XXXVIII CICLO 

A critical piece in drug discovery and development is conducting DMPK (Drug Metabolism and Pharmacokinetics) studies, often referred to as ADME-T (Absorption, Distribution, Metabolism, Elimination, Toxicity). ADME studies are designed to investigate how a chemical (e.g. a drug candidate) is processed by a living organism and how ADME properties could affect its activity. For a drug candidate, "optimizing" ADME properties before clinical investigation is of utmost importance to ensure it is as effective and safe as possible; it is estimated that close to 50% of drug candidates fail because of unacceptable efficacy due to an unfavourable ADME profile. This course aims to provide PhD students engaged in the early drug discovery process awareness about the importance of preclinical ADME investigation, the strategies and the methodologies that assist to achieve efficiency in the hit-to-lead process.

Food safety is a critical requirement in modern nutrition. Traces of contaminants - from biological/environmental and/or anthropic origin - are always present in our dishes, potentially triggering adverse reactions (acute, chronic) in consumers. Exposition, diet, age and personal susceptibility are parameters involved in the risk correlated to the ingestion of food contaminants. Among the contaminants classes, mycotoxins and food allergens represent a big challenge for the exposed consumers. The presence of mycotoxins in food can be related to the quality of the raw materials, but also strictly linked to the climate change. Masked mycotoxins open new requirements in food science and food technology. Beside mycotoxins, the presence of food allergens represents another key risk for sensitized consumers. More particularly, the detection of hidden allergens (or allergenic ingredients) in foods requires sensitive methods of analysis (direct or indirect analysis), also depending on the crucial role of the personalized response in sensitized people. All these findings will be debated in these lectures, focusing on analytical and safety perspectives.
Prof. Chiara Dall'Asta (CHIM/10) currently serves as Associate Professor of Food Chemistry affiliated with Drug and Food Department (University of Parma), deeply working in collaboration with European Food Safety Agency (EFSA). She is working on mycotoxins since many years, with a deep expertise in analytical detection of mycotoxins, metabolomics and masked mycotoxins in food.
Prof. Patrizia Restani (CHIM/10) is Full Professor of Food Chemistry affiliated with University of Milan. She is working since many years in collaboration with the Ministry of Health (Rome) in the Technical Board for Food Allergies. The main expertise of Prof. Restani is focused on protein food allergens and adverse reaction to foods, particularly focusing on the establishment of the threshold values for food allergens and the development of new analytical methods.

The development of new ingredients for food and food supplements is a cool topic in Food Science and Technology. Circular economy for the food and drink industry means an efficient use of resources (water, energy, raw materials), from the sourcing of agricultural raw materials to the consumption of the food products, including the need to prevent food losses and wastage at each and every stage wherever possible. Through continuous improvement and product innovation, many food and drink manufacturers have developed by-product and co-product lines to maximise the use of raw materials and minimise food waste. The availability and the transformation of new sustainable sources (also facing with the problem of the production of 'novel foods' as defined in Reg. (UE) 2015/2283) is another key topic in this area. Enzyme-driven production of new bioactive ingredients and industrial scale-up, as well as the analytical profiling of new ingredients under the metabolomic and proteomic umbrellas, will be the main topic of the lectures, debating some case studies.
Dr. Fabrizio Rivardo is currently R&D Manager at A. Costantino & C. S.p.A.. Dr. Rivardo is a specialist in enzymatic hydrolysis process at industrial level, with a deep expertise in food and food ingredients.
Prof. Luigi Lucini currently serves as Associate Professor (Agr/13) at Universita Cattolica di Piacenza, teaching Physical Chemistry and Biochemistry of food. Since 2014 is responsible for the metabolomics facility at his Faculty, dealing with plant, food, microbiology and environmental metabolomics.

This course aims to provide a comprehensive overview of the design, formulation, preparation, control and regulatory aspects of Advanced Therapy Medicinal Products (ATMPs). In the first part, the regulatory framework and scientific basis of ATMPs will be presented, while the second part of the course will be focused on the formulation and technological aspects as well as the industrial production according to the Good Manufacturing Practice (GMP).

Biomaterials used in orthopedic applications: advantages and disadvantages. - Tissue engineering may offer new treatment alternatives: scaffolds and cells. - Regenerative medicine: want to replace and repair lost or damaged tissues by stimulating the natural regeneration process. The gap between the damaged fragments has to be filled with functional materials that act as a substrate and as a physical three-dimensional microenvironment for inducing the migration and organization of cells from the native tissue. - Differentiation and maturation signals that positively promote osteogenesis or chondrogenesi.

Bioorganic chemistry deals with the understanding of biochemical processes and their application for the development of novel organic chemistry tools. Throughout the course, you will gain a basic understanding of bioorganic chemistry: starting from its key concepts, the course will develop through the analogies between organic reactions and biochemical transformations (Biomimetic Chemistry), the catalytic mechanisms of several classes of enzymes, and how some of the effects we observe in enzyme mechanisms can be applied to organic synthesis as well. Prerequisites Basic knowledge: acid-base theories; principles of chemical kinetics and fundamentals of thermodynamics. Knowledge of organic chemistry: structure, properties, and activities of the main functional groups of organic chemistry; fundamentals of stereochemistry.

Nociceptors are peripheral sensory neurones which respond to painful (noxious) stimuli thanks the expression of nociceptive ion channels. Nociceptors express a unique repertoire of voltage-gated channels, as well as cation channels of the transient receptor potential (TRP), acid-sensing ion channel (ASIC), and purinergic P2X families. The course will focus on the specific properties of nociceptive channels and their role in a number of pain modalities, including inflammatory pain, neuropathic pain, visceral pain, and pain associated to certain pathological conditions, including cancer or migraine.

The recent years have witnessed a dramatic development of computational methods for the prediction of protein structures, and the advent of artificial intelligence has dramatically changed the tools used by scientists for the prediction of protein structures and of protein-protein complexes. This has also marked a dramatic advancement in the de novo design of proteins, enabling the engineering of new nanomaterials. I will present the most recent breakthroughs in experimental protein structure analysis and computational protein structure predictions, with a focus on drug discovery and on the development of protein nanomaterials.

The chemistry of life is commonly associated to a handful of elements, usually identified with the mnemonic acronym CHNOPS, summarizing the key elements of organic chemistry. However, surprisingly, this small list is much shorter than is believed. The human body contains at least 60 detectable chemical elements and about 25 of them play a role in its healthy functioning. Moreover, more than 45 elements (including radionuclides) are used as metallodrugs in diagnostics or in therapy. A journey through the periodic table will provide an overview of the elements, their role in the living organism and the application of their compounds in medicine.

This short course is targeted at those who wish to learn the basics and challenges of drug screening on information rich cell based models. Cell-based assays, because of their advantages in terms of predictability, multiplexing, miniaturization and automation seem the most appealing tool for the high demands and high quality standards of the early stages of the drug-discovery process. Nevertheless,scientists working on assay development for cellular screening still face a variety of challenges. Aspects of assay design ranging from cell type choice, readout selection, standardization, miniaturization, data analysis, will be covered. Moreover, advantages of targeted versus phenotypic assays in drug screening will be discussed.

Medicines have changed in the last 70 years: many progresses on the bases of technologies and target selectivity have been made. The course will give an overview of the pharmaceutical drugs other than the chemical entities, such as biological and biotechnological drugs, cell therapy and gene therapy. The course aims to explain how the biotechnological drugs are produced, how they are administered and use in the clinic and the advantages/disadvantages over the small molecules.

Discovery of Green Fluorescent Protein (GFP) has revolutionized Biomedical Sciences, making it possible optical visualization and imaging of organs, cells, sub-cellular structures and proteins in living animals and plants. Generation of full color palette of fluorescent proteins (PFs) and biotechnological engineering of fluorescent probes, based on FRET (fluorescence resonance energy transfer) and cpGFP (circularly permuted GFP), enabled monitoring of dynamic changes of intracellular concentrations of ions and second messengers. Split-GFP probes allowed dynamic visualization of interaction between proteins and organelles. All this made the fluorescent proteins an integral part of the discovery process from basic research to biotechnological tools and products. This course will provide a basic knowledge on structure and usage of GFP and its analogues/derivatives. Examples will include multicolor transgenic animals, structure and usage of probes for investigation of cellular signaling processes, protein-protein interaction and drug screening.

The natural compounds are an endless source of ideas for the discovery of new drugs to treat diseases, and the total synthesis of complex natural products still represents a big challenge for the organic chemist. While many strategies applied to the synthesis of complex natural products are based on the construction of individual rings or fragments of the natural products followed by a unification step, or by the iterative annulation of one ring onto a preexisting ring, an efficient alternative strategy could be represented by the transannular cyclization reactions. Transannular reactions are defined as those reactions which lead to the formation of covalent bond between atoms on opposite sides of the ring compound. 1 They usually occur in macrocyclic compounds that, to minimize transannular strain (Prelog strain), are constricted in rigid conformations that force some functional groups to be close to each other. 2 This intimacy between functional groups confers entropic advantages to enable transformations that are otherwise difficult in intermolecular and intramolecular settings, 3 making transannular reactions a highly efficient tool for the construction of complex polycyclic architectures. Transannular reactions are classified according to the reaction type involved in the cyclization process [Diels-Alder (TADA), ene reaction, [2+2] and other cycloadditions, Michael addition, aldol condensation, Mannich and miscellaneous reaction]. 4 The transannular cyclisation process is the result of a series of cascade reactions that allow us to obtain a complex polycyclic architecture from an easily accessible macrocyclic compound, representing a shortcut in the synthesis of complex natural products. The entire process can be highly influenced by several factors such as the conformation of the macrocycle and the activation strategy. This course will outline the main features and the applications of transannular ring closure reactions and examples will be given to validate this approach as a versatile, efficient and flexible strategy to access new polycyclic structures on the way to the synthesis of important natural products.

Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models are two-dimensional cell lines established from primary tumors or fluids. While these have provided some important insights into cancer biology, these cell models have significant limitations. In order to address some of these limitations, spheroids, tumor- derived organoids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment. Efforts have also been made to develop animal models, including genetically modified mice and patient-derived xenografts. We will highlight strengths and weaknesses of the available in vitro and in vivo models.

For PhD students, the prospect of writing their very own scientific research paper may be both exciting and hard. The goal of this course is to provide effective tools to improve writing skills and manuscript writing process.

The course is devoted to providing PhD students engaged in the early drug discovery process with the concepts, the strategies and the methodologies that assist the identification of high-quality drug candidates. This is of utmost importance, as of the thousands of novel compounds that a drug discovery project leads to, only a fraction of these have sufficient ADMET properties to become a clinical candidate. 

Organic chemistry and pharmacognosy have long been an almost unique discipline, with natural products acting as a major driver of advancement for both areas. With the advent of molecular assays, the development of spectroscopy, and the growing sophistication of current synthetic organic chemistry, a comprehensive technical expertise in both fields has become impossible and natural products research has become sectarian and articulated in several sub-disciplines. In this scenario, the role of organic chemistry has undergone a change, moving from a tool of structure elucidation to a mean to manipulate natural products structures and explore their associated biological space. In this context, organic chemistry is metamorphosing into medicinal chemistry, but the transition is essentially molecular in nature, and has been well managed, with organic chemistry retaining a critical role in the development of a scalable synthesis for natural products difficult and/or expensive to obtain by isolation. 1 On the other hand, there is growing evidence that, rather than magic bullets, natural products are magic shotguns, targeting a host of molecular end-points that are often part of homeostatic feed-back loops difficult to perturb with focused monomolecular agents. 2 In this context, mixtures of products like extracts might play an important role, but working with mixtures rather than monomolecular agents is a challenging task that is only now coming of age. 

The course will give an overview of the molecular mechanisms underlying immune recognition in cancer, the up-to date approaches to harness anti-tumor activities of immune cells and the major challenges that remain to be overcome. (The course will be held in Italian).

The interdisciplinary course will provide an overview of the immunomodulatory activity of gut microbiota and its impact on cancer onset, progression and response to therapy. Approaches to modulate gut microbiota composition to enhance response to cancer therapy will be also discussed. Particular attention will be given to the study of the dominant members of the gut microbial ecosystem, their spatial distribution among physical niches and their crucial functions in human health.

The course aims to enrich the theoretical knowledge of statistics and probability with suitable data analysis skills; the course focuses also on data visualization and is based on the free and open source software R.

Formulation step represents a key point in the development of finished pharmaceutical and cosmetic products. The aim of this course is to provide a theoretical and practical overview of formulation approaches and strategies to obtain a successful product.

The course will be focused on the analytical techniques necessary to characterize the volatile component of the various food matrices. Using an appropriate technique is essential in understanding the impact that food processing has on the final product, in particular on the volatile component. The techniques for analyzing the aroma of foods such as extraction, identification and quantification methods will also be described in depth. Gas chromatography-olfactometry will also be treated in relation to its principles and applications. At the same time, the course aims to provide the basis for understanding the main analytical technique for monitoring and characterizing the volatile profile of foods (gas chromatography). Other aspects will also be treated such as molecular sensory sciences (sensomics) and the detection of powerful odorant compounds in food by GC-MS-Olfactometry. The latter will be analyzed in detail for three fundamental aspects that concern it: a) dilution analysis (dilution analysis of the aromatic extract), b) time intensity method, c) detection frequency method.

Cancers promote immunological stresses that induce alterations of the myelopoietic output, defined as emergency myelopoiesis, which lead to the generation of different myeloid populations endowed with tumor-promoting activities. New evidence indicates that acquisition of this tumor-promoting phenotype by myeloid cells is the result of a multistep process, encompassing initial events originating into the bone marrow and later steps operating in the tumor microenvironment. The careful characterization of these sequential mechanisms is likely to offer new potential therapeutic opportunities. The course will describe relevant mechanisms of myeloid cell reprogramming that establish immune dysfunctions and promote tumor progression, thus limiting the efficacy of anticancer therapies. 

Il corso si propone di raccontare la vita e le più importanti scoperte scientifiche di alcuni giganti della chimica dei tempi passati, con particolare enfasi sulle nuove reazioni da loro individuate. In questo ciclo verranno ricordati i seguenti chimici: Francesco Selmi, Cesare Bertagnini, Tetsuo Nozoe, Vladimir Prelog. Il corso sarà tenuto in italiano ed in presenza.

The aim of this course is to present and show the potentiality of the archetypical click reactions (CuAAC, Bertozzi copper free click chemistry, Staudinger ligation, SuFex, Thiolo-ene reaction) in different areas of research such as drug discovery, bioconjugation, in vivo imaging. In the first part, the molecular mechanisms of these reactions will be presented and discussed, while in the second part of the course will be presented real applications of these techniques.

The scope of this presentation is to give an overview of the different bioanalytical approaches used to support New Biological Entities (NBE) and Antibody Drug Conjugates (ADC) projects. Ligand Binding Assays are considered the gold standard for the determination of the concentration of proteins and antibodies in pharmacokinetic (PK) and toxicokinetic (TK) studies (serum, plasma); different approaches will be presented including ELISA, Gyrolab, Mesoscale Discovery (MSD), and Simoa Quanterix technologies. Immunogenicity risk associated with the development of anti-drug antibodies (ADAs) following administration of biotherapeutics is considered one of the main issues in the development of New Biological Entities. For this reason, different approaches to detect ADA in in-vivo studies will be presented. LC-MS technique is also emerging as an alternative tool for the determination of the concentration of total Antibody in biological samples. In addition, LC-MS/MS techniques can be employed to support in vivo ADC pharmacokinetics studies: they can be dedicated to the quantitation of the conjugated toxin, detecting the active molecule, after the capture of the entire ADC and enzymatic cleavage of the linker. Moreover, LC-MS/MS methods are used to quantify the unconjugated toxin potentially released from the ADC. Cell-based assays are playing a crucial role in the development of NBEs. Different approaches based on flow cytometry will be presented for the understanding of the mechanism of action of novel drugs in in-vitro (target internalization) and in-vivo (receptor occupancy) studies. Finally, an overview of the pharmacokinetic properties of NBE will be provided including the different data analysis approaches used for PK parameters determinations.