field of experimental studies on laboratory animal is of interest for:
• identification and evaluation of experimentally induced lesions
• setting of animal models of human diseases
• efficacy and safety studies
• phenotyping of transgenic mice
To date multiple collaborations within our Institute have been settled in order to analyze the morphological
and immunophenotipical patterns of murine models of diseases, treated with different therapeutic approaches
and to analyze the efficacy of genic therapy and safety of the use of viral vectors.
Francesca Sanvito
FACILITIES - 163
CLINICAL DEPARTMENTS - 165
THE CLINICAL DEPARTMENTS
The following staffs are officially approved
DEPARTMENT OF ARRHYTHMOLOGY
Head of Department: Carlo Pappone
DEPARTMENT AREA COORDINATOR: Vincenzo Santinelli
Electrophysiology and cardiac pacing
HEAD OF UNIT: Carlo Pappone
RESEARCHER:Vincenzo Santinelli
PHYSICIANS: Giuseppe Augello, Cristiano Ciaccio, Simone Gulletta, Patrizio Mazzone, Gabriele Paglino, Alessia Pappone,
Simone Sala, Andreina Santagostino, Nicoleta Sora, Pasquale Vergara, Gabriele Vicedomini
RESIDENTS: Francesco Arioli, Maria Avitabile, Giuseppe Ciconte, Amarild Cuko, Enrico Frigoli, Emma Gelera, Alessandra Marzi,
Rita Naio, Andrea Radinovic, Stefania Sacchi, Massimo Saviano, Roberto Spoladore
BIO ENGINEERS: Simonetta Crisà, Giorgio Maida
FELLOWS: Ombretta Osnago, Francesca Zuffada
In the Arrhythmology Department, which has both clinical
and invasive autonomy, all types of cardiac arrhythmias and
associated diseases are treated and most of them are definitively cured by catheter ablation. The most important clinical activities are as follows:
• Ablation of Atrial Fibrillation
• Electric treatment of Heart Failure
• Device implantation (Pacemakers, ICD, Biventricular
pacing)
• Treatment of inherited arrhythmias (Brugada syndrome,
long QT syndrome, Arrhythmogenic Right Ventricular
Carlo Pappone
Dysplasia, etc.)
• Robotic remote approach for ablation of supraventricular
tachyarrhythmias, including WPW syndrome
• Robotic remote approach for the identification of the best site and lead positioning within coronary
sinus during Biventricular implantation in patients with Heart Failure
• Diagnostic and Therapeutic Telemedicine (home ECG and remote device monitoring and interrogation)
• Recently, in the Department of Arrhythmology has been set up a clinical-electrophysiology training
center, the Academy of Arrhythmology, where foreign physicians come to learn and discuss procedures in real-time.
Another area of research is the development of new technologies for catheter design (tip-irrigated, flexible or stiff catheters) and new software for real-time accurate 3D anatomical reconstruction of cardiac
chambers for atrial fibrillation ablation.
The Arrhythmology Department also cooperates with international biotechnology laboratories, and
with the Miami University in both clinical and scientific field.
In addition, the Arrhythmology Department is involved in writing several textbook chapters.
Carlo Pappone
CARDIO-THORACIC-VASCULAR DEPARTMENT
Head of Department: Ottavio Alfieri*
DEPARTMENT AREA COORDINATORS: Stefano Benussi, Renata Clotilde Castellano, Domenico Cianflone*, Guglielmo Cornero,
Stefano Gerosa, Giovanni La Canna, Silvio Magrin, Giovanni Marino, Enrico Maria Marone, Germano Melissano,
Stefano Moriggia, Carlopietro Voci*
Cardiac surgery
HEAD OF UNIT: Ottavio Alfieri*
CLINICAL UNIT LEADERS: Michele De Bonis, Francesco Maisano, Alessandra Rossodivita
CLINICAL UNIT COORDINATOR: Alessandro Castiglioni
PHYSICIANS: Irina Arendar, Stefano Benussi, Andrea Blasio, David Ferrara, Andrea Fumero, Andrea Galanti, Antonio Grimaldi,
Giuseppe Iaci, Giovanni Laino, Elisabetta Lapenna, Stefano Moriggia, Simona Nascimbene, Maria Grazia Pala,
Alessandro Verzini
RESIDENTS: Maria Chiara Calabrese, Micaela Cioni, Egidio Collu, Paolo Denti, Enrica Dorigo, Andrea Giacomini, Mario Manca,
Maurizio Taramasso, Giorgio Viganò
FELLOWS: Andrea Guidotti, Ylenia Privitera, Davide Schiavi
Cardiac ultrasound imaging
HEAD OF UNIT: Giovanni La Canna
Cardiovascular rehabilitation and prevention
HEAD OF UNIT: Domenico Cianflone*
CLINICAL UNIT LEADER: Carlo Meloni
Physician: Alice Calabrese
Cath Lab
HEAD OF UNIT: Antonio Colombo
CLINICAL UNIT LEADERS: Mauro Carlino, Matteo Montorfano
PHYSICIANS: Alfredo Castelli, Alaide Chieffo, Iassen Michev
RESIDENTS: Raffaele Lacquaniti, Marco Mussardo
FELLOWS: Marta Bande, Cosmo Godino, Alfonso Ielasi, Azeem Mohamed Latib, Valeria Magni
TECHNICIANS: Gianfranco Accarino, Raimondo Bellanca, Salvatore Cannavale, Andrea Di Marco, Fanny Lavazza, Matteo
Longoni, Davide Maccagni, Massimo Angelo Messa, Marcello Murino, Vittorio Romano, Mario Squilla
Clinical cardiology
CLINICAL UNIT LEADERS: Fabrizio Bonetti, Alberto Cappelletti, Andrea Conversano, Gabriele Fragasso, Andrea Macchi, Michele
Oppizzi
PHYSICIANS: Eustachio Agricola, Fabio Buzzetti, Chiara Camesasca, Cristina Canciani, Stefano Gerosa, Alessandra Mailhac,
Cinzia Nitti, Alessandra Pancaldi, Marco Papa, Cristina Pedrigi, Patrizia Puccetti, Carmen Silipigni
Coronary Care Unit (CCU)
CLINICAL UNIT LEADERS: Carlo Ballarotto, Giuseppe Pizzetti
PHYSICIANS: Giorgio Bassanelli, Luca Falqui
Functional Rehabilitation
HEAD OF UNIT: Alessandra Raschi
Intensive Care Unit (ICU) and Post Operatory Care Unit (POCU)
CLINICAL UNIT LEADERS: Giovanni Landoni, Giovanni Marino
CLINICAL UNIT COORDINATORS: Antonella Crescenti, Andrea Carozzo, Jaques Ntzepa Batonga, Rossana Fiori
PHYSICIANS: Elena Bignami, Tiziana Bove, Maria Grazia Calabrò, Giuseppina Maria Casiraghi, Remo Daniel Covello,
Monica De Luca, Greta Fano, Annalisa Franco, Chiara Gerli, Roberta Mennella, Fabrizio Monaco, Massimiliano Nuzzi,
Federico Pappalardo, Tiziana Quattrocchi, Dino Rapati, Anna Mara Scandroglio
Thoracic surgery
HEAD OF UNIT: Piero Zannini*
CLINICAL UNIT LEADERS: Giulio Melloni, Giampiero Negri*
CLINICAL UNIT COORDINATOR: Angelo Carretta
PHYSICIANS: Paola Ciriaco, Armando Puglisi, Carlopietro Voci*
RESIDENTS: Alessandro Bandiera, Michele Giovanardi, Annamaria Gremmo, Piergiorgio Muriana, Stefano Sestini
Vascular surgery
HEAD OF UNIT: Roberto Chiesa*
CLINICAL UNIT LEADER: Efrem Civilini
CLINICAL UNIT COORDINATOR: Renata Clotilde Castellano
PHYSICIANS: Domenico Astore, Laura Dordoni, Gloria Esposito, Enrico Maria Marone, Massimiliano Marrocco-Trischitta,
Germano Melissano, Yamume Tshomba
The clinical activity of the Department is devoted to the diagnosis and treatment of cardiac, thoracic and vascular disease.
In 2008, new techniques and technologies have been introduced to offer to the patients the entire spectrum of the therapy
options in a multidisciplinary environment.
Patients centered care is the philosophy behind the daily clinical practice.
The interaction among different specialists (anesthesiologists,
cardiovascular and thoracic surgeons, interventional and clinical
cardiologists) is favored by the contiguity of the areas devoted to
surgery, cath lab procedures and intensive care.
Patients with acute disease coming on emergency basis as well
as patients with chronic diseases admitted electively are submitted to diagnostic investigation, treatment, an then rehabilitation
Ottavio Alfieri
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.
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.
During the year 2008, transcatheter aortic valve implantation has been widely introduced 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 has been also initiated in patients with heart failure
and our series represents one of the very first in Europe.
Innovative modalities of medical treatment for patients with congestive heart failure have been recently introduced, particularly in the field of improvement of cardiac metabolism, achieving a significant increase of survival/quality of life as compared to figures reported in the literature.
A structurized program for the treatment of patients with end-stage heart failure has been developed.
Aim of the program is to provide a comprehensive treatment for the failing heart, including mechanical
circulatory support (short and long term) in different clinical settings: post cardiotomy cardiogenic shock,
acute myocardial infarction, bridge to transplant, destination therapy. Also treatment of acute hypoxia
and ARDS by ECMO is now offered as a life-saving procedure.
A wide spectrum of aortic pathologies, including aneurysms, dissection, traumatic injuries, coarctation
etc., are treated using both conventional and endovascular approaches. For high risk patients with complex aortic arch and thoracoabdominal pathology, hybrid open and endovascular strategies are selectively performed, and endovascular branch-technology is currently under evaluation. Both open and endovascular procedures are also used for carotid and lower limb revascularization.
A great recent achievement in thoracic surgery has been the treatment of lung cancer in patients with
emphysema. The respiratory impairment due to this disease used to be a surgical contraindication in the
past. Today different strategies have been introduced in our Department to extend surgical indication in
lung cancer including parenchyma-sparing bronchoplasty techniques, lung volume reduction surgery and
bronchoscopic lung volume reduction.
Finally, in 2008, 3-D echocardiography has been introduced as a routine imaging modality to assess patients with structural heart disease, with considerable enhancement of diagnostic capabilities.
Ottavio Alfieri
DEPARTMENT OF GENERAL
AND SPECIALISTIC SURGERY
Head of Department: Carlo Staudacher*
DEPARTMENT AREA COORDINATORS: Marco Braga*, Carlo Castoldi, Renato Castoldi, Francesco Deni, Renato Finazzi, Emiliano
Giorgi, Gilberto Mari, Michele Paganelli, Danilo Parolini, Sandro Passaretti, Carlo Socci, Marco Stella, Walter Zuliani
Gastroenterologic surgery
CLINICAL UNIT LEADERS: Saverio Di Palo, Elena Orsenigo
CLINICAL UNIT COORDINATORS: Paolo Aldo Raul Baccari, Paola De Nardi
PHYSICIANS: Renato Castoldi, Andrea Marco Tamburini, Andrea Vignali, Walter Zuliani
RESIDENTS: Michele Carvello, Tiziana Casiraghi, Carmen Forestieri, Francesco Luparini, Alessio Mocci, Danilo Parolini, Carlo
Socci,Valentina Tomajer, Roberta Varale
TECHNICIAN: Alessandra Castiglioni
General and pancreatic surgery
CLINICAL UNIT LEADERS: Marco Braga*, Marco Cristallo, Alessandro Zerbi
PHYSICIANS: Gianpaolo Balzano, Enrico Fiacco, Marco Stella
RESEARCHER: Lorenzo Piemonti
RESIDENTS: Vanessa Capitanio, Giovanni Capretti, Federica Merlini, Federica Milani, Cristina Ridolfi, Simone Squillante
FELLOWS: Alessia Mercalli, Valeria Sordi
Hepatobiliary and week surgery
CLINICAL UNIT LEADERS: Luca Aldrighetti, Edoardo Beretta, Alberto Marassi
PHYSICIANS: Marco Catena, Enrico Fiacco, Renato Finazzi, Gilberto Mari, Mvunde Mukenge, Michele Paganelli
CONSULTANT: Veronica Zuber
RESIDENTS: Matteo Frasson, Cristina Gilardini, Eleonora Guzzetti, Ines Mulas, Carlo Pulitanò
Orthopaedics
HEAD OF UNIT: Gianfranco Fraschini*
CLINICAL UNIT LEADERS: Francesco Camnasio, Maurizio De Pellegrin, Giuseppe Gioia, Crispino Grispigni, Eliseo Mainetti
RESEARCHER: Giuseppe M. Peretti
PHYSICIANS: Arianna Banfi, Carlo Castoldi, Pietro Ciampi, Alessandro De Ponti, Dario Fracassetti, Davide Mandelli, Gianluigi
Moro, Paola Rivoltini, Paolo Sirtori, Corrado Sosio, Matteo Vitali, Umberto Mezzadri
RESIDENTS: Niky Mancini, Laura Mangiavini, Celeste Scotti
POST-DOCTORAL FELLOW: Daniela Deponti
Gastroenterology-Endoscopy
HEAD OF UNIT: Pier Alberto Testoni*
CLINICAL UNIT LEADERS: Paolo Giorgio Arcidiacono, Mario Guslandi, Sandro Passaretti
PHYSICIANS: Silvia Carrara, Lorella Fanti, Alberto Mariani, Edi Viale
FELLOWS: Cinzia Boemo, Antonella Giussani, Chiara Notaristefano, Cristian Vailati
CONSULTANTS: Maura Corsetti, Gianni Mezzi, Cristina Ogliari, Maria Chiara Petrone
Anaesthesiology and resuscitation
CLINICAL UNIT COORDINATORS: Massimo Agostoni, Eleonora Colnaghi, Laura Comotti, Carla Martani, Valeria Perotti, Roberto
Valeri, Giovanna Valentini
CLINICAL UNIT LEADER: Sergio Colombo
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 and 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 for sentinel node identification in early cancer stage and neoadiuvant chemotherapy and HIPEC in the
advanced ones. The activity volume is very high. The Colorectal
Surgery Unit offers the most advanced surgical and minimally inCarlo Staudacher
vasive options not only to eradicate the disease, but also to preserve
patients’ ability to normal function. The team includes specialists in
colorectal surgery, in hepatobiliary surgery (for patients with liver metastasis) radiotherapist and medical
oncologist . This is a high volume Unit. The Pancreatic Surgery Unit has one of the highest pancreatic
surgery volume in Europe. In 2008, 168 pancreatic resections have been performed: 94 pancreatoduodenectomy, 60 left pancreatectomy, 9 enucleation, 5 total pancreatectomy. 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. 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 parathyroid (PTH) assay determination , and laparoscopic adrenalectomy. The Area of Transplant Surgery focused its clinical activity on Simultaneous Pancreas and Kidney Transplantation and
Pancreas Alone Transplantation in IDDM patients. There is also a program regarding 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. In the year 2008, 14,400 endoscopic procedures
have been performed. In the 2009 about 15,700 procedures are expected. 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 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.
Carlo Staudacher
HEAD AND NECK DEPARTMENT
Head of Department: Giuseppe Scotti*
DEPARTMENT AREA COORDINATOR: 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
PHYSICIANS: Antonio Dell’Acqua, Fabio Bernasconi, Maria Rosa Calvi, Marco Cerri, Antonella Cipriani, Assunta De Vitis,
Cristina Frascoli, Marco Gemma, Luigi Gioia, Elisabetta Grandi, Maurizio Mungo, Susanna Piccoli, Alfredo Ravizza,
Luisa Sacchi
Ophthalmology
HEAD OF UNIT: Paolo Rama
CLINICAL UNIT LEADERS: Francesco Fasce
CLINICAL AREA COORDINATORS: Gianluigi Bolognesi, Luisa Pierro
PHYSICIANS: Nicola Baccelli, Paolo Bettin, Stefania Bianchi Marzoli, Elena Bruschi, Gabriella Cammarata, Roberto Carassa,
Stefano Ciaccia, Carlo Ciampi, Paola Ciasca, Marco Codenotti, Annalisa Colucci, Umberto De Benedetto, Federico Di
Matteo, Federica Ferrario, Marina Fiori, Maddalena Forti, Marco Gagliardi, Matteo Ghidoni, Silvia Giatsidis, Antonio
Giordano Resti, Lauretta Guarisco, Chiara Insacco, Ugo Introini, Rosangela Lattanzio, Francesca Legorini, Francesco
Loperfido, Gisella Maestranzi, Abu Amria Majed, Angela Malegori, Maria Pia Manitto, Elena Mantovani, Elisabetta
Martina, Stanislav Matuska, Paolo Mauceri, Lisa Melzi, Elisabetta Miserocchi, Giulio Modorati, Veronica Odazio,
Giorgio Paganoni, Flavio Paratore, Matteo Prati, Andrea Ramoni, Laura Regali, Carmen Rojo, Michela Rossi, Fabrizio
Scotti, Marco Setaccioli, Alessandra Spinelli, Monica Stoppani, Gemma Tremolada, Maurizia Viganò
TECHNICIANS: Giorgio Alto, Adriana Angiolini, Alessio Buzzotta, Enrico Delfino, Elisa Restelli, Antonella Ribecca
Otorhinolaryngology
PHYSICIANS: Stefano Bondi, Leone Giordano, Francesca Lira Luce, Lucia Oriella Piccioni, Matteo Trimarchi
CONSULTANTS: Fabrizio Ferrario, Andrea Muzza, Francesca Palonta, Rosaria Taverna, Roberto Teggi
RESIDENTS: Chiara Bellini, Beatrice Fabiano, Pietro Limardo, Paola Recanati
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, Lorenzo Gioia, Silvia Snider, Micol Valle
CONSULTANTS: Luca Attuati, Marzia Medone, Paola Castellazzi
Giuseppe Scotti
The clinical activity of the Head and Neck department includes diagnosis and treatment of diseases of the central nervous system, peripheral
nervous system, eye, ear, nose and throat diseases.
The Department has a total of 103 beds, of which 6 in the neurointensive care unit, 49 in neurosurgery, 26 in ophthalmology and 22 in the
ENT unit.
The people involved in the Department activity are 280, of which 100
physicians.
In 2008, 4363 surgical procedures have been performed (1736 ophthalmology; 931 ENT; 1696 neurosurgery). Intensive care admissions: 300.
Anaesthesiological procedures for surgery or sedations, in children and
adults: about 4.000. Gamma knife treatments: 615. Neuroradiological
examinations: 38.000. Endovascular neuroradiological treatments: 70.
The Head and Neck Department is composed by five units:
Neurosurgery Unit
Neurosurgical procedures are performed in adult and paediatric age, with main interest in brain tumors, base of the skull and pituitary tumors, spine surgery, peripheral nervous system, stereotactic and
functional neurosurgery. The unit is responsible for the gamma knife activity.
Otolaryngology and ENT
Main fields of activity are oncological surgery of larynx, mouth and throat, Vertigo and imbalance disturbances, otosurgery. Phoniatric rehabilitation.
Neurointensive care
Every year 300 patients are admitted, 50% from the Emergency 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 Anaesthesia Group provide for general anaesthesia in neurosurgical, interventional neuroradiology, ENT and ophthalmic surgery for approximately 3000 cases per year and for conscious sedations in
children and adults (1000 cases per year) submitted to diagnostic or therapeutic procedures.
Ophthalmology
Ophthalmology Unit has 53 medical doctors divided into 13 sub-Units which include Cornea and Ocular Surface, General Ophthalmology, Glaucoma, Neuro-Ophthalmology, Oculoplastics and Orbit,
Oncology, Cataract Surgery, Out-patient Cataract Surgery, Pediatrics Genetics and Strabismus, Surgical
and Medical Retina, and Uveitis.
Neuroradiology
The Dept is equipped with three 1.5T MR systems, one 3T System (CERMAC), two CT scanners (64
and 16 slices respectively), an angio suite biplane rotational, a digital xray conventional system.
Both diagnostic and interventional procedures are performed, in adult and paediatric age.
Giuseppe Scotti
DEPARTMENT OF INFECTIOUS DISEASES
Head of Department: Adriano Lazzarin*
DEPARTMENT AREA COORDINATORS: Nicola Gianotti, Paolo Scarpellini
Infectious diseases
CLINICAL UNIT LEADERS: Antonella Castagna, Massimo Cernuschi, Paolo Scarpellini, Giuseppe Tambussi, Caterina Uberti-Foppa
PHYSICIANS: Paola Cinque, Fulvio Crippa, Anna Danise, Luca Fumagalli, Nicola Gianotti, Monica Guffanti, Myriam Maillard
RESEARCHERS: Alberto Beretta, Claudio Fortis, Laura Galli, Lucia Lopalco, Giulia Morsica, Claudia Pastori
CONSULTANTS: Priscilla Biswas, Simona Bossolasco, Giuliana Fusetti, Giovanni Gaiera, Andrea Galli, Clara Ronchetti, Vega
Rusconi, Flavia Salmaso, Stefania Salpietro
FELLOWS: Sabrina Bagaglio, Francesca Cossarini, Giulia Gallotta, Hamid Ibrahim Hasson, Silvia Nozza, Annamaria Pazzi,
Deborah Ratti, Gianluca Semeraro, Alessandro Soria, Vincenzo Spagnuolo, Chiara Tassan Din, Simon Tiberi, Giovanna
Travi, Francesca Visco
TECHNICIAN: Arabella Bestetti
The general aim of the Department of Infectious Diseases is to
maintain and improve excellence in the management of infectious
diseases. The Department activity is organized in five 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). In particular, the Department aims at optimizing treatment of HIV infection by clinical trials and data analyses, infectious
Adriano Lazzarin
diseases other than HIV, including tropical diseases, central nervous
system infections and hepatitis, hospital-acquired infections, and opportunistic infections in the immune deficient host.
In this view, two Clinical Trial Units have been set up and collaborations with basic research laboratories are continuously sought. Also, a clinical database 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 findings with clinical findings.
The Department includes three ordinary admission units, with 34 beds cumulatively (one unit with 10
beds is currently borrowed from the Neurology Department), one day-hospital unit with six beds, and
nine ambulatory rooms. The staff amounts to 57 people (27 medical doctors, 22 ward nurses, three study
nurses, three study coordinators, one data manager, and one statistician). About 3500 outpatients with
HIV infection (80% on treatment with antiretroviral drugs) are currently followed-up, each of them attending about four visits per year.
During 2008, 35 clinical trials were ongoing at the Department, including phase II and III clinical trials. Research collaborations with European and NIH academic initiatives are also well established, particularly in the field of HIV infection: the Department is member of the following study groups: Italian
Cohort of Antiretroviral Naïve patients (ICONA), EUROSIDA (both of them taking part in the inter-
continental Data Collection on Adverse events of Anti-HIV Drugs - D:A:D: study group), European
AIDS Treatment Network (NEAT), and COHERE.
The ongoing clinical research lines include: the development of new drugs against HIV, new approaches to the treatment of HIV infection (including vaccines and immune-based therapies), the pathogenesis
of HIV drug-resistance, HIV encephalopathy, metabolic disorders and cardiovascular complications of
HIV disease, co-infection with HIV and hepatitis viruses, new strategies for the management of patients
with highly drug-resistant HIV infection, central nervous system involvement, metabolic complications,
and co-infection with hepatitis viruses. With regard to HIV treatment, the Department is also collaborating with the Regione Lombardia in order to investigate strategies aimed at reducing health costs without jeopardizing treatment efficacy. Moreover, though the analysis of data from more than 7000 HIV-infected patients recorded in its clinical database, prognostic factors of HIV disease are continuously studied and the results are transferred into clinical practice.
The Department is also involved in the research of new diagnostic tools for the management of viral
diseases different from HIV, particularly those affecting the central nervous system. It 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 able to assist
each other Department in the management of infectious diseases. Furthermore, the Department participates in national initiatives aimed 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 aimed
at improving the cures in low-income countries, in collaboration with AISPO.
Due to its high ranking in the management of HIV infection, the Department organizes many 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, Laura Bosio, Stefania Di Candia, Margherita Franco, Maria Pia Guarneri, Karen Marenzi,
Marta Odoni, Antonella Poloniato, Gabriella Pozzobon, Rosanna Rovelli, Paola Sgaramella, Maria Cristina Vigone,
Matteo Viscardi
RESEARCHER: Stefano Mora
RESIDENTS: Valentina Biffi, Maddalena Bove, Maria Francesca Brambillasca, Giuseppe Cannalire, Valeria Cerioni, Ilaria
Colombo, Francesca Cortinovis, Stefania Ferrari, Matilde Ferrario, Gisella Garbetta, Alessandra Giardelli, Stefano
Giardino, Cristina Lui, Emilio Palumbo, Barbara Parma, Arianna Passoni, Alessandra Perduca, Maria Antonietta
Piscopo, Marco Pitea, Andrea Rigamonti, Elisa Rizzato, Elisa Letizia Sabbioni, Raed Suliman Salmi Selmi, Paola Sogno
Valin, Maria Cristina Villa
FELLOWS: Maria Puzzovio, Ilaria Zamproni
Gynaecology and obstetrics
CLINICAL UNIT LEADERS: Claudio Brigante, Maria Teresa Castiglioni, Enrico Conti, Giorgia Mangili, Daniele Spagnolo, Luca
Valsecchi, Riccardo Viganò
CLINICAL UNIT COORDINATOR: Francesco Fusi
PHYSICIANS: Ferdinando Bombelli, Guido Candotti, Anna Cardani, Gabriella Colombo, Moreno Dindelli, Davide Ferrari,
Stefano Ferrari, Luca Gandini, Elisabetta Garavaglia, Stefania Luchini, Guido Marelli, Elena Marsiglio, Micaela Petrone,
Maria Teresa Potenza, Emanuela Rabaiotti, Susanna Rosa, Maddalena Smid
RESEARCHER: Massimo Origoni*
CONSULTANTS: Giada Almirante, Luigi Caputo, Paolo Cavoretto, Raffaella Chionna, Patrizia De Marzi, Rossana Favia,
Susanna Filippis, Paolo Giardina, Michela Molgora, Nicoletta Panacci, Enrico Papaleo, Massimo Pileri, Simone Rofena
RESIDENTS: Francesca Di Sebastiano, Dania Gambini, Cinzia Gentile, Serena Montoli, Federica Pasi, Paola Persico, Serena
Pirola, Chiara Stefani
Pediatric immuno-hematology Unit
CLINICAL UNIT LEADER: Sarah Marktel
PHYSICIANS: Alessandro Aiuti, Rosa Bacchetta, Alessandra Biffi, Barbara Cappelli, Robert Chiesa
RESIDENTS: Erika Biral, Costanza Evangelio, Valentina Finizio, Marco Fossati, Ilaria Frugnoli, Anna Noè
CHARGE NURSE: Clara Soliman
RESEARCH NURSES: Luciano Callegaro, Miriam Casiraghi
The obstetrical outpatient management focuses on the clinical control of physiological and pathological
pregnancies, with particular attention to gestational and pre-gestational diabetes, hypertension, autoimmune diseases, thrombophilia and recurrent abortion. In 2008, 3300 outpatient evaluations have been
performed. A complementary first and second level ultrasound service and prenatal diagnosis is available, with nearly 3600 examinations performed in 2008. The obstetrical inpatient activities are mostly
dedicated to delivery assistance (in 2008, 1910 deliveries) of which 66% are vaginal deliveries and 34%
caesarean sections. The obstetrical admissions for medical complications of pregnancy represent less than 10% of total admissions underlining the predominant outpatient management of high risk
pregnancies.
Other activities include Day surgery procedures, conservative and
demolitive laparotomy, laparoscopy, vaginal surgery, and surgical
treatment of urogenital prolapse and stress incontinence. Diagnosis,
radical surgery, and chemotherapy for genital tumors, treatment for
trophoblastic diseases, and diagnostic/operative hysteroscopy are also performed.
Infertile couples are managed with the most advanced treatments
and assisted reproduction techniques such as intra uterine inseminaGiuseppe Chiumello
tion (IUI), in vitro fertilization & embryo transfer (IVF), and intra
cytoplasmic sperm Injection (ICSI) with fresh or frozen-thawed
ejaculated semen or spermatozoa from surgically retrieved testicles.
The activities concerning pediatric emergencies mainly involve general pediatric diseases. Particular attention is also given to the collaboration with the family paediatrician.
Neonatal care is inspired by the most modern criteria of assistance for healthy newborns, and particular
importance is given to the relationship between the mother and the newborn. Specialized assistance is
provided to both premature and unhealthy newborns.
Approximately 700 patients with congenital hypothyroidism are followed by an integrated multidisciplinary approach involving the pediatric endocrinologist and neuropsychologist.
More than 750 cases of Type 1 Diabetes Mellitus are currently followed and 80 patients are newly diagnosed each year, representing one of the broadest case records in Italy and Europe. Particular focus is given to diabetes self-management education. A global therapeutic approach is followed in collaboration
with psychologists and social workers, also involving family and school environments.
The management of Willi-Prader Syndrome involves a medical-psychological evaluation, close relationship with the family and motor-skills intervention, all of which have determined improvements in
the prognosis of this disease.
The case records of children with genital ambiguity is the greatest in Italy, and its management includes a collaboration with surgeons and psychologists.
The number of patients with GH disorders under growth hormone treatment is one of the greatest in
Italy.
Other main fields are bone diseases and hyperinsulinemic hypoglicemia.
The department closely cooperates with parent associations which actively participate in organizing
support and educational activities.
The field of immunohematology is dedicated to the diagnosis and cure of children with immunological,
hematological diseases and other genetic disorders. In this context children are offered in addition to
standard care also experimental therapeutic options, among these cellular therapy and gene therapy.
From 2005 in partnership with the Mediterranean Institute of Hematology, programs for research, diagnosis and cure of blood disorders in patients from Mediterranean countries have been developed. This
partnership allowed 64 children affected by beta thalassemia from Syria, Lebanon, Palestine, Iraq, Jordan and Egypt to receive allogeneic bone marrow transplantation. The clinical activity of HSR-TIGET
with focus on the pathogenesis and therapy for genetic diseases, with particular regards to primary immunodeficiencies and autoimmune diseases with known or unknown genetic defects are being hosted.
Clinical studies for gene therapy of pediatric genetic diseases are ongoing (ADA-SCID) or in preparation
(Wiskott-Aldrich Syndrome, Metachromatic Leukodystrophy, Thalassemia). Finally, a cell therapy clinical study for Duchenne muscular dystrophy is being implemented.
Giuseppe Chiumello
DEPARTMENT OF INTERNAL AND
SPECIALISTIC MEDICINE
Head of Department: Emanuele Bosi*
DEPARTMENT AREA COORDINATORS: Giselda Colombo, Matteo Rocco Pastore, Moreno Tresoldi
General medicine, diabetes, endocrinology and metabolic diseases
CLINICAL UNIT LEADERS: Luca Falqui, Gabriella Galimberti, Roberto Lanzi, Matteo Rocco Pastore, Piermarco Piatti
CLINICAL UNIT COORDINATOR: Marco Federico Manzoni
PHYSICIANS: Alberto Davalli, Sabina Martinenghi (till July), Maria Grazia Perfetti, Alessandro Saibene, Maurizio Storti
RESIDENTS: Chiara Cappelletti, Valentina Crippa, Valentina Doria, Ilaria Formenti, Manuela Fortunato, Giulia Franchi, Claudia
Guerra, Andrea Laurenzi, Pietro Lucotti, Sara Madaschi, Laura Molteni, Francesca Perticone, Cecilia Piani, Elena
Peretti, Maria Grazia Radaelli, Alessandro Rossini, Annachiara Uccellatore
NUTRITIONIST: Monica Marchi
Clinical transplantation
CLINICAL UNIT LEADERS: Rossana Caldara, Paola Maffi
PHYSICIANS: Sabina Martinenghi (from July)
CONSULTANTS: Francesca De Taddeo, Chiara Gremizzi, Rosa Pedale
RESIDENTS: Alessandra Petrelli, Andrea Vergani
General medicine, clinical immunology and rheumatology
HEAD OF UNIT: Maria Grazia Sabbadini*
CLINICAL UNIT LEADERS: Giselda Colombo, Luisa Praderio, Moreno Tresoldi
PHYSICIANS: Enrica P. Bozzolo, Lorenzo Dagna, Massimo Memoli, Chiara Salmaggi, Nicoletta Saporiti, Raffaella Scotti, Magda
Vecellio
CONSULTANTS: Elena Baldissera, Teresa D’Aliberti, Stefano Franchini, Mona-Rita Yacoub, Patrizia Tanina Aiello
RESIDENTS: Mattia Baldini, Emmanuel della Torre, Barbara Guglielmi, Alessandro Marinosci, Francesca Motta, Fulvio Salvo,
Mirta Tiraboschi
Nephrology and dialysis
HEAD OF UNIT: Donatella Spotti
CLINICAL UNIT LEADERS: Giorgio Slaviero, Giuseppe Vezzoli
PHYSICIANS: : Teresa Arcidiacono, Chiara Lanzani, Marco Melandri, Luisa Persichini, Rita Quartagno, Maria Teresa Sciarrone
Alibrandi, Paola Stella
RESIDENTS: Giovanna Bonavida, Maria Bracale, Vera Paloschi, Marialuisa Querques, Francesco Rainone, Marco Simonini,
Cristina Tantardini
The Department of Internal Medicine is composed of four inpatient Clinical Units
and many Outpatient Clinics and Services covering General Medicine and the
medical specialties of Allergology, Clinical Immunology, Clinical Transplantation,
Diabetes, Dialysis, Endocrinology, Hypertension, Metabolic Diseases, Nephrology,
Nutrition and Rheumatology. Moreover, the Department of Internal Medicine
works in close interaction with the Emergency Department, representing the main
structure for hospitalization of patients presenting at the Emergency Medicine.
Within the Department, physicians, nurses, technicians, students and volunteers are
Emanuele Bosi
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. Integration between clinical care and research is a general theme across the Department, with 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 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. The scientific production by physicians and clinical investigators
from the Department is remarkable, with internationally recognized areas of excellence in clinical immunology, diabetes and metabolism, hypertension, islet and pancreas transplantation.
Emanuele Bosi
DEPARTMENT OF CLINICAL NEUROSCIENCE
Head of Department: Enrico Smeraldi*
DEPARTMENT AREA COORDINATORS: Barbara Barbini, Francesco Benedetti, Maria Cristina Cavallini, Andrea Fossati*,
Ernestina Politi, Paolo Ronchi
General psychiatry
HEAD OF UNIT: Enrico Smeraldi*
CLINICAL UNIT LEADERS: Roberto Cavallaro, Marco Locatelli
PHYSICIANS: Sara Angelone, Laura Bianchi, Mirella Brunetta, Michele Cucchi, Ernestina Politi, Adriana Pontiggia, Paolo Ronchi,
Laura Sforzini, Francesca Siliprandi
RESIDENTS: Marta Bosia, Eugenia Fauci, Chiara Insacco, Laura Liperi, Fausto Panigada, Chiara Ruffini
TECHNICIANS: Simona Anselmetti, Margherita Bechi, Elena Ermoli, Francesco Fresi, Alessia Santoro
Clinical health psychology
HEAD OF UNIT: Lucio Sarno*
PSYCHOLOGISTS: Valentina Di Mattei, Claudia Finocchiaro, Samantha Gabrielli, Serena Giuliani, Carola Iris Ferrari, Rita Milesi,
Chiara Motta, Liliana Novella, Valentina Nuzzaci, Gianluca Palermo, Valeria Pezzani, Alissia Pistarà, Alessandra Pradella,
Maria Monica Ratti, Camilla Testa, Laura Tirloni, Silvana Villa
RESIDENTS: 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*
CONSULTANTS: Francesca Biondini, Serena Borroni, Raffaella Braga, Valentina Bregani, Paola Broggi, Elena Campanini, Ilaria
Carretta, Paolo Casati, Elisabetta Cattaneo, Rosaria Devoti, Michela Donini, Marina Fiore, Sara Gaietta, Salvatore La
Viola, Gema Moelia Moreno Granados, Anna Ogliari*, Alessandro Pieri, Sergio Premoli, Roberto Vanni, Daniele Villa
RESIDENTS: Ilaria Aina, Roberta Alesiani, Silvia Boccalon, Alessandra Bosaia, Naima Coppolino, Cinzia Facchi,
Maria Chiara Fiorin§, Gianluca Franciosi, Roberta Gallese, Laura Giarolli, Valeria Parlatini, Paola Pesenti Gritti§,
Caterina Antonia Eloisa Rocco di Torrepadula, Erica Rossi, Chiara Spatola§, Martina Testa, Annalisa Zanoni
§ External residents
Eating disorders
HEAD OF UNIT: Laura Bellodi*
CLINICAL UNIT LEADERS: Stefano Erzegovesi, Giampaolo Perna
CLINICAL UNIT COORDINATORS: Marco Catalano, Giuseppina Diaferia, Paolo Cavedini
PHYSICIANS: Cinzia Arancio, Silvia Cocchi, Daniela Di Molfetta, Angela Gabriele
RESEARCHERS: Angelo Bertani, Daniela Caldirola, Maria Cristina Cavallini
RESIDENT: Claudia Zorzi
FELLOWS: Clementina Baraldi, Elisa Galimberti, Monica Piccinni, Giuliana Salomoni
Mood disorders
HEAD OF UNIT: Cristina Colombo
CLINICAL UNIT LEADERS: Linda Franchini, Adelio Lucca, Raffaella Zanardi
PHYSICIANS: Barbara Barbini, Francesco Benedetti, Fanny Bongiorno, Euridice Campori, Mara Cigala Fulgosi, Sara Dallaspezia,
Danilo Dotoli, David Rossini
Neurology
HEAD OF UNIT: Stefano F. Cappa*
CLINICAL UNIT LEADER: Sandro Iannaccone
CLINICAL UNIT COORDINATOR: Marco Zucconi
PHYSICIANS: Luca Bernasconi, Maria Cristina Giusti, Valeria Golzi, Alessandra Marcone, Barbara Sferrazza, Michele Zamboni
RESEARCHERS: Jubin Abutalebi*, Nicola Canessa, Eleonora Catricalà, Pasquale Della Rosa
PSYCHOLOGISTS: Valentina Esposito, Paola Frasson, Elena Farina, Valeria Ginex
The first and main committment of the Department is to define and to develop
a common guideline for the clinical approach to the different aspects of behavioural disorders, according to the funding principles of our Institution, in order to
overcome the strict meaning of each symptom, to adequately consider the nature
and the whole of the individual suffering.
Enrico Smeraldi
The public psychiatric structure is based on the model of Mental Health Department (DSM). Our department, in its psychiatric and psychological component, is based on long term therapeutical assistance, hence resembling DSM and their mode of function,
but it differs from DSM in its objectives.
In DSM, the main aim is to take care of the mental health of a community (differently defined) and it
must be addressed to it 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 theraeutical 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.
In 2008, the number of patients discharged from the Department has been 3.111, with a mean hospital
stay of 19,1 days and a subsequent employment rate of 91,72%.
As regards the outpatient activity, the final balance 2008 was 70.381 consults, corresponding to a
turnover of eur 2.981.836,00
Moreover, the activity of the Daily Center has to be considered: 456 consults, for a turnover of eur
55.719,00
The profit and loss statement of the Department realizes a total turnover of 18.676.000 with a first contribution margin of 29,64 and a gross margin of 42,32.
Enrico Smeraldi
DEPARTMENT OF NEUROLOGY
Head of Department: Giancarlo Comi*
CLINICAL UNIT LEADERS: Mauro Comola, Ubaldo Del Carro, Vittorio Martinelli, Fabio Minicucci
DISEASE UNIT COORDINATORS: Bruno Colombo, Raffaella Fazio, Giuseppe Magnani, Paolo Marchettini, Vittorio Martinelli, Maria
Antonietta Volontè, Maria Sessa, Giulio Truci, Letizia Leocani
PHYSICIANS: Stefano Amadio, Francesco Corea, Giovanna Franca Fanelli, Roberta Guerriero, Fabio Formaglio, Silvia Mammi,
Filippo Martinelli-Boneschi, Stefania Medaglini, Lucia Moiola, Antonella Poggi, Mariaemma Rodegher, Paolo Rossi,
Luisa Roveri, Marina Scarlato
RESIDENTS: Martina Absinta, Marco Bacigaluppi, Beatrice Benedetti, Mariangela Bianco, Sebastiano Bucello, Calogera Butera,
Francesca Caso, Daniela Ceppi, Federica Cerri, Raffaella Chieffo, Dacia Dalla Libera, Donatella De Feo,
Luisa De Toni Franceschini, Francesca Fumagalli, Sebastiano Galantucci, Chiara Ghidinelli, Elda Judica, Sara La Gioia,
Ignazio Diego Lopez, Maria Merello, Giulia Pavan, Elisabetta Stefania Perego, Luca Peruzzotti Jametti,
Francesco Peschechera, Annalisa Rizzo, Eliana Schiatti, 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
Giancarlo Comi
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 co-operation with pharmaceutical industries and generated by the Department itself make it possible to provide patients with more advanced
therapeutic strategies. Points of excellence of the clinical research are etiologic and symptomatic treatment of multiple sclerosis, epidemiological studies on multiple sclerosis, and the evaluation of the disease
pathogenesis and pathophysiology. Ischemic stroke researches are focused on the risk factors for the occurrence in young adults and on the organisational aspect of the early intervention. Studies on dementia
are conducted in co-operation with Imaging and clinical neurophysiology laboratories and aims to define
biomarkers specific for dementia subtypes and to assess the risk for evolution to Alzheimer Disease in patients with minimal cognitive impairment. In Amyotrophic Lateral Sclerosis the contribution of instrumental test to the early diagnosis, the characterisation of cognitive dysfunction, the assessment of the value of new treatments are the key research activities.
The recovery medicine is one of the more recent area of research activated in the Department, because
of the possibility to follow neurological dysfunctions due to acute central nervous system lesions, from the
onset to the recovery phase. The impact of various therapeutic strategies to enhance recovery, the functional and molecular bases underlying brain plasticity after acute damage with imaging and neurophysiological examinations are deeply investigated.
Giancarlo Comi
DEPARTMENT OF ONCOLOGY
Head of Department: Federico Caligaris-Cappio*
DEPARTMENT AREA COORDINATORS: Gianni Bordogna, Gianfranco Ciboddo, Consuelo Corti, Andrès Jose Maria Ferreri,
Michele Reni
Internal medicine
CLINICAL UNIT LEADERS: Marco Foppoli, Giovanna Petrella
CLINICAL UNIT COORDINATOR: Aurelio Vicari
PHYSICIANS: Gianfranco Ciboddo, Giovanni Citterio, Manuela Pacchioni
RESIDENTS: Giovanni Donadoni, Giada Licata, Chiara Miggiano, Federica Pozzi, Gilda Rossoni, Irene Vandoni,
Chiara Francesca Verona, Angela Zanoni
Haematology and bone marrow transplantation
CLINICAL UNIT LEADERS: Massimo Bernardi, Consuelo Corti, Jacopo Peccatori
PHYSICIANS: Andrea Assanelli, Lionello Camba, Matteo Carrabba, Elena Guggiari, Francesca Lunghi, Magda Marcatti, Maria
Teresa Lupo Stanghellini
Medical oncology
HEAD OF UNIT: Eugenio Villa
CLINICAL UNIT LEADERS: Daniela Aldrighetti, Monica Ronzoni
PHYSICIANS: Gianni Bordogna, Andrés Jose Maria Ferreri, Vanesa Gregorc, Elena Mazza, Michele Reni, Giordano Pietro Vitali,
Patrizia Zucchinelli
CONSULTANTS: Carmen Belli, Stefano Cereda, Monica Giovannini, Vincenzo Ricci, Alessia Rognone, Maria Grazia Viganò
Nuclear medicine
HEAD OF UNIT: Luigi Gianolli
CLINICAL UNIT COORDINATOR: Daniela Perani*
RESEARCHERS: Sara Belloli, Valentino Bettinardi, Assunta Carpinelli, Isabella Castiglioni, Elisa Galli, Maria Carla Gilardi,
Adelmo Grimaldi, Valeria Masiello,Mario Matarrese, Maria Grazia Minotti, Rosa Maria Moresco, Maria Picchio,
Marco Rigamonti, Annarita Savi, Paola Scifo, Marco Tettamanti, Sergio Todde, Elia Anna Turolla
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: Mark Anthony Aquilina, Elena Busnardo, Rosella Collivasone, Giampiero Giovacchini, Pietro Spagnolo
RESIDENTS: Cinzia Crivellaro, Giuseppe Di Pisa, Anna Giudice, Rita Garcia Parra, Paola Mapelli, Annalisa Pepe,
Maria Antonia Rimicci, Elena Spinapolice, Vincenzo Tripoli
FELLOWS: Manuela Giglio, Eugenio Rapisarda
PHD STUDENTS: Francesca Gallivanone, Cristina Monterisi
TECHNICIANS: Matteo Barbagli, Luca Brioschi, Maurizio Carenzi, Patrizia Cerè, Antonia Compierchio, Paola Cordisco,
Valeria Crippa, Silvia Debbia, Andrea Fabro, Davide Gatti, Vincenzo Giori, Paola Lanzoni, Stefania Longari,
Claudia Francesca Maddé, Claudio Mannu, Raffaele Menichini, Felice Neutro, Giacomo Orlandi, Massimiliano Papagni,
Jacopo Perego, Carlo Pizzamiglio, Riccardo Rigamonti, Sabrina Riolo, Silvana Romano, Simone Rossi, Lucia Rozza,
Pasquale Simonelli, Stefano Stucchi, Francesco Sudati, Mauro Vaghi, Raffaele Vannulli
Radiotherapy
HEAD OF UNIT: Nadia Di Muzio
CLINICAL UNIT LEADER: Angelo Bolognesi
PHYSICIANS: Fodor Andrei, Saverio Beatrice, Genoveffa Berardi, Anna Chiara, Cesare Cozzarini, Italo Dell’Oca, Micaela Motta,
Marcella Pasetti, Paolo Passoni, Stefano Schipani
RESIDENT: Filippo Alongi
TECHNICIANS: Fabio Baratto, Nietta Barricella, Roberta Bin, Rita Calaciura, Alessandro Capelli, Alberta De Leonardis,
Letizia Erre, Caterina Fiordelisi, Laura Longoni, Marilena Martulano, Lidio Palumbo, Diana Parutto, Vincenzo Sacco,
Giovannella Salvadori, Andrea Sbalchiero, Simone Selli, Antonella Soccio, Marco Spagnuolo, Alessandro Tavilla
The general aims of the Department of Oncology are the
optimization of care and the acceleration of cure. The specific
aims are: 1) to rationalize clinical activity with the purpose of
maintaining/reaching the state of the art in all the different
types of cancer; 2) to improve logistic and organization thereby ameliorating the arrangement of patient care; 3) to expand
and strengthen research in the field of oncology with the instruments of Translational Research and an interdisciplinary
approach: this aim foresees the establishment of a Clinical
Trial Unit essentially devoted to Phase I and Phase II clinical
trials; 4) to join efforts with the Division of Molecular OncolFederico Caligaris-Cappio
ogy to create a network organization, multidisciplinary teams
and defined programmes for different tumours.
The Department includes the Division of Medicine 1Q, the Division of Hematology and Bone Marrow
Transplantation, the Unit of Medical Oncology, the Unit of Radiotherapy and the Unit of Nuclear Medicine. The number of beds is 63, the personnel amounts to 193 people; there are both a management coordinator and a nurse coordinator. In the year 2008 the overall number of cancer patients the Department
has taken care of, including both patients admitted to the wards as well as patients followed in the Day
Hospital or as outpatients, is about 4500.
The Department cultural organization follows the Disease Unit model and is based upon a fruitful interaction with other Departments involved in the field of Oncology such as the Departments of Surgery,
Head and Neck and Imaging. The active Disease Units are Lymphoid, Lung, Pancreas, Breast, Head
and Neck, GastroIntestinal, Melanoma, NeuroOncology, Genito-Urinary and Gynecological Oncology.
In 2008 the Departmental Area of Lymphoid Tumors has been established with 25 ongoing clinical trials
(HSR is the coordinating center of 11). In the same year the Bone Marrow Transplantation Unit has
ranked among the firsts in Italy as for the number of allogeneic transplantations performed. Overall in
the year 2008 more than 50 clinical trials have been at hand including numerous Phase I and Phase II
trials. Blood, lung, pancreas and brain tumors are the Areas where the Department is especially active,
not to mention the urological cancers in collaboration with the Department of Urology.
The Department has become member of the European Organization of Cancer Centers (OECI), the
Southern Europe for New Drugs Organization (SENDO), the Swiss Group for Clinical Cancer Research (SAKK), the CLL US/Europe Alliance Organization (driven by the MD Anderson Cancer Center) and is also member of the Network Italiano BioImmunoterapia dei Tumori (NIBIT) and of the Italian Melanoma Intergroup.
The currently ongoing research takes advantage of basic, translational and clinical research projects.
We are building up teams of laboratory-based and clinical investigators with the aim of defining molecular endpoints in clinical material and use them to develop studies on the pathobiology and pathogenesis
of specific tumors and to organize pilot studies and investigator-driven clinical trials. On these basis the
currently ongoing projects can be summarized under three main headings: 1) Molecular mechanisms of
disease, one example being the notion that a number of infectious agents are associated with the development of specific types of cancer; 2) New diagnostic and prognostic approaches to define new tools and new
biologically-based prognostic and predictive markers, one example being the validation of a number of
new markers with proteomic technologies; 3) New treatment strategies to develop new approaches and
novel treatments by increasing Phase I and I-II studies and by clinically translating the results of HSRbased 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, 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, Antonio Esposito, Claudio Losio
Radiology HSRT
HEAD OF UNIT: Giuseppe Balconi
CLINICAL UNIT LEADER: Gianpiero Cardone
PHYSICIANS: Francesca Di Sebastiano, Rossana Favia, Cristiana Iabichino, Roberto Lanzi, Paolo 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
166.137, diagnostic and interventional procedures (including emergency)
per year. The Department includes six sections:
1. Conventional and Digital Radiology
2. Breast Imaging
3. Ultrasound
4. Computed Tomography
5. Magnetic Resonance Imaging and Spectroscopy
6. Diagnostic and Interventional Radiology/Angiography
Moreover we developed many collaborations with internal and external
groups, in particular:
• with the Section of Nutrition/Metabolism and the Faculty of Exercise Sciences, Università degli Studi
di Milano with Prof. Perseghin and Prof. Luzi it has been developed a tight cooperation on Magnetic
resonance spectroscopy of the heart and of the liver in order to evaluate the functional and metabolic
effects 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 group of Dr. Malosio 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 Unit of Radiation Therapy and Medical Physics of Dr. Di Muzio and Dr. Calandrino we
sought to implement the radiotherapy planning by new imaging-techniques. We have use different imaging technique 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.
• with the Department of Mechanics, Politecnico di Torino, with the Department of Bioengineering, Politecnico di Milano, with the Istituto di Bioimmagini e Fisiologia Molecolare, Research National Council, Milan in order to develop a method for quantifying helical flow in vivo employing time-resolved
cine phase contrast magnetic resonance imaging to obtain the complete spatio-temporal description of
the three-dimensional pulsatile blood flow patterns in aorta.
DEPARTMENT OF UROLOGY
Head of Department: Patrizio Rigatti*
DEPARTMENT AREA COORDINATORS: Roberto Bertini, Luigi Broglia, Andrea Cestari, Valerio Di Girolamo, Francesco Montorsi*,
Luciano Nava,Vincenzo Scattoni
Urology HSR
HEAD OF UNIT: Patrizio Rigatti*
CLINICAL UNIT COORDINATORS: Roberto Bertini, Renzo Colombo, Andrea Salonia
PHYSICIANS: Alberto Briganti, Lina Bua, Andrea Gallina, Massimo Ghezzi, Caterina Lania, Arianna Lesma, Marco Raber,
Marco Roscigno, Vincenzo Scattoni, Nazareno Suardi,Giuseppe Zanni
RESIDENTS: Abdollah Firas, Diego Angiolilli, Marco Bianchi, Tommaso Camerota, Umberto Capitanio, Dario Di Trapani,
Matteo Ferrari, Andrea Gallina, Salvatore Grimaldi, Carmen Maccagnano, Federico Pellucchi, Giovanni Petralia,
Lorenzo Rocchini, Antonino Saccà, Francesco Sozzi, Elena Strada, Manuela Tutolo
Urological endoscopy service and day surgery
HEAD OF UNIT: Valerio Di Girolamo
Strategic program for Urology
HEAD OF UNIT: Francesco Montorsi*
Urology HSRT
HEAD OF UNIT: Giorgio Guazzoni*
CLINICAL UNIT LEADERS: Piera Bellinzoni, Luciano Nava
PHYSICIANS: Luigi Broglia, Antonia Centemero, Andrea Cestari, Andrea Losa, Tommaso Maga
CONSULTANTS: Nicolò Maria Buffi, Fabio Fabbri, Lorenzo Rigatti, Mattia Sangalli, Emanuele Scapaticci, Matteo Zanoni
RESIDENT: Giovanni Lughezzani
The Department of Urology, Vita-Salute San Raffaele, Milan, headed
by Professor Patrizio Rigatti, represents one of the most important International institutions for the diagnosis and the treatment of urological
malignancies. The Department takes account weekly of 25 operating
rooms, serving 110 beds for ordinary recovery. Every year, about 1000,
500 and 250 surgeries are performed for prostate, bladder and kidney
cancer, respectively.
The clinical investigations performed in the last years leaded to the
publication of 571 scientific contributions for a overall citation index of
5503 with a significant boost in the last three years (citation index last
three years: 2262; h index 37) [Source SCOPUS January 2009]. Every
year, the Department substantially contributes with a significant numPatrizio Rigatti
ber of accepted abstracts to the most important international and national meetings.
The main research areas consist of prostate cancer, kidney cancer, bladder cancer, infertility and andrology, female sexual medicine, benign prostatic hyperplasia. The clinical research relied on analyses of clinical, pathological and follow-up prospectively collected data regarding thousands of patients treated at
San Raffaele Hospital. The records are collected within specific databases developed in the last years.
Patrizio Rigatti
CLINICAL SERVICES
Medical physics
HEAD OF UNIT: Riccardo Calandrino
PHYSICISTS: Sara Broggi, Giovanni Mauro Cattaneo, Antonella Del Vecchio, Claudio Fiorino, Barbara Longobardi,
Paola Mangili, Lucia Perna, Patrizia Signorotto
RESEARCHER: Antonello Spinelli
FELLOWS: Angelo Maggio, Veronica Ardu
Pathology
HEAD OF UNIT: Claudio Doglioni*
CLINICAL UNIT COORDINATORS: Gianluigi Arrigoni, Massimo Freschi, Maurilio Ponzoni, Isabella Sassi, Gianluca Taccagni,
Maria Rosa Terreni
PHYSICIANS: Luca Albarello, Giacomo Dell’Antonio, Nathalie Rizzo
RESEARCHER: Francesca Sanvito
CONSULTANTS: Anna Cremonini, Graziana Famoso
BIOLOGISTS: Mariagiulia Cangi, Lorenza Pecciarini
POST-DOCTORAL FELLOWS: 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, 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
HEADS OF DIVISION: Ferruccio Ceriotti, Massimo Clementi*, Fernanda Dorigatti, Maurizio Ferrari*
HEADS OF UNIT: Armando D’Angelo(#), Alberto Sanna
CLINICAL UNIT LEADERS: Paola Cichero, Stefania Del Rosso, Fulvio Ferrara, Anna Maria Girardi, Massimo Locatelli,
Cristina Ossi, Marina Pontillo, Sara Racca, Armando Soldarini, Laura Soldini, Silvana Viganò D’Angelo
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, Silvia Carletti Anna Carobene, Carlo Alberto Ferrero, Rossella Ieri, Rosanna Latino,
Marcello Marinelli, Gabriella Passerini, Elisabetta Pattarini, Flavia Piccini, Barbara Maria Pirola, Laura Seghezzi,
Barbara Sioli, Ivana Spiga, Annunziata Spina, Monica Zanussi
BIOENGINEER: Davide Alessio
CONSULTANTS: Pierangelo Bonini*, Emanuele Bosi*(#), Roberto Burioni*, Orsetta Zuffardi*
RESEARCHERS: Paola Carrera(*), Laura Cremonesi(*), Patrizia Della Valle(#), Isabella Fermo(*), Vito Lampasona(*),
Annapaola Andolfo(*)
RESEARCH FELLOWS: Marco Bianchi, Luca Bolzoni, Sara Bonalumi(*), Angela Brisci(*), Francesca Bruno(*), Filippo Canducci,
Davide Carcione, Emanuela Castiglioni(*), Vincenza Causarano(*), Alessio Colombo, Donata De Marco, Roberta Diotti,
Silvia Galbiati(*), Stefano Gerola(*), Nadia Ghidoli, Nicola Maganetti, Maria Chiara Marinozzi, Angelica Morandi,
Marco Nalin, Fabio Perotti, Nicola Perrelli, Sabina Piccinini, Monica Ramponi, Monica Sassi, Riccardo Serafin, Elena
Sommariva(*), Stefania Stenirri(*), Sauro Vicini, David Williams.
TECHNICIANS: Rose Mary Carletti(*), Cinzia Magagnotti(*), Michela Sanpaolo, Francesca Sanpietro(#), Nadia Soriani(*).
(*) reporting to the CENTER FOR GENOMICS, BIOINFORMATICS, AND BIOSTATISTICS
(#) reporting to the DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES
Service of immunohematology and transfusion medicine
HEAD OF UNIT: Silvano Rossini
CLINICAL UNIT LEADERS: Lorena Barzizza, Laura Bellio
PHYSICIANS: Cinzia Bargiggia, Alketa Bolentini, Katharina Fleischhauer, Salvatore Gattillo, Lucia Malabarba, Lilian Romero,
Paola Ronchi
BIOLOGISTS: Lia Parma, Oriana Perini, Cristina Tresoldi, Elisabetta Zino
CHEMIST: Benedetta Mazzi
TECHNICIANS: Daniela Ceresa, Silvia Corno, Luigi D’Amato, Stefania Dell’Orco, Giuseppe Di Leo, Dina Di Sciacca,
Alessandra Galli, Emanuela Grioni, Maria Antonia Introini, Giuseppina Marabelli, Ilaria Mazzi, Gabriella Salomoni,
Massimo Sacconi, Elisabetta Sironi, Serenesse Tomasi, Gabriele Torriani, Federica Valtorta, Matilde Zambelli,
Paola Zappalalio
Emergency medicine
HEAD OF UNIT: Michele Carlucci
DIRECTOR OF EMERGENCY MEDICINE PROGRAM: Marzia Spessot
CLINICAL UNIT COORDINATORS: Anna Borri, Roberto Faccincani, Maria Vittoria Lavorato, Federica Mariani
PHYSICIANS: Aldo Beneduce, Pietro Bisagni, Giuseppe Capasso, Barbara Demarchi, Laura Ferrario, Federico Furlan, Giulia
Gallotta, Elisa Gatti, Francesca Gavazzi, Simona Mauri, Enrico Ortolano, Annamaria Pazzi, Simona Rocchetti, Maria
Vittoria Taglietti, Luca Tomaello, Valentina Tomajer
RESIDENTS: Chiara Cappelletti, Federica Dilani, Carmen Forestieri, Manuela Fortunato, Matteo Frasson, Francesca Luisi,
Francesco Luparini, Alessandro Marinosci, Federica Merlini, Alessandro Rossini, Simone Squillante, Roberta Varale,
Veronica Zuber
CLINICAL UNIT COORDINATORS: Gabriele Cornaggia, Paolo Silvani
Anesthesia and resuscitation
CLINICAL UNIT COORDINATORS: Massimo Caldi, Daniela Giudici
MEDICAL PHYSICS
A) Advantages of using a Helical Tomotherapy (HT): planning comparisons vs other radiotherapy (RT) delivery modalities
HT is an innovative solution in RT that offers advantages in creating deep dose gradients between planning
target volume (PTV) and organs at risk (OARs). Main results:
• In case of prostate, head-neck and lung diseases significant advantages of using HT both in PTV coverage
and in OARs sparing.
• In case of prostate, HT and intensity-modulated arc therapy have been compared. The two modalities are
similar with a slightly better PTV coverage obtained with HT.
• For nasopharynx cancer, HT was compared with intensity-modulated proton therapy. Both modalities
guarantee an excellent PTV coverage and sparing of the OARs in the high-to-medium dose range.
B) Modeling toxicity in RT by correlating clinical data with dose-volume parameters (DVHs)
Individual 3D DVHs may be used to model the clinically reported effects in order to define quantitative estimators of toxicity after RT. A number of investigations have been conducted on patients (PTs) treated at our
and other Institutions. Important results were found for:
• late rectal bleeding and acute bowel toxicity.
• correlation between DVH, genes involved in DNA repair and late rectal bleeding in PTs treated for
prostate cancer.
• preliminary results concerning hypofractionated clinical protocols with HT in pelvis diseases.
C) Treatment planning optimization by means of integrated imaging modalities
The availability of multi-modal images allows:
1) a more accurate definition of the real extension of neoplastic disease and the definition of “metabolic” tumor maps;
2) a better visualization of OARs;
3) the evaluation of breathing related tumor/organ mobility;
4) the analysis of geometric uncertainties by means of daily MVCT.
A number of investigations have been conducted evaluating the impact of multi-modal approach in treatment
planning optimization for malignancies of different anatomical districts.
D) Methods for risk evaluation in workers in Medical Cyclotron Facilities
Two main items have been investigated:
• the contamination of the exhausted air from the hot cells dedicated to the synthesis of PET radiopharmaceuticals.
• the risk evaluation and the doses due to internal contamination.
Riccardo Calandrino
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 approximately 25.000 surgical and 24.000 cytologic specimens in 2008. The diversity of
the specimen material reflects the specialized medical and surgical practice of San Raffaele Hospital. Pathologists with particular interest and expertise in various pathology areas (e.g., hematopathology, uropathology,
neuropathology, gynecologic pathology, etc.) interpret and signout the cases that fall into the subspecialty categories. This approach ensures excellent diagnostic interpretations, enhancing collaboration with the large variety of specialized clinical services present in San Raffaele Hospital.
A broad, continuously updated, array of specialized techniques is available to complement routine morphologic examination, including an ever-expanding menu of immunohistochemical stains, immunofluorescence
studies, molecular pathology analyses, cell cultures, karyotyping of solid tumors and molecular cytogenetic
techniques.
Claudio Doglioni
LABORATORY MEDICINE
Standardization in clinical chemistry. Two types of activities were running: the definition of reference intervals for several quantities (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase,
creatinine) and the implementation of reference methods to be applied to set target values to control materials
for external quality assessment schemes and to validate and certify other field methods and routine laboratories.
Microbiology and Virology. Several research lines both in microbiology and in virology. Microbiology: resistance and susceptibility to antibiotics and antifungal of bacteria and fungi; molecular diagnosis of sepsis.
Virology: viruses involved in respiratory syndromes (Coronavirus, respiratory syncytial virus and viruses identified recently in infants with acute respiratory disease); molecular epidemiology and pathogenic potential of
human papillomavirus; perspectives and opportunities of novel antiviral treatments targeting virus fitness; Hepatitis C virus: utilization of neutralizing human monoclonal antibodies as anti-HCV drugs; 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; HIV-1 replication capacity and genotype changes in patients undergoing treatment interruption or lamivudine monotherapy; AntiHIV-1 Response Elicited in Rabbits by Anti-Idiotype Monoclonal Antibodies mimicking the CD4-Binding Site.
Fernanda Dorigatti
SERVICE OF IMMUNOHEMATOLOGY AND TRANSFUSION MEDICINE
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. In addition, it collects and prepares the blood components
and cellular therapy products used in patient care at the HSR, maintains an accredited Immunohematology
Reference Lab, and runs a training program in Blood Banking.
We strive for sustained excellence using our talents as innovators, inventors, investigators, and instructors to
advance safe and effective transfusion practices, to train the leaders of tomorrow’s science, and to deliver the
services and products that make creative clinical research possible. An RFID project is underway with the goal
of increasing safety by implementing radiofrequency identification technology in the daily management of
transfusions and transfusion products. This system is a model for process traceability from donor to patient, for
automation in the identification of patients, blood units and/or cellular products.
Our Mission:
The mission of the San Raffaele Immunohematology and Transfusion Medicine Service is to provide high
quality patient care and hospital services in support of HSR clinical research programs, to pursue research that
contributes to our knowledge and practice of transfusion medicine and related technologies, and to provide advanced training in transfusion medicine.
Our Goals:
• To provide outstanding clinical, consultative, laboratory, and blood component manufacturing services to
HSR Clinical patients or other Institutions in a way that: a) maintains the highest standards for safety and
quality, b) meets the needs of the Institute for unique services and innovative approaches, and c) assures
optimal utilization of resources.
• To advance the practice of transfusion medicine by: a) improving the effectiveness of standard blood
components, b) exploring new approaches to the use of standard components, and c) developing new cellular components, techniques, and technologies to support novel therapeutic strategies.
• To improve blood safety by: a) reducing the risk of transfusion-transmitted infections, and b) minimizing
non-infectious, transfusion-associated adverse reactions.
• To advance the science of transfusion medicine by: a) sustaining active, innovative research programs, b)
communicating new knowledge gained through research, and c) training others to carry on the pursuit of
innovative research and leading edge clinical care.
Silvano Rossini
EMERGENCY MEDICINE
In 2008 the Emergency Department of San Raffaele Hospital provided care for 61.809 patients.
807 of the patients triaged were given red code (that is, to be seen immediately in the resuscitation area).
8967 cases were given yellow code (that is, to be seen within 30 minutes of arrival). The largest amount of them
(49.138 ) were given lower priority (green code, that means they had to be seen within 1 hour of arrival). Only
2897 (%) were given a white code (that is, patients whose conditions are not true emergencies).
In 2008 we have seen 20.494 patients with medical problems, 16.812 with surgical problems and 11832 with
minor trauma. 6878 children have been treated in the pediatric area. In the dedicated area for obstetrics 5835
women received treatment.
9944 patients, after initial evaluation, were admitted to different wards for further investigations and treatments.
In 2008, 600 patients received surgery in the Emergency Room.
Major trauma (patients with multiple injuries) is treated by a trauma team who have 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 Hospital every year.
Staff members received Emergency Medicine Up-to date meetings every two weeks.
Università Vita e Salute medical students are trained on application of classical emergency medicine principals in a humanistic and supportive patient environment.
In 2008 physicians attended the following meetings and courses: Trauma: Update and organization (Bologna,
February ); 27° Congresso nazionale ACOI, (Bergamo, May); Trauma Update: Morbidity and mortality on
Trauma patients (Milano, May ); Trauma Update: Il trauma grave:the days after (Rome, September); Trauma
Update. Il sistema trauma: imparare dall’errore (Cesena, November ); VI Congresso nazionale SIMEU (Rimini,
November); Benchmarking in Pronto Soccorso: SIMEU Lombardia (Milan, November); Antibiotici ed antifungini per le infezioni gravi (Pisa, November); XXXVI Congresso nazionale SICUT (Bari, December); Trauma
Update: Incidenti stradali: dalla prevenzione alla riabilitazione (Milan, December)
Michele Carlucci
GENERAL INTENSIVE CARE
In 2008 our General ICU admitted 491 patients, half of them for postoperative monitoring after major elective surgery. The occupational rate was 95%.
We’re currently changing our admission strategy, improving the early postoperative care in the recovery
room, in order to guarantee the care for hospital and territorial emergencies.
In 2008 the principal critical illnesses admitted to our unit included:
Trauma patients (traffic and work accidents accounting for 20% of all intensive treatments) as 2nd level hospital in Milan county.
Respiratory failure (40% of intensive treatments). Primary and secondary ARDS (acute respiratory distress
syndrome) are evolutions of pneumonia or systemic sepsis, especially in immune-compromised patients such as
after transplantation.
Cardiovascular failure or multiple organ dysfunctions (20%). Patients rescued from cardiac arrest or with severe cardiac congestive failure.
Septic shock (10%), a dreadful complication after major surgery or transplantation.
In our general ICU can provide a wide range of therapeutic options for the above cited pathologies, following
updated international guidelines: the newest strategies in mechanical ventilation including extracorporeal life
support; updated antibiotic therapy; hypothermic therapy after cardiac arrest; developments in continuous renal replacement therapy. Staff was trained to the use of echography in ICU.
We also managed hospital emergencies 24 hours a day through the “medical emergency team” (MET) com-
posed by anesthesiologists working both in operating theatre and ICU. MET provides adult and pediatric anesthesia (in a dedicated operatory room) and critical care for non-cardiosurgical emergencies, for the Casualty
Department and for critical patients treated outside the Intensive Care Units. This kind of organization allows
MET to perform safely a non invasive ventilation treatment for mild or chronic respiratory failure in non intensive areas. Day shift is covered by two anesthesiologists with the supervision of a coordinator. Night shift is covered by two anesthesiologists with a supervision of a senior consultant on call.
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 for general anaesthesia in neurosurgical, interventional neuroradiology, ENT and ophthalmic surgery for approximately 3000 cases per year and for conscious sedations in
children and adults (1000 cases per year) submitted to diagnostic or therapeutic procedures in Neuroradiology.
The General Anaesthesia Staff provides for 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
Medical physics
PUBLICATIONS - 195
PUBLICATIONS
PUBLICATIONS - 197
BEST PAPERS 2008
1. Gandin, V; Miluzio, A; Barbieri, AM; Beugnet, A; Kiyokawa, H; Marchisio, PC; Biffo, S. Eukaryotic initiation
factor 6 is rate-limiting in translation, growth and transformation. Nature: 2008; 455(7213): 684-688 - Article
IF 2008: 31,434
2. Comi, G; Pulizzi, A; Rovaris, M; Abramsky, O; Arbizu, T; Boiko, A; Gold, R; Havrdova, E; Komoly, S; Selmaj, K; Sharrack, B; Filippi, M. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study.
Lancet: 2008; 371(9630): 2085-2092 - Article
IF 2008: 28,409
3. Gargioli, C; Coletta, M; De Grandis, F; Cannata, SM; Cossu, G. PlGF-MMP-9-expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle. Nat.Med.: 2008; 14(9): 973-978 - Article
IF 2008: 27,553
4. De Palma, M; Mazzieri, R; Politi, LS; Pucci, F; Zonari, E; Sitia, G; Mazzoleni, S; Moi, D; Venneri, MA; Indraccolo, S; Falini, A; Guidotti, LG; Galli, R; Naldini, L. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell: 2008; 14(4): 299-311 - Article
IF 2008: 24,962
5. Ferreri, AJM; Dognini, GP; Govi, S; Crocchiolo, R; Bouzani, M; Bollinger, CR; D’Incan, M; Delaporte, E;
Hamadani, M; Jardin, F; Martusewicz-Boros, M; Montanari, M; Szomor, A; Zucca, E; Cavalli, F; Ponzoni, M.
Can rituximab change the usually dismal prognosis of patients with intravascular large B-cell lymphoma? J. Clin.
Oncol.: 2008; 26(31): 5134 - 5136 - Letter
IF 2008: 17,157
6. Caligaris-Cappio, F; Ghia, P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J. Clin. Oncol.: 2008; 26(27): 4497-4503 - Article
IF 2008: 17,157
7. Malnati, MS; Scarlatti, G; Gatto, F; Salvatori, F; Cassina, G; Rutigliano, T; Volpi, R; Lusso, P. A universal real-time PCR assay for the quantification of group-M HIV-1 proviral load. Nat. Protoc.: 2008; 3(7): 1240 - 1248 Article
IF 2008: 16,821
8. Monti, P; Scirpoli, M; Maffi, P; Ghidoli, N; De Taddeo, F; Bertuzzi, F; Piemonti, L; Falcone, M; Secchi, A;
Bonifacio, E. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J. Clin. Invest.: 2008; 118(5): 1806-1814 - Article
IF 2008: 16,559
9. Silvestri, L; Pagani, A; Nai, A; De Domenico, I; Kaplan, J; Camaschella, C. The Serine Protease Matriptase-2
(TMPRSS6) Inhibits Hepcidin Activation by Cleaving Membrane Hemojuvelin. Cell Metab.: 2008; 8(6): 502511 - Article
IF 2008: 16,107
10. Panattoni, M; Sanvito, F; Basso, V; Doglioni, C; Casorati, G; Montini, E; Bender, JR; Mondino, A; Pardi, R.
Targeted inactivation of the COP9 signalosome impairs multiple stages of T cell development. J. Exp. Med.:
2008; 205(2): 465-477 - Article
IF 2008: 15,219
P.1. Fätkenheuer, G; Nelson, M; Lazzarin, A; Konourina, I; Hoepelman, AI; Lampiris, H; Hirschel, B; Tebas, P; Raffi, F; Trottier, B; Bellos, N; Saag, M; Cooper, DA; Westby, M; Tawadrous,
M; Sullivan, JF; Ridgway, C; Dunne, MW; Felstead, S; Mayer,
H; van der Ryst, E; MOTIVATE 1 and MOTIVATE 2 Study
Teams. Subgroup analyses of maraviroc in previously treated R5
HIV-1 infection. N. Engl. J. Med.: 2008; 359(14): 1442-1455 Article
IF 2008: 50,017
P.2. Yusuf, S; Diener, HC; Sacco, RL; Cotton, D; Ounpuu, S;
Lawton, WA; Palesch, Y; Martin, RH; Albers, GW; Bath, P;
Bornstein, N; Chan, BP; Chen, ST; Cunha, L; Dahlöf, B; De
Keyser, J; Donnan, GA; Estol, C; Gorelick, P; Gu, V; Hermansson, K; Hilbrich, L; Kaste, M; Lu, C; Machnig, T; Pais, P;
Roberts, R; Skvortsova, V; Teal, P; Toni, D; VanderMaelen, C;
Voigt, T; Weber, M; Yoon, BW; PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N.
Engl. J. Med.: 2008; 359(12): 1225-1237 - Article
IF 2008: 50,017
P.3. Sacco, RL; Diener, HC; Yusuf, S; Cotton, D; Ounpuu, S;
Lawton, WA; Palesch, Y; Martin, RH; Albers, GW; Bath, P;
Bornstein, N; Chan, BP; Chen, ST; Cunha, L; Dahlöf, B; De
Keyser, J; Donnan, GA; Estol, C; Gorelick, P; Gu, V; Hermansson, K; Hilbrich, L; Kaste, M; Lu, C; Machnig, T; Pais, P;
Roberts, R; Skvortsova, V; Teal, P; Toni, D; Vandermaelen, C;
Voigt, T; Weber, M; Yoon, BW; PRoFESS Study Group. Aspirin and extended-release dipyridamole versus clopidogrel for re-
current stroke. N. Engl. J. Med.: 2008; 359(12): 1238-1251 - Article
IF 2008: 50,017
P.4. Steigbigel, RT; Cooper, DA; Kumar, PN; Eron, JE; Schechter,
M; Markowitz, M; Loutfy, MR; Lennox, JL; Gatell, JM; Rockstroh, JK; Katlama, C; Yeni, P; Lazzarin, A; Clotet, B; Zhao, J;
Chen, J; Ryan, DM; Rhodes, RR; Killar, JA; Gilde, LR;
Strohmaier, KM; Meibohm, AR; Miller, MD; Hazuda, DJ;
Nessly, ML; DiNubile, MJ; Isaacs, RD; Nguyen, BY; Teppler,
H; BENCHMRK Study Teams. Raltegravir with optimized
background therapy for resistant HIV-1 infection. N. Engl. J.
Med.: 2008; 359(4): 339-354 - Article
IF 2008: 50,017
P.5. Cooper, DA; Steigbigel, RT; Gatell, JM; Rockstroh, JK; Katlama, C; Yeni, P; Lazzarin, A; Clotet, B; Kumar, PN; Eron, JE;
Schechter, M; Markowitz, M; Loutfy, MR; Lennox, JL; Zhao, J;
Chen, J; Ryan, DM; Rhodes, RR; Killar, JA; Gilde, LR;
Strohmaier, KM; Meibohm, AR; Miller, MD; Hazuda, DJ;
Nessly, ML; DiNubile, MJ; Isaacs, RD; Teppler, H; Nguyen,
BY; BENCHMRK Study Teams. Subgroup and Resistance
Analyses of Raltegravir for Resistant HIV-1 Infection. N. Engl. J.
Med.: 2008; 359(4): 355-365 - Article
IF 2008: 50,017
P.6. Gulick, RM; Lalezari, J; Goodrich, J; Clumeck, N; DeJesus,
E; Horban, A; Nadler, J; Clotet, B; Karlsson, A; Wohlfeiler, M;
Montana, JB; McHale, M; Sullivan, J; Ridgway, C; Felstead, S;
Dunne, MW; van der Ryst, E; Mayer, H; MOTIVATE Study
Teams. Maraviroc for previously treated patients with R5 HIV-1
infection. N. Engl. J. Med.: 2008; 359(14): 1429-1441 - Article
IF 2008: 50,017
P.7. Gandin, V; Miluzio, A; Barbieri, AM; Beugnet, A; Kiyokawa,
H; Marchisio, PC; Biffo, S. Eukaryotic initiation factor 6 is ratelimiting in translation, growth and transformation. Nature:
2008; 455(7213): 684-688 - Article
IF 2008: 31,434
P.8. Battaglia, M; Roncarolo, MG. In vivo neutralization of inflammatory cytokines might not be necessary for regulatory Tcell immunotherapy [2]. Nat. Rev. Immunol.: 2008; 8(1): - Letter
IF 2008: 30,006
P.9. Amadeus Investigators; Bousser, MG; Bouthier, J; Büller, HR;
Cohen, AT; Crijns, H; Davidson, BL; Halperin, J; Hankey, G;
Levy, S; Pengo, V; Prandoni, P; Prins, MH; Tomkowski, W;
Thorp-Pedersen, C; Wyse, DG. Comparison of idraparinux with
vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet: 2008; 371(9609): 315-321 - Article
IF 2008: 28,409
P.10. Molina, JM; Andrade-Villanueva, J; Echevarria, J; Chetchotisakd, P; Corral, J; David, N; Moyle, G; Mancini, M; Percival,
L; Yang, R; Thiry, A; McGrath, D; CASTLE Study Team. Oncedaily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir,
each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week
efficacy and safety results of the CASTLE study. Lancet: 2008;
372(9639): 646-655 - Article
IF 2008: 28,409
P.11. D:A:D Study Group, Sabin, CA; Worm, SW; Weber, R;
Reiss, P; El-Sadr, W; Dabis, F; De Wit, S; Law, M; D’Arminio
Monforte, A; Friis-Møller, N; Kirk, O; Pradier, C; Weller, I;
Phillips, AN; Lundgren, JD. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected
patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet: 2008; 371(9622): 1417-1426 - Article
IF 2008: 28,409
P.12. Comi, G; Pulizzi, A; Rovaris, M; Abramsky, O; Arbizu, T;
Boiko, A; Gold, R; Havrdova, E; Komoly, S; Selmaj, K; Sharrack, B; Filippi, M. Effect of laquinimod on MRI-monitored dis-
ease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled
phase IIb study. Lancet: 2008; 371(9630): 2085-2092 - Article
IF 2008: 28,409
P.13. Gargioli, C; Coletta, M; De Grandis, F; Cannata, SM; Cossu,
G. PlGF-MMP-9-expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle. Nat.Med.: 2008;
14(9): 973-978 - Article
IF 2008: 27,553
P.14. De Palma, M; Mazzieri, R; Politi, LS; Pucci, F; Zonari, E;
Sitia, G; Mazzoleni, S; Moi, D; Venneri, MA; Indraccolo, S;
Falini, A; Guidotti, LG; Galli, R; Naldini, L. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell: 2008; 14(4): 299-311 Article
IF 2008: 24,962
P.15. SMART Study Group; El-Sadr, WM; Grund, B; Neuhaus, J;
Babiker, A; Cohen, CJ; Darbyshire, J; Emery, S; Lundgren, JD;
Phillips, A; Neaton, JD. Risk for opportunistic disease and death
after reinitiating continuous antiretroviral therapy in patients
with HIV previously receiving episodic therapy: a randomized trial. Ann. Intern. Med.: 2008; 149(5): 289-299 - Article
IF 2008: 17,457
P.16. Ferreri, AJM; Dognini, GP; Govi, S; Crocchiolo, R;
Bouzani, M; Bollinger, CR; D’Incan, M; Delaporte, E;
Hamadani, M; Jardin, F; Martusewicz-Boros, M; Montanari, M;
Szomor, A; Zucca, E; Cavalli, F; Ponzoni, M. Can rituximab
change the usually dismal prognosis of patients with intravascular
large B-cell lymphoma? £J. Clin. Oncol.: 2008; 26(31): 5134 5136 - Letter
IF 2008: 17,157
P.17. Tarella, C; Zanni, M; Magni, M; Benedetti, F; Patti, C; Barbui, T; Pileri, A; Boccadoro, M; Ciceri, F; Gallamini, A; Cortelazzo, S; Majolino, I; Mirto, S; Corradini, P; Passera, R; Pizzolo,
G; Gianni, AM; Rambaldi, A. Rituximab improves the efficacy of
high-dose chemotherapy with autograft for high-risk follicular
and diffuse large B-cell lymphoma: a multicenter Gruppo Italiano
Terapie Innnovative nei linfomi survey. J. Clin. Oncol.: 2008;
26(19): 3166-3175 - Article
IF 2008: 17,157
P.18. Caligaris-Cappio, F; Ghia, P. Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the
pathogenesis of the disease? £J. Clin. Oncol.: 2008; 26(27):
4497-4503 - Article
IF 2008: 17,157
P.19. Hyun, I; Lindvall, O; Ahrlund-Richter, L; Cattaneo, E;
Cavazzana-Calvo, M; Cossu, G; De Luca, M; Fox, IJ; Gerstle,
C; Goldstein, RA; Hermeren, G; High, KA; Kim, HO; Lee,
HP; Levy-Lahad, E; Li, L; Lo, B; Marshak, DR; McNab, A;
Munsie, M; Nakauchi, H; Rao M; Rooke, HM; Valles, CS; Srivastava, A; Sugarman, J; Taylor, PL; Veiga, A; Wong, AL;
Zoloth, L; Daley, GQ. New ISSCR Guidelines Underscore Major
Principles for Responsible Translational Stem Cell Research. Cell
Stem Cell: 2008; 3(6): 607-609 - Article
IF 2008: 16,826
P.20. Malnati, MS; Scarlatti, G; Gatto, F; Salvatori, F; Cassina, G;
Rutigliano, T; Volpi, R; Lusso, P. A universal real-time PCR assay for the quantification of group-M HIV-1 proviral load. Nat.
Protoc.: 2008; 3(7): 1240 - 1248 - Article
IF 2008: 16,821
P.21. Monti, P; Scirpoli, M; Maffi, P; Ghidoli, N; De Taddeo, F;
Bertuzzi, F; Piemonti, L; Falcone, M; Secchi, A; Bonifacio, E.
Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T
cells. J. Clin. Invest.: 2008; 118(5): 1806-1814 - Article
IF 2008: 16,559
P.22. Silvestri, L; Pagani, A; Nai, A; De Domenico, I; Kaplan, J;
Camaschella, C. The Serine Protease Matriptase-2 (TMPRSS6)
PUBLICATIONS - 199
Inhibits Hepcidin Activation by Cleaving Membrane Hemojuvelin. Cell Metab.: 2008; 8(6): 502-511 - Article
IF 2008: 16,107
P.23. Panattoni, M; Sanvito, F; Basso, V; Doglioni, C; Casorati, G;
Montini, E; Bender, JR; Mondino, A; Pardi, R. Targeted inactivation of the COP9 signalosome impairs multiple stages of T cell
development. J. Exp. Med.: 2008; 205(2): 465-477 - Article
IF 2008: 15,219
P.24. Urbonaviciute, V; Fürnrohr, BG; Meister, S; Munoz, L; Heyder, P; De Marchis, F; Bianchi, ME; Kirschning, C; Wagner, H;
Manfredi, AA; Kalden, JR; Schett, G; Rovere-Querini, P; Herrmann, M; Voll, RE. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the
pathogenesis of SLE. J. Exp. Med.: 2008; 205(13): 3007-3018 Article
IF 2008: 15,219
P.25. Benedetti Panici, P; Basile, S; Maneschi, F; Alberto Lissoni,
A; Signorelli, M; Scambia, G; Angioli, R; Tateo, S; Mangili, G;
Katsaros, D; Garozzo, G; Campagnutta, E; Donadello, N;
Greggi, S; Melpignano, M; Raspagliesi, F; Ragni, N; Cormio, G;
Grassi, R; Franchi, M; Giannarelli, D; Fossati, R; Torri, V;
Amoroso, M; Crocè, C; Mangioni, C. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J. Natl. Cancer Inst. :
2008; 100(23): 1707-1716 - Article
IF 2008: 14,933
P.26. Andrassy, M; Volz, HC; Igwe, JC; Funke, B; Eichberger, SN;
Kaya, Z; Buss, S; Autschbach, F; Pleger, ST; Lukic, IK; Bea, F;
Hardt, SE; Humpert, PM; Bianchi, ME; Mairbäurl, H;
Nawroth, PP; Remppis, A; Katus, HA; Bierhaus, A. High-mobility group box-1 in ischemia-reperfusion injury of the heart.
CIRCULATION: 2008; 117(25): 3216-3226 - Article
IF 2008: 14,595
P.27. Menasché, P; Alfieri, O; Janssens, S; McKenna, W; Reichenspurner, H; Trinquart, L; Vilquin, JT; Marolleau, JP; Seymour,
B; Larghero, J; Lake, S; Chatellier, G; Solomon, S; Desnos, M;
Hagège, AA. The Myoblast Autologous Grafting in Ischemic
Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. CIRCULATION:
2008; 117(9): 1189-11200 - Article
IF 2008: 14,595
P.28. Bakshi, R; Thompson, AJ; Rocca, MA; Pelletier, D; Dousset,
V; Barkhof, F; Inglese, M; Guttmann, CR; Horsfield, MA; Filippi, M. MRI in multiple sclerosis: current status and future
prospects. Lancet Neurol.: 2008; 7(7): 615 - 625 - Review
IF 2008: 14,270
P.29. Mikol, DD; Barkhof, F; Chang, P; Coyle, PK; Jeffery, DR;
Schwid, SR; Stubinski, B; Uitdehaag, BM; REGARD study
group. Comparison of subcutaneous interferon beta-1a with
glatiramer acetate in patients with relapsing multiple sclerosis
(the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label
trial. Lancet Neurol.: 2008; 7(10): 903-914 - Article
IF 2008: 14,270
P.30. Trenkwalder, C; Benes, H; Poewe, W; Oertel, WH; GarciaBorreguero, D; de Weerd, AW; Ferini-Strambi, L; Montagna, P;
Odin, P; Stiasny-Kolster, K; Hogl, B; Chaudhuri, KR; Partinen,
M; Schollmayer, E; Kohnen, R. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised,
double-blind, placebo-controlled trial. Lancet Neurol.: 2008;
7(7): 595 - 604 - Article
IF 2008: 14,270
P.31. Sessa, A; Mao, C; Hadjantonakis, AK; Klein, WH; Broccoli,
V. Tbr2 Directs Conversion of Radial Glia into Basal Precursors
and Guides Neuronal Amplification by Indirect Neurogenesis
in the Developing Neocortex. Neuron,: 2008; 60(1): 56-69 - Article
IF 2008: 14,170
P.32. Pennuto, M; Tinelli, E; Malaguti, M; Del Carro, U; D’Antonio, M; Ron, D; Quattrini, A; Feltri, ML; Wrabetz, L. Ablation
of the UPR-Mediator CHOP Restores Motor Function and Reduces Demyelination in Charcot-Marie-Tooth 1B Mice. Neuron:
2008; 57(3): 393-405 - Article
IF 2008: 14,170
P.33. Berghella, L; De Angelis, L; De Buysscher, T; Mortazavi, A;
Biressi, S; Forcales, SV; Sirabella, D; Cossu, G; Wold, BJ. A
highly conserved molecular switch binds MSY-3 to regulate myogenin repression in postnatal muscle. Genes Dev.: 2008; 22(15):
2125 - 2138 - Article
IF 2008: 13,623
P.34. Briganti, A; Rigatti, P; Montorsi, F. The importance of the
extent of pelvic-lymph-node dissection in the diagnosis of
lymph-node metastases in prostate cancer. Lancet Oncol.: 2008;
9(10): 915-917 - Short Report
IF 2008: 13,283
P.35. Balzano, G; Di Carlo, V. Is CA 19-9 useful in the management of pancreatic cancer? £Lancet Oncol.: 2008; 9(2): 89-91 Letter
IF 2008: 13,283
P.36. Bonnal, S; Martínez, C; Förch, P; Bachi, A; Wilm, M; Valcárcel, J. RBM5/Luca-15/H37 regulates Fas alternative splice site
pairing after exon definition. Mol. Cell: 2008; 32(1): 81-95 - Article
IF 2008: 12,903
P.37. Allan, SE; Broady, R; Gregori, S; Himmel, ME; Locke, N;
Roncarolo, MG; Bacchetta, R; Levings, MK. CD4+ T-regulatory
cells: Toward therapy for human diseases. Immunol. Rev.: 2008;
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P.65. Dahl, R; Kapp, A; Colombo, G; de Monchy, JGR; Rak, S;
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expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure.
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EM; Tacchetti, C; Bennett, DC; Schiaffino, MV. The ocular albinism type 1 protein, an intracellular G protein-coupled receptor,
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Cosma, MP. Multistep, sequential control of the trafficking and
function of the multiple sulfatase deficiency gene product,
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P.110. Savio, MG; Rotondo, G; Maglie, S; Rossetti, G; Bender, JR;
Pardi, R. COP1D, an alternatively spliced constitutive photomorphogenic-1 (COP1) product, stabilizes UV stress-induced
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P.111. Ji, Y; Shah, S; Soanes, K; Islam, MN; Hoxter, B; Biffo, S;
Heslip, T; Byers, S. Eukaryotic initiation factor 6 selectively regulates Wnt signaling and Î?-catenin protein synthesis. Oncogene:
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P.112. Pinton, P; Giorgi, C; Siviero, R; Zecchini, E; Rizzuto, R.
Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the
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P.113. Bernardi, R; Papa, A; Pandolfi, PP. Regulation of apoptosis
by PML and the PML-NBs. Oncogene: 2008; 27(48): 6299-6312
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P.114. Org, T; Chignola, F; Hetényi, C; Gaetani, M; Rebane, A;
Liiv, I; Maran, U; Mollica, L; Bottomley, MJ; Musco, G; Peterson, P. The autoimmune regulator PHD finger binds to nonmethylated histone H3K4 to activate gene expression. EMBO
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P.115. Mavilio, F; Ferrari, G. Genetic modification of somatic
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P.116. Wang, L; Wang, L; Vavassori, S; Li, S; Ke, H; Anelli, T;
Degano, M; Ronzoni, R; Sitia, R; Sun, F; Wang, CC. Crystal
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P.117. Minen, F; Barbi, E; Ventura, A; Carrera, P; Zennaro, F;
Chiodera, P. Twins with severe recurrent chest infections. Thorax: 2008; 63(12): - - Article
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P.118. Burioni, R; Perotti, M; Mancini, N; Clementi, M. Perspectives for the utilization of neutralizing human monoclonal antibodies as anti-HCV drugs. J. Hepatol.: 2008; 49(2): 299-300 Article
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P.119. Girelli, D; De Domenico, I; Bozzini, C; Campostrini, N;
Busti, F; Castagna, A; Soriani, N; Cremonesi, L; Ferrari, M;
Colombari, R; McVey Ward, D; Kaplan, J; Corrocher, R. Clinical, pathological, and molecular correlates in ferroportin disease:
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P.120. Raucci, A; Cugusi, S; Antonelli, A; Barabino, SM; Monti, L;
Bierhaus, A; Reiss, K; Saftig, P; Bianchi, ME. A soluble form of
the receptor for advanced glycation endproducts (RAGE) is
produced by proteolytic cleavage of the membrane-bound form
by the sheddase a disintegrin and metalloprotease 10
(ADAM10). Faseb J.: 2008; 22(10): 3716-3727 - Article
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P.121. Garibotto, V; Borroni, B; Kalbe, E; Herholz, K; Salmon, E;
Holtoff, V; Sorbi, S; Cappa, SF; Padovani, A; Fazio, F; Perani,
D. Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology: 2008; 71(17):
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P.122. Previtali, SC; Malaguti, MC; Riva, N; Scarlato, M; Dacci, P;
Dina, G; Triolo, D; Porrello, E; Lorenzetti, I; Fazio, R; Comi,
G; Bolino, A; Quattrini, A. The extracellular matrix affects axon-
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P.123. Zivadinov, R; Reder, AT; Filippi, M; Minagar, A; Stüve, O;
Lassmann, H; Racke, MK; Dwyer, MG; Frohman, EM; Khan,
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volume changes in multiple sclerosis. Neurology: 2008; 71(2):
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P.124. Borroni, B; Malinverno, M; Gardoni, F; Alberici, A; Parnetti, L; Premi, E; Bonuccelli, U; Grassi, M; Perani, D; Calabresi, P; Di Luca, M; Padovani, A. Tau forms in CSF as a reliable
biomarker for progressive supranuclear palsy. Neurology: 2008;
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P.125. Gorno-Tempini, ML; Brambati, SM; Ginex, V; Ogar, J;
Dronkers, NF; Marcone, A; Perani, D; Garibotto, V; Cappa,
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progressive aphasia. Neurology: 2008; 71(16): 1227-1234 - Article
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P.126. Rovaris, M; Riccitelli, G; Judica, E; Possa, F; Caputo, D;
Ghezzi, A; Bertolotto, A; Capra, R; Falautano, M; Mattioli, F;
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structural brain damage in benign multiple sclerosis. Neurology:
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P.127. Rocca, MA; Tortorella, P; Ceccarelli, A; Falini, A; Tango,
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in MS: A 3 tesla fMRI study. Neurology: 2008; 70(4): 255-262 Article
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P.128. Amato, MP; Goretti, B; Ghezzi, A; Lori, S; Zipoli, V; Portaccio, E; Moiola, L; Falautano, M; De Caro, MF; Lopez, M;
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and juvenile MS. Neurology: 2008; 70(20): 1891-1897 - Article
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P.129. Riva, N; Bezzi, G; Ponzoni, M; Epis, R; Previtali, SC; Cerri,
F; Nemni, R; Comi, G; Quattrini, A. Lymphomatous neuropathy
in cold agglutinin disease. Neurology: 2008; 70(19 PART 1):
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P.130. Frohman, TC; Galetta, S; Fox, R; Solomon, D; Straumann,
D; Filippi, M; Zee, D; Frohman, EM. Pearls & Oy-sters: The
medial longitudinal fasciculus in ocular motor physiology. Neurology: 2008; 70(17): e57-e67 - Review
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P.131. Mesaros, S; Rocca, MA; Absinta, M; Ghezzi, A; Milani, N;
Moiola, L; Veggiotti, P; Comi, G; Filippi, M. Evidence of thalamic gray matter loss in pediatric multiple sclerosis. Neurology:
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P.132. Grossi, S; Regis, S; Rosano, C; Corsolini, F; Uziel, G; Sessa,
M; Di Rocco, M; Parenti, G; Deodato, F; Leuzzi, V; Biancheri,
R; Filocamo, M. Molecular analysis of ARSA and PSAP genes in
twenty-one italian patients with metachromatic leukodystrophy:
Identification and functional characterization of 11 novel ARSA
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P.133. Cotton, RGH; Auerbach, AD; Beckmann, JS; Blumenfeld,
OO; Brookes, AJ; Brown, AF; Carrera, P; Cox, DW; Gottlieb,
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Marsh, S; Nebert, DW; Povey, S; Rossetti, S; Scriver, CR; Summar, M; Tolan, DR; Verma, IC; Vihinen, M; Den Dunnen, JT.
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P.134. Comi, G. Clinically isolated syndrome: The rationale for early treatment. Nat. Clin. Pract. Neurol.: 2008; 4(5): 234-235 - Article
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P.135. Ammirati, E; Vermi, AC; Cianflone, D; Banfi, M; Foglieni,
C; Godino, C; Airoldi, F; Ferri, LA; Gorman, CL; Manfredi,
AA; Maseri, A; Cope, AP; Monaco, C. Expansion of T-cell receptor zeta dim effector T cells in acute coronary syndromes. Arteriosclerosis, thrombosis, and vascular biology: 2008; 28(12):
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P.136. Olivotto, E; Borzi, RM; Vitellozzi, R; Pagani, S; Facchini,
A; Battistelli, M; Penzo, M; Li, X; Flamigni, F; Li, J; Falcieri, E;
Facchini, A; Marcu, KB. Differential requirements for IKKÎ±
and IKKÎ? in the differentiation of primary human osteoarthritic
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P.137. Peikert, T; Finkielman, JD; Hummel, AM; McKenney, ME;
Gregorini, G; Trimarchi, M; Specks, U. Functional characterization of antineutrophil cytoplasmic antibodies in patients with
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P.138. Valtuena, S; Pellegrini, N; Franzini, L; Bianchi, MA; Ardigo, D; Del Rio, D; Piatti, P; Scazzina, F; Zavaroni, I; Brighenti,
F. Food selection based on total antioxidant capacity can modify
antioxidant intake, systemic inflammation, and liver function
without altering markers of oxidative stress. Am. J. Clin. Nutr.:
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P.139. Picchio, M; Beck, R; Haubner, R; Seidl, S; Machulla ,HJ;
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Intratumoral Spatial Distribution of Hypoxia and Angiogenesis
Assessed by 18F-FAZA and 125I-Gluco-RGD Autoradiography.
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P.140. Cabrini, L; Beccaria, P; Landoni, G; Biondi-Zoccai, GGL;
Sheiban, I; Cristofolini, M; Fochi, O; Maj, G; Zangrillo, A. Impact of impedance threshold devices on cardiopulmonary resuscitation: A systematic review and meta-analysis of randomized controlled studies. Crit. Care Med.: 2008; 36(5): 1625-1632 - Review
IF 2008: 6,594
P.141. Ogliari, AC; Caldara, R; Socci, C; Sordi, V; Cagni, N;
Moretti, MP; Dell’Acqua, A; Mercalli, A; Scavini, M; Secchi, A;
Bonifacio, E; Bosi, E; Piemonti, L. High levels of donor
CCL2/MCP-1 predict graft-related complications and poor graft
survival after kidney-pancreas transplantation. Am. J. Transplant.: 2008; 8(6): 1303-1311 - Article
IF 2008: 6,559
P.142. Briganti, A; Chun, FK; Karakiewicz, PI; Rigatti, P; Montorsi, F. Is Node-Positive Prostate Cancer Always a Systemic Disease? £Eur. Urol.: 2008; 54(2): 243-246 - Editorial
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P.143. Bertini, R; Suardi, N; Marone, EM; Roscigno, M; Petralia,
G; Strada, E; Cestari, A; Arrigoni, G; Guazzoni, G; Montorsi,
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P.144. Salonia, A; Gallina, A; Zanni, G; Briganti, A; Deho, F; Sacca, A; Suardi, N; Barbieri, L; Guazzoni, G; Rigatti, P; Montorsi,
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P.145. Cozzarini, C. Editorial Comment on: Adjuvant Radiothera-
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B; Briganti, A; Franceschelli, A; Sanguedolce, F; Bertaccini, A;
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Montorsi, F; Rigatti, P; Martorana, G. 11C-Choline Positron
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P.147. Salonia, A. Editorial Comment on: Comparable Efficacy of
Once-Daily Versus On-Demand Vardenafil in Men with Mildto-Moderate Erectile Dysfunction: Findings of the RESTORE
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P.148. Salonia, A. Editorial Comment on: Ejaculation Elicited by
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P.149. Capitanio, U; Briganti, A; Shariat, SF; Karakiewicz, PI. The
Importance of the Quantification of the Extent of Cancer in
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P.150. Briganti, A; Capitanio, U; Chun, FKH; Gallina, A; Suardi,
N; Salonia, A; Da Pozzo, LF; Colombo, R; Di Girolamo, V;
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P. Impact of Surgical Volume on the Rate of Lymph Node Metastases in Patients Undergoing Radical Prostatectomy and Extended Pelvic Lymph Node Dissection for Clinically Localized
Prostate Cancer. Eur. Urol.: 2008; 54(4): 794-804 - Article
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P.151. Capitanio, U; Scattoni, V; Freschi, M; Briganti, A; Salonia,
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P.152. Karam, JA; Margulis, V; Montorsi, F; Karakiewicz, PI;
Lotan, Y; Kikuchi, E; Weizer, A; Zigeuner, R; Bolenz, C; Shariat, SF. Carcinoma in situ of the Upper Urinary Tract Treated with
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P.153. Capitanio, U; Jeldres, C; Shariat, SF; Karakiewicz, P. Clinicians are Most Familiar with Nomograms and Rate their Clinical Usefulness Highest, Look-up Tables are Second Best. Eur.
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P.154. Barbagli, G; Guazzoni, G; Lazzeri, M. One-Stage Bulbar
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P.155. Salonia, A. Editorial Comment on: Validation of the Contemporary Epstein Criteria for Insignificant Prostate Cancer in
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P.156. Bhojani, N; Jeldres, C; Patard, JJ; Perrotte, P; Suardi, N;
Hutterer, G; Patenaude, F; Oudard, S; Karakiewicz, PI. Toxicities Associated with the Administration of Sorafenib, Sunitinib,
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P.157. Shariat, SF; Margulis, V; Lotan, Y; Montorsi, F;
PUBLICATIONS - 205
Karakiewicz, PI. Nomograms for Bladder Cancer. Eur. Urol.:
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P.158. Raber, M; Scattoni, V; Roscigno, M; Dehò, F; Briganti, A;
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Topical prilocaine-lidocaine cream combined with peripheral
nerve block improves pain control in prostatic biopsy: results from
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P.159. Cloutier, V; Capitanio, U; Zini, L; Perrotte, P; Jeldres, C;
Shariat, SF; Arjane, P; Patard, JJ; Montorsi, F; Karakiewicz, PI.
Thirty-Day Mortality After Nephrectomy: Clinical Implications
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P.160. Da Pozzo, L. Editorial Comment on: Adjuvant Radiotherapy for Patients with Locally Advanced Prostate Cancer-A New
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P.161. Salonia, A. Editorial Comment on: Preoperative Serum Sex
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P.162. Roscigno, M; Cozzarini, C; Bertini, R; Scattoni, V; Freschi,
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P.163. Giuliano, F; Patrick, DL; Porst, H; La Pera, G; Kokoszka,
A; Merchant, S; Rothman, M; Gagnon, DD; Polverejan, E;
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IF 2008: 6,512
P.164. Montorsi, F; Brock, G; Lee, J; Shapiro, J; Stief, C. Effect of
Nightly versus On Demand Vardenafil on Recovery of Erectile
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P.165. Barbisan, F; Mazzucchelli, R; Santinelli, A; Lopez-Beltran,
A; Cheng, L; Scarpelli, M; Montorsi, F; Montironi, R. Overexpression of ELAV-like Protein HuR is Associated with Increased COX-2 Expression in Atrophy, High-grade Prostatic
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P.166. Paciaroni, M; Agnelli, G; Corea, F; Ageno, W; Alberti, A;
Lanari, A; Caso, V; Micheli, S; Bertolani, L; Venti, M; Palmerini, F; Biagini, S; Comi, G; Previdi, P; Silvestrelli, G. Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective
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P.167. Pino, MS; Balsamo, M; Di Modugno, F; Mottolese, M;
Alessio, M; Melucci, E; Milella, M; McConkey, DJ; Philippar,
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IF 2008: 6,488
P.168. Maccalli, C; Di Cristanziano, V; Fodale, V; Corsi, D;
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Zagonel, V; Tartaglia, M; Parmiani, G; Belardelli, F. Induction of
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P.169. Shariat, SF; Karam, JA; Walz, J; Roehrborn, CG; Montorsi,
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P.170. Ponzoni, M; Ferreri, AJ; Guidoboni, M; Lettini, AA; Cangi, MG; Pasini, E; Sacchi, L; Pecciarini, L; Grassi, S; Dal Cin, E;
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P.171. Radaelli, F; Meucci, G; Sgroi, G; Minoli, G; Italian Association of Hospital Gastroenterologists (AIGO). Technical performance of colonoscopy: the key role of sedation/analgesia and
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IF 2008: 6,444
P.172. Perseghin, G. Is a nutritional therapeutic approach unsuitable for metabolically healthy but obese women? £DIABETOLOGIA: 2008; 51(9): 1567 - 1569 - Note
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P.173. Williams, AJK; Aitken, RJ; Chandler, MAM; Gillespie,
KM; Lampasona, V; Bingley, PJ. Autoantibodies to islet antigen-2 are associated with HLA-DRB1*07 and DRB1*09 haplotypes as well as DRB1*04 at onset of type 1 diabetes: The possible role of HLA-DQA in autoimmunity to IA-2. Diabetologia:
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P.174. Giordano, T; Brigatti, C; Podini, P; Bonifacio, E; Meldolesi, J; Malosio, ML. Beta cell chromogranin B is partially segregated in distinct granules and can be released separately from
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P.175. Losa, M; Gioia, L; Picozzi, P; Franzin, A; Valle, M; Giovanelli, M; Mortini, P. The role of stereotactic radiotherapy in patients with growth hormone-secreting pituitary adenoma. J. Clin.
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P.176. Corradi, A; Zanardi, A; Giacomini, C; Onofri, F; Valtorta,
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P.177. Cocucci, E; Racchetti, G; Rupnik, M; Meldolesi, J. The regulated exocytosis of enlargeosomes is mediated by a SNARE machinery that includes VAMP4. J. Cell Sci.: 2008; 121(18): 29832991 - Article
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P.178. Carrara, S; Arcidiacono, PG; Albarello, L; Addis, A; Enderle, MD; Boemo, C; Neugebauer, A; Campagnol, M;
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P.180. Mangiavillano, B; Arcidiacono, PG; Carrara, S; Masci, E;
Testoni, PA. EUS-guided rendezvous technique for difficult cannulation of an intradiverticular papilla. Endoscopy: 2008; Suppl
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P.181. Zambelli, A; Villanacci, V; Buscarini, E; Bassotti, G; Albarello, L. Collagenous colitis: A case series with confocal laser
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P.182. Mangiavillano, B; Mezzi, G; Testoni, PA. Usefulness of
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P.183. Mangiavillano, B; Mariani A, A; Petrone, MC. An Intrapancreatic Cholangiocarcinoma Detected With Optical Coherence Tomography During Endoscopic Retrograde Cholangiopancreatography. Clin. Gastroenterol. Hepatol.: 2008; 6(6): Article
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P.184. Pech, O; Rabenstein, T; Manner, H; Petrone, MC; Pohl, J;
Vieth, M; Stolte, M; Ell, C. Confocal Laser Endomicroscopy for
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P.185. Ferrarini, M; Delfanti, F; Gianolini, M; Rizzi, C; Alfano, M;
Lazzarin, A; Biswas, P. NF-kappa B modulates sensitivity to
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P.186. de Lalla, C; Festuccia, N; Albrecht, I; Chang, HD; Andolfi,
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P.187. Manfredi, AA; Capobianco, A; Esposito, A; De Cobelli, F;
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Del Maschio, A. Maturing dendritic cells depend on RAGE for
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P.188. Maiuri, L; Luciani, A; Giardino, I; Raia, V; Villella, VR;
D’Apolito, M; Pettoello-Mantovani, M; Guido, S; Ciacci, C;
Cimmino, M; Cexus, ON; Londei, M; Quaratino, S. Tissue
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P.189. Baev, DV; Caielli, S; Ronchi, F; Coccia, M; Facciotti, F;
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nonobese diabetic mice. J. Immunol.: 2008; 181(2): 869 - 877 Article
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P.190. Camaschella, C; Silvestri, L. New and old players in the hepcidin pathway. Haematol-Hematol. J.: 2008; 93(10): 1441-1444 Editorial
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P.191. Galbiati, S; Foglieni, B; Travi, M; Curcio, C; Restagno, G;
Sbaiz, L; Smid, M; Pasi, F; Ferrari, A; Ferrari, M; Cremonesi, L.
Peptide-nucleic acid-mediated enriched polymerase chain reaction
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P.192. D’Angelo, A; Viganò D’Angelo, S. Protein S deficiency.
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P.193. Angelucci, E; Barosi, G; Camaschella, C; Cappellini, MD;
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P.194. Biasiotto, G; Camaschella, C; Forni, GL; Polotti, A;
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P.195. Pagani, A; Silvestri, L; Nai, A; Camaschella, C. Hemojuvelin N-terminal mutants reach the plasma membrane but do not
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P.196. Sala, C; Ciullo, M; Lanzara, C; Nutile, T; Bione, S; Massacane, R; D'Adamo, P; Gasparini, P; Toniolo, D; Camaschella,
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P.197. De Bonis, M; Alfieri, O. Mitral regurgitation should be corrected in patients with dilated cardiomyopathy: Commentary.
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P.198. Corradi, D; Callegari, S; Maestri, R; Benussi, S; Alfieri, O.
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P.199. Allan, SE; Alstad, AN; Merindol, N; Crellin, NK; Amendola, M; Bacchetta, R; Naldini, L; Roncarolo, MG; Soudeyns,
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P.200. Hoshiya, H; Kazuki, Y; Abe, S; Takiguchi, M; Kajitani, N;
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Cossu, G; Oshimura, M. A highly Stable and Nonintegrated Human Artificial Chromosome (HAC) Containing the 2.4 Mb Entire Human Dystrophin Gene. Mol. Ther.: 2008; 17(2): 309-317 Article
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P.201. Guerini, FR; Calabrese, E; Agliardi, C; Zanzottera, M;
Franceschi, M; Grimaldi, LME; Nemni, R; Ferrante, P. Association study of the HLA-A2 allele in Italian Alzheimer disease patients. Neurobiol. Aging: 2008; (): - - Article in Press
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P.202. Del Bo, R; Scarlato, M; Ghezzi, S; Martinelli-Boneschi, F;
Corti, S; Locatelli, F; Santoro, D; Prelle, A; Briani, C; Nardini,
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Absence of angiogenic genes modification in Italian ALS patients.
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P.203. Siri, S; Tettamanti, M; Cappa, SF; Della Rosa, P; Saccuman,
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P.204. Ambrosi, A; Cattoglio, C; Di Serio, C. Retroviral integration process in the human genome: is it really non-random? A
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P.205. Borroni, B; Garibotto, V; Agosti, C; Brambati, SM; Bellelli,
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P.206. Mesaros, S; Rovaris, M; Pagani, E; Pulizzi, A; Caputo, D;
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P.207. Simo, C; Bachi, A; Cattaneo, A; Guerrier, L; Fortis, F;
Boschetti, E; Podtelejnikov, A; Righetti, PG. Performance of
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P.208. Bachi, A; Simo, C; Restuccia, U; Guerrier, L; Fortis, F;
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P.209. Borch, J; Torta, F; Sligar, SG; Roepstorff, P. Nanodiscs for
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P.210. Fichorova, RN; Richardson-Harman, N; Alfano, M; Belec,
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Landay, A; Margolis, L; Mayer, KH; Pasicznyk, JM; PallanschCokonis, M; Poli, G; Reichelderfer, P; Roberts, P; Rodriguez, I;
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P.211. Chimenti, C; Hamdani, N; Boontje, NM; DeCobelli, F; Esposito, A; Bronzwaer, JGF; Stienen, GJM; Russo, MA; Paulus,
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P.212. Calabrese, M; Filippi, M; Rovaris, M; Mattisi, I; Bernardi,
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P.213. Bello, L; Gambini, A; Castellano, A; Carrabba, G; Acerbi,
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P.214. Tettamanti, M; Manenti, R; Della Rosa, PA; Falini, A;
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P.215. Ceccarelli, A; Rocca, MA; Pagani, E; Ghezzi, A; Capra, R;
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P.216. Pagani, E; Agosta, F; Rocca, MA; Caputo, D; Filippi, M.
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P.217. Agosta, F; Valsasina, P; Caputo, D; Stroman, PW; Filippi,
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P.218. Bosnell, R; Wegner, C; Kincses, ZT; Korteweg, T; Agosta,
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P.219. Ceccarelli, A; Rocca, MA; Pagani, E; Colombo, B; Martinelli, V; Comi, G; Filippi, M. A voxel-based morphometry
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P.220. Perani, D; Garibotto, V; Gorini, A; Moresco, RM; Henin,
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P.221. Panfoli, I; Musante, L; Bachi, A; Ravera, S; Calzia, D; Cattaneo, A; Bruschi, M; Bianchini, P; Diaspro, A; Morelli, A;
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P.222. De Monte, L; Sanvito, F; Olivieri, S; Vigano, F; Doglioni,
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P.223. Strategies for Management of Antiretroviral Therapy
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P.224. Soriano, V; Mocroft, A; Rockstroh, J; Ledergerber, B;
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P.225. Strategies for Management of Antiretroviral Therapy
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P.226. Feltri, ML; Relvas, JB; Suter, U. The function of RhoGTPases in axon ensheathment and myelination. Glia: 2008; 56(14):
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P.227. Scherer, SS; Wrabetz, L. Molecular Mechanisms of Inherited
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P.228. Taveggia, C; Thaker, P; Petrylak, A; Caporaso, GL; Toews,
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P.229. Bizzi, A; Blasi, V; Falini, A; Ferroli, P; Cadioli, M; Danesi,
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P.230. Ceriotti, F; Boyd, JC; Klein, G; Henny, J; Queralto, J;
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P.231. Battistella, S; Damin, F; Chiari, M; Delgrosso, K; Surrey, S;
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P.232. Cattozzo, G; Guerra, E; Ceriotti, F; Franzini, C. Commutable calibrator with value assigned by the IFCC reference
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P.233. Cappa, SF. Imaging studies of semantic memory. Curr.
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P.234. Migliori, GB; Lange, C; Girardi, E; Centis, R; Besozzi, G;
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P.235. Migliori, GB; Lange, C; Centis, R; Sotgiu, G; Mütterlein, R;
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P.236. Spitaleri, A; Mari, S; Curnis, F; Traversari, C; Longhi, R;
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P.237. Mager GM, Ward RM, Srinivasan R, Jang SW, Wrabetz L,
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P.238. Zanone Poma, B; Riva, A; Nasi, M; Cicconi, P; Broggini, V;
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P.239. Bannister, WP; Ruiz, L; Cozzi-Lepri, A; Mocroft, A; Kirk,
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P.242. Ensoli, B; Fiorelli, V; Ensoli, F; Lazzarin, A; Visintini, R;
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P.243. Angus, B; Lampe, F; Tambussi, G; Duvivier, C; Katlama, C;
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P.275. Stocchetti, N; Zanaboni, C; Colombo, A; Citerio, G;
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P.276. Wolfler, A; Silvani, P; Musicco, M; Antonelli, M; Salvo, I.
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Ventura, A; Zaniboni, MG. Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national
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P.282. Colombo, A; Latib, A. Late incomplete stent apposition after drug-eluting stent implantation: A true risk factor or “an innocent bystander”? £Heart: 2008; 94(3): 253-254 - Editorial
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P.283. Mangili, G; Montoli, S; De Marzi, P; Sassi, I; Aletti, G;
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P.284. Santoro, A; Comandone, A; Rimassa, L; Granetti, C;
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Chlamydia psittaci-eradicating antibiotic therapy in patients with
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P.287. Caligaris-Cappio, F. Autoimmune disorders and lymphoma.
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P.288. Balzano, G; Zerbi, A; Braga, M; Rocchetti, S; Beneduce,
AA; Di Carlo, V. Fast-track recovery programme after pancreaticoduodenectomy reduces delayed gastric emptying. Br. J. Surg.:
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P.289. Masciarelli, S; Sitia, R. Building and operating an antibody
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Gobbo, C; Isaias, IU; Goldwurm, S; Bonaldi, L; Carpinelli, A;
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P.293. Gallina, A; Suardi, N; Montorsi, F; Capitanio, U; Jeldres,
C; Saad, F; Graefen, M; Shariat, SF; Widmer, H; Arjane, P;
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P.294. Cangi, MG; Piccinin, S; Pecciarini, L; Talarico, A; Dal Cin,
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patients with ocular adnexal lymphoma: Results of a single-center
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P.296. Mora, S. Celiac disease in children: Impact on bone health.
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P.297. Tortorano, AM; Prigitano, A; Dho, G; Esposto, MC; Gianni, C; Grancini, A; Ossi, C; Viviani, MA. Species distribution
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Manservigi, R; Vicenzi, E. Inhibition of herpes simplex virus
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P.299. Pirone, L; Bragonzi, A; Farcomeni, A; Paroni, M; Auriche,
C; Conese, M; Chiarini, L; Dalmastri, C; Bevivino, A; Ascenzioni, F. Burkholderia cenocepacia strains isolated from cystic fibrosis patients are apparently more invasive and more virulent
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P.306. Villablanca, EJ; Zhou, D; Valentinis, B; Negro, A; Raccosta,
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P.307. Valentinis, B; Capobianco, A; Esposito, F; Bianchi, A; Rovere-Querini, P; Manfredi, AA; Traversari, C. Human recombinant heat shock protein 70 affects the maturation pathways of
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P.309. Vitolo, U; Ferreri, AJM; Montoto, S. Lymphoplasmacytic
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P.362. Melli, G; Taiana, M; Camozzi, F; Triolo, D; Podini, P;
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P.374. Brocca, L; D’Antona, G; Bachi, A; Pellegrino, MA. Amino
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P.387. Marturano, J; Longhi, R; Casorati, G; Protti, MP. MAGEA3161-175 contains an HLA-DRß4 restricted natural epitope
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P.388. Iero, M; Filipazzi, P; Castelli, C; Belli, F; Valdagni, R;
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P.389. Degryse, B; Fernandez-Recio, J; Citro, V; Blasi, F; Cubellis,
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P.390. Tshomba, Y; Bertoglio, L; Marone, EM; Melissano, G;
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P.391. Marone, EM; Tshomba, Y; Brioschi, C; Calliari, FM;
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P.392. Rocca, MA; Pagani, E; Colombo, B; Tortorella, P; Falini, A;
Comi, G; Filippi, M. Selective diffusion changes of the visual
pathways in patients with migraine: a 3-T tractography study.
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P.393. Hansen, JM; Thomsen, LL; Marconi, R; Casari, G; Olesen,
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Cephalalgia: 2008; 28(4): 367-375 - Article
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P.394. Capobianco, A; Manfredi, AA; Monno, A; Rovere-Querini,
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P.395. D’Angelo, E; Koutsoukou, A; Della Valle, P; Gentile, G;
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Ferrero, E; Li Volsi, L; Coli, S; Sinagra, G; Zingone, B; Alfieri,
O; Becker, AE; Maseri, A. Mild inflammatory activation of
mammary arteries in patients with acute coronary syndromes.
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P.397. Corica, F; Corsonello, A; Apolone, G; Mannucci, E; Lucchetti, M; Bonfiglio, C; Melchionda, N; Marchesini, G. Metabolic syndrome, psychological status and quality of life in obesity:
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P.398. Gao, WG; Qiao, Q; Tuomilehto, J; Balkau, B; Ruotolo, G;
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P.399. Kukavica-Ibrulj, I; Bragonzi, A; Paroni, M; Winstanley, C;
Sanschagrin, F; O’Toole, GA; Levesque, RC. In vivo growth of
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Schwartz, M. Immunotherapy for neurological diseases. Clin. Immunol.: 2008; 128(3): 294 - 305 - Short Survey
IF 2008: 3,606
P.401. Meloni, F; Accapezzato, D; Agresti, C; Aloisi, F; Ristori, G;
Salvetti, M; Furlan, R; Martino, G; Barnaba, V; Paroli, M. Dendritic cells loaded with apoptotic oligodendrocytes as a source of
myelin T-cell epitopes in multiple sclerosis. Clin. Immunol.:
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P.402. Landoni, G; Fochi, O; Torri, G. Cardiac protection by
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P.403. Locatelli, F; Zoccali, C; Acciarri, P; Menegato, MA; Ancarani, E; Andreucci, V; Antonelli, A; Auricchio, MR; Balducci, A;
Bassi, A; Battaglia, G; Bellingheri, G; Beltrame, A; Biagini, M;
Bonfante, L; Bonofiglio, R; Bonomini, M; Borghi, M; Brigante,
M; Buccianti, G; Buongiorno, E; Cabibbe, M; Cancarini, G;
Capistrano, M; Cappelli, G; Capuano, M; Cascone, C; Catizone, L; Catucci, AE; Cavatorta, F; Chiarinotti, D; Cicchetti, T;
Concas, G; Concetti, M; Conte, F; Conti, M; Coratelli, P; Corti,
MM; Costanzo, R; Dal Canton, A; D’Apice, L; David, S; De
Cristofaro, V; Deferrari, G; Della Grotta, F; De Nicola, L; De
Santo, NG; De Simone, W; Di Daniele, N; Di Giulio, S; Di Landro, D; Di Luzio, V; Di Maggio, A; Fagugli, R; Farina, M; Feriani, M; Gallieni, M; Gambaro, G; Giordano, R; Greco, S; Grillo, C; Huber, W; Liuzzo, G; Lombardi, L; Lopez, T; Malberti,
F; Mancini, W; Manenti, F; Manisco, G; Marrocco, A; Matocci,
G; Merico, G; Messa, P; Minutolo, R; Monardo, P; Moriconi,
L; Murrone, P; Nardo, A; Naso, A; Nobile, R; Panarello, G;
Paone, A; Parravano, M; Pedrini, L; Piazza, V; Pistis, R; Procida, M; Quarello, F; Rapisarda, F; Ricciardi, B; Rindi, P; Ronco,
C; Rotolo, U; Russo, G; Saraniti, A; Sasdelli, M; Savica, V;
Scanziani, R; Sidoti, A; Spotti, D; Stalteri, A; Stefoni, S; Stella,
A; Strippoli, P; Teatini, U; Teodoro, C; Tozzo, C; Triolo, G.
Clinical policies on the management of chronic kidney disease patients in Italy. Nephrol. Dial. Transplant.: 2008; 23(2): 621-626 Article
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P.404. Benedini, S; Cortelli, P; Caumo, A; Terruzzi, I; Beelke, M;
Perseghin, G; Montagna, P; Lugaresi, E; Luzi, L. Insulin resistance to both glucose and aminoacid metabolism in a patient with
Fatal Familial Insomnia. Nutr. Metab. Carbiovasc. Dis.: 2008;
18(9): - Letter
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P.405. Battezzati, A; Benedini, S; Sereni, LP; DeTaddeo, F; Maffi,
P; Secchi, A; Luzi, L. Protein and glutamine kinetics during
counter-regulatory failure in type 1 diabetes. Nutr. Metab. Carbiovasc. Dis.: 2008; (): - - Article in Press
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P.406. Chung, SH; Marzban, H; Croci, L; Consalez, GG; Hawkes,
R. Purkinje cell subtype specification in the cerebellar cortex:
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P.407. Clementi, M. Perspectives and opportunities for novel antiviral treatments targeting virus fitness. Clin. Microbiol. Infect.: 2008; 14(7): 629-631 - Editorial
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P.408. Lienard, BMR; Garau, G; Horsfall, L; Karsisiotis, AI;
Damblon, C; Lassaux, P; Papamicael, C; Roberts, GCK; Galleni, M; Dideberg, O; Frere, JM; Schofield, CJ. Structural basis
for the broad-spectrum inhibition of metallo-ß- lactamases by thiols. Org. Biomol. Chem.: 2008; 6(13): 2282-2294 - Article
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P.409. Pagani, F; Sibilia, V; Cavani, F; Ferretti, M; Bertoni, L;
Palumbo, C; Lattuada, N; De Luca, E; Rubinacci, A;
Guidobono, F. Sympathectomy alters bone architecture in adult
growing rats. J.Cell.Biochem.: 2008; 104(6): 2155 - 2164 - Article
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P.410. Polonis, VR; Brown, BK; Borges, AR; Zolla-Pazner, S;
Dimitrov, DS; Zhang, MY; Barnett, SW; Ruprecht, RM; Scarlatti, G; Fenyo, EM; Montefiori, DC; McCutchan, FE; Michael,
NL. Recent advances in the characterization of HIV-1 neutralization assays for standardized evaluation of the antibody response
to infection and vaccination. VIROLOGY: 2008; 375(2): 315320 - Short Survey
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P.411. Stenirri, S; Cretich, M; Rech, I; Restelli, A; Ghioni, M; Cova, S; Ferrari, M; Cremonesi, L; Chiari, M. Dual-color microchip
electrophoresis with single-photon avalanche diodes: application
to mutation detection. Electrophoresis : 2008; 29(24): 49724975 - Short Communication
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P.412. Galbiati, S; Damin, F; Di Carlo, G; Ferrari, M; Cremonesi,
L; Chiari, M. Development of new substrates for high-sensitive
genotyping of minority mutated alleles. Electrophoresis: 2008;
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P.413. Giovannini, M; Belli, C; Villa, E; Gregorc, V. Estrogen receptor (ER) and epidermal growth factor receptor (EGFR) as
targets for dual lung cancer therapy: Not just a case? £J. Thorac. Oncol.: 2008; 3(6): 684-685 - Letter
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P.414. Fernandez, LC; Errico, MC; Bottero, L; Penkov, D;
Resnati, M; Blasi, F; Care, A. Oncogenic HoxB7 requires TALE
cofactors and is inactivated by a dominant-negative Pbx1 mutant
in a cell-specific manner. Cancer Lett.: 2008; 266(2): 144-155 Article
IF 2008: 3,504
P.415. Mangili, G; Garavaglia, E; Cavoretto, P; Gentile, C; Scarfone, G; Rabaiotti, E. Clinical presentation of hydatidiform mole
in northern Italy: has it changed in the last 20 years? £Am. J. Obstet. Gynecol.: 2008; 198(3): - - Article
IF 2008: 3,453
P.416. Agosta, F; Valsasina, P; Rocca, MA; Caputo, D; Sala, S; Judica, E; Stroman, PW; Filippi, M. Evidence for enhanced functional activity of cervical cord in relapsing multiple sclerosis.
Magn. Reson. Med.: 2008; 59(5): 1035-1042 - Article
IF 2008: 3,449
P.417. Biffi, A; Lucchini, G; Rovelli, A; Sessa, M. Metachromatic
leukodystrophy: An overview of current and prospective treatments. Bone Marrow Transplant.: 2008; 42(SUPPL. 2): S2-S6 Review
IF 2008: 3,400
P.418. Biral, E; Chiesa, R; Cappelli, B; Roccia, T; Frugnoli, I; Noe,
A; Soliman, C; Fiori, R; Cursi, L; Cattaneo, F; Evangelio, C;
Miniero, R; Ciceri, F; Roncarolo, MG; Marktel, S. Multiple BM
harvests in pediatric donors for thalassemic siblings: safety, efficacy and ethical issues. Bone Marrow Transplant.: 2008; 42(6):
379-384 - Article
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P.419. Gaziev, J; Sodani, P; Lucarelli, G; Polchi, P; Marktel, S; Paciaroni, K; Marziali, M; Isgro, A; Simone, MD; Roveda, A;
Montuoro, A; Lanti, A; Alfieri, C; De Angelis, G; Gallucci, C;
Ciceri, F; Roncarolo, MG. Second hematopoietic SCT in patients
with thalassemia recurrence following rejection of the first graft.
Bone Marrow Transplant.: 2008; 42(6): 397-404 - Article
IF 2008: 3,400
P.420. Muzza, M; Persani, L; Filippis, TD; Gastaldi, R; Vigone,
MC; Sala, D; Weber, G; Lorini, R; Beck-Peccoz, P; Fugazzola,
L. Absence of sonic hedgehog (Shh) germline mutations in patients with thyroid dysgenesis. Clin. Endocrinol. : 2008; 69(5):
828-829 - Letter
IF 2008: 3,398
P.421. Valentini, LG; Casali, C; Chatenoud, L; Chiaffarino, F;
Uberti-Foppa, C; Broggi, G. Surgical site infections after elective
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P.422. Marrocco-Trischitta, MM; Marone, EM; Kahlberg, A;
Tshomba, Y; Setacci, F; Chiesa, R. Iatrogenic sigmoid perforation by aortobifemoral left graft limb. Surgery: 2008; 144(1):
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IF 2008: 3,389
P.423. Morara, S; Wang, LP; Filippov, V; Dickerson, IM; Grohovaz, F; Provini, L; Kettenmann, H. Calcitonin gene-related peptide (CGRP) triggers Ca2+ responses in cultured astrocytes and
in Bergmann glial cells from cerebellar slices. Eur. J. Neurosci.:
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P.424. Iovane, E; Giabbai, B; Muzzolini, L; Matafora, V; Fornili,
A; Minici, C; Giannese, F; Degano, M. Structural basis for sub-
PUBLICATIONS - 217
strate specificity in group I nucleoside hydrolases. Biochemistry:
2008; 47(15): 4418-4426 - Article
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P.425. Krug, I; Treasure, J; Anderluh, M; Bellodi, L; Cellini, E; di
Bernardo, M; Granero, R; Karwautz, A; Nacmias, B; Penelo, E;
Ricca, V; Sorbi, S; Tchanturia, K; Wagner, G; Collier, D; Fernandez-Aranda, F. Present and lifetime comorbidity of tobacco,
alcohol and drug use in eating disorders: A European multicenter
study. Drug Alcohol Depend.: 2008; 97(1-2): 169-179 - Article
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P.426. Corradi, D; Callegari, S; Maestri, R; Benussi, S; Bosio, S;
De Palma, G; Alinovi, R; Caglieri, A; Goldoni, M; Mozzoni, P;
Pastori, P; Manotti, L; Nascimbene, S; Dorigo, E; Rusconi, R;
Astorri, E; Alfieri, O. Heme oxygenase-1 expression in the left
atrial myocardium of patients with chronic atrial fibrillation related to mitral valve disease: its regional relationship with structural
remodeling. Hum. Pathol.: 2008; 39(8): 1162 - 1171 - Article
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P.427. Gatti, R; Corti, M; Govetto, S; Bonzani, K; Boccardi, S.
Electromyographic activity to keep a lower limb in a raised position in healthy subjects and subjects with multiple sclerosis.
Mult. Scler.: 2008; 14(5): 691-693 - SHORT REPORT
IF 2008: 3,312
P.428. Bar-Zohar, D; Agosta, F; Goldstaub, D; Filippi, M. Magnetic resonance imaging metrics and their correlation with clinical outcomes in multiple sclerosis: A review of the literature
and future perspectives. Mult. Scler.: 2008; 14(6): 719 - 727 Review
IF 2008: 3,312
P.429. Manconi, M; Rocca, MA; Ferini-Strambi, L; Tortorella, P;
Agosta, F; Comi, G; Filippi, M. Restless legs syndrome is a common finding in multiple sclerosis and correlates with cervical cord
damage. Mult. Scler.: 2008; 14(1): 86-93 - Article
IF 2008: 3,312
P.430. Rovaris, M; Judica, E; Ceccarelli, A; Ghezzi, A; Martinelli,
V; Comi, G; Filippi, M. Absence of diffuse cervical cord tissue
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P.431. Centonze, D; Furlan, R; Gasperini, C; Salvetti, M; Battistini, L. Early relapses after the first dose of natalizumab in active
multiple sclerosis patients. Mult. Scler.: 2008; 14(8): 1137-1138 Article
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P.432. Gironi, M; Martinelli-Boneschi, F; Sacerdote, P; Solaro, C;
Zaffaroni, M; Cavarretta, R; Moiola, L; Bucello, S; Radaelli, M;
Pilato, V; Rodegher, M; Cursi, M; Franchi, S; Martinelli, V;
Nemni, R; Comi, G; Martino, G. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult. Scler.:
2008; 14(8): 1076-1083 - Article
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P.433. Miller, DH; Weinshenker, BG; Filippi, M; Banwell, BL;
Cohen, JA; Freedman, MS; Galetta, SL; Hutchinson, M; Johnson, RT; Kappos, L; Kira, J; Lublin, FD; McFarland, HF; Montalban, X; Panitch, H; Richert, JR; Reingold, SC; Polman, CH.
Differential diagnosis of suspected multiple sclerosis: a consensus
approach. Mult. Scler.: 2008; 14(9): 1157-1174 - Article
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P.434. Martinelli-Boneschi, F; Colombo, B; Annovazzi, P; Martinelli, V; Bernasconi, L; Solaro, C; Comi G. Lifetime and actual
prevalence of pain and headache in multiple sclerosis. Mult.
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P.435. Gatti R, Corti M, Govetto S, Bonzani K, Boccardi S. Electromyographic activity to keep a lower limb in a raised position
in healthy subjects and subjects with multiple sclerosis. Mult.
Scler.: 2008; 14(5): 691-693 - Article
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P.436. Ronchi, F; Falcone, M. Immune regulation by invariant
NKT cells in autoimmunity. Front. Biosci.: 2008; 13(13): 48274837 - Review
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P.437. Vangelista, L; Secchi, M; Lusso, P. Rational design of novel
HIV-1 entry inhibitors by RANTES engineering. Vaccine: 2008;
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P.438. Tops, LF; Kapadia, SR; Tuzcu, EM; Vahanian, A; Alfieri,
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P.439. Clementi, E; Manfredi, AA. The immune system facing injured tissues and stem cells: More of a healer or a fighter?
£Pharmacol.Res.: 2008; 58(2): 87 - Editorial
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P.440. Brunelli, S; Rovere-Querini, P. The immune system and the
repair of skeletal muscle. Pharmacol.Res.: 2008; 58(2): 117-121 Review
IF 2008: 3,287
P.441. Favaro, A; Santonastaso, P; Monteleone, P; Bellodi, L;
Mauri, M; Rotondo, A; Erzegovesi, S; Maj, M. Self-injurious behavior and attempted suicide in purging bulimia nervosa: Associations with psychiatric comorbidity. J. Affective Disord.: 2008;
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P.442. Lopalco, L; Burastero, SE. HIV-1 and the self-nonself connection: How to sleep with the enemy and be much better off.
AIDS Reviews: 2008; 10(3): 162-171 - Review
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P.443. Cecconi, V; Moro, M; Del Mare, S; Dellabona, P; Casorati,
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P.444. Combi, R; Ferini-Strambi, L; Tenchini, M. Compound heterozygosity with dominance in the Corticotropin Releasing
Hormone (CRH) promoter in a case of nocturnal frontal lobe
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P.445. Ferri, R; Manconi, M; Plazzi, G; Bruni, O; Vandi, S; Montagna, P; Ferini-Strambi, L; Zucconi, M. A quantitative statistical analysis of the submentalis muscle EMG amplitude during
sleep in normal controls and patients with REM sleep behavior
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P.446. Carassa, RG. Surgical alternative to trabeculectomy. Prog.
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P.447. Orsenigo, E; Tomajer, V; Di Palo, S; Albarello, L; Doglioni,
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P.448. Viassolo, V; Previtali, SC; Schiatti, G; Magnani, G; Minetti,
C; Zara, F; Grasso, M; Dagna-Bricarelli, F; Di Maria, E. Inclusion body myopathy, Paget’s disease of the bone and frontotemporal dementia: Recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling. Clin. Genet.:
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P.449. Biffi, A; Cesani, M; Fumagalli, F; Del Carro, U; Baldoli, C;
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P.450. Passerini, L; Allan, SE; Battaglia, M; Di Nunzio, S; Alstad,
AN; Levings, MK; Roncarolo, MG; Bacchetta, R. STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+
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P.451. Giovacchini, G; Samanes Gajate, AM; Messa, C; Fazio, F.
Increased C-11 choline uptake in pagetic bone in a patient with
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IF 2008: 3,181
P.452. Benedetti, F; Fresi, F; Maccioni, P; Smeraldi, E. Behavioural sensitization to repeated sleep deprivation in a mice model of
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P.453. Corbetta, S; D’Adamo, P; Gualdoni, S; Braschi, C; Berardi,
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P.454. Raggi, A; Perani, D; Giaccone, G; Iannaccone, S; Manconi,
M; Zucconi, M; Garibotto, V; Marcone, A; Zamboni, M; Limido, L; Tagliavini, F; Ferini-Strambi, L; Cappa SF. The behavioural features of fatal familial insomnia: A new Italian case with
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P.455. Ferini-Strambi, L; Aarskog, D; Partinen, M; Chaudhuri,
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RLS symptoms and sleep: A randomized, double-blind, placebocontrolled trial. Sleep Med.: 2008; 9(8): 874 - 881 - Article
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P.456. Tschernatsch, M; Klotz, M; Probst, C; Hosch, J; Valtorta,
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P.457. Bus, SA; Valk, GD; van Deursen, RW; Armstrong, DG;
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P.458. Luzi, L; Zoppini, G; Targher, G; Battezzati, A; Muggeo, M;
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P.459. Bus, SA; Valk, GD; van Deursen, RW; Armstrong, DG;
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P.460. Sesti, G; Andreozzi, F; Bonadonna, RC; De Mattia, G;
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P.473. Melissano, G; Bertoglio, L; Kahlberg, A; Baccellieri, D;
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P.484. Baldan, R; Cavallerio, P; Parlato, C; Rocchetti, A; Lomolino, G; Vellini, S; Pesce, F; Cirillo, DM; Fossati, L. Meticillin-resistant Staphylococcus aureus SCCmec type IV: nosocomial
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P.492. La Colla, L; Poli, D; Albertin, A; La Colla, G; Mangano, A.
Preoperative gum chewing may increase gastric fluid retention.
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P.494. Colombo, A; Latib, A. Treatment of drug-eluting stent
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P.503. Sordi, V; Bertuzzi, F; Piemonti, L. Diabetes mellitus: an opportunity for therapy with stem cells? £Regen. Med.: 2008; 3(3):
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P.506. Barone, A; Santini, S; Marconcini, S; Giacomelli, L; Gher-
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P.508. Manenti, R; Cappa, SF; Rossini, PM; Miniussi, C. The role
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P.512. Rubinacci, A; Marenzana, M; Cavani, F; Colasante, F; Villa,
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P.515. Cotelli, M; Manenti, R; Cappa, SF; Zanetti, O; Miniussi, C.
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PUBLICATIONS - 221
Novel exon 1 progranulin gene variant in Alzheimer’s disease.
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P.518. Benninghoff, U; Cattaneo, F; Aiuti, A; Flores-D’Arcais, A;
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P.519. Levi, S; Rovida, E. The role of iron in mitochondrial function. Biochim. Biophys. Acta-Gen. Subj.: 2008; (-): - Article in
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P.520. Riboldi, SA; Sadr, N; Pigini, L; Neuenschwander, P; Simonet, M; Mognol, P; Sampaolesi, M; Cossu, G; Mantero, S.
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P.521. Giavaresi, G; Fini, M; Chiesa, R; Giordano, C; Sandrini, E;
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P.522. Gallina, A; Chun, FKH; Suardi, N; Eastham, JA; Perrotte,
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Nephrectomy improves the survival of patients with locally advanced renal cell carcinoma. BJU Int.: 2008; 102(11): 1610-1614
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P.526. Briganti, A; Gallina, A; Suardi, N; Chun, FKH; Walz, J;
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P.528. Margulis, V; Lotan, Y; Montorsi, F; Shariat, SF. Predicting
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P.529. Benussi, S. Invited Commentary. Ann. Thorac. Surg.: 2008;
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P.531. Aranzulla, TC; Cosgrave, J; La Canna, G; Maisano, F;
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PUBLICATIONS - 223
grey matter damage progression during the earliest clinical stage
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P.686. Sessa, M. Intracerebral hemorrhage and hypertension. Neurol. Sci.: 2008; 29(SUPPL.2): S258-S259 - Conference Paper
IF 2008: 1,435
P.687. Zaffaroni, M; Rizzo, A; Baldini, SM; Ghezzi, A; Comi, G.
Induction and add-on therapy with Mitoxantrone and Interferon
beta in multiple sclerosis. Neurol. Sci.: 2008; 29(SUPPL.2):
S230-S232 - Article
IF 2008: 1,435
P.688. Radaelli, D; Bernasconi, A; Benedetti, F. Psychiatric diseases. Neurol. Sci.: 2008; 29(SUPPL. 3): - - Article
IF 2008: 1,435
P.689. Colombo, B; Libera, D; Annovazzi, PO; Comi, G.
Headache therapy with neuronal stabilising drugs. Neurol. Sci.:
2008; 29(SUPPL. 1): 131 - 136 - Article
IF 2008: 1,435
P.690. Furlan, R. Definition of non-responders: Biological markers.
Neurol. Sci.: 2008; 29(SUPPL.2): - Article
IF 2008: 1,435
P.691. Comi, G. Induction vs. escalating therapy in Multiple Sclerosis: Practical implications. Neurol. Sci.: 2008; 29(SUPPL.2):
S253-S255 - Article
IF 2008: 1,435
P.692. Leocani, L; Colombo, B; Comi, G. Physiopathology of fatigue in Multiple Sclerosis. Neurol. Sci.: 2008; 29(SUPPL.2):
S241-S243 - Article
IF 2008: 1,435
P.693. Leocani, L; Comi, G. Neurophysiological markers. Neurol.
Sci.: 2008; 29(SUPPL.2): S218-S221 - Article
IF 2008: 1,435
P.694. Pincherle, A; Villani, F; Ferini Strambi, L; Livia Fantini, M;
Dylgjeri, S; Spreafico, R; Antozzi, C. Immunoadsorption for the
treatment of narcolepsy with cataplexy. Neurol. Sci.: 2008; 29:
499-500 - Article
IF 2008: 1,435
P.695. Galluzzi, S; Beltramello, A; Filippi, M; Frisoni, GB. Aging.
Neurol. Sci.: 2008; 29(Suppl3): 296-S300 - Article
IF 2008: 1,435
P.696. Filippi, M; Rocca, MA. Headache and migraine. Neurol.
Sci.: 2008; 29(SUPPL. 3): S33-S338 - Article
IF 2008: 1,435
P.697. Filippi, M; Rocca, MA. Multiple sclerosis and allied white
matter diseases. Neurol. Sci.: 2008; 29(SUPPL. 3): S319-S322 Article
IF 2008: 1,435
P.698. Di Mattei, VE; Prunas, A; Novella, L; Marcone, A; Cappa,
SF; Sarno, L. The burden of distress in caregivers of elderly demented patients and its relationship with coping strategies. Neurol. Sci.: 2008; 29(6): 383-389 - Article
IF 2008: 1,435
P.699. Falini, A; Romano, A; Bozzao, A. Tumours. Neurol. Sci.:
2008; 29(SUPPL. 3): - - Article
IF 2008: 1,435
P.700. Anselmetti, S; Poletti, S; Ermoli, E; Bechi, M; Cappa, S;
Venneri, A; Smeraldi, E; Cavallaro, R. The brief assessment of
cognition in schizophrenia. Normative data for the Italian population. Neurol. Sci.: 2008; 29(2): 85-92 - Article
IF 2008: 1,435
P.701. Pagani, E; Bizzi, A; Salle, F; Stefano, N; Filippi, M. Basic
concepts of advanced MRI techniques. Neurol. Sci.: 2008;
29(SUPPL. 3): S290-S295 - Review
IF 2008: 1,435
P.702. Teggi, R; Lanzani, C; Zagato, L; Delli Carpini, S; Manunta,
P; Bianchi, G; Bussi, M. Gly460Trp alpha-adducin mutation as a
possible mechanism leading to endolymphatic hydrops in
Ménière’s syndrome. Otol. Neurotol.: 2008; 29(6): 824-828 - Article
IF 2008: 1,410
P.703. Zanardi, R; Barbini, B; Rossini, D; Bernasconi, A; Fregni,
F; Padberg, F; Rossi, S; Wirz-Justice, A; Terman, M; Martiny,
K; Bersani, G; Hariri, AR; Pezawas, L; Roiser, JP; Bertolino, A;
Calabrese, G; Magri, L; Benedetti, F; Pontiggia, A; Malaguti, A;
Smeraldi, E; Colombo, C. New perspectives on techniques for
the clinical psychiatrist: Brain stimulation, chronobiology and
psychiatric brain imaging. Psychiatry Clin. Neurosci.: 2008;
62(6): 627-637 - Review
IF 2008: 1,394
P.704. Calzolari, F; Sartori, PV; Talarico, C; Parmeggiani, D;
Beretta, E; Pezzullo, L; Bovo, G; Sperlongano, P; Monacelli, M;
Lucchini, R; Misso, C; Gurrado, A; D’Ajello, M; Uggeri, F;
Puxeddu, E; Nasi, I; Testini, M; Rosato, L; Barbarisi, A; Avenia,
N. Surgical treatment of intrathyroid metastases: Preliminary results of a multicentric study. Anticancer Res.: 2008; 28(5 B):
2885 - 2888 - Article
IF 2008: 1,390
P.705. Scipioni, A; Calesini, G; Micarelli, C; Coppe, S; Scipioni, L.
Morphogenic bone splitting: Description of an original technique
and its application in esthetically significant areas. Int. J.
Prosthodont.: 2008; 21(5): 389-397 - Article
IF 2008: 1,374
P.706. Della Marca, G; Vollono, C; Ferraro, D; Mariotti, P; Mazza, M; Ferini-Strambi, L; Mazza, S. Left thalamomegaly in a patient with partial epilepsy. Clin. Neurol. Neurosurg.: 2008;
110(3): 298-301 - Article
IF 2008: 1,323
P.707. Schetz, M; Bove, T; Morelli, A; Mankad, S; Ronco, C; Kellum, JA. Prevention of cardiac surgery-associated acute kidney injury. Int. J. Artif. Organs: 2008; 31(2): 179-189 - Review
IF 2008: 1,299
P.708. Lapenna, E; De Bonis, M; Sorrentino, F; La Canna, G;
Grimaldi, A; Torracca, L; Maisano, F; Alfieri, O. Commissural
closure for the treatment of commissural mitral valve prolapse or
flail. J. Heart Valve Dis.: 2008; 17(3): 261-266 - Article
IF 2008: 1,112
P.709. Scotti, C; Camnasio, F; Rizzo, N; Fontana, F; De Cobelli,
F; Peretti, GM; Fraschini, G. Mammary-type myofibroblastoma
of popliteal fossa. Skeletal Radiol.: 2008; 37(6): 549-553 - Case
Report
IF 2008: 1,085
P.710. Mosam, A; Hurkchand, HP; Cassol, E; Page, T; Cassol, S;
Bodasing, U; Aboobaker, J; Dawood, H; Friedland, GH;
Coovadia, HM. Characteristics of HIV-1-associated Kaposi’s sarcoma among women and men in South Africa. Int. J. STD AIDS:
2008; 19(6): 400 - 405 - Article
IF 2008: 1,075
P.711. Perego, GB; Landolina, M; Vergara, G; Lunati, M; Zanotto, G; Pappone, A; Lonardi, G; Speca, G; Iacopino, S; Varbaro,
A; Sarkar, S; Hettrick, DA; Denaro, A. Implantable CRT device
diagnostics identify patients with increased risk for heart failure
hospitalization. J. Interv. Card. Electrophysiol.: 2008; 23(3):
235-242 - Article
IF 2008: 1,075
PUBLICATIONS - 229
P.712. Miserocchi, E; Modorati, G; Rama, P. Effective treatment
with topical cyclosporine of a child with steroid-dependent interstitial keratitis. Eur. J. Ophthalmol.: 2008; 18(5): 816-818 Article
IF 2008: 1,010
P.713. Milani, P; Pierro, L; Scialdone, A. OCT-guided photodynamic therapy for angiographic occult CNV in pathologic myopia.
Eur. J. Ophthalmol.: 2008; 18(5): 837-840 - Article
IF 2008: 1,010
P.714. Roasio, A; Lobreglio, R; Santin, A; Landoni, G; Verdecchia, C. Fenoldopam Reduces the Incidence of Renal Replacement Therapy After Cardiac Surgery. J. Cardiothorac. Vasc.
Anesth.: 2008; 22(1): 23-26 - Article
IF 2008: 0,994
P.715. Landoni, G; Zangrillo, A; Fochi, O; Maj, G; Scandroglio,
AM; Morelli, A; Tritapepe, L; Montorfano, M; Colombo, A.
Cardiac Protection With Volatile Anesthetics in Stenting Procedures. J. Cardiothorac. Vasc. Anesth.: 2008; 22(4): 543 - 547 Article
IF 2008: 0,994
P.716. Casati, V; Barbato, L; D’Angelo, A; Masotti, C; Nocera, G;
Grasso, MA; Porta, A; Guerra, F. Complex Cardiac Surgery in
Jehovah’s Witnesses With Chronic Renal Failure. J. Cardiothorac. Vasc. Anesth.: 2008; 22(3): 453-454 - Article
IF 2008: 0,994
P.717. Landoni, G; Biondi-Zoccai, GGL; Marino, G; Bove, T;
Fochi, O; Maj, G; Calabro, MG; Sheiban, I; Tumlin, JA; Ranucci, M; Zangrillo, A. Fenoldopam Reduces the Need for Renal Replacement Therapy and In-Hospital Death in Cardiovascular
Surgery: A Meta-Analysis. J. Cardiothorac. Vasc. Anesth.: 2008;
22(1): 27-33 - Article
IF 2008: 0,994
P.718. Porter, CR; Suardi, N; Kodama, K; Capitanio, U; Gibbons,
RP; Correa, R; Jeldres, C; Perrotte, P; Montorsi, F;
Karakiewicz, PI. A nomogram predicting metastatic progression
after radical prostatectomy. Int. J. Urol.: 2008; 15(10): 889-894 Article
IF 2008: 0,982
P.719. Sardanelli, F; Bacigalupo, L; Carbonaro, L; Esseridou,
A; Giuseppetti, GM; Panizza, P; Lattanzio, V; Del Maschio, A.
What is the sensitivity of mammography and dynamic MR imaging for DCIS if the whole-breast histopathology is used as a
reference standard? £Radiol. Med.: 2008; 113(3): 439-451 - Article
IF 2008: 0,955
P.720. Sardanelli, F; Giuseppetti, GM; Canavese, G; Cataliotti, L;
Corcione, S; Cossu, E; Federico, M; Marotti, L; Martincich, L;
Panizza, P; Podo, F; Rosselli Del Turco, M; Zuiani, C; Alfano,
C; Bazzocchi, M; Belli, P; Bianchi, S; Cilotti, A; Calabrese, M;
Carbonaro, L; Cortesi, L; Di Maggio, C; Del Maschio, A; Esseridou, A; Fausto, A; Gennaro, M; Girometti, R; Ienzi, R; Luini, A; Manoukian, S; Morassutt, S; Morrone, D; Nori, J; Orlacchio, A; Pane, F; Panzarola, P; Ponzone, R; Simonetti, G; Torricelli, P; Valeri, G. Indications for breast magnetic resonance imaging. Consensus Document “Attualita` in Senologia”, Florence
2007. Radiol. Med.: 2008; 113: 1085-1095 - Article
IF 2008: 0,955
P.721. Gianotti, N; Maillard, M; Gaiera, G; Bestetti, A; Cernuschi, M; De Bona, A; Lazzarin, A; Cinque, P; Bossolasco, S.
Leishmania infection can hamper immune recovery in virologically suppressed HIV-infected patients. New Microbiol.: 2008; :
435-438 - Short Communication
IF 2008: 0,912
P.722. Menegazzi, P; Reho, E; Ulivi, M; Varnier, OE; Lillo, FB;
Tagliaferro, L. Rapid and accurate quantification of different
HCV genotypes by LightCycler Real Time PCR and direct se-
quencing of HCV amplicons. New Microbiol.: 2008; 31(2):
181-187 - Article
IF 2008: 0,912
P.723. Miotto, P; Piana, F; Migliori, GB; Cirillo, DM. Evaluation
of the GenoCard as a tool for transport and storage of samples
for tuberculosis molecular drug susceptibility testing. New Microbiol.: 2008; 31(1): 147-150 - Article
IF 2008: 0,912
P.724. Tete, S; Mastrangelo, F; Scioletti, AP; Tranasi, M; Raicu, F;
Paolantonio, M; Stuppia, L; Vinci, R; Gherlone, E; Ciampoli,
C; Sberna, MT; Conti, P. Microarray expression profiling of human dental pulp from single subject. Clin. Invest. Med.: 2008;
31(2): E55-E61 - Article
IF 2008: 0,905
P.725. Giammusso, B; Colpi, GM; Cormio, L; Ludovico, G; Soli,
M; Ponchietti, R; Montorsi, F; Panzironi, C; Guastella, B. An
open-label, randomized, flexible-dose, crossover study to assess
the comparative efficacy and safety of sildenafil citrate and apomorphine hydrochloride in men with erectile dysfunction. Urol.
Int.: 2008; 81(4): 409-415 - Article
IF 2008: 0,891
P.726. Vezzoni, L; Parmiani, G. Limitations of the cancer stem cell
theory. Cytotechnology: 2008; 58(1): 3-9 - Article
IF 2008: 0,875
P.727. Melissano, G; Venturini, M; Baccellieri, D; Calliari, F; Del
Maschio, A; Chiesa, R. Distal embolization and proximal stentgraft deployment: A dual approach to endovascular treatment
of ruptured superior gluteal artery aneurysm. Tex. Heart Inst.
J.: 2008; 35(1): 50-53 - Article
IF 2008: 0,873
P.728. Chiesa, R; Melissano, G; Civilini, E; Bertoglio, L; Setacci,
F; Baccellieri, D. Giant aneurysm: 25 Years after patch aortoplasty for aortic coarctation. Tex. Heart Inst. J.: 2008; 35(2): 220 221 - Article
IF 2008: 0,873
P.729. Marioni, G; Gaio, E; Giacomelli, L; Bertolin, A; D’Alessandro, E; Stramare, R; Facco, E; Staffieri, A; Blandamura, S.
MASPIN subcellular localization and expression in oral cavity
squamous cell carcinoma. Eur. Arch. Oto-Rhino-Laryn.: 2008;
265(SUPPL. 1): - - Conference Paper
IF 2008: 0,843
P.730. Pech, O; Petrone, MC; Manner, H; Rabenstein, T; May, A;
Pohl, J; Ell, C. One-step chromoendoscopy and structure enhancement using balsamic vinegar for screening of Barrett’s
esophagus. Acta Gastro-Enterol. Belg.: 2008; 71(2): 243-245 Article
IF 2008: 0,832
P.731. Teggi, R; Ceserani, N; Lira Luce, F; Lazzarin, A; Bussi, M.
Otoneurological findings in human immunodeficiency virus positive patients. J. Laryngol. Otol.: 2008; 122(12): 1289-1294 - Article
IF 2008: 0,796
P.732. Maio, M; Fonsatti, E; Burigo, A; Parmiani, G. The Italian
Network for Tumor Biotherapy (NIBIT). Sharing visions, goals
and efforts at European level. Suppl. Tumori: 2008; 94(2): 179181 - Conference Paper
IF 2008: 0,791
P.733. Alongi, F; Di Muzio, N; Motta, M; Broggi, S; De Martin, E;
Bolognesi, A; Cattaneo, M; Calandrino, R; Fazio, F. Adenoid
cystic carcinoma of trachea treated with adjuvant hypofractionated tomotherapy. Case report and literature review. Suppl. Tumori: 2008; 94(1): 121-125 - Case Reports
IF 2008: 0,791
P.734. Ludovini, V; Pistola, L; Gregorc, V; Floriani, I; Rulli, E; Di
Carlo, L; Semeraro, A; Daddi, G; Darwish, S; Stocchi, L; Tofanetti, FR; Bellezza, G; Sidoni, A; Tognellini, R; Crino, L; Tonato, M. Biological markers and DNA flow cytometric analysis in
radically resected patients with non-small cell lung cancer. A
study of the perugia multidisciplinary team for thoracic tumors.
Suppl. Tumori: 2008; 94(3): 398 - 405 - Article
IF 2008: 0,791
P.735. Labanca, M; Azzola, F; Vinci, R; Rodella, LF. Piezoelectric
surgery: Twenty years of use. Br. J. Oral Maxillofac. Surg.: 2008;
46(4): 265-269 - Article
IF 2008: 0,787
P.736. Gerevini, S; Mandelli, C; Cadioli, M; Scotti, G. Diagnostic
value and surgical implications of the magnetic resonance imaging in the management of adult patients with brachial plexus
pathologies. Surg. Radiol. Anat.: 2008; 30(2): 91-101 - Article
IF 2008: 0,782
P.737. Chiaroni, D; Chiesa, V; De Massis, A; Frattini, F. The
knowledge-bridging role of Technical and Scientific Services in
knowledge-intensive industries. Int. J. Technol. Manage.: 2008;
41(3-4): 249-272 - Article
IF 2008: 0,526
P.738. Chiesa, R; Melissano, G; Bertoglio, L; Campos Moraes Amato, A; Tshomba, Y; Civilini, E; Calliari, FM; Marone, EM. The
risk of spinal cord ischemia during thoracic aorta endografting.
Acta Chir. Belg.: 2008; 108(5): 492 - 502 - Article
IF 2008: 0,474
P.739. Mandelli, C; Porras, L; Lopez-Sanchez, C; Sicuri, GM;
Lomonaco, I; Garcia-Martinez, V. The partial labyrinthectomy
petrous apicectomy approach to petroclival meningiomas. A
quantitative anatomic comparison with other approaches to the
same region. Neurocirugia: 2008; 19(2): 133 - 142 - Article
IF 2008: 0,277
P.740. Miniussi, C; Cappa, SF; Cohen, LG; Floel, A; Fregni, F;
Nitsche, MA; Oliveri, M; Pascual-Leone, A; Paulus, W; Priori,
A; Walsh, V. Efficacy of repetitive transcranial magnetic stimulation/transcranial direct current stimulation in cognitive neurorehabilitation. Brain Stimul.: 2008; 1(4): 326-336 - Review
IF 2008: Indexed by JCR 2008
AUTHOR INDEX - 231
AUTHOR INDEX
A
Abdollah, Firas
187
P255
Absinta, Martina
27, 182
P131
Abutalebi, Jubin
24, 181
P617, P685
Accarino, Gianfranco 167
Acerno, Stefania
172
Agosta, Chiara
25
Agosta, Federica
27
P216, P217, P218, P416, P428, P429,
P514, P563, P608, P624, P631
Agostoni, Massimo 170
Agresti, Alessandra 127, 133
Agricola, Eustachio 55, 167
P466, P467, P468, P639
Aiello, Patrizia Tanina 97, 178
Aina, Ilaria
25, 180
Aiuti, Alessandro
72, 73, 74, 90, 91, 176
P47, P186, P518
Albarello, Luca
188
P95, P104, P178, P179, P181, P447
Alberigo, Giada
73
Albieri, Ilaria
23
Aldrighetti, Daniela 4, 183
Aldrighetti, Luca
98, 115, 170
P320, P355, P377, P542, P570, P588,
P589
Alemanno, Federica 24
Alesiani, Roberta
25, 180
Alessio, Davide
188
Alessio, Massimo
145, 150
P167, P222, P497, P605, P679
Alfano, Massimo
96
P185, P210
Alfieri, Beatrice
96
Alfieri, Ottavio
55, 66, 167, 169
P27, P77, P197, P198, P383, P396,
P426, P438, P472, P530, P611, P613,
P614, P615, P708
Allievi, Elisa
159
Almirante, Giada
176
Alongi, Filippo
183
P302, P305, P357, P511, P625, P733
Alto, Giorgio
24, 172
Amadio, Stefano
27, 182
P325, P449, P559, P575
Amato, Ninfa
Amendola, Mario
26
72
P199
Ammirati, Enrico
55
P135
Anand, Santosh
127
Andolfi, Grazia
73
P186
Andolfo, Annapaola 145, 188
P482
Andrei, Fodor
183
Anelli, Tiziana
127
P83, P116
Angelone, Sara
25, 180
Angiolilli, Diego
187
Angiolini, Adriana
172
Annoni, Andrea
73
Anselmetti, Simona 25, 180
P700
Antonelli, Antonella 127
P120
Anzalone, Nicoletta 24, 172
P264, P509, P583
Apollonio, Benedetta 1 P53
Aquilina, Mark
183
Anthony
Arancio, Cinzia
25, 180
Arcidiacono, Paolo 3, 15, 170
Giorgio
P178, P179, P180, P552, P626, P657
Arcidiacono, Teresa 129, 178
Ardu, Veronica
188
Arendar, Irina
167
Arioli, Francesco
166
P339, P464, P592
Arrigoni, Gianluigi 188
P143, P273, P532
Ascagni, Miriam
159
Asperti, Claudia
23
Assanelli, Andrea
72, 183
P571, P634, P636
Astore, Domenico
168
Astro, Veronica
23
Attuati, Luca
24, 172
Augello, Giuseppe
55, 166
Avitabile, Maria
166
Azzoni, Emanuele
71
B
Baccari, Paolo Aldo
Raul
Baccelli, Nicola
Bacchetta, Rosa
3, 170
172
72, 73, 88, 176
P37, P48, P63, P199, P450, P518
Bacchi, Fabrizio
XI
Bachi, Angela
127, 135
P36, P207, P208, P221, P222, P315,
P316, P374, P481, P497, P535, P545
Bacigaluppi, Marco 26, 182
P582, P655
Badaloni, Aurora
23
Badami, Ester
98
Bagaglio, Sabrina
97, 174
Balconi, Giuseppe
185
Baldan, Rossella
96
P483, P484
Baldelli, Sara
72
Baldini, Mattia
178
Baldissera, Elena
97, 178
Baldoli, Cristina
24, 172
P449
Ballarotto, Carlo
167
Ballis, Rosa
129
Balzano, Gianpaolo 3, 170
P35, P288, P375, P657
Bande, Marta
54, 167
Bandiera, Alessandro 3, 168
P537
Banfi, Arianna
170
Banfi, Michela
55
P135
Baraldi, Clementina 180
Baratto, Fabio
183
Barbagli, Matteo
183
Barbini, Barbara
25, 180
P343, P539, P703
Barcella, Valeria
27
Barera, Graziano
54, 62, 176
P281
Bargiggia, Cinzia
188
Barili, Valeria
23
Baroni, Miriam
96
Barricella, Nietta
183
Barzaghi, Lina
24, 172
Raffaella
P620
Barzizza, Lorena
188
Bassanelli, Giorgio
167
P339, P592
Basso, Veronica
96
P23, P94
Battaglia, Manuela
98, 119
P8, P450
Battaglia, Marco
180
P661
Battistella, Stefania
Bazzigaluppi, Elena
Beatrice, Saverio
Bechi, Margherita
Belfiore, Marcello
Bellanca, Raimondo
Bellani, Serena
Belli, Carmen
Bellini, Chiara
Bellinzoni, Piera
Bellio, Laura
Bellodi, Laura
Belloli, Sara
Bellomo, Daniela
Bellone, Matteo
Belloni, Daniela
Belloni, Ilaria
Benasciutti, Elisa
Bencardino, Katia
Benedetti, Beatrice
Benedetti, Francesco
Benedetti, Sara
Benedetti, Sara
Benedicenti, Fabrizio
Benedini, Stefano
Beneduce, Aldo
Alberto
Benussi, Stefano
Benveniste, Marina
Benzoni, Ivana
Berardi, Genoveffa
Beretta, Alberto
Beretta, Edoardo
Beretta, Luigi
Bergamante, Valentina
Bergamaschi, Andrea
Bergami, Alessandra
Bernardi, Massimo
Bernardi, Rosa
145
P231
188
183
25, 180
P700
23
167
23
4, 183
P413
3, 172
P658
187
72, 188
25, 180
P220, P425, P441
153, 183
P317
XI
96, 107
P62, P91, P279, P471
1
55
127
4
27, 182
25, 39, 180
P343, P379, P452, P533, P539, P688,
P703
71
145
P371
73
53
P404, P405, P597
189
P288, P375
55, 167
P198, P426, P472, P529, P614, P615
185
159
153, 183
174
170
P704
24, 36, 170, 172, 189, 193
P275, P583
74
26
P68, P497
26
P325, P326
3, 183
P46, P48, P81, P634
1, 10
P113
AUTHOR INDEX - 233
Bernascone, Ilenia
128
P535
Bernasconi,
25
Alessandro
P343, P379, P539, P688, P703
Bernasconi, Fabio
172
Bernasconi, Luca
181
P434
Bertani, Angelo
180
Bertilaccio, Maria
1
Teresa Sabrina
P91, P471
Bertini, Diego Maria XI
Bertini, Roberto
4, 187
P143, P150, P162, P568, P602
Bertocchi, Cecilia
185
Bertoglio, Luca
55
P390, P473, P477, P728, P738
Bertolazzi, Mara
188
Bertolo, Alessandro 128
Bertolotti, Milena
127
Bestetti, Arabella
97, 174
P721
Bettegazzi, Barbara 23
Bettin, Paolo
24, 172
Bettinardi, Valentino 153, 183
P322, P361
Beugnet, Anne
2
P7
Biagetti, Raffaella
XI
Bianchi Marzoli, 24, 172
Stefania
P620
Bianchi, Giada
127
Bianchi, Laura
25, 180
Bianchi, Marco
4, 187
Bianchi, Marco
188
Bianchi, Marco E.
127, 130, 132, 159, 161
P24, P26, P120, P187, P265, P616
Bianchi, Veronica
24
Bianco, Mariangela 26, 182
Bianconi, Irene
95
Biasco, Luca
73
Biffi, Alessandra
73, 74, 86, 176
P382, P417, P449
Biffi, Valentina
176
Biffo, Stefano
2, 13
P7, P111, P344
Bignami, Elena
55, 168
P272, P676
Bin, Roberta
183
Biondini, Francesca 180
Bione, Silvia
128
P107, P196
Biral, Erika
72, 176
P418
Bisagni, Pietro
189
Biswas, Priscilla
96, 174
P185
Biziato, Daniela
Bizzozero, Laura
Blasi, Francesco
Blasi, Valeria
Blasio, Andrea
Boari, Nicola
Boccalatte, Francesco
Boccalon, Silvia
Boemo, Cinzia
Boeri, Enzo
Bogni, Silvia
Bolentini, Alketa
Boletta, Alessandra
Bolino, Alessandra
Bolis, Annalisa
Bolognesi, Angelo
Bolognesi, Gianluigi
Bolzoni, Luca
Bombardelli, Lorenzo
Bombelli, Ferdinando
Bombelli, Giovanna
Bonalumi, Sara
Bonavida, Giovanna
Bondanza, Attilio
Bondardo, Flavia
Bondi, Stefano
Bonetti, Fabrizio
Bonfanti, Riccardo
Bongiorno, Fanny
Boni, Andrea
Bonini, Chiara
Bonini, Pierangelo
Bordogna, Gianni
Bornaghi, Viviana
Borri, Anna
Borroni, Barbara
Borroni, Emanuele
Borroni, Serena
Bortolanza, Sergia
Bosaia, Alessandra
72
72
128, 137
P389, P414
24, 159
P213, P229
167
24, 172
P280
72
25, 180
3, 170
P178, P179
188
P558
128
188
128, 137
27, 47
P122
27
183
P327, P625, P733
172
188
95
176
P186
XI
145, 188
P371
129, 178
72
P48
55
3, 172
167
99, 123, 176
P63
180
128
72, 81
P48, P81, P342, P386, P622
188
P256, P648
183
145
189
P375
25
P121, P124, P205, P278, P587
96
25, 180
P629
71
25, 180
Bosi, Emanuele
53, 54, 61, 98, 99, 117, 122, 178, 179,
188
P141, P256, P383, P488, P504, P647,
P681
Bosia, Marta
25, 180
Bosio, Laura
176
Bossolasco, Simona 97, 174
P572, P721
Bosticardo, Marita
73
Bosurgi, Lidia
71
P44
Botti, Francesca
23
Botti, Renato
XXI, XXII
Bove, Maddalena
176
Bove, Tiziana
55, 168
P707, P717
Bozzolo, Enrica P.
97, 178
Bracale, Maria
178
Braga, Marco
98, 170
P222, P288, P538, P541
Braga, Raffaella
180
Bragonzi, Alessandra 95, 103
P299, P351, P399
Brambilla, Elena
26
P68, P325, P326
Brambilla, Marina
188
Brambilla, Riccardo 26, 43
Brambilla, Roberta 188
Brambillasca, Maria 176
Francesca
Brasca, Laura
185
Breda, Daniela
95
Bregani, Valentina
180
P682
Brendolan, Andrea 1, 10
Brigante, Claudio
176
Briganti, Alberto
4, 187
P34, P142, P144, P146, P149, P150,
P151, P158, P162, P251, P253, P267,
P367, P522, P526, P637, P665
Brigatti, Cristina
99
P174
Brigida, Immacolata 73
Brina, Daniela
2
Brioschi, Luca
183
Brisci, Angela
145, 188
P51
Broccoli, Vania
24, 35
P31, P58, P90, P98
Broggi, Paola
180
Broggi, Sara
188
P302, P303, P305, P357, P359, P360,
P511, P733
Broglia, Luigi
187
Brunelli, Silvia
71, 77
P89, P340, P440
Brunetta, Mirella
180
Bruno Ventre, Marta
Bruno, Francesca
Bruschi, Elena
Bua, Lina
Bucello, Sebastiano
3
145, 188
172
187
27, 182
P432
Buetti, Ivan
128
Buffi, Nicolò Maria 4, 187
Buffo, Paola
25
Buono, Roberta
72
Burastero, Samuele E. 95, 102
P442, P544
Burioni, Roberto
188
P118, P260, P263, P610
Busnardo, Elena
153, 183
Bussi, Mario
3, 16, 25, 39, 172
P658, P702, P731
Butera, Calogera
27, 182
P559
Butti, Erica
26
P325, P326
Buzzetti, Fabio
55, 167
Buzzotta, Alessio
24, 172
C
Cabianca, Daphne
Cabinio, Monia
Cabrini, Luca
71
24, 159
55
P140, P670
Caielli, Simone
98
P189
Caimi, Mariangela
153
Caiolfa, Valeria R.
1, 9
P74, P482
Cairella, Roberto
188
Calabrese, Alice
167
Calabrese, Donato
96
Calabrese, Giovanna 23
Calabrese, Maria 167
Chiara
Calabrò, Maria
168
Grazia
P717
Calaciura, Rita
183
Calamita, Piera
24
Calandrino, Riccardo 188, 190
P302, P303, P305, P357, P359, P360,
P511, P733
Calbi, Valeri
72
Caldara, Rossana
97, 178
P141
Caldi, Massimo
189
Caldirola, Daniela
180
Caligaris-Cappio,
1, 3, 5, 7, 183, 184
Federico
P18, P50, P53, P54, P57, P82, P287,
P328, P634
AUTHOR INDEX - 235
Callegaro, Luciano
74, 176
P518
Calliari, Fabio
55
Massimo
P391, P473, P727, P738
Calori, Giliola
XI
P398, P464
Calvi, Maria Rosa
24, 172
P583
Camaschella, Clara 128, 139
P22, P52, P190, P193, P194, P195,
P196, P274, P329, P353
Camba, Lionello
183
Cambiaghi, Marco
26
Camerota, Tommaso 187
Camesasca, Chiara
167
Cammarata, Gabriella 172
Camnasio, Francesco 170
P709
Campana, Lara
71
P44
Campanella,
23
Alessandro
Campanini, Elena
180
Campori, Euridice
180
P343
Canciani, Cristina
167
Candotti, Guido
176
Canducci, Filippo
188
P261, P555
Canessa, Nicola
24, 181
P566
Canevari, Carla
153, 183
P634
Cangi, Maria Giulia 188
P170, P285, P294, P295
Cannalire, Giuseppe 176
Cannavale, Salvatore 167
Cannistraci, Carlo
145
Vittorio
P497
Canonico, Emanuele 159
Cantarelli, Elisa
98
Cantore, Alessio
72
Canu, Tamara
153
P42, P187, P486
Capasso, Giuseppe 189
P381
Capelletti, Alberto
55
Capelli, Alessandro 183
Capitanio, Umberto 4, 187
P149, P150, P151, P153, P159, P162,
P257, P269, P293, P525, P527, P568,
P601, P603, P718
Capitanio, Vanessa
98, 170
Capobianco, Annalisa 71
P187, P307, P394
Capossela, Simona
128
Capotondo, Alessia 73
Cappa, Stefano F.
24, 37, 181
P121, P125, P203, P214, P233, P480,
P508, P513, P515, P516, P517, P566,
P679, P698, P700, P740
Capparé, Paolo
129
Cappellari, Ornella 71
Cappelletti, Alberto 167
Cappelletti, Chiara
54, 178, 189
P681
Cappelli, Barbara
72, 176
P418, P652
Cappio, Stefano
185
P361
Capretti, Giovanni
98, 170
Caputo, Alessandra 98
Caputo, Luigi
97, 176
Carassa, Roberto
172
P446
Carbone, Teresa
188
Carcione, Davide
188
Cardani, Anna
176
Cardone, Gianpiero 185
Carenzi, Maurizio
183
Carletti, Rose Mary 188
Carletti, Silvia
188
Carlino, Mauro
54, 167
P347, P372, P464, P600
Carlucci, Michele
189, 192
Carlucci, Silvia
53
Carobene, Anna
188
Carozzo, Andrea
168
Carpanelli, Roberta 185
Carpinelli, Assunta 25, 153, 183
P220, P292
Carrabba, Matteo
3, 183
Carrabino, Salvatore 128
P351
Carrara, Silvia
3, 170
P178, P179, P180
Carrera, Paola
145, 188
P81, P117, P133, P371, P681
Carretta, Angelo
3, 168
P537
Carretta, Ilaria
180
Carvello, Michele
3, 170
Casamassima, Nunzia 129
P270, P271, P463
Casari, Giorgio
145, 146, 147
P100, P383, P393, P478, P643
Casati, Paolo
180
Casiraghi, Giuseppina 55, 168
Maria
Casiraghi, Miriam
74, 176
Casiraghi, Tiziana
170
Caso, Francesca
27, 182
Casorati, Giulia
96
P23, P186, P387, P443
Cassella, Patrizia
Cassetta, Luca
27
96
P576
Cassina, Giulia
95
P20
Cassina, Laura
145
P100, P383
Castagna, Antonella 97, 174
P345, P556, P558
Castagnaro, Laura
1
Castellano, Antonella 24, 159
P213
Castellano, Renata
55, 167, 168
Clotilde
Castellazzi, Paola
24, 172
Castelli, Alfredo
54, 167
Castelli, Maddalena 128
Castiglioni, Alessandra 3, 71, 170
Castiglioni, Alessandro 167
Castiglioni, Emanuela 145, 188
Castiglioni, Isabella 25, 153, 183
Castiglioni, Maria
54, 63, 176
Teresa
Castoldi, Carlo
170
Castoldi, Renato
170
Casucci, Monica
72
Catalano, Marco
25, 180
Catena, Marco
98, 170
P377, P542, P570, P588
Catenaccio, Barbara 55
Catricalà, Eleonora 24, 181
Cattaneo, Angela
127
P207, P221, P535
Cattaneo, Elisabetta 180
P682
Cattaneo, Giovanni 188
Mauro
P303, P358, P359, P360, P361, P511
Cattoglio, Claudia
128
P204
Catucci, Alessandro 127
Catucci, Marco
73
Caumo, Andrea
53
P106, P404
Causarano, Vincenza 145, 188
Cavallaro, Roberto
25, 180
P700
Cavallini, Maria
25, 180
Cristina
Cavarelli, Mariangela 96
P556
Cavazzin, Chiara
73
Cavedini, Paolo
25, 180
Cavoretto, Paolo
54, 176
P415
Ceccarelli, Antonella 27
P127, P215, P219, P430, P564
Cecconi, Virginia
Celona, Barbara
Cenci, Simone
Centemero, Antonia
Ceppi, Daniela
Cera, Michela
Cerè, Patrizia
Cereda, Stefano
Ceresa, Daniela
Cerioni, Valeria
Ceriotti, Ferruccio
Cernuschi, Massimo
Cerri, Federica
Cerri, Marco
Cesana, Daniela
Cesani, Martina
Cestari, Andrea
Chiara, Anna
Chiaravalli, Marco
Chieffo, Alaide
Chieffo, Raffaella
Chiesa, Robert
Chiesa, Roberto
Chignola, Francesca
Chionna, Raffaella
Chiumello, Giuseppe
Ciaccia, Stefano
Ciaccio, Cristiano
Ciampi, Carlo
Ciampi, Pietro
Cianflone, Domenico
Ciasca, Paola
Ciboddo, Gianfranco
Ciceri, Fabio
Cichero, Paola
Ciconte, Giuseppe
96
P443
127
127, 131
187
27, 182
55
P373, P574
183
4, 183
P510, P657
188
P650
176
188
P230, P232
174
P721
26, 182
P129, P559
172
73
73, 74
P382, P449
4, 187
P143, P637
153, 183
128
54, 167
P40, P347, P348, P372, P373, P465
26, 182
72, 176
P418
55, 67, 168
P143, P258, P390, P391, P422, P473,
P477, P727, P728, P738
145
P114
176
53, 54, 99, 176, 177
P63
172
166
24, 172
170
55, 64, 167
P135, P574
172
183
3, 18, 71, 72, 75, 82, 183
P17, P48, P49, P81, P331, P342, P386,
P418, P419, P610, P622, P634
188
P483
55, 166
P338
AUTHOR INDEX - 237
Cigala Fulgosi, Mara 25, 180
P343, P539
Cigana, Cristina
95
Cino, Ilaria
54
Cinque, Paola
97, 112, 174
P572, P721
Cioni, Micaela
167
P614
Cipriani, Antonella 172
Ciriaco, Paola
3, 168
P532, P537
Cirillo, Daniela Maria 96, 108
P84, P234, P235, P370, P483, P484,
P585, P590, P591, P723
Cirillo, Sara
159
Ciscato, Diana
188
Citterio, Giovanni
183
Citterio, Lorena
129
P270, P271, P383, P463
Civilini, Efrem
55, 168
P477, P728, P738
Clementi, Emilio
72, 80
P323, P340, P439, P474
Clementi, Massimo 188
P118, P260, P261, P263, P407, P495,
P555, P558, P610
Clerici, Daniela
72
P610, P634
Clerici, Stefano
180
Clissi, Barbara
95
Cocchi, Federica
25
Cocchi, Silvia
180
Codazzi, Franca
23
P479
Codella, Roberto
53
Codenotti, Marco
24, 172
Colasante, Gaia
24
P98
Coli, Stefano
55
P396
Collivasone, Rosella 183
Collu, Egidio
167
Colnaghi, Eleonora 170
Colombelli, Cristina 128
P97
Colombo, Alessio
188
P371
Colombo, Antonio
54, 64, 167
P38, P39, P40, P41, P78, P79, P282,
P347, P348, P349, P372, P373, P383,
P465, P494, P531, P598, P599, P600,
P715
Colombo, Barbara
2
P279
Colombo, Bruno
27, 182
P219, P392, P434, P689, P692
Colombo, Cristina
Colombo, Gabriella
Colombo, Giselda
Colombo, Ilaria
Colombo, Renzo
Colombo, Sergio
Coltella, Nadia
Colucci, Annalisa
Comi, Giancarlo
Comola, Mauro
Comotti, Laura
Compierchio,
Antonia
Comuzzi, Barbara
Consalez, Gian
Giacomo
Consogno, Giuseppe
Consonni, Alessandra
Consonni, Monica
25, 180
P343, P379, P533, P539, P703
176
97, 178
P65
176
4, 187
P150, P151, P162, P602
55, 170
P483, P670
1
24, 172
26, 41, 182
P12, P68, P122, P126, P127, P128,
P129, P131, P134, P166, P206, P215,
P219, P250, P325, P326, P363, P392,
P429, P430, P432, P449, P559, P562,
P564, P579, P687, P689, P691, P692,
P693
182
P559
170
P588
153, 183
145
23, 32
P406, P475
96
23
24
P480
Conti, Antonio
145
P605, P679
Conti, Enrico
176
Conti, Valentina
71
Contrino, Elena
185
Conversano, Andrea 55, 167
Coppi, Giovanni
55
Coppolino, Naima
25, 180
Coradin, Tiziana
97
P298
Corbetta, Sara
23
P453
Cordisco, Paola
183
Corea, Francesco
27, 182
P166
Corna, Gianfranca
71
Cornaggia, Gabriele 189
Cornero, Guglielmo 167
Corno, Daniela
71
Corno, Laura
55
Corno, Silvia
188
Corre, Tanguy
128
Corsetti, Maura
170
P540
Corsin, Patrizia
54
Cortella, Carlo
Alberto
Corti, Angelo
Corti, Consuelo
Corti, Laura
Corti, Valeria
Cortini, Margherita
Cortinovis, Francesca
Cosciotti, Miriam
Cossarini, Francesca
Cossetti, Chiara
Cossu, Giulio
Costa, Sabrina
Cottonaro, Sara
Cottone, Lucia
Covarello, Diego
Covello, Remo
Daniel
Coviello, Silvia
Covino, Cesare
Cozzarini, Cesare
Cozzi, Anna
Cozzi, Silvano
Cremona, Ottavio
Cremonesi, Laura
Cremonini, Anna
Crescenti, Antonella
Crespi, Giulia Maria
Crespi, Roberto
Crippa, Ambra
Crippa, Fulvio
Crippa, Luca
Crippa, Luciano
Crippa, Massimo
Crippa, Valentina
Crippa, Valeria
Crisà, Simonetta
Cristallo, Marco
Cristell, Nicole
Crivellaro, Cinzia
Crivello, Pietro
Croci, Laura
Crotta, Alessandro
Cucchi, Michele
129
Cuko, Amarild
2, 14
P55, P62, P92, P236, P279, P471
3, 183
145
145
P497
127
176
188
97, 174
26
71, 75, 76
P13, P19, P33, P89, P90, P200, P520
53
P504
145
71
71
P89
55, 168
P676, P677
27
159
153, 183
P145, P162, P302, P305, P322, P357,
P511, P625
23
172
2, 13
P71
145, 188
P51, P119, P191, P231, P371, P376,
P411, P412, P551, P646
188
168
185
129
128
174
2
P92
53, 188
128, 138
54, 178
183
166
170
55
P347
183
71
23
P406, P475
3
180
Curci, Francesco
Curnis, Flavio
Cursi, Marco
Cusimano, Melania
166
P592
XI
2
P55, P92, P236, P279
26
P432
26
D
D’Adamo, Patrizia
24, 34
P196, P453
23
P324
128
178
127
188
145
D’Alessandro,
Rosalba
D’Alessio, Silvia
D’Aliberti, Teresa
D’Amato, Alfonsina
D’Amato, Luigi
D’Ambrosio, Rosa
Lucia
D’Angelo, Armando 53, 59, 188
P192, P716
D’Annibale, Sara
145
D’Antoni, Angela
26
D’Antonio, Maurizio 127
P32
D’Isa, Raffaele
26
Dacci, Patrizia
26
P122
Dagklis, Antonis
1
P54
Dagna, Lorenzo
97, 178
Dal Cin, Elena
188
P170, P294
Dall’Occhio, Luca
27
Dalla Libera, Dacia 26, 182
Dallaspezia, Sara
25, 180
P343, P379, P539
Daneri, Riccarda
XI
Daniele, Tiziana
145
Danise, Anna
174
P558
Davalli, Alberto
54, 178
Daverio, Rita
188
P256
De Benedetto,
24, 172
Umberto
De Bonis, Michele
55, 167
P197, P530, P612, P613, P708
De Cesare, Stefania 71
De Cobelli,
153, 185
Francesco
P42, P187, P486, P709
De Curtis, Ivan
23, 30
P453, P498
De Feo, Donatella
182
AUTHOR INDEX - 239
De Fusco, Maurizio
145
P643
De Gaspari, Angela 185
De Lalla, Claudia
96
P186
De Leonardis, Alberta 183
De Luca, Monica
168
P676
De Marchis,
127
Francesco
P24
De Marco, Donata
188
P260, P610
De Martino,
95
Emanuela
De Marzi, Patrizia
4, 176
P283, P489
De Monte, Lucia
96
P222, P679
De Nardi, Paola
3, 170
P540
De Palma, Clara
72
P323, P474
De Palma, Michele 72, 81
P14
De Pellegrin,
26, 170
Maurizio
P674
De Ponti, Alessandro 170
De Santis, Lucia
54
P350
De Taddeo,
97, 178
Francesca
P21
De Toni Franceschini, 27, 182
Luisa
De Vitis, Assunta
24, 172
Debbia, Silvia
183
Degano, Massimo
96, 107
P116, P424
Deidda Vigoriti,
71
Vivian
Del Carro, Ubaldo
27, 49, 182
P32, P97, P325, P449, P575
Del Mare, Sara
96
P443
Del Maschio,
99, 153, 155, 185, 186
Alessandro
P42, P187, P361, P486, P680, P719,
P720, P727
Del Maschio,
185
Maurizia
Del Rosso, Stefania 188
Del Vecchio, 188
Antonella
P359
Delai, Stefania
73
Delfino, Enrico
172
Deli, Aniko Maria
153
Dell’Acqua, Antonio 172
P141
Dell’Antonio,
Giacomo
Dell’Oca, Italo
188
P502
153, 183
P303, P360
Dell’Orco, Stefania 188
Della Chiara, Giulia 96
Della Rosa, Pasquale 24, 181
P203, P214
Della Torre,
178
Emmanuel
Della Valle, Patrizia 53, 188
P395, P630
Dellabona, Paolo
96, 108
P186, P222, P443
Dellavalle, Arianna 71
P89
Delli Carpini, Simona 129
P102, P270, P702
Delogu, Marta
96
Demarchi, Barbara 189
Demasi, Stefania
188
Deni, Francesco
170
Denti, Paolo
167
Deponti, Daniela
129, 170
Devoti, Rosaria
180
Di Candia, Stefania 54, 176
Di Carlo, Valerio
3, 18, 98, 170
P35, P95, P288, P375, P541, P549,
P657
Di Girolamo, Valerio 187
P150, P158
Di Leo, Giuseppe
188
Di Leo, Milena
3
Di Lullo, Giulia
96
Di Marco, Andrea
167
Di Mattei, Valentina 180
P698
Di Matteo, Federico 24, 172
Di Molfetta, Daniela 180
Di Muzio, Nadia
153, 156, 183
P302, P303, P305, P357, P360, P361,
P511, P625, P733
Di Nunzio, Sara
73
P450
Di Palo, Saverio
3, 170
P447
Di Pietro, Caterina 98
Di Pisa, Giuseppe
183
Di Resta, Chiara
145
Di Ruvo, Barbara
188
Di Sciacca, Dina
188
Di Sebastiano,
176, 185
Francesca
Di Stefano, Bruno
24
Di Tomaso, Tiziano 2
Di Trapani, Dario
187
Diaferia, Giuseppina 180
Diaz, Jordie
Dilani, Federica
Dina, Giorgia
71
189
26
P97, P122
Dindelli, Moreno
176
Diomede, Lorenzo
95
Diotti, Roberta
188
P260, P263, P610
Dispinseri, Stefania 96
Distefano, Gianfranco 128
Doglioni, Claudio
159, 188, 190
P23, P63, P91, P95, P170, P178, P179,
P187, P222, P273, P285, P286, P294,
P295, P321, P447, P571
Donadoni, Giovanni 183
Dondossola, Eleonora 2
Donini, Annalisa
53
Donini, Michela
180
Dordoni, Laura
55, 168
Doria, Valentina
54, 178
Dorigatti, Fernanda 188, 191
Dorigo, Enrica
167
P426, P614
Dosio, Flaviano
183
Dotoli, Danilo
25, 180
Draghici, Elena
73
Dugani, Erica
98
Durante, Alessandro 55
E
Ekkirala, Chaitanya
Ermoli, Elena
Erre, Letizia
Erzegovesi, Stefano
Esposito, Antonio
Esposito, Federica
Esposito, Gloria
Esposito, Marianna
Esposito, Valentina
Evangelio, Costanza
96
180
P700
183
25, 180
P441
153, 185
P42, P187, P211, P486
27
55, 168
26
P325
181
176
P418
F
Fabbri, Fabio
Fabbri, Monica
Fabiano, Beatrice
Fabro, Andrea
187
P256
95
P101
3, 172
P658
153, 183
P317
Facchi, Cinzia
Facchini, Alberto
Faccincani, Roberto
Faccio, Lucia
Fagioli, Claudio
Falcone, Marika
Falcone, Sestina
Falini, Andrea
Fallanca, Federico
Falqui, Luca
Falqui, Luca
Famoso, Graziana
Fanelli, Giovanna
Franca
Fano, Greta
Fanti, Lorella
Fanto, Manolis
Farina, Elena
25, 180
55
189
XI
127
P346
98, 119
P21, P189, P436
72
P323
24, 38, 172
P14, P127, P213, P214, P215, P229,
P379, P392, P642, P699
153, 183
P331
99, 178
167
188
P571
27, 182
168
3, 170
24, 34
181
P642
Fasano, Stefania
26
Fasce, Francesco
172
Fattorini, Annalisa
53, 188
Fauci, Eugenia
25, 180
Favia, Rossana
176, 185
Fazi, Claudia
1
P54
Fazio, Raffaella
27, 50, 182
P122, P559
Fedeli, Maya
96
Feltri, Maria Laura 128, 138
P32, P73, P97, P226
Ferenderes, Federica 1
Ferini-Strambi, Luigi 25, 40
P30, P332, P334, P378, P429, P444,
P445, P454, P455, P694, P706
Ferla, Gianfranco
3, 17, 98, 170
P355, P377, P542, P570, P588
Fermo, Isabella
145, 188
P277, P488
Ferrai, Carmelo
128
P98
Ferrara, David
167
Ferrara, Fulvio
188
Ferrari Da Passano, 172
Camillo
Ferrari, Angela
54
Ferrari, Augusto
4, 54, 97, 176
P191
Ferrari, Carola Iris
180
Ferrari, Davide
176
AUTHOR INDEX - 241
Ferrari, Giuliana
73, 87
P70, P115
Ferrari, Matteo
187
Ferrari, Maurizio
145, 149, 188
P51, P81, P119, P191, P231, P371,
P411, P412, P646, P681
Ferrari, Patrizia
188
Ferrari, Stefania
176
Ferrari, Stefano
176
P327
Ferrarini, Marina
1, 8
P56, P185, P328
Ferrario, Fabrizio
25, 172
Ferrario, Federica
172
Ferrario, Laura
189
Ferrario, Matilde
176
Ferraro, Alessandra 98
Ferreri, Andrès Jose 3, 19, 183
Maria
P16, P76, P170, P285, P286, P295,
P309, P310, P311, P313, P327, P571,
P634, P635, P636
Ferrero, Carlo Alberto 188
Ferrero, Elisabetta
1, 11
P92, P396
Ferri, Cinzia
127
Ferro, Mattia
23
Ferron, Simona
2
Ferrua, Francesca
74
Fesce, Riccardo
145, 148
Fiacco, Enrico
170
Filippi, Massimo
27, 46
P12, P28, P59, P60, P123, P126, P127,
P130, P131, P206, P212, P215, P216,
P217, P218, P219, P250, P334, P392,
P416, P428, P429, P430, P433, P514,
P534, P562, P563, P564, P577, P581,
P608, P631, P695, P696, P697, P701
Filippis, Susanna
176
Finazzi, Renato
98, 170
P239, P570
Finizio, Valentina
176
Finocchiaro, Claudia 180
Fiordelisi, Caterina 183
Fiore, Marina
180
Fiori, Marina
172
Fiori, Rossana
168
P418
Fiorin, Maria Chiara 180
Fiorino, Claudio
188
P301, P302, P303, P304, P305, P357,
P358, P360, P511
Fleischhauer,
71, 78, 188
Katharina
P48, P81
Flore, Marilena
188
Florea, Ioana
153
Fodor, Andrei
153
Foglieni, Chiara
96
P135, P396
Foglio, Alessandra
145
Fontana, Barbara
53
P504
Fontana, Raffaella
2
Foppoli, Marco
183
P76
Forestieri, Carmen
170, 189
Formaglio, Fabio
27, 182
Formenti, Ilaria
54, 178
Formicola, Roberta 97
Fornasiero, Eugenio 23
Forti, Maddalena
172
Fortis, Claudio
95, 106, 174
Fortunato, Manuela 54, 178, 189
Fossati, Andrea
25, 180
P629
Fossati, Marco
176
Fracassetti, Dario
170
Fragasso, Enrico
27
Fragasso, Gabriele
55, 167
P339, P464, P468, P592
Franchi, Giulia
178
P493, P681
Franchini, Linda
25, 180
Franchini, Stefano
97, 178
Franciosi, Gianluca 25, 180
Franco, Annalisa
168
Franco, Margherita 176
François, Stephanie 71
Franzin, Alberto
24, 172
P175
Franzoni, Irene
55
Fraschini, Gianfranco 129, 170
P709
Frascoli, Cristina
172
P583
Frasson, Matteo
170, 189
P222, P541
Frasson, Paola
181
Fratta, Pietro
127
Frenquelli, Michela 1
P53
Freschi, Massimo
188
P91, P151, P162, P322, P365, P471
Fresi, Francesco
25, 180
P452
Frigoli, Enrico
166
Frugnoli, Ilaria
176
P418
Fucci, Rita Nunzia
127
Fumagalli, Francesca 27, 74, 182
P449
Fumagalli, Luca
174
Fumero, Andrea
167
P614
Furlan, Federico
Furlan, Roberto
Fusetti, Giuliana
Fusi, Francesco
189
26, 45
P325, P326, P401, P431, P621, P690
174
54, 63, 176
P350
G
Gabellini, Daniela
Gabellini, Davide
Gabriele, Angela
Gabrielli, Samantha
Gaetani,
Massimiliano
Gagliani, Nicola
Gagliardi, Filippo
Gagliardi, Marco
Gaiera, Giovanni
Gaietta, Sara
Galanti, Andrea
Galantucci,
Sebastiano
Galbiati, Silvia
53
71, 78
180
180
145
P114
98
24
24, 172
174
P572, P721
180
167
P614
27, 182
145, 188
P191, P412
Galimberti, Elisa
180
Galimberti, Gabriella 54, 178
Gallese, Roberta
25, 180
Galli, Alessandra
188
Galli, Andrea
97, 174
P557
Galli, Elisa
183
Galli, Franco
188
Galli, Laura
97, 174
P558
Galli, Rossella
71, 79
P14
Galliani, Alberto
XXI
Gallina, Andrea
4, 187
P144, P150, P151, P158, P162, P251,
P255, P256, P293, P522, P526, P637,
P638
Gallivanone,
153, 183
Francesca
Gallo, Simone
2
Gallotta, Giulia
97, 174, 189
Galluccio, Elena
53
P383, P488, P504
Galvano, Enza
185
Gambaro, Margherita XXI
Gambini, Dania
176
Gandini, Luca
176
Gangemi, Fabrizio
96
Garavaglia, Claudio 96
Garavaglia, Elisabetta 4, 176
P415
Garbetta, Gisella
176
Garcia-Manteiga, Jose 127
Gardini, Chiara
55
Garibotto, Valentina 25
P121, P125, P205, P220, P278, P292,
P454
Garuti, Elda
185
Gasparri, Anna
2
P92, P279
Gatti, Davide
183
Gatti, Elisa
189
P488
Gatti, Roberto
25, 40
P427
Gattillo, Salvatore
188
Gavazzi, Francesca 189
Gavina, Manuela
23
Gazzetta, Paolo
3
Gelera, Emma
166
Gemma, Marco
24, 172
Genovese, Pietro
72
Genovese, Silvia
53
Gentile, Cinzia
4, 176
P415, P489
Gentner, Bernhard R. 72
Gerasi, Laura
128
Gerevini, Simonetta 153, 172
P449, P736
Gerli, Chiara
168
Gerola, Stefano
188
Gerosa, Stefano
55, 167
P464
Gherlone, Enrico
129, 140
P506, P507, P724
Gherner, Daniela
3, 172
Ghezzi, Massimo
187
Ghezzi, Silvia
97
P261, P298
Ghia, Paolo
1, 8
P18, P53, P54, P57, P80, P248
Ghidinelli, Chiara
27, 182
Ghidinelli, Monica 128
Ghidoli, Nadia
188
P21, P260, P610
Ghidoni, Matteo
172
Ghio, Domenico
185
P87
Ghirardelli, Luca
3
Ghitti, Michela
145
Giacomini, Andrea 167
Giammarresi,
95
Antonella
Giannandrea, Maila 24
Giannelli, Serena
24
AUTHOR INDEX - 243
Giannese, Francesca 96
P424
Gianolli, Luigi
153, 157, 183
P331, P464, P574, P634
Gianotti, Nicola
97, 174
P557, P558, P572, P721
Giardelli, Alessandra 176
Giardina, Paolo
176
Giardino, Stefano
176
Giarolli, Laura
25, 180
Giatsidis, Silvia
24, 172
Giglio, Fabio
3
Giglio, Manuela
153, 183
Gilardi, Maria Carla 153, 183
P361
Gilardini, Cristina
170
Ginex, Valeria
181
P125
Gioia, Giuseppe
170
Gioia, Lorenzo
172
P175
Gioia, Luigi
172
Giordano, Leone
3, 172
Giorgi, Emiliano
170
Giori, Vincenzo
183
Giovacchini,
183
Giampiero
P146, P322, P331, P451
Giovanardi, Michele 3, 168
Giovannini, Monica 4, 183
P413
Girardi, Anna Maria 188
Gismano, Elena
54
Giudice, Anna
183
Giudici, Daniela
189
Giuliani, Serena
180
Giussani, Antonella 3, 170
Giusti, Maria Cristina 24, 181
Giusto, Elena
26
Godino, Cosmo
54, 167
P135, P347, P372, P373, P574, P600
Godio, Cristina
71
Golzi, Valeria
181
Gonzalez-Rosa, Javier 26
Govi, Silvia
3
P16, P636
Granata, Anna
97
Grandi, Elisabetta
172
Grassi, Stefano
188
P170, P294
Grassini, Greta
3, 188
Greco, Raffaella
72
Gregorc, Vanesa
4, 21, 183
P87, P413, P734
Gregori, Silvia
73, 89
P37, P291
Gremizzi, Chiara
97, 178
Gremmo, Annamaria 3, 168
Grimaldi, Adelmo
Grimaldi, Antonio
Grimaldi, Salvatore
Grioni, Emanuela
Grioni, Matteo
Grispigni, Crispino
Gritti, Angela
Grogan, Pauline
Grohovaz, Fabio
Grosso, Stefano
Guarisco, Lauretta
Guarneri, Maria Pia
Guarnerio, Ylenia
Guazzoni, Giorgio
Guerra, Claudia
Guerriero, Roberta
Guffanti, Monica
Guggiari, Elena
Guglielmi, Barbara
Guidotti, Andrea
Guidotti, Luca G.
Gulletta, Simone
Guslandi, Mario
Gusmini, Simone
Guzzetti, Eleonora
Guzzoni, Samantha
183
167
P530, P613, P708
187
188
96
P91, P471
170
73, 86
P86
99
23, 31, 159, 160
P423, P479
2
P344
172
176
1
P94
4, 187
P143, P144, P150, P154, P162, P251,
P305, P357, P365, P637
178
27, 182
174
P572
3, 183
178
55, 167
96, 98, 109, 117
P14, P69
166
P338
98, 116, 170
P462, P633, P675
185
P361, P680
3, 170
P355, P377, P542, P570, P588
26
H
Hasson, Hamid
Ibrahim
Hellriegel, Christian
Heltai, Silvia
Hess-Michelini,
Rodrigo
Hidetoshi, Hoshia
97, 174
P345
1
95
96
P91
71
I
Iabichino, Cristiana
Iaci, Giuseppe
Iadanza, Antonella
185
167
24, 159
P264, P509
Iannaccone, Sandro
24, 181
P454, P480, P605, P679
Iannacone, Matteo
96
P69
Ianniello, Margherita XI
Ianzano, Dina
55
Ielasi, Alfonso
54, 167
P78
Ierardi, Rossella
73
Ieri, Rossella
188
Indrigo, Marzia
26
Innocenzi, Anna
71
Insacco, Chiara
172
Insacco, Chiara
180
Introini, Maria
188
Antonia
Introini, Ugo
24, 172
Inuggi, Alberto
26
J
Jachetti, Elena
Jofra Hernandez,
Raisa
Jofra, Tatiana
Judica, Elda
96
P91, P279, P471
73
98
27, 182
P126, P416, P430, P564
K
Kahlberg, Andrea
Kajaste-Rudnitski,
Anna
Kusamura, Shigeki
55
P422, P473
97
P298, P461
3
L
La Canna, Giovanni
167
P530, P531, P613, P708
La Gioia, Sara
27, 182
La Marca, Rosa
27
La Viola, Salvatore
180
Lacerenza, Marco
24
Lacquaniti, Raffaele 54, 167
Lage Crespo, Carolina 95
Laino, Giovanni
167
Lambiente, Camilla 188
Lamonaca, Grazia
188
Lampasona, Vito
Landoni, Claudio
Landoni, Giovanni
Landsberger,
Nicoletta
Lanfranchi, Barbara
Lania, Caterina
Lanzani, Chiara
145, 188
P173, P621
153, 183
P574, P634
55, 168
P140, P272, P402, P669, P671, P676,
P677, P714, P715, P717
24
127
187
129, 178
P102, P271, P702
Lanzi, Roberto
185
Lanzi, Roberto
54, 178
P488
Lanzoni, Paola
153, 183
Lapenna, Elisabetta 167
P530, P602, P613, P708
Laterza, Cecilia
26
Latib, Azeem
54, 167
Mohamed
P38, P78, P282, P347, P372, P373,
P494, P599, P600
Latino, Rosanna
188
Lattanzi, Annalisa
73
Lattanzio, Rosangela 24, 172
Lattuada, Guido
53
P42
Laurenzi, Andrea
54, 178
Lavazza, Fanny
167
Lavorato, Maria
189
Vittoria
Lavorgna, Giovanni 145
P321
Lazzarin, Adriano
95, 97, 100, 174, 175
P1, P4, P5, P185, P239, P242, P244,
P247, P318, P319, P345, P354, P556,
P557, P558, P572, P573, P597, P721,
P731
Legnani, Giulio
188
Legorini, Francesca 172
Lenti, Elisa
1
Leo, Loredana
145
Leocani, Letizia
26, 43, 182
P692, P693
Leporati, Ennio
53
Lepore, Marco
96
Lesma, Arianna
187
Levi, Sonia
23, 33
P519
Licata, Giada
183
Lidonnici, Maria Rosa 73
Limardo, Pietro
3, 172
Liperi, Laura
25, 180
Lira Luce, Francesca 3, 172
P731
Liu, Jaron
127
AUTHOR INDEX - 245
Locatelli, Marco
Locatelli, Massimo
Locatelli, Simona
Locci, Michela
Logaldo, Davide
Lombardo, Angelo L.
Longaretti, Roberta
Longari, Stefania
Longo, Alessandro
Longobardi, Barbara
25, 180
188
XI
73
55
72
159
183
XXI
188
P359
Longoni, Giulia
27
Longoni, Laura
153, 183
Longoni, Matteo
167
Lopalco, Lucia
95, 105, 174
P442
Lopalco, Sara
24
Loperfido, Francesco 172
Lopez, Ignazio Diego 26, 182
Lorè, Nicola Ivan
95
Lorenzetti, Isabella 26
P122
Lorenzi, Cristina
25
P343, P379, P533
Lorenzi, Mara
53
Lorusso, Anna
23
Losa, Andrea
187
Losa, Marco
24, 172
P175, P488, P620
Losio, Claudio
153, 185
Lucca, Adelio
25, 180
Luchini, Stefania
176
Lucotti, Pietro
54, 178
P383, P488, P504, P647
Lughezzani, Giovanni 4, 187
Lui, Cristina
176
Luisi, Francesca
189
Lukacs, Anna
95
Lunghi, Francesca
3, 183
P634
Luparini, Francesco 3, 170, 189
Lupo Stanghellini,
72, 183
Maria Teresa
P48, P49, P81, P634
Luzi, Livio
53, 57
P42, P106, P404, P405, P458, P460,
P597
M
Maccagnano, Carmen 187
P255
Maccagni, Davide
167
Maccalli, Cristina
2
P168, P491
Macchi, Andrea
55, 167
Macco, Romina
Madaschi, Sara
Maddé, Claudia
Francesca
Maderna, Claudio
Maestranzi, Gisella
Maestroni, Anna
Maestroni, Silvia
Maffei, Cesare
23
P479
54, 178
183
73
24, 172
53
53
25, 40, 180
P682
Maffi, Paola
99, 122, 178
P21, P106, P405
Maga, Tommaso
187
P365
Magagnotti, Cinzia 188
Maganetti, Nicola
188
Maggio, Angelo
188
Maggioni, Daniela
2
Magistretti, Paola
99
Magnani, Chiara
73
Magnani, Giuseppe 27, 49, 182
P448
Magnani, Patrizia
153, 183
Magnani, Zulma
72
Magni, Valeria
54, 167
Magnoni, Marco
55
Magri, Laura
71
Magrin, Silvio
167
Maida, Giorgio
55, 166
Mailhac, Alessandra 167
Maillard, Myriam
174
P271, P721
Mainetti, Eliseo
170
Mainetti, Lara
96
Mainetti, Marta
96
Maiorino, Chiara
26
Maisano, Francesco 55, 167
P77, P396, P466, P530, P531, P611,
P613, P639, P708
Maj, Giulia
55
P140, P272, P715, P717
Majed, Abu Amria
172
Malabarba, Lucia
188
P295
Malaguti, Alessia
25
P703
Malato, Simona
3
Malegori, Angela
172
Malgaroli, Antonio 23, 33
P316, P497
Malnati, Mauro S.
95, 102
P20
Malosio, Maria Luisa 99, 121
P95, P174, P324
Maltecca, Francesca 145
P100
Mammi, Silvia
Manca, Mario
Mancini, Nicasio
27, 182
167
188
P118, P260, P263, P483, P610
Mancini, Niky
170
Manconi, Mauro
25
P334, P378, P429, P445, P454
Mandelli, Carlo
24, 172
P736, P739
Mandelli, Davide
170
Mandelli, Giacomo 73
Mandelli, Maria Rosa XI
Mandelli, Paolo
185
Manenti, Rosa
24
P214, P508, P515
Manfredi, Angelo A. 71, 79
P24, P45, P135, P187, P307, P340,
P394, P439
Mangiavini, Laura
129, 170
Mangili, Giorgia
4, 19, 176
P25, P283, P415, P489
Mangili, Paola
188
P305, P511
Manitto, Maria Pia 24, 172
P646
Mannella, Valeria
145
Mannu, Claudio
183
Mantovani, Elena
24, 172
Manunta, Paolo
129, 141
P102, P249, P271, P463, P702
Manzo, Teresa
96
Manzoni, Marco
54, 178
Federico
P681
Mapelli, Paola
183
Mappa, Silvia
3
Marabelli,
188
Giuseppina
Marangoni, Francesco 73
Maranta, Francesco 55
Marassi, Alberto
170
Marcatti, Magda
3, 183
Marchettini, Paolo
27, 182
Marchi, Monica
54, 178
Marchisio, Pier Carlo 2
P7, P344
Marcone, Alessandra 24, 181
P125, P454, P516, P517, P698
Marelli, Guido
176
Marenzi, Karen
54, 176
Margittai, Eva
127
Margonato, Alberto 55, 65, 167
P339, P464, P466, P468, P574, P592,
P639
Mari, Gilberto
170
Mari, Silvia
145
P236
Mariani, Alberto
3, 170
P103, P550, P627
Mariani, Elisabetta
127
Mariani, Federica
189
Mariani, Samanta
96
Marinaro, Cinzia
26
Marinelli, Marcello 188
Marinelli, Matteo
128
Marino, Elena
25
P539
Marino, Giovanni
55, 167, 168
P677, P717
Marinosci, Alessandro 178, 189
Marinozzi, Maria
188
Chiara
P555
Marktel, Sarah
72, 176
P418, P419
Marone, Enrico Maria 55, 167, 168
P143, P258, P390, P391, P422, P738
Marrella, Veronica
73
P43, P61
Marrocco-Trischitta, 55, 168
Massimiliano
P422, P473
Marsiglio, Elena
176
Martani, Carla
170
Martina, Elisabetta 172
Martinelli, Vittorio
27, 48, 182
P126, P206, P219, P430, P432, P434,
P564
Martinelli-Boneschi, 27, 182
Filippo
P202, P432, P434, P487
Martinenghi, Carlo 185
P680
Martinenghi, Sabina 99, 178
Martino, Gianvito
23, 26, 28, 44
P67, P68, P325, P326, P400, P401,
P432, P578, P582
Martulano, Marilena 183
Marzi, Alessandra
166
Marzorati, Patrizia
128
Masciullo, Corrado 128
Masiello, Valeria
153, 183
Masperi, Carla
XXI
Masserdotti, Giacomo 23
Mastaglio, Sara
72
P622
Matafora, Vittoria
127
P424
Matarrese, Mario
25, 153, 183
P220, P317
Mattarucchi, Roberta 3, 72
Mattioli, Cristina
172
Matuska, Stanislav
172
Mauceri, Paolo
172
Maugeri, Norma
55, 71
P595
AUTHOR INDEX - 247
Mauri, Anna
Mauri, Simona
Mavilio, Fulvio
188
189
128, 136
P115, P325, P326
Mazza, Elena
4, 183
P308, P510, P657
Mazzavillani, Monica 55
Mazzi, Benedetta
188
P48, P81, P650
Mazzi, Ilaria
188
Mazzieri, Roberta
72
P14
Mazzoleni, Stefania 71
P14
Mazzone, Patrizio
166
P338
Mazzuconi, Roberts XXI
P483
Meani, Alessandro
27
Medaglini, Stefania 27, 182
Medone, Marzia
24, 172
Meini, Maria
2
Alessandra
Melandri, Marco
178
P249
Meldolesi, Jacopo
23, 31
P72, P174, P177, P324
Melissano, Germano 55, 167, 168
P390, P473, P477, P727, P728, P738
Mellone, Renata
185
P486
Melloni, Giulio
3, 168
P537
Meloni, Carlo
167
Melzi, Lisa
24, 172
Melzi, Raffaella
99
Memoli, Massimo
97, 178
Menegon, Andrea
159
Menichini, Raffaele 183
Mennella, Roberta
168
Merati, Valentina
95
Mercalli, Alessia
99, 170
P141
Merello, Maria
182
Merlini, Federica
98, 170, 189
Merlino, Lino
129
Meschi, Franco
54, 62, 176
P63
Messa, Maria Cristina 153
P322, P451, P574
Messa, Massimo
167
Angelo
Messaggio, Elisabetta 129
Messina, Graziella
71
P90, P200
Mezzadri, Umberto 170
Mezzi, Gianni
Micali, Nicola
Micheletti, Luisa
Michev, Iassen
Miggiano, Chiara
Mignogna, Giovanna
Milani, Davide
Milani, Federica
Milesi, Rita
Miluzio, Annarita
Minici, Claudia
Minicucci, Fabio
Minotti, Maria Grazia
Miotto, Paolo
Misci, Paolo
Miserocchi,
Elisabetta
Mizzi, Anna Maria
Mocci, Alessio
Modorati, Giulio
Moi, Davide
Moiola, Lucia
Molgora, Michela
Mollica, Luca
Molteni, Laura
Molteni, Raffaella
Monaco, Fabrizio
Monari, Marta
Mondino, Anna
Monello, Alberto
Monno, Antonella
Montanaro, Claudio
Monterisi, Cristina
Montesano, Anna
Monteverde, Stefania
Monti, Alberto
Monti, Giacomo
Monti, Lucilla D.
Montini, Eugenio
Montoli, Serena
Montorfano, Matteo
3, 170
P182
128
23
54, 167
183
53
24
3, 170
180
2
P7
96
P424
27, 50, 182
25, 153, 183
96
P370, P723
27
24, 172
P712
55
3, 170
24, 172
P712
72
P14
27, 182
P128, P131, P432
54, 176
145
P114, P616
99, 178
95
168
23
96, 109
P23, P62, P94, P386
55
71
P187, P394
55
153, 183
53
71
P90
27
55
53, 59
P105, P120, P383, P488, P504, P647
73, 87
P23
4, 176
P283
54, 167
P347, P372, P531, P715
Montorsi, Francesco 4, 21, 187
P34, P142, P143, P144, P146, P150,
P151, P152, P157, P158, P159, P162,
P164, P165, P169, P251, P252, P253,
P255, P256, P257, P258, P267, P268,
P269, P293, P357, P365, P366, P367,
P369, P501, P522, P524, P525, P526,
P527, P528, P568, P594, P601, P628,
P637, P638, P664, P718, P725
Montrasio, Cristina 145
P371
Mora, Stefano
53, 60, 176
P296, P619
Morandi, Angelica
188
Moreno Granados, 180
Gema Moelia
Mores, Federica
172
Moresco, Rosa Maria 25, 153, 183
P220, P292, P317
Mori, Silvia
128
Moriggia, Stefano
167
Moro, Andrea
24
P214
Moro, Gianluigi
53, 170
P512
Morsica, Giulia
97, 174
Mortini, Pietro
24, 37, 172
P175, P280, P571, P620
Motta, Andrea
188
Motta, Chiara
180
Motta, Francesca
178
Motta, Micaela
153, 183
P625, P733
Movalli, Mariagrazia 25, 180
Mrak, Emanuela
53
Mukenge, Mvunde 3, 170
Mulas, Ines
170
Mungo, Maurizio
172
Muriana, Piergiorgio 168
Murino, Marcello
167
Musco, Giovanna
145, 150
P114, P236, P616
Musner, Nicolò
127
Mussardo, Marco
54, 167
Muzio, Luca
26
P68
Muzio, Marta
1, 9
P53
Muzza, Andrea
172
N
Nai, Antonella
Naio, Rita
128
P22, P195
166
Naldini, Luigi
Nalin, Marco
Nano, Rita
71, 72, 84, 85
P14, P86, P199
188
99, 123
P106, P384
96
24
Napoletano, Anna
Napoletano,
Francesco
Nascimbene, Simona 167
P426, P614
Nassif, Reem
55
Natali Sora, Maria
27
Grazia
Nava, Luciano
4, 187
P365
Negri, Anna
XI
Negri, Giampiero
3, 168
Negri, Giulio
XI
Negro, Aurora
2
P306
Neri, Margherita
73
P86
Neutro, Felice
183
Nicoletti, Roberto
185
P657, P680
Nifosi, Jacopo
3
Nigro, Annamaria
26
Nigro, Elisa
127
Nisoli, Ilaria
24
Nitti, Cinzia
167
Noè, Anna
176
P418
Notaristefano, Chiara 3, 170
Novella, Liliana
180
P698
Noviello, Maddalena 72
Nozza, Silvia
97, 174
Ntoufa, Stavroula
1
Ntzepa Batonga,
168
Jaques
Nuzzaci, Valentina
180
Nuzzaco, Grazia
27
Nuzzi, Massimiliano 168
P272
O
Occhi, Francesca
Occhi, Simona
Odazio, Veronica
Odoni, Marta
Ogliari, Anna
Ogliari, Cristina
97
P350
24
P97
172
176
180
P661
170
AUTHOR INDEX - 249
Oldani, Alessandro
Oliva, Laura
Olivieri, Stefano
Oppizzi, Michele
Orellana, Daniel
Origoni, Massimo
Orlandi, Giacomo
Ornaghi, Francesca
Orsenigo, Elena
Ortolano, Enrico
Osnago, Ombretta
Ossi, Cristina
Ottolina, Jessica
25
P378
127
145
P222, P384, P679
55, 167
P466, P468, P639
26
97, 114, 176
183
127
3, 170
P447
189
P375
166
188
P297, P483
4
P
Pacchioni, Manuela 183
Padovani, Alessandro 25
P121, P124, P205, P278, P587
Paesano, Pierluigi
185
Paganelli, Michele
3, 98, 115, 170
Pagani, Alessia
128
P22, P52, P195
Pagani, Elisabetta
27
P206, P215, P216, P219, P392, P701
Paganoni, Giorgio
172
Paglino, Gabriele
166
P338
Pajoro, Ursola
183
Pala, Maria Grazia
167
Pala, Mauro
71
Palermo, Gianluca
180
Palini, Alessio
159, 161
P48, P81
Palmigiano, Angela 145
P108
Palmisano, Ilaria
145
P108
Palmisano, Michela 95
Palonta, Francesca
172
Paloschi, Vera
178
Palumbo, Emilio
176
Palumbo, Lidio
183
Palumbo, Roberta
127
P265
Panacci, Nicoletta
54, 176
Panattoni, Martina
95
P23
Pancaldi, Alessandra 167
Panigada, Fausto
25, 180
Panizza, Pietro
153, 185
P719, P720
Pannese, Maria
128
Panzacchi, Andrea
153, 183
P220, P292
Panzeri, Maria Carla 159
Papa, Ilenia
188
Papa, Marco
167
Papagni, Massimiliano 183
Papale, Alessandro 26
Papaleo, Enrico
54, 176
P350
Pappalardo, Federico 55, 168
P272, P671
Pappone, Alessia
55, 166
P711
Pappone, Carlo
55, 166
P338, P341, P606, P673
Paratore, Flavio
172
Pardi, Ruggero
95, 100, 101
P23, P110
Pardini, Celia
145
Paris, Simona
23
Parlatini, Valeria
25, 180
Parma, Barbara
176
Parma, Lia
188
Parmiani, Giorgio
1, 2, 5, 11
P88, P168, P388, P490, P726, P732
Parolini, Danilo
170
Parolo, Caterina
185
Paroni, Moira
95
P299, P399
Parra, Rita Garcia
183
Parutto, Diana
183
Pasetti, Marcella
153, 183
P360
Pasi, Federica
54, 176
P191
Pasi, Massimo
129
Pasqualetto, Elena
127
Passaretti, Sandro
98, 116, 170
P540, P554
Passarin, Olga
24
Passerini, Gabriella 188
Passerini, Laura
73
P63, P450
Passoni, Arianna
176
Passoni, Paolo
153, 183
P361, P657
Pastore, Angela
96
Pastore, Matteo
99, 178
Rocco
Pastori, Claudia
95, 174
Patricelli, Maria
188
Grazia
P659
Pattarini, Elisabetta 188
Pavan, Giulia
27, 182
Pavani, Giulia
Pavoni, Ernesto
Pazzi, Annamaria
Peccatori, Jacopo
53
128
97, 174, 189
72, 183
P48, P81, P634
Pecciarini, Lorenza 188
P170, P285, P294, P295
Pedale, Rosa
97, 178
Pedrigi, Cristina
167
Pelizzoni, Ilaria
23
P479
Pella, Francesca
4
Pellegatta, Marta
128
Pellucchi, Federico 187
P255
Pema, Monika
128
Pengo, Niccolò
127
Pennucci, Roberta
23
Pepe, Annalisa
183
Pepe, Gino
183
Perani, Daniela
25, 38, 183
P121, P124, P125, P205, P214, P220,
P278, P292, P454, P480, P587
Perani, Laura
71
Perduca, Alessandra 176
Perego, Elisabetta
27, 182
Stefania
Perego, Jacopo
183
Peretti, Elena
54, 178
Peretti, Giuseppe M. 129, 142, 170
P709
Perfetti, Maria Grazia 178
Perini, Oriana
188
Perlini, Laura
23
Perna, Giampaolo
25, 180
Perna, Lucia
188
P359, P360, P511
Perotti, Fabio
188
Perotti, Valeria
170
Perrelli, Nicola
188
Perrotta, Cristiana
72
P474
Perseghin, Gianluca 53, 58
P42, P172, P404, P486
Persichini, Luisa
129, 178
Persico, Paola
176
Perticone, Francesca 54, 178
Perucca, Simone
128
Peruzzotti Jametti,
26, 182
Luca
Pesce, Elisa
2
Peschechera,
27, 182
Francesco
Pesenti-Gritti, Paola 180
P661
Pessina, Annalisa
55
Pessina, Patrizia
71
Petralia, Giovanni
187
P143, P602
Petrella, Giovanna
183
Petrelli, Alessandra 97, 178
Petrolini, Melissa
27
Petrone, Maria Chiara 3, 170
P183, P184, P552, P626, P730
Petrone, Micaela
4, 176
P489
Pezzani, Valeria
180
Piani, Cecilia
54, 178
P681
Piantoni, Lara
27
Piatti, Piermarco
54, 61, 178
P138, P383, P488, P504, P647
Picchio, Maria
153, 183
P139, P146, P322
Piccini, Flavia
188
Piccinini, Sabina
188
Piccinni, Monica
180
Piccioni, Lucia Oriella 25, 172
Piccoli, Susanna
172
Picozzi, Paola
71
Picozzi, Piero
24, 172
P175, P668
Piemonti, Lorenzo
98, 99, 120, 170
P21, P95, P106, P141, P503
Pieralli, Sandra
172
P620
Pieri, Alessandro
180
Pierro, Luisa
24, 172
P713
Pievani, Michela
27
Pileri, Massimo
176
Pilla, Lorenzo
2
Pintonello, Maria
159
Luisa
Pirola, Barbara Maria 188
Pirola, Serena
54, 176
Pirovano, Adele
25
P539
Pisani, Matteo
55
P466, P468, P639
Piscopo, Maria
176
Antonietta
Pisoni, Serena
72
Pistarà, Alissia
180
Pistis, Giorgio
128
Pistocchi, Anna
71
Pistoni, Mariaelena 71
Pitea, Marco
176
Pizzamiglio, Carlo
153, 183
Pizzetti, Giuseppe
167
Pizzi, Sara
153
Pizzo, Riccardo
XXI
Pizzocolo, Cecilia
97
Plati, Tiziana
73, 74
AUTHOR INDEX - 251
Pluchino, Stefano
Podini, Paola
Poggi, Alessandra
Poggi, Antonella
Poggiali, Erika
Pogliaghi, Manuela
Poletti, Sara
Poletti, Valentina
Poli, Davide
Poli, Guido
Politi, Ernestina
Politi, Letterio
Salvatore
Poloniato, Antonella
Polverigiani, Silvia
Pontesilli, Silvia
Pontiggia, Adriana
Pontillo, Marina
Pontiroli, Barbara
Ponzi, Elena
Ponzoni, Maurilio
Porrello, Emanuela
Porrino, Lucy
Potenza, Maria Teresa
Pozzi, Alessandro
Pozzi, Federica
Pozzi, Paola
Pozzobon, Gabriella
Prada, Ilaria
Pradella, Alessandra
Praderio, Luisa
Prati, Matteo
Premoli, Sergio
Previtali, Stefano C.
Privitera, Daniela
Privitera, Ylenia
Prodi, Dionigio
Protti, Maria Pia
Provasi, Elena
Psacharopulo, Daniele
Puccetti, Patrizia
Pucci, Ferdinando
Puglisi, Armando
26, 45
P67, P68, P325, P578, P582, P641
23
P174, P324, P362
185
27, 182
128
97
25
P700
128
24
P492
96, 106
P210, P261, P298, P496
25, 180
153, 157, 172
P14, P286, P684
54, 176
159
24, 172
25, 180
P343, P703
188
P256
55
XI
188
P16, P70, P76, P129, P170, P273,
P285, P286, P295, P327, P331, P571
26
P122
97
176
129
183
XI
54, 176
23
180
97, 178
172
180
26, 44
P97, P100, P122, P129, P448, P565
27
167
24
96, 110
P96, P222, P387
72
55
167
72
P14
3, 168
P537
Pulitanò, Carlo
Pultrone, Cinzia
Pusterla, Tobias
Puzzovio, Maria
98, 170
P320, P355, P377, P542, P570, P588,
P589
97
127
53, 176
Q
Quartagno, Rita
Quattrini, Angelo
178
26, 42
P32, P97, P100, P122, P129, P362,
P502, P559
Quattrocchi, Tiziana 168
Querques, Marialuisa 129, 178
R
Rabaiotti, Emanuela 4, 176
P415, P489
Raber, Marco
187
P158, P365
Racanicchi, Leda
98
Racca, Sara
188
Racchetti, Gabriella 23
P177
Raccosta, Laura
2
P306
Radaelli, Maria Grazia 54, 178
Radaelli, Marta
27
P432
Radinovic, Andrea
55, 166
P338, P341
Ragogna, Francesca 53
P42
Rainelli, Cristina
2
Rainone, Francesco 129, 178
Raiteri, Elisabetta
2
Rama, Paolo
24, 36, 172
P546, P547, P640, P660, P678, P712
Ramella, Barbara
3, 172
Ramoni, Andrea
24, 172
Rampoldi, Luca
128, 140
P535
Ramponi, Monica
188
Ranzani, Marco
73
Rapallo, Maria Pia
185
Rapati, Dino
168
Rapisarda, Eugenio 153, 183
Raschi, Alessandra
25, 167
Ratti, Deborah
174
P572
Ratti, Manuela
95
Ratti, Maria Monica 25, 180
Raucci, Angela
127
P120, P187
Ravanetti, Lara
Ravizza, Alfredo
Rebagliati, Paola
Recanati, Paola
Recchia, Alessandra
Redaelli, Chiara
Regali, Laura
Reiss, Laura
Reni, Michele
96
172
XI
3, 172
128
145
24, 172
XI
4, 20, 183
P95, P308, P312, P314, P361, P510,
P636, P657
Resnati, Massimo
128
P414
Restelli, Elisa
172
Resti, Antonio
172
Giordano
P285, P286, P295
Restuccia, Umberto 127
P208
Riba, Michela
145
Ribecca, Antonella
172
Ricci, Vincenzo
183
Ricciardi, Sara
24
P58
Riccitelli, Gianna
27
P126
Ricupito, Alessia
96
Ridolfi, Cristina
3, 170
Rigamonti, Andrea 176
Rigamonti, Marco
153, 183
Rigamonti, Nicolò
96
Rigamonti, Riccardo 183
Rigatti, Lorenzo
187
Rigatti, Patrizio
4, 187
P34, P142, P143, P144, P146, P150,
P151, P158, P162, P251, P255, P256,
P258, P357, P365, P367, P526, P602,
P637
Righi, Claudio
153, 172
P509
Rigoni, Lara
153
Rimicci, Maria
183
Antonia
Rinaldi, Rosanna
159
Riolo, Sabrina
183
Ripamonti, Anna
73
Ripamonti,
23
Maddalena
Riva, Elisabetta
XI
Riva, Marco
24
P365
Riva, Nilo
26
P122, P129, P559
Rivoltini, Paola
170
Rizzato, Elisa
176
Rizzi, Chiara
96
P185
Rizzo, Annalisa
182
P687
Rizzo, Nathalie
188
P586, P709
Rocca, Alda
24
Rocca, Maria Assunta 27, 46
P28, P127, P131, P215, P216, P218,
P219, P250, P392, P416, P429, P514,
P562, P563, P608, P696, P697
Rocchetti, Simona
189
P288
Rocchi, Martina
159, 188
Rocchini, Lorenzo
4, 187
P255
Rocco di Torrepadula, 25, 180
Caterina Antonia
Eloisa
Rodegher,
27, 182
Mariaemma
P250, P432
Rodighiero, Maria
185
Grazia
Rofena, Simone
54, 176
Rognone, Alessia
4, 183
Rojo, Carmen
172
Rolla, Serena
188
Roma, Andrea
XXI
Romano, Maria
XXI
Romano, Silvana
183
Romano, Vittorio
167
Romero, Lilian
188
Roncarolo, Maria
XI, XII-XV, 72, 73, 74, 83, 88, 91, 176
Grazia
P8, P37, P47, P48, P63, P199, P291,
P418, P419, P449, P450, P518
Ronchetti, Clara
174
Ronchi, Paola
188
Ronchi, Paolo
180
Rondinelli, Beatrice 2
Ronfani, Lorenza
159
Ronzoni, Monica
4, 183
P284, P377
Ronzoni, Riccardo
127
P116
Rosa, Isabella
55
Rosa, Susanna
54, 176
Roscigno, Marco
4, 187
P143, P158, P162, P365, P602
Roselli, Emanuela
73
Anna
Rossetti, Maura
73
Rossi, Claudia
73
P70
Rossi, Erica
25, 180
Rossi, Michela
172
Rossi, Paolo
27, 182
P580
Rossi, Simone
183
Rossini, Alessandro 54, 178, 189
AUTHOR INDEX - 253
Rossini, David
Rossini, Silvano
Rossodivita,
Alessandra
Rossoni, Gilda
Rovani, Stefano
Rovelli, Elisabetta
Rovelli, Rosanna
Rovere-Querini,
Patrizia
180
P703
72, 82, 188, 191
P48, P81, P295
167
183
185
23
54, 176
71, 80
P24, P44, P45, P187, P307, P340,
P394, P440
Roveri, Luisa
27, 182
Rowe, Isaline
128
Rozza, Lucia
183
Ruberto, Carlo
98
Rubinacci, Alessandro 53, 58
P409, P512
Ruffini, Chiara
25, 180
Ruffini, Francesca
26
Ruggeri, Annalisa
72
P330
Ruggeri, Laura
55
Ruggeri, Valentina
2
Rusconi, Vega
174
Russo, Alberto
XXI
Russo, Gianni
54, 176
Russo, Vincenzo
2, 12
P96, P306, P321, P490, P609
S
Sabbadini, Maria
97, 113, 178
Grazia
Sabbioni, Elisa Letizia 176
Saccà, Antonino
187
P144, P251, P258
Sacchi, Angelina
2
P92, P279
Sacchi, Luisa
172
Sacchi, Stefania
166
P338
Sacco, Vincenzo
183
Sacconi, Massimo
188
Saccucci, Stefania
128
Saccuman, Cristina 25
P203
Saibene, Alessandro 54, 178
Sala, Cinzia
128
P461
Sala, Simone
55, 166
P338
Sala, Stefania
27
P416
Sala, Stefania
Salandini, Maria
Chiara
Salani, Giuliana
96
P556
3
26
P68
Salaris, Davide
55
Salerno, Anna
55
P339
Salmaggi, Chiara
178
Salmaso, Flavia
174
P572
Salomoni, Gabriella 188
Salomoni, Giuliana 180
Salonia, Andrea
4, 187
P144, P147, P148, P150, P151, P155,
P158, P161, P251, P254, P255, P256,
P357, P367, P526, P637
Salpietro, Stefania
174
Salvadori, Giovannella 183
Salvioni, Marco
185
Salvo, Fulvio
97, 178
Samanes Gajate, Ana 153, 183
Maria
P451
Samarati, Maria
XI
Sammartino,
XXI
Piergiorgio
Sampietro, Francesca 53
Sangalli, Mattia
187
P365
Sanna, Alberto
XXI, 188
Sanpaolo, Michela
188
Sanpietro, Francesca 188
Santagostino,
166
Andreina
Santagostino, Ilaria 3
Santambrogio,
188
Graziella
P285
Santambrogio, Paolo 23
Santambrogio, Sara 73
P535
Santarella, Roberto XI
Santinelli, Vincenzo 55, 68, 166
P338, P341
Santoro, Alessia
180
P284
Sanvito, Francesca
159, 162, 188
P23, P70, P187, P222, P384
Saporiti, Nicoletta
178
Sarno, Lucio
180
P698
Sartirana, Claudia
73
Sartori, Serenella
128
Sassi, Isabella
188
P283
Sassi, Monica
188
P260
Sauer, Aisha
Saveri, Paola
Savi, Annarita
Savi, Maurizio
Saviano, Massimo
Savio, Michol
73
127
183
XI
55, 166
95
P110
Sbalchiero, Andrea 183
Scandroglio, Anna
168
Mara
P715
Scapaticci, Emanuele 4, 187
Scaramuzza,
73, 74
Samantha
Scarfò, Lydia
1
Scarlato, Marina
26, 182
P122, P202
Scarlatti, Gabriella
96, 111
P20, P410, P470, P556
Scarpellini, Paolo
174
P483
Scattoni, Vincenzo
4, 187
P146, P151, P158, P162, P267, P322,
P365
Scavini, Marina
99, 122
P141, P256
Schaeffer, Céline
128
Schiaffino, Maria
145, 148
Vittoria
P108
Schiatti, Eliana
27, 182
Schiavi, Davide
167
Schipani, Stefano
153, 183
Schira, Giulia
72
Sciarrone Alibrandi, 129, 178
Maria Teresa
Scielzo, Cristina
1
P53, P54, P57
Scifo, Paola
25, 153, 159, 183
P42, P203, P356
Sciorati, Clara
72
Scola, Elisa
24, 159
Scomazzoni,
153, 172
Francesco
P264, P509
Scotti, Celeste
129, 170
P709
Scotti, Fabrizio
24, 172
Scotti, Giuseppe
153, 159, 162, 172, 173
P127, P213, P215, P264, P356, P379,
P509, P642, P736
Scotti, Raffaella
178
Scotti, Roberta
24, 172
Secchi, Antonio
97, 99, 113, 178
P21, P106, P141, P405
Secchi, Massimiliano 95
P437
Seghezzi, Laura
188
Selleri, Silvia
73
Selli, Simone
153, 183
Selmi, Raed Suliman
Salmi
Semeraro, Gianluca
Senesi, Pamela
Serafin, Riccardo
Serafini, Audrey
Serafini, Giorgia
Seresini, Samantha
Sergi Sergi, Lucia
Serra, Carlo
Sessa, Alessandro
176
174
53
188
54
73
96
72
24
24
P31
Sessa, Giuseppina
23
Sessa, Luca
127
Sessa, Maria
27, 48, 74, 92, 182
P132, P417, P449, P686
Sestini, Stefano
3, 168
Setaccioli, Marco
24, 172
Setola, Emanuela
54
P383, P488, P504, P647
Sferrazza, Barbara
181
P480, P679
Sforzini, Laura
25, 180
Sgaramella, Paola
176
Sibilia, Mauro
27
Siccardi, Antonio
127, 132
Sigismondi, Cristina 4
Signorotto, Patrizia 188
Silipigni, Carmen
167
Siliprandi, Francesca 180
Silva, Carlo
188
Silvani, Paolo
55, 189
P276
Silvestri, Laura
128
P22, P52, P190, P195, P274
Simionato, Franco
153, 172
P509
Simonelli, Pasquale 153, 183
Simonetti, Giorgia
1
Simonini, Marco
129, 178
P102, P271
Sinem, Kara
26
Sioli, Barbara
188
Sioli, Fabrizio
55
Sironi, Elisabetta
188
P81
Sironi, Francesca
95
Sirri, Alessandra
128
Sirtori, Marcella
53
Sirtori, Paolo
170
Sitia, Giovanni
96
P14, P69
Sitia, Roberto
127, 130, 131
P83, P109, P116, P289, P328, P346
Sizzano, Federico
71
Slaviero, Giorgio
178
Slim, Najla
153
AUTHOR INDEX - 255
Smeraldi, Enrico
180, 181
P343, P379, P452, P533, P539, P700,
P703
Smid, Maddalena
54, 176
P191
Snider, Silvia
24, 172
Socci, Carlo
98, 117, 170
P141
Soccio, Antonella
183
Sogno Valin, Paola
176
Soldarini, Armando 188
Soldini, Laura
188
Soliman, Clara
176
P418
Sommariva, Elena
145, 188
Soprana, Elisa
127
Sora, Nicoleta
55, 166
Sordi, Valeria
98, 170
P141, P503
Soria, Alessandro
174
P556
Soriani, Nadia
188
P119
Sosio, Corrado
129, 170
Sovena, Gloria
2
Sozzi, Francesco
187
Spada, Danilo
25
Spagnolo, Daniele
176
Spagnolo, Francesca 26, 182
Spagnolo, Pietro
153, 183
Spagnuolo, Marco
183
Spagnuolo, Vincenzo 97, 174
Spatola, Chiara
180
P661
Spelta, Sara
55
Spessot, Marzia
189
Spiga, Ivana
188
Spiliotoupulos,
145
Dmitrios
Spina, Annunziata
188
Spinapolice, Elena
183
Spinelli, Alessandra 24, 172
Spinelli, Antonello
188
Spinelli, Maria
27
Carmela
Spitaleri, Andrea
145
P236
Spoladore, Roberto 55, 166
P339, P592
Spotti, Donatella
129, 178
P249, P403
Spreafico, Anna
4
P87
Squadrito, Mario
72
Squilla, Mario
167
Squillante, Simone
170, 189
P540
Stabilini, Angela
Staudacher, Carlo
Stefani, Chiara
Stefani, Rossella
Stella, Marco
Stella, Paola
Stenirri, Stefania
Stoppani, Monica
Storti, Maurizio
Strada, Elena
Straffi, Laura
Strauss, Laura
Stucchi, Stefano
Suardi, Nazareno
Sudati, Francesco
98
3, 16, 98, 170, 171
P447, P540, P657
97, 176
XI, XVI-XVII
98, 170
178
P249, P271
145, 188
P371, P411, P646
172
178
187
P143, P602
26, 182
73
153, 183
4, 187
P143, P144, P150, P156, P252, P257,
P259, P268, P269, P293, P367, P522,
P523, P524, P526, P527, P638, P718
153, 183
P317
T
Taccagni, Gianluca
188
P283, P327
Tacchini, Simona Irma 185
Taglietti, Maria
189
Vittoria
Talarico, Anna
188
P294
Talarico, Daniela
128
Tambani, Laura
23
Tamburini, Andrea 3, 170
Marco
Tambussi, Giuseppe 97, 112, 174
P241, P243
Tantardini, Cristina 178
P102, P271
Taramasso, Maurizio 167
Tarlasco, Camilla
55
Tassan Din, Chiara 174
Tassara, Michela
3
P634
Tassi, Elena
96
Taveggia, Carla
27, 47
P228
Taverna, Rosaria
172
Tavilla, Alessandro
183
Tedesco, Saverio
71
Teggi, Roberto
25, 172
P658, P702, P731
Tei, Laura
XI
Terreni, Maria Rosa
Terruzzi, Ileana
Tesfaghebriel,
Habtom
Testa, Camilla
Testa, Manuela
Testa, Martina
Testoni, Pier Alberto
188
P571, P620
53
P404, P597
27, 182
180
97
25, 180
3, 15, 98, 170
P66, P103, P178, P179, P180, P182,
P505, P540, P548, P550, P626, P627,
P633
Testoni, Sabrina
3
Tettamanti, Andrea 25
Tettamanti, Marco
25, 183
P203, P214
Teuta, Domi
26
Tiberi, Simon
174
P558
Tiboni, Francesca
73
Tinelli, Elisa
127
P32
Tiraboschi, Mirta
97, 178
Tirloni, Laura
180
Todde, Sergio
153, 183
Todeschini, Paola
153, 183
Toffolo, Franca
188
Tomaello, Luca
189
Tomajer, Valentina
170, 189
P447
Tomasi, Serenesse
188
Tomasoni, Daniela
73
Tomasoni, Romana 96
Tomassini, Loredana 188
Toniolo, Daniela
128, 136
P54, P107, P196, P659
Tonlorenzi, Rossana 71
Tonon, Giovanni
2, 12
Tonti, Elena
96
Tornaghi, Paola
96
Torriani, Gabriele
188
Torta, Federico
127
P209, P316
Totaro, Antonio
23
Touvier, Thierry
71
Travi, Giovanna
174
Trbos, Mladen
188
Tremolada, Gemma 24, 53, 172
Tresoldi, Cristina
188
Tresoldi, Eleonora
73
Tresoldi, Moreno
97, 178
Trimarchi, Matteo
3, 172
P137
Trimarco, Amelia
27
Triolo, Daniela
26
P122, P362
Tripoli, Vincenzo
Trisciuoglio, Lisa
Truci, Giulio
Tshomba, Yamume
Tuoro, Antonio
Turchiano,
Giandomenico
Turi, Stefano
Turolla, Elia Anna
Tuscano, Antonella
Tutolo, Manuela
183
127
182
55, 168
P390, P391, P422, P738
3
71
55
153, 183
96
187
U
Uberti-Foppa,
Caterina
Uccellatore,
Annachiara
Ugarte, Gonzalo
Ungari, Silvia
Ungaro, Daniela
Ungaro, Federica
Usuelli, Vera
97, 174
P247, P421
54, 178
71
73
27, 182
24
127
P316
V
Vaccari, Ilaria
Vaghi, Mauro
Vago, Luca
Vago, Riccardo
Vailati, Cristian
Valentini, Giovanna
Valeri, Roberto
Valle, Andrea
Valle, Micol
Valsasina, Paola
Valsecchi, Luca
Valtolina, Veronica
Valtorta, Federica
Valtorta, Flavia
Vandoni, Irene
Vangelista, Luca
Vanni, Roberto
Vannulli, Raffaele
Vanoli, Giovanna
Vanzulli, Laura
Varagona, Roberto
27
153, 183
P317
72
P48, P81
145
3, 170
170
170
98
172
P175
27
P217, P416, P534, P631
54, 176
72
188
23, 28, 29
P98, P176, P456, P649
183
P53
95, 103
P437, P672
180
183
183
25, 180
185
AUTHOR INDEX - 257
Varale, Roberta
Vassena, Lia
Vavassori, Stefano
170, 189
95
96
P116
Vecellio, Magda
178
Velikova, Svetla
26
Venditti, Alessandra 72
Venneri, Mary Anna 72
P14
Venturini, Massimo 153, 185
P377, P727
Vergani, Andrea
97, 178
P385
Vergara, Pasquale
55, 166
Vermi, Anna Chiara 55
P135
Verona, Chiara
183
Francesca
P327
Verzini, Alessandro 167
P530
Veschini, Lorenzo
1
Vezzoli, Giuseppe
129, 178
P368
Vezzoli, Michela
71
Vezzulli, Paolo
24, 159, 172
Viale, Edi
3, 170
P447, P505
Vicari, Aurelio
183
Vicedomini, Gabriele 166
P338
Vicenzi, Elisa
97, 111
P261, P298, P461, P576
Vicini, Sauro
188
Viganò D’Angelo,
53, 188
Silvana
P192
Viganò, Fiammetta 128
P222
Viganò, Giorgio
167
Viganò, Maria Grazia 4, 183
P87
Viganò, Maurizia
172
Viganò, Riccardo
4, 176
P489
Vignali, Andrea
3, 170
P538, P541
Vigone, Maria
54, 176
Cristina
P420
Villa, Anna
73, 90
P43, P61, P64
Villa, Chiara
159
Villa, Daniele
180
Villa, Eugenio
4, 183
P87, P377, P413
Villa, Isabella
53
P512
Villa, Maria Cristina 176
Villa, Silvana
180
Villa, Valentina
Vinci, Raffaele
54
129
P724, P735
Vino, Arianna
3
Viscardi, Matteo
54, 176
P518
Visciano, Maria Luisa 95
Visco, Francesca
174
Visigalli, Ilaria
73
Visintini, Raffaele
25, 180
P242, P682
Vismara, Chiara
27, 182
Vitali, Giordano
4, 183
Pietro
P377
Vitali, Matteo
170
Vizzuso, Domenica 127
Voci, Carlopietro
3, 167, 168
Volontè, Maria
27, 182
Antonietta
Volta, Viviana
2
P344
Vuotto, Roberto
27
W
Weber, Giovanna
Williams, David
Wodarczyk, Claas
Wozinska, Monika
Wrabetz, Lawrence
54, 61, 176
P420
188
128
128
127, 134
P32, P73, P97, P227, P499
Y
Yacoub, Mona-Rita
95, 178
Z
Zacchetti, Daniele
Zagato, Laura
Zallocco, Diego
Zamai, Moreno
Zambelli, Matilde
Zamboni, Michele
Zambroni, Desirée
Zamproni, Ilaria
Zanardi, Raffaella
Zanella, Elisa
23
P479
129
P102, P702
96
1
P74, P482
188
24, 181
P454, P480
128
P97
53, 176
25, 180
P703
128
Zangrillo, Alberto
Zanni, Giuseppe
Zannini, Piero
Zanoni, Angela
Zanoni, Annalisa
Zanoni, Matteo
Zanotti, Lucia
Zanussi, Monica
Zappalalio, Paola
Zatti, Alessandra
Zeni, Daniele
Zerbi, Alessandro
Zerbi, Valerio
Zerbini, Gianpaolo
Zimarino, Vincenzo
55, 66, 168, 170, 189, 193
P140, P272, P669, P671, P676, P677,
P715, P717
187
P144, P251, P255, P256, P637
3, 17, 168
P532, P537
183
180
187
P365, P367
26
188
P81
188
2
145
98, 115, 170
P95, P288, P375, P549, P657
55
P614
53, 57
23
Zino, Elisabetta
Zito, Ester
Zito, Laura
Zocchi, Maria
Raffaella
Zonari, Erika
Zoppei, Gianna
Zordan, Paola
Zorzi, Claudia
Zuber, Veronica
Zucchelli, Chiara
Zucchinelli, Patrizia
Zucconi, Marco
Zuffada, Francesca
Zuffardi, Orsetta
Zuliani, Walter
188
P48
127
P109
71
95, 104
P82
72
P14
XXI
23
P475
180
170, 189
145
183
25, 181
P333, P335, P378, P445, P454
166
188
P659
3, 170
P541
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