The development of biomarkers and their clinical application can have an important impact on both basic knowledge and patient care and on the resulting socio-economic aspects.

In fact, there is a widely-shared view on the need to complement the diagnostic routine with molecular tests, in order to optimise treatment by stratifying patients into subgroups that may or may not benefit from medical treatment. It is in this context
that precision medicine, based on the study of the patient’s phenotype/genotype, can predict his or her susceptibility to the disease, the prognosis and the response to treatment and thereby improve the person’s health.

Available estimates suggest that, in clinical medicine, from 38 percent to 75 percent of patients do not respond to the administered drugs: it is therefore essential to identify and validate biomarkers for selecting the correct treatment for the individual patient: 'the right drug for the right patient'.

The School of Medicine and Surgery considers the interdisciplinary approach fundamental as a constituent element that is essential today for being competitive in research, innovative in teaching and at the forefront in care.

The presence in the School of Medicine and Surgery of “general” researchers and expert clinicians is indispensable for translational research aimed at the development of precision medicine. In fact, innovation, originality of approaches and scientific creativity find their most favourable milieu in laboratories dedicated to discoveries on disease mechanisms, in clinical facilities and in the research centres already active in the School of Medicine and Surgery.

The cornerstone of the project strategy is the strong and continuous synergy between different research groups, which takes place with the “under the same roof” strategy, to create the conditions for continuous cross-fertilisation, both cultural and technological, and to obtain critical mass.

The Chronic FPDs under study are chronic, rare diseases, orphan to effective drugs, with a severe prognosis and, therefore, with a high impact on the patient’s quality of life and on healthcare expenditure. Therefore, the project also aims at implementing scientific networks of national and international collaboration, typically necessary in rare diseases, in order to establish Clinical Registries and Clinical Trials that allow consolidating research on diagnostic-therapeutic pathways, as well as attracting research funds in the field of FPDs.

The development objectives of the School of Medicine and Surgery within the PREMIA Project are:

• addressing the challenges posed by precision medicine with the study of molecular pathways and biomarkers and with their biological and preclinical validation, as well as validation and application in the clinic for diagnosis, prognosis and treatment, in a virtuous loop;
• applying translational research ‘from bench to bedside and from bedside to bench’ in a broad and original field not yet fully explored in medicine and in the School of Medicine and Surgery, in order to place itself at the forefront in the international arena;
• stimulating highly qualified teaching with the recruitment of PhD students included in an in-depth study on these new areas of research and also stimulating young assistant professors and graduate students to deepen the research methodology.

The ultimate and prestigious objective of this project is to achieve growth and qualitative improvement in the following fields of knowledge:

• molecular mechanisms of disease,
• biomedical statistics and bioinformatics for translational research for ‘big data’
• advanced technologies in the field of high-throughput screening, molecular and pharmacological,
• cutting-edge technologies in the field of molecular, cellular and clinical-radiological imaging,
• development of disease models representative of the clinical reality, including cell models, animal models and the use of primary and organ cultures,
• anatomical pathology and molecular pathology,
• rare diseases: diagnosis and treatment.

In particular, for PhD teaching, the ultimate objective is also the achievement of the third “I” (“Internationalisation”), which will complete the picture of total innovativeness of the 3 PhDs belonging to the School of Medicine and Surgery.

The School of Medicine and Surgery provides the project with important and advanced technological and methodological platforms for research, in particular:

• Genomics platform
• Advanced microscopy platform
• Molecular pathology and advanced diagnostics platform
• In-vivo Diagnostic Imaging Platform with cyclotron for radionuclide production
• Proteomics and clinical metabolomics platform (unique in Italy with molecular imaging)
• A certified animal model development enclosure with BSL2 safety level
• A biostatistics centre for clinical epidemiology

Chronic FPDs, which include pulmonary fibrosis, chronic kidney disease, inflammatory bowel disease, bone marrow fibrosis, cardiac fibrosis and liver fibrosis, are a major health problem today. In fact, it is estimated that, in developed countries, 45% of all deaths are attributed to Chronic FPDs resulting in significant consumption of social and healthcare resources.

Regardless of the aetiology of each disease, chronic inflammation appears to be a common factor with the release of inflammatory mediators that stimulate proliferation and the excessive production of extra-cellular matrix by fibroblasts/myofibroblasts, causing damage to the organ architecture and leading to functional decline.

The scientific objectives (SO) on specific pathologies in the area of Chronic FPDs are:

• SO1 and SO2: respiratory diseases (idiopathic pulmonary fibrosis and acute respiratory distress syndrome)
• SO3: liver disease (primary sclerosing cholangitis)
• SO4: haematological diseases (myelofibrosis)
• SO5: cardiovascular diseases (cardiac fibrosis)

SO1 - Idiopathic Pulmonary Fibrosis

Scientific Director Prof. Alberto Pesci

Idiopathic Pulmonary Fibrosis (IPF) is a rare disease with a prevalence of 12-35 cases per 100,000 people. The disease is associated with an average survival of only 3-5 years from diagnosis with a 5-year mortality of 50%. Its natural history is characterised by the development of numerous complications and acute events of respiratory failure, the so-called accelerated phases, which require prolonged hospital admissions and which are burdened by a high mortality rate, thus involving a large consumption of social and healthcare resources.

There are no treatments that can stop the progression of fibrosis and improve survival. The Pneumological Clinic is involved in the national network of expert centres in interstitial diseases (ILDInet).

The primary objective of the project is to identify serological biomarkers of disease and to compare them with imaging (high-resolution CT, CAT-PET) and functional biomarkers, in order to achieve an early diagnosis, predict the clinical course (rapidly evolving or not) and the response to treatment. A further objective of the study is to verify whether IPF is a disease that affects only the lung or if it is possible to highlight subclinical fibrosing alterations of other organs. Given that patients with IPF, along with smokers, have an increased incidence of lung cancer compared to those who are not affected by this disease, we will try to highlight the existence of epigenetic biomarkers predictive of a potential neoplastic evolution.

SO2 - Acute Respiratory Distress Syndrome (ARDS)

Scientific Director Prof. Giacomo Bellani

ARDS is an acute inflammatory lung disease that can be triggered by both primitive lung (e.g. pneumonia) and extrapulmonary (e.g. sepsis) pathologies.

The disease is frequent; in fact, it is estimated that it affects 10% of patients admitted to intensive care and about 23% of those undergoing positive pressure ventilation.

The global hospital mortality of ARDS patients is around 35%, but it exceeds 50% in the most severe forms. Moreover, unfortunately, survival does not correspond in many cases to a “restitutio ad integrum”: many of the patients who survive are burdened by permanent morbidity, which can have consequences impacting the duration and the quality of life of the patient, as well as important socio-economic costs.
The project seeks to identify biomarkers of fibrotic evolution of ARDS in different biological fluids, such as blood, alveolar lavage fluid and condensed exhalation, using imaging and respiratory function tests performed in patient follow-up.

SO3 - Primary Sclerosing Cholangitis

Scientific Director Prof. Pietro Invernizzi

Primary Sclerosing Cholangitis (PSC) represents a paradigmatic model of liver disease in which fibrosis plays a fundamental pathogenetic role. PSC is a rare disease of the intrahepatic and/or extrahepatic biliary tract that predominantly affects men with an average age of 40 years. The disease is characterised by chronic inflammation and obliterating fibrosis of the bile ducts, resulting in the development of chronic cholestasis, fibrosis and cirrhosis. Prevalence ranges from 8 to 14 per 100,000 people.

Cholangiocarcinoma is a feared complication of the disease. The aetiology is unknown and there are no effective medical treatments in PSD; the only curative treatment for end-stage patients is liver transplantation. The median survival time is 12 years from diagnosis.

Within the project, the primary objective is the identification of serological biomarkers associated with fibrosis, to be correlated with disease progression and outcomes (development of complications of the disease and liver failure) for a better staging and for prognostic purposes. Oxidative stress (and in particular, the enzyme complex NADPH oxidase -NOX) is a key mediator of inflammation and fibrosis in numerous diseases, identified as a possible new target in treatment.

A further objective of the study is to evaluate the efficacy and safety of NOX-4 inhibitors on the progression of the disease in PSD by evaluation with invasive (liver biopsy) and non-invasive (liver elastography, enhanced liver fibrosis, etc.) procedures.

SO4 - Medullary fibrosis

Scientific Director Prof. Rocco Giovanni Piazza

Medullary fibrosis is a pathological process characterised by abnormal accumulation of reticulin and collagen deposits. This process finds its maximum expression in myelofibrosis (MF), a clonal pathology belonging to the group of chronic myeloproliferative neoplasms. The progressive occupation of the medullary spaces by reticulin and collagen fibres results in a process of extramedullary hematopoiesis that is the cause of massive splenomegaly. To date, the only curative approach for MF remains allogeneic hematopoietic stem cell transplantation, whose applicability is unfortunately very limited, due to the often advanced age of MF patients.
It is known that the presence of bone marrow fibrosis is associated with a significant increase in pro-inflammatory biomarkers. In particular, TGF-beta1, LOX 1, Interleukin (IL) 8 and IL-2R were increased in MF cases compared to controls, but it has not been possible, to date, to identify the mechanism responsible for such activation.

Within the project, the objective is to characterise the molecular processes of bone marrow fibrosis in MF patients, primarily using an approach based on single cell 3’RNA-Seq sequencing techniques of bone marrow samples of MF patients and other patients. This approach will make it possible to identify cell types, Gene Ontologies and signalling pathways significantly associated with fibrosis phenomena in MF, thus making it possible to characterise the profibrotic pathways prevalent in MF and to identify the cell types mainly responsible for the phenomenon. A greater understanding of the mechanisms of development and scavenging of the fibrotic deposit at the bone marrow level can lead to the development of rational treatments aimed at counteracting the deposition and/or increasing the reabsorption of the fibrotic deposit itself.

SO5 - Cardiac fibrosis

Scientific Director Prof. Cristina Giannattasio

Cardiovascular fibrosis is involved in multiple passages at the continuum level, ranging from endothelial dysfunction to the actual cardiovascular event. At the cardiac level, the myocardial tissue undergoes significant changes with activation of biochemical patterns that determine a greater fibrosis of the interstitial and perivascular tissue which, together with an increased apoptosis of cardiomyocytes, is the basis of the structural changes found in hypertensive heart disease and in advanced dilated heart disease. At the vascular level, on the other hand, the process begins with endothelial dysfunction which, in turn, results in the activation of pathways (mainly of the metalloproteinase pathway) that determine a reduction in the content of elastin and an increase in collagen at the level of the tunica media, from which derives the increase in arterial rigidity. The relationship between endothelial dysfunction and chronic heart failure has received many scientific confirmations, as well as the relationship between dilated heart disease and the increase in cardiac and vascular fibrosis.

As part of the project, the objective is to study all the patients who will face a circular assistance positioning surgery or a heart transplantation for chronic heart failure at the Niguarda Hospital. Both endothelial function and fibrosis biomarkers (TGFbeta periostin and galectin-3) will be evaluated prior to surgery and during follow-up, in order to study the association between modifications of these instrumental and biochemical markers with the clinical course of patients and response to the
treatments.

1. Diagnostic imaging Core facility

Director Prof. Maria Rosaria Moresco

Due to the high information content associated with them, biomedical images (CAT, NMR, PET) analysed with advanced imaging processing methodologies are the basis of the so-called radiomics, a new technique for typing tissues and organs to be used together
with genetic, molecular and clinical data for the complex phenotyping of patients. Different radiological imaging methods, already being implemented or under development, make it possible to visualise and quantify the tissue deposition of fibrotic matrix.

Within this project, we will apply in-vivo diagnostic imaging in patient cohorts identified in SOs 1-5 in D2. The NMR 3T will be strengthened with its dedicated professional figures.

Specifically, the development actions of the initial phase will be:

• verifying if, in the course of overt fibrosis of an organ, there is potential fibrosing subclinical involvement or if there are molecular alterations predictive to the detriment of other organs
• validating the animal models developed on the basis of the diagnostic framing characterising the patients. 

Consolidation phase actions:

• developing new radiopharmaceuticals for tissue targets potentially predictive of fibrotic transformation
• developing at the preclinical and clinical level and validating according to the existing guidelines also in association with circulating molecular markers, new diagnostic/prognostic protocols or analysis algorithms for patient stratification.

2. Laboratory research Core facility

Director Prof. Paolo Brambilla

This core facility consists of a network of functional platforms for the project and it will deal with the complex phenotyping of patients, providing “omics”, molecular and clinical data. In addition to these platforms, mainly dedicated to research support activities, the School of Medicine and Surgery has an agreement with a large university-run laboratory (San Gerardo Hospital) dedicated to both services and research, consisting of a team of 37 persons, including technical staff and medical managers.

For over ten years, it has had a biobank and the expertise to manage it. The role of this laboratory will be to support the transfer of the most promising markers to the clinic with targeted analyses. Moreover, it is functional to the project, as it is also able to develop and validate analytical methods of Immunometry and Proteomics and Metabolomics in Mass Spectrometry (MS) for biomarker discovery and validation.

The strengthening of the facility will be implemented both in terms of recruitment and infrastructure.
Initial phase actions:

• Definition of diagnostic and follow-up pathways of the patients
• Development of new procedures for the evaluation of the biomarkers of interest

Consolidation phase actions:

• Complex phenotyping of the patients of the SO 1-5 (D2) cohorts to support validation of the biomarkers of interest.

3. Animal research Core facility

Director Prof. Guido Angelo Cavaletti

A project such as this, which seeks to evaluate the role of possible biomarkers in human pathology, cannot ignore animal experimentation aimed at testing the hypotheses generated by clinical experience and evaluating the potential efficacy of targeted therapeutic
approaches, as well as the verification of new potential biomarkers.

To this end, it is intended to strengthen the current animal enclosure, in particular, the in-vivo imaging platform (microCT, infrared tomographic system) with suitable technical staff and with infrastructural strengthening.
Initial phase:

• Preclinical support for evaluation and discovery of new biomarkers

Consolidation phase:

• Preclinical support for the validation of new biomarkers and possible new therapeutic approaches
• Optimisation of protocols and procedures (SOP) for the management of the platform, also for its enhancement towards use by external clients.

4. Biomedical statistics and bioinformatics Core facility

Director Prof. Stefania Galimberti

For the development of the project, the support of medical statisticians with extensive experience in collaboration with clinicians, basic researchers, biologists and pharmacologists for the definition, conduction and analysis of preclinical and clinical studies is fundamental. Precision medicine requires innovative study designs for rare diseases, which allow an adequate statistical efficiency even with an economical use of resources (cases and biological samples).

It requires appropriate statistical methodologies of evaluation (prognostic and predictive) and of validation of the biomarkers for use in clinical practice. In this sense, the IDEA project (SIR MIUR, RBSI14LOVD) and the experience of the Biostatistics Centre for Clinical Epidemiology
constitute an excellent starting point with knowledge on complex methods for studying the dynamic nature of the progression of the disease. The synergy with bioinformaticians is fundamental for managing and carrying out the research on ‘big data’ that emerge from omics biomarkers.
This core facility will be implemented with staff and infrastructure and it will assist in the following aspects:
Initial phase:

• support to the design of studies in SOs 1-5 (D2) and to the drafting of study protocols
• structuring of databases for the collection of data from cohorts and clinical registries (with the support of the software recently acquired by the University, REDCap)
• collaboration with bioinformaticians for data integration
• definition of procedures and standardised codes for data collection and management, in order to raise the standards of data replicability in contexts common to the different SOs

Consolidation phase:

• support to the SOs for data analysis and the writing of manuscripts
• development of innovative statistical methodologies for the analysis and clinical validation of biomarkers.

The interventions on graduate training teaching are part of a structure that is of high strategic interest for the University, which will therefore see long-term attention given to quality and internationalisation.

The PhD courses linked to the department recruit 25-30 students with a wide range of backgrounds per year, being already oriented to the interdisciplinary nature of research in the three reference fields (DIMET, Neuroscience and Public Health): doctors, biologists, biotechnologists, pharmacologists, research nurses and obstetricians, statisticians, bioengineers and mathematicians.

The project will be a stimulus for the enrichment of the training course with thematic courses and interventions (visiting professors, collaborations with international research institutions) related to the developments of the project, in order to train PhD students within an international scientific
environment, providing them with the appropriate tools, and to educate them not only to the sectoral dissemination, but also to that aimed at civil society so as to arouse positive empathy towards scientific research.

In order to strengthen the link between basic and clinical research, the educational activities detailed below will be shared with the Specialisation Schools of Medicine, facilitating the routing of doctors in training towards a translational research path. At
the same time, the exposure of PhD students to clinical figures will complete their training course.

Initial phase:

• Integration of the three PhD courses with international scientific institutions for the achievement of the third “I” (“Internationalisation”), the issue of joint PhD degrees and the support for actions aimed at participation in European networks of excellence and in European projects, with the support of an Education Manager
• Funding of scholarships for PhD courses of the School of Medicine and Surgery (SMS) on research related to the project that include support for the mobility of PhD students (12 months of stay abroad in international research facilities)
• Teaching contracts/assignments with native English lecturers, in order to raise the degree of familiarisation and use of the written and oral language of the PhD students.

Consolidation phase:

• Teaching assignments with lecturers having complementary skills aimed at training PhD students in the drafting and management of projects, writing scientific articles and oral presentations
• Teaching assignments for visiting professors with synergistic expertise to the objectives of the project
• Scientific events on the research topics of the project
• Participation of the PhD students in the educational activities directed toward the general public (public meetings; social networks; thematic brochures).

Calendar of the 2020-21 academic year - Interdisciplinary courses in English

RESEARCH ETHICS – 30th, 31st July 2020

The Research Ethics course has been planned in order to provide students with an overview of the main ethical and legal issues related to scientific research. The course has been designed with the objective of fostering an ethical attitude in the relationship with the patients and/or with the lab animals (research ethics and animal ethics) and with the colleagues (research integrity). Methodology is interactive with a focus on critical evaluation of case studies that shed light on the complex interplay of the bioethical, scientific, and legal implications that characterise medical research.

Learning Outcomes: at the end of the course, students are able to:

- comprehend the main ethical and legal challenges related to clinical research;

- commit to the better management and governance of clinical research;

- carry out scientific research on humans and animals in line with research and animal ethics and the law;

- avoid serious breaches of research integrity (i.e. fabrication, falsification and plagiarism).

SCIENTIFIC COMMUNICATION & WRITING – Feb.-March 2021

Communicating science in a clear and effective way is one of the fundamental requirements for the dissemination of scientific progress. This scientific writing and communication course aim to provide the basic knowledge and skills for successfully sharing research results in various contexts: from publications, to conferences, including social media.

Learning Outcome: At the end of the course, students should be able to:

- Know how to distinguish the various forms of scientific communication;

- Be familiar with the process of publishing a manuscript;

- Know the different formats of scientific publication and the related writing techniques;

- Know how to recognise the most appropriate journals in which to publish;

- Know how to write results in an abstract and communicate them in meetings and conferences in the form of posters or oral communication;

- Know how to use scientific communication on social media;

- Know how to effectively communicate research results to society;

- Understand how to write a CV effectively.

TUTORING – How to get the best out of yourself & others – 15th, 16th Sept. 2020

This course is designed for junior scientists (PhD students, Postdocs) serving as current or prospective Tutors to undergraduate students in the lab. The objective of the course is to give the basic principles on how to build an effective tutoring and learning relationship.

Learning Outcome: At the end of the course, participants are able to:

- Set the learning objectives in a tutoring relationship

- Determine the learning rhythm

- Understand how to practically teach laboratory techniques

- Serve as a tutor in a hands-on teaching environment

- Understand the critical moments in tutoring

- Develop effective communication techniques

- Understand the basics of trust-based relationships

ACADEMIC SEMINAR - SARS-CoV2 Vaccine Development – 21st Nov. 2020

As the COVID-19 pandemic continues to wreak havoc on public health and the global economy, the search for a vaccine has taken on an intensity never seen before in the history of medical research.

The seminar includes talks by leading Scientists aimed at sharing knowledge on leading vaccine trials and foster discussion and exchange of ideas amongst medicine students and young scientists.

Session 1:

“COVID-19 and Immunity: the little we know, the challenges ahead”

Prof. Alberto Mantovani, Vice-Rector for Research, Humanitas University &       President, Humanitas Foundation for Research

Session 2:

COVID-19 Vaccine Development - how science is speeding up the process

Dr. Anthony Fauci, MD - NIAID Director

JOINT CONFERENCE with European MD PhD Association – 22nd, 23rd April 2021

In planning, the details will be available soon.

Staff

The PREMIA project provides for a recruitment that supports all the research areas involved in the project, even if with different figures in terms of resources.

Due to the interdisciplinary nature of the project, the acquisition of 3 Associate Professors in strategic areas is expected: Diagnostic Imaging and Radiotherapy (MED/36), Clinical Pathology and Biochemistry, (BIO/12), Pneumology (MED/10), 2 RtdB, 4 RtdA, 1 D Technician, 2 Technologists, 5 Research Fellowships, 6 PhD Scholarships.

The School of Medicine and Surgery contributes to the ATMA Expert Centre, a public-private partnership that aims to effectively apply the knowledge of biology and molecular medicine to clinical practice with the objective of supporting biomarker verification and validation projects using biobanked tissues.

The Biomarkers Expert Centre was implemented as part of the initiatives of the BBMRI-ERIC European Research Infrastructure.

The School of Medicine and Surgery, as part of its participation in the BBMRI-ERIC infrastructure, is home to the Common Service ELSI (Ethical-Legal-Societal Issues), a service structure for addressing the challenges and the critical issues of advanced research and biobanking and the related ethical, legal and social issues in a good practice perspective.

The Italian node of the BBMRI infrastructure is chaired by Prof. Maria Luisa Lavitrano.

The SMS has as its reference centre a large hospital such as the San Gerardo Hospital in Monza, which is flanked by prestigious hospitals, such as the Papa Giovanni XXIII Hospital in Bergamo, the Niguarda Hospital and the San Luca Auxologico Institute in Milan.

All these institutions are dedicated to research for the improvement of care and guarantee collaboration in the definition of clinical cases and in the conduction of the studies.

The School of Medicine and Surgery has an international scope, as demonstrated by the activities carried out in recent years:

• Participation as an Italian centre in five European Reference Networks (ERN): Rare Liver Diseases ERN RARE-liver; paediatric tumours ERN PaedCan; craniofacial abnormalities ERN CRANIO, haematological diseases ERN EuroBloodNet, inherited metabolic diseases MetabERN
• Coordination of important international studies in paediatric oncology (Esphall-COG) and in intensive care (LUNG SAFE and WEAN SAFE) 29 Visiting professors and 5 Erasmus professors from foreign universities
• Creation of partnerships with the University of Surrey (UK) for the launch of a new International Degree Course in Medicine and Surgery and with Université Paris 7 for a double Master’s Degree in Biotechnology in Medicine
• Organisation of international conferences and courses: Meeting of the International Biometric Society (2015); Summer School Biomarkers & Classifiers for Diagnostic and Therapeutic Research: Discovery, Study Design and Analysis (2016). 2nd Liver immunology meeting (2017), NEUROINTENSIVE CARE: Bicocca Update 2017 (2017)
• Personalised Medicine in Multiple Sclerosis (2017);
• Executive Master in Management of Research Infrastructures funded by the RITRAIN project (ongoing).

Executive Committee

Coordinator and General Director:

Prof. Maria Grazia Valsecchi

Project Manager Representative:

Dr. Paola Di Rienzo

Director of Core Facilities Actions:

• Prof. Maria Rosaria Moresco
• Prof. Paolo Brambilla
• Prof. Guido Angelo Cavaletti
• Prof. Stefania Galimberti

Managers of OSS Scientific Projects:

• Prof. Alberto Pesci
• Prof. Giacomo Bellani
• Prof. Pietro Invernizzi
• Prof. Rocco Giovanni Piazza
• Prof. Cristina Giannattasio

Scientific Advisory Board (SAB):

• Prof. Alberto Bravin
• Dr. Francesco Bonella
• Prof. Massimo Pinzani