System Diseases 1

The System Diseases 1 course takes the students into clinical medicine with the study of the "Diseases of the Kidney and Urinary System" (Nephrology) and the "Diseases of the Heart and Vessels" (Cardiology). Such studies will be dealt on a comprehensive basis, i.e. including Diagnostic Imaging, Pathology, Clinical Biochemistry and Microbiology, in relation to the diseases of the organ.
CARDIOVASCULAR DISEASES
This module will focus on some relevant aspects of cardiology, which shall be discussed with a predominantly pathophysiological approach. A more clinical and therapy oriented approach will be in place at 5th year, in the exam of Translational Cariovascular Medicine and Surgery.
NEPHROLOGY
The purpose of this module is to provide essential knowledge of the kidney role in maintaining the body homeostasis, both in patients with renal diseases and in patients with other conditions, such as arterial hypertension and diabetes mellitus, in which kidneys play a pivotal role in the genesis and the response of the organism to the disease process. The module offers the unique opportunity to systematically explore specific renal disorders, like the glomerulopathies, and an introduction to very relevant clinical syndromes, such as acute and chronic kidney disease.
Course Relevance: The knowledge of signs and symptoms (semeiotics) in nephrology and the ability to identify the clinical presentation of renal diseases represent an essential part of the medical heritage and practice. It is of utmost importance in the everyday clinical and surgical practice, if we consider the high incidence of both acute (mostly in surgical setting) and chronic kidney injury (mostly in internal medicine). Also, the ability to detect the first signs and symptoms of a specific renal disease is crucial for an early nephrology referral. Despite the intended field of specialization in medicine, we believe that this module is very important both for the future physician and the future surgeon.
MICROBIOLOGY
The main purpose of the module is the understanding of the role of microorganisms, as etiological agents or cofactors, in the pathogenesis of myocardial/cardiac (cardiology module) and urinary tract diseases (nephrology module).
Every lecture will focus on four main aspects: the epidemiology of the involved microorganisms, the mechanisms of pathogenesis employed by the microorganisms, the diagnostic approaches for the detection of the microorganisms, and, when available, the antimicrobial therapies.
PATHOLOGY
The first part of the course will focus on the definition of Anatomic Pathology and on its contribution in modern medicine. The organization of the work flow at a Pathology Department, with particular focus on its three major sections (histology, cytology and autopsy) will be described, together with the structure and the contents of a modern pathological report. Principles, applications and clinical implications of some ancillary techniques of the anatomic pathology such as immunohistochemistry and molecular pathology will also be considered in detail.
The second part of the course will deal with the anatomic pathology of the heart. In particular, lectures will be focused on the pathogenetic mechanisms, morphologic changes, evolution and complications of the diseases involving the most important structures of the heart (myocardium, endocardium and valves, pericardium) and the blood vessels.
DIAGNOSTIC IMAGING
The module is focused on explaining the different interactions between iodizing and non iodizing radiation and matter in order to obtain diagnostic images (i.e. x rays, sonography and magnetic resonance imaging) and the use of radiopharmaceuticals in Nuclear Medicine. The course is also designed to highlight the different diagnostic capabilities of imaging techniques in detecting and characterizing pathologic conditions in the cardiovascular and urinary systems.
In particular, the course will focus on conditions such as ischemic heart disease, valvular heart disease, urinary tract stones, infections and tumors.

BLOCK 1
Adaptation of cellular growth and differentiation
Mechanisms of cellular injury and cell death (necrosis, apoptosis, autophagy, pyroptosis, necroptosis)
Reactive oxygen species (ROS): types, source, effects
Balance between ROS and antioxidants in human health and unbalance in human disease
Intracellular accumulations of endogenous and exogenous substances
Molecular and cellular aspects of protein misfolding and mechanisms of protein-folding diseases
The stem cell and the concept of pluripotency
Main properties of embryonic and adult stem cells
The hematopoietic stem cell as a paradigm of adult stem cells
Reprogrammed cells and induced pluripotency
Somatic cell reprogramming by nuclear transfer ("therapeutic cloning")
Hallmarks of aging
Genetic and biochemical changes in aging
Cellular senescence
Stem cell exhaustion
Altered intercellular communication
Sources, biochemical functions, and health benefits of energy-releasing and energy-converting vitamins (B1, B2, B3, B5, B6, B7), and deficiency-related diseases
Sources, biochemical functions, and health benefits of hematopoietic vitamins (B9, B12), vitamin C, and deficiency-related diseases
Lipid-soluble vitamins (A, D, E, K), and deficiency/excess-related diseases

BLOCK 2
Effect of mutations on protein function
Mechanism linking mutations to disease
Same gene, different phenotypes; different genes, same phenotype
Mutation not affecting coding gene sequences
Molecular basis of reduced penetrance in human inherited diseases
Identification of genetic risk factors in complex diseases
Common versus rare variant hypothesis in neurodegenerative disorders
Lessons from studying monogenic disease for common disease: the genetics of Alzheimer disease and mellitus diabetes
Epigenetic mechanisms
Epigenetic modifications and environment
Role of epigenetics in human diseases
Mechanisms of action of miRNA and lncRNA
Role of miRNA and lncRNA in human diseases
Genetic variation and drug response
Genetic variation and personalized medicine

BLOCK 3
Microbiota in health and disease
Basics of bacterial cell structure
Properties of bacterial cell walls (Gram staining, structure of peptidoglycan, LPS structure and role in human pathogenesis, target sites for antibiotics)
The genetic makeup of bacteria
Mechanisms of bacterial virulence: secretory, membrane-associated, and cytosolic factors. Structure, regulation, expression and their contribution to pathogenesis and immune evasion.
The eukaryotic nature of fungi and their classification
The fungal relationships with humans: basic pathogenic mechanisms for opportunistic and invasive infections.
Structure, morphology, genome organization and virulence factors of parasites
Pathogenesis of Giardia, Trichomonas, Plasmodii, and intestinal nematodes
Structure, morphology, genome organization and evolution theories of viruses
Classification of the viruses infecting humans Replication's strategies
Mechanisms of viral pathogenesis Determinants of communicable diseases

BLOCK 4
Structures, genome organization, replication properties and pathogenesis of clinical relevant human picornaviruses.
Structures, genome organization, replication properties and pathogenesis of clinical relevant human flaviviruses.
Structures, genome organization, replication properties and pathogenesis of the human viruses belonging to the viral families: togaviridae, coronaviridae, rhabdoviridae
Structures, genome organization, replication properties and pathogenesis of the viruses belonging to the viral families: orthomixoviridae, paramixoviridae, and pneumoviridae.
Structures, genome organization, replication properties and pathogenesis of the viruses belonging to the viral families: filoviridae, arenaviridae, bunyaviridae.
Structures, genome organization, replication and pathogenesis of the major viruses causing hepatitis.
Structures, genome organization, replication and pathogenesis of the major viruses causing hepatitis (II).
Structures, genome organization, replication properties and pathogenesis of the human herpesviruses.
Structures, genome organization, replication properties and pathogenesis of the viruses belonging to the viral families: parvoviridae, adenoviridae, papillomaviridae.
Structures, genome organization, replication properties and pathogenesis of the human polyomaviruses.
Structures, genome organization, and replication properties of HIV.
Pathogenesis of HIV.
Structures, genome organization, replication properties and pathogenesis of the human delta retroviruses (HTLV-I and II). Structures and pathogenesis of the prions.


BLOCK 5
Classification, pathogenetic mechanisms and diagnostic aspects of most clinically relevant bacteria.
Staphylococcus, Streptococcus, Enterococcus.
Corynebacterium diphtheriae.
Listeria monocytogenes, Legionella pneumophila, Chlamydiae, Neisseriae.
Haemophilus influenzae.
Bordetella pertussis.
Campylobacter, Helicobacter pylori, Vibrio cholerae, Pseudomonas aeruginosa, Acinetobacter.
Clostridia and bacilli
Mycobacteria
Fungi (Candida, Cryptococcus, Aspergillus, dermatophytes, Blastomyces, Coccidioides, Histoplasma, Pneumocystis).
The burden of nosocomial infections
Anti-microbial resistance
Superbugs (MRSA, VRE, KPC)

BLOCK 6
The hematopoietic niche and hematopoietic stem cells
Hematopoietic lineages and cytokines
The normal and altered blood counts
Biological and physical barriers of innate immunity
Cardinal signs of acute inflammation
Blood flow alterations and vascular permeability
The endothelium as a reactive biological structure
Mast cells, phagocytes and NK cells
Molecular mediators active on vessels
Molecular mediators active on leukocytes
Primary inflammatory cytokines
Eicosanoids
Cell adhesion: adhesion molecules and cell migration, the chemokine system
Pathogen-Associated Molecular Patterns (PAMPs) and Pathogen Recognition Receptors (PRRs)
Danger-Associated Molecular Patterns (DAMPs) and their receptors
The TLR system
Intracellular PRR
Opsonic receptors
Genetic defects in pathogen recognition
Complement system: Activation pathways, functions, regulatory mechanisms, genetic defects in the complement system
Mechanisms of cell-mediated cytotoxicity: phagocytosis and degranulation
Oxygen-dependent mechanisms, oxygen independent mechanisms, opsonic agents
Genetic defects in pathogen killing mechanisms
Energy for immunity
Metabolic signatures and profiles of key immune cells
Metabolic control of immune responses
Neutrophils metabolism and bioenergetics of anti-microbial action
Metabolism of macrophages
Metabolic shifts in macrophage activation and polarization
Negative regulators of the inflammatory response
The hypothalamic-pituitary-adrenal axis
Anti-inflammatory cytokines and eicosanoids
Stem cells and growth factors in tissue renewal
Multistep process of tissue repair, fibrosis, anomalies in wound healing
Distinct types of chronic inflammation
Cellular and molecular effectors of chronic inflammation
Macrophage polarization in chronic inflammatory responses
Systemic inflammation: Fever, leukocytosis, acute phase proteins

BLOCK 7
Key features of acquired immunity: specificity, memory, tolerance
The lymphoid system
Primary and secondary lymphoid tissues, lymphatic vessels
The antigen: source, structure, processing
Thymus-dependent and thymus-independent antigens
Structure and function of Major Histocompatibility Complex I and II
MHC-I and MHC-II loci organization
Superantigens
Professional and non-professional antigen presenting cells
Dendritic cells origin and subsets
Dendritic cells maturation and migration
Costimulatory molecules
Intrathymic development
Positive and negative selection of T lymphocytes
TCR structure and repertoire generation
Central and peripheral tolerance
The TCR/CD3 signalling complex and transduction pathways
Helper and cytotoxic T lymphocytes
BCR signalling and B cell activation
Antibody classes: structure and functions Isotype switch
Antibody classes in primary and secondary immune responses
Affinity maturation
T helper subsets and polarized immune responses
Differentiation and signalling in T helper cells
Immune response polarization in pathology
T cell / macrophage crosstalk in chronic inflammatory responses
Impact on effector cells
Immune granulomata: an immune perspective
Regulatory T cells
Myeloid regulatory cells
Metabolic differences between innate and adaptive immunity
Metabolism of specific T cell lineages
T cell metabolism changes during immune response
Vaccines and their development

BLOCK 8
Recognition of viral infection by the immune system
Effector mechanisms against viral infections
Viral strategies for evading antiviral immune responses
Recognition of intracellular infection by the immune system
Microbial strategies for evading immune responses
The mucosal immune system
Mucosal immunity and commensal microorganisms
Mucosal immunity to pathogenic microbes
General issues on hypersensitivity reactions
Type I hypersensitivity
Type II hypersensitivity
Type III hypersensitivity
Type IV hypersensitivity
The multifactorial pathogenesis of autoimmune diseases
Failure mechanisms of the central and peripheral tolerance
Effector mechanisms of autoimmune reactions
Immune mechanisms of the most common autoimmune diseases
Differential features of autoimmune vs autoinflammatory diseases
Immune deficiency caused by defects in innate immunity
Immune deficiency caused by defects in B and T maturation
Iatrogenic immunodeficiencies
HIV infection and immune response
Acquired immune deficiency syndrome (AIDS) pathogenesis
Animal models to assess HIV-1 infection and AIDS pathogenesis
Immunological basis of allograft rejection
Major and minor histocompatibility antigens
Molecular basis of direct and indirect allorecognition
Mechanisms of hyperacute, acute and chronic rejection graft-versus-host disease
Age-related changes in the innate immune system
Age-related changes in the adaptive immune system
Impact of immunosenescence on diseases and vaccination
Tissue immunometabolism: relationships in the gastrointestinal tract, liver, and adipose tissue
Relationships between systemic metabolism and immunity
Vitamins in the control of immunity
Obesity as a multifactorial disease
Immunological implications of obesity

BLOCK 9
Definition of cancer and epidemiology
Tumor nomenclature, TNM classification
Differentiation and cell grading, rate of growth
Local invasion
Metastasis, pathways of spread
Oncogenic signaling and tumor microenvironment as drivers of cancer metabolism
Tumor sensing and metabolic adaptations to hypoxia and nutrient deprivation
Signals and targets of metabolic reprogramming in cancer cells
Advantages and liabilities of tumor cell metabolism
Genes in which mutations cause cancer: oncogenes, tumor suppressor genes (gatekeepers and caretakers genes)
Type of genetic alterations responsible for initiating cancer
Activating or gain of function mutations
Ectopic or heterochronic mutations
Chromosome translocations
Loss of function mutations
Genomic instability and tumor progression
Activated oncogenes in hereditary cancer syndrome: MEN2
Gatekeeper tumor suppressor genes in AD cancer syndromes
The two-hit origin of cancer: the hereditary and sporadic forms of retinoblastoma
The Li-Fraumeni syndrome
Caretaker gene in autosomal dominant cancer syndromes
BRCA1 and BRCA2 mutations in familial breast cancer
Familial colon cancer
Counselling and germline mutation testing
The hallmarks of cancer
The cancer-associated genes involved in the hallmarks of cancer
Genomic instability and multistep carcinogenesis
Cancer stem cells
UV and ionizing radiations
Chemical carcinogenesis: initiation, promotion and progression
Metabolic activation of chemical compounds in vivo
Factors that control chemical carcinogenesis
Genotoxic and non-genotoxic effects of carcinogens
Oncogenic DNA and RNA viruses
Genetic mechanisms underlying the oncogenic process
Host interaction with oncogenic viruses
Pathogenic role of viruses into the oncogenic process
Role of bacteria into the oncogenic process: the H. pylori case
The immunosurveillance hypothesis
Determinants of tumor antigenicity
Defensive mechanisms against tumors
Mechanisms of cancer immune evasion
Cancer immunoediting
Principles of cancer immunotherapy
Epidemiologic evidence
Myeloid-derived suppressor cells
Tumor-associated macrophages and neutrophils
Mechanisms of angiogenesis and vasculogenesis
Endothelial progenitors and other pro-angiogenetic bone marrow-derived cells
Angiogenetic cytokines and their receptors
Common and distinctive features of blood and lymphatic vessels
Role of angiogenesis to tumor survival and growth
The role of the tumor microenvironment
Cancer-related anorexia and cachexia
Metabolic mechanisms of neoplastic cachexia
Molecular mediators of neoplastic cachexia
Tumor factors contributing to cancer cachexia
Clinical characteristics of neoplastic cachexia
Paraneoplastic syndromes

BLOCK 10
Platelets
Primary and secondary hemostasis and coagulation cascade
Fibrinolytic system
Mechanisms of atherosclerotic plaque generation: risk factors, clinical manifestations and complications
Thrombus formation and evolution
Thromboembolism and immunothrombosis
Pathogenesis and stages of shock
Disseminated intravascular coagulopathy
Biology of the red blood cell and classification of anemias

BLOCK 11
iPCs-technology as a tool to investigate pathogenesis and therapy of human diseases
Modern translational approaches in immunologic disorders
Bio-informatics approaches in the diagnosis of a new primary immune deficiencies
Regulatory agencies and policies of physicians facing new challenges and technologies
Flow cytometry in diagnosis and therapy of hematologic malignancies
Bone marrow reconstitution