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Artificial Intelligence applied to Collagen Imaging data in physiologic, pathologic and tissue-engineered conditions Alessandra Giuliani (DISCO) Project area MEDICINE Presentation Supervisor Project Idea Goals Mechanical stimuli are regulators not only in cell but also of the extracellular matrix (ECM) activity, with special reference to ...collagen bundles: sustained mechanical stimulation may lead to modifications of the collagen composition, amount and distribution. These interactions can determine pathophysiological processes, including developmental defects, fibrosis, inflammatory diseases, tumor growth and metastasis. Mechanical stimuli of the ECM can also support the bodys reaction to a therapy and the long-term therapeutic outcome. Thus, the maintaining or re-establishment of tissue tension, modulating external forces, is key to successful and regulated tissues remodeling/repairing and wound healing. In this context, this Project has two main objectives: (1) the identification of three-dimensional morphometric parameters deriving from the tomographic images analysis of pathological (fibrotic or cancerous) and regenerated collagen-based tissues (with comparison with healthy twin contexts); (2) to reconstruct volume forces and contact forces acting locally in these contexts. The morphometric parameters are those that will be extracted by the big amount of high-resolution phase-contrast synchrotron imaging data, contained in the archive of the Supervisor research group. Segmentations guided by artificial intelligence will be also implemented and followed by data mining. |
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The Impact of Early Life Stress on the Vulnerability to Obesity Antonio Giordano (DIMSC) Project area MEDICINE Presentation Supervisor Project Idea Goals Environmental stimuli acting during critical periods of postnatal development permanently shape individual behavior and metabolism...; early life stress (ELS) is associated with overweight and obesity in humans and animal models, however, how it impacts the development of white and brown adipose tissues and the circuitry regulating energy balance needs to be elucidated. ELS reduces plasma levels of two important energy balance modulators: oxytocin (Oxt), a neurohormone released by hypothalamic nuclei, and leptin (Lep), a fat-derived hormone. Both induce satiety and hold central and peripheral differentiative functions during early post-natal life. Importantly, Lep anorectic effect is in part mediated by Oxt. The main study hypothesis is that ELS increases the vulnerability to obesity in adulthood permanently shaping the development of: i) adipose tissues, ii) neural circuitry regulating feeding behavior, and iii) the Lep and Oxt systems and their reciprocal interaction. In this project, C57BL/6 mice exposed to ELS consisting of limited bedding and or to ELS plus high-fat diet in adulthood will be used to establish the ELS effect on obesity vulnerability in adulthood. To this end we will mainly employ our expertise in the performance of morphological studies, but also perform behavioral and molecular biology assessments. |
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Nicotinamide N-methyltransferase enzyme as molecular target for effective anticancer therapies Davide Sartini (DISCO) Project area MEDICINE Presentation Supervisor Project Idea Goals The first part of the experimental work will be focused on cloning, expression and purification of human recombinant NNMT enzyme, ...by using a eukaryotic expression system. This approach would provide good yields, in terms of protein expression, as well as guarantee the presence of post-translational modifications relevant to NNMT activity, which otherwise would be lost when expressing in E. coli. During the subsequent phase of the experimental plan, catalytic assays will be carried out to evaluate the effect induced by small molecules on NNMT activity, in order to identify compounds that could act as efficient enzyme inhibitors. Further in vitro cell-based assays will explore the ability of these compounds to affect tumor cell phenotypic traits, such as proliferation, migration and chemosensitivity. The final step of the project will be devoted to the obtention of crystals, related to purified NNMT in combination with efficient inhibitors, suitable for X-ray crystallography experiments. This will elucidate the high-resolution structure of different protein-ligand complexes, thus allowing to unveil the inhibitory mechanism-of-action. |
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MUST study: MUlti-omics phenotyiping of non-Specific pleuriTis Federico Mei (DISBSP) Project area MEDICINE Presentation Supervisor Project Idea Goals Diagnosis in pleural diseases often hinges upon the findings following pleural biopsy. However, in approximately 40% of cases, the... histological findings show non-specific patterns of inflammation and fibrosis (non-specific pleuritis, NSP), including a heterogenous group of pathologic conditions that remain poorly understood. Therefore, there are still significant uncertainties for both patients and clinicians in diagnostic work-up and subsequent management, due to the lack of an accurate identification of underlining etiology. Most of the research have focused on identification of a limited subgroup of patients with NSP who eventually develop malignancy, mainly malignant pleural mesothelioma (MPM), leaving the large majority of patients with no diagnosis, besides an heterogenic and empirical treatment, and a protean investigation approach. Therefore, a definitive assessment of yet unmet needs in NSP is required. These include the need for standardized investigation protocols and for a better understanding of biological and mechanistic pathways responsible for the different clinical characteristics and evolution observed in patients all labeled with the broad name of NSP. The MUST study, allied to our research network (EPIC: European Pleural disease Investigators Collaboration), aims to conduct a prospective longitudinal study creating a translational platform. We will conduct multi compartment sampling and omics analysis with the aim to identify disease endotypes, treatable traits and future targets for precision medicine (including repurposing of currently available medications). |
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The effects of plant-based foods on lipid metabolism and adipogenesis Francesca Giampieri (DISCO) Project area MEDICINE Presentation Supervisor Project Idea Goals Obesity, which has been associated with many chronic disorders, is one of the major epidemiological problems of the 21st century w...orldwide. Approximately 30% of the worlds adult population is obese (about 2.1billion) and more than 3 million people die every year as result of this illness. It is well known that obesity is caused by a sustained imbalance between energy intake and expenditure that leads to an expansion of adipose tissue mass, the so called adipogenesis process, as well as to a dysregulation of lipid metabolism. Several plant-based foods have demonstrated not only to inhibit adipogenesis but also to ameliorate obesity by increasing thermogenesis, promoting white adipose tissue browning and improving lipid metabolism, but the mechanisms are still elusive. The main objective of this project is to evaluate the effects of plant-based foods on lipid metabolism and adipogenesis in both pre-adipocytes and mature adipocytes by assessing the: - pre-adipocytes differentiation - induction of brown fat-like phenotype - intracellular levels of lipids and the total lipid accumulation - markers of lipid oxidation - main biomarkers of oxidative stress and inflammation - principal molecular pathways involved - mitochondrial respiration |
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Design and construction of a non-invasive device to trap magnetic nanoparticles in pancreatic cancer for a more efficient anti-tumour agent delivery Francesco Piva (DISCO) Project area MEDICINE Presentation Supervisor Project Idea Goals Pancreatic cancer is the least responsive to chemotherapy treatments because it is composed of a microenvironment that protects it... from external actions. Today it is possible to conjugate magnetic nanoparticles to peptides that recognize target proteins in the membrane of tumour cells and simultaneously conjugate them to chemotherapy drugs. These nanoparticles should be administered directly into the pancreas via ultrasound guidance. This project aims to design and create a prototype that generates a special configuration of magnetic fields that can retain the nanoparticles deposited in the pancreas. Through this magnetic trap, we want to maintain a high concentration of chemotherapeutics in the pancreas to make the therapies more effective and not involve the other organs to reduce the side effects. The equipment will be placed outside the patient and will not pose any risk. For this project we are looking for a researcher with experience in using magnetic field simulation software and who has had practical experience. We test the prototype on a physical model that has viscosity and liquid flows like those of the body. |
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Multi-omics and AI approach in rare diseases: implementing an innovative diagnostic pathway and precision medicine tool for fibrotic diseases Gianluca Moroncini (DISCLIMO) Project area MEDICINE Presentation Supervisor Project Idea |
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NAD Metabolism and Programmed Axon Death Giuseppe Orsomando (DISCO) Project area MEDICINE Presentation Supervisor Project Idea Goals We focus on human neurodegeneration and neuropathologies characterized by a preventable, non-apoptotic mechanism of cell death ter...med Programmed Axon Death or Wallerian degeneration (WD), that our team has contributed to unveiling in recent years. Key molecular players in this process include NMNAT2, a vital enzyme leading to NAD synthesis within axoplasm, and SARM1, a recently discovered tightly regulated multidomain protein with multicatalytic NAD-consuming activity. These are both crucial for NAD metabolism in neurons by regulating levels of NAD intermediates or sensing their fluctuations, ultimately determining the fate of axons, either survival or death. However, the mechanism downstream of SARM1 activation is presently unknown. In this view, we propose an experimental plan outlined as follows: 1) further exploration of the role of NAD pathway in regulating axon survival or death; 2) deeper investigation into neurodegenerative diseases associated with NMNAT2 or SARM1; 3) development of novel drugs targeting SARM1 or NMNAT2 to treat neurological disorders. |
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Acting on miRNA expression to overcame drug-resistance of thoracic malignancy Marco Tomasetti (DISCLIMO) Project area MEDICINE Presentation Supervisor Project Idea Goals Chemoresistance is a hallmark of thoracic malignancy management including malignant pleural mesothelioma (MPM) and lung cancer (LC...). The cancer heterogeneity, stroma environment, immunological factors, as well cancer stem cells (CSCs) all contributed to the acquirement of the chemo-resistant phenotype. Several studies have focused on miRNAs impact on chemotherapeutic resistance in cancers. There have also been several meta-analyses and systematic reviews considering the link between miRNAs and chemoresistance and disease recurrence. Therefore, the identification of a specific drug-resistance miRNA profile may predict drug response and contribute to sensitize cancer cells to the standard treatment. Organoid from patients display similar genotypic and phenotypic characteristics, making them ideal for investigating individualized treatment strategies and for integration as a core platform to be used in prediction models. Using organoid-derived patient model, the project will identify a miRNA panel involved in chemotherapy (CHT) and immune therapy (IMT) resistance in thoracic malignancies. The identified miRNAs will be check for their capacity to sensitize cancer-resistant cells to CHT and IMT by restoring multiple pathways. Next, by evaluating miRNA pathways involved in CHT and IMT resistance, biomarkers for prediction of drug response will be identified. The identification of miRNA-pathways involved in drug resistance will open new approach to overcome chemoresistance. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with thoracic malignancies. the regulation of many molecular pathways. Several studies have focused on miRNAs impact on chemotherapeutic resistance in cancers. |
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Telerehabilitation and telemonitoring based on wearable sensor data analysis Maria Gabriella Ceravolo (DIMSC) Project area MEDICINE Presentation Supervisor Project Idea Goals Non communicable disorders affect up to 2,3 billion people in the world, being the major cause of chronic disability and accountin...g for the 63% increase in the total amount of disability-adjusted life years after 1990 (https://vizhub.healthdata.org/rehabilitation/ ) Chronically disabled people need regular appointments with Physical and Rehabilitation Medicine (PRM) physicians to check their health status and disability progression. Rehabilitation therapy has been identified as a suitable solution to fight functional decline and improve quality of life. Albeit training regularity and intensity are crucial factors to ensure effectiveness, performing training sessions at clinical centres is neither feasible nor economically sustainable for all those who are in need of rehabilitation. Tele-rehabilitation is regarded as an alternative to delivering tailored rehabilitation interventions in the post-acute and/or the long-term phase, using digital telecommunication technologies. The combination of tele-rehabilitation with tele-monitoring via wearable sensors, allowing objective patient data collection continuously, in the real-world, can improve patient-clinician interactions and empower patients over their health. We propose to test the feasibility, safety and effectiveness of a tele-rehabilitation and tele-monitoring system, exploiting commercial wearable sensors, in a large population of people with disabling non communicable disorders, either due to neurological, oncological or musculoskeletal damage. |
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Anticancer effects of dietary bioactive compounds in mammospheres and colonspheres enriched with Cancer Stem (-like) Cells Maurizio Battino (DISCO) Project area MEDICINE Presentation Supervisor Project Idea Goals Breast and colon cancer represent the most common neoplastic disease worldwide. Many epidemiological studies have found that a die...t rich in fruits and vegetables exerts a preventive role in these cancers and, from a preventive point of view, numerous investigations have been made on plant bioactive compounds. The main objective of this project is to evaluate the effect of dietary polyphenols in mammospheres and colonspheres enriched with Cancer Stem (-like) Cells (CSCs-like). The specific objectives will be: 1. To characterize the dietary polyphenols and their antioxidant capacity. 2. To evaluate the ability of dietary polyphenols to decrease the morphological and physical parameters of mammo/colonspheres enriched with CSCs-like. 3. To investigate the effect of dietary polyphenols on intracellular ROS and apoptotic rate in mammo/colonspheres enriched with CSCs-like. 4. To evaluate the effect of dietary polyphenols to decrease the self-renewal ability of CSCs-like. 5. To investigate the effect of dietary polyphenols to reduce the migration capacity of CSCs-like. 6. To assess the effect of dietary polyphenols on pro-angiogenic factors. 7. To study the effect of dietary polyphenols on the length of telomeres. |
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StrategIes for the developmeNt oF custOmized 3D meNIscAl substitutes (SINFONIA) Monica Mattioli (DISCLIMO) Project area MEDICINE Presentation Supervisor Project Idea Goals Meniscal injury reduces its capability to act for shock absorption, load distribution, proprioception, and protection of the carti...lage from accelerated degeneration and meniscus surgery is one of the most performed orthopaedic procedures worldwide even if meniscectomy always alters normal joint biomechanics and can lead to the development and/or progression of osteoarthritis. Since current commercially available meniscal substitutes have not been convincing according to clinical feedback, the project aims to validate in vitro customized 3D meniscal substitute(s) replicating the biomechanical and biochemical properties of the meniscus. Three are the pillars on which the research project is built: Clinical study analyzing MRI scans obtained from the PACS database to select appropriate patients cohort and identify the main characteristics for the production of the meniscal structure Additive manufacturing and in-depth structural, physicochemical, and mechanical characterization of the obtained structures In vitro evaluation with appropriate cell models. The physic-chemical data will be key elements to get insight in structure capability to modulate the cell population in terms of the expression of genes/proteins involved in cell differentiation and mutual crosstalk. |
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Lipid droplets mitochondria contact as a key driver for cancer progression Saverio Marchi (DISCLIMO) Project area MEDICINE Presentation Supervisor Project Idea Goals For cells to function properly, it is necessary for cell organelles to communicate with each other. In this context, mitochondria ...establish functionally crucial connections with virtually all other intracellular structures. These interactions not only impact mitochondrial behavior and activity but also influence a wide variety of cellular functions. In recent years, it has been showed that mitochondria interact with lipid droplets (LDs) and this association induces a drastic remodelling of the cellular bioenergetics. However, the mechanisms regulating the LDs-mitochondria contacts, or their potential role in driving some pathological conditions (i.e cancer development), are still elusive. In this project, we aim to elucidate different aspects of the LDs-mitochondria tethering in the context of cancer progression, by providing fundamental clues on the molecular pathways that control contact formation, how the mitochondrial network rearranges, the metabolic changes that occur at these contact sites, and how they affect the tumorigenic potential of cancer cells. We recently collected some interesting preliminary findings on clear cell renal cell carcinoma (ccRCC), ensuring a perfect starting point for a MRSCA post-doctoral fellowship. |
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Transition to new technologies in the field of "in vitro" cytotoxicity testing Tatiana Armeni (DISCO) Project area MEDICINE Presentation Supervisor Project Idea Goals In recent years, also following specific EU directives, robust "in vitro" experimental models have been developed to predict poten...tial adverse effects associated with the exposure of organisms or biological systems to compounds including human drugs but also cosmetics, biocides, medical devices and other products. In recent years, the scientific community has relied on the principles of the 3Rs (Replacement, Reduction and Refinement) in the transition from animal models to "in vitro" models. To date, advanced technologies for developing increasingly complex "in vitro" models are available and evolving, breaking down limitations of animal models, such as difficult extrapolation between species, high cost, artifacts in addition to ethical questions. The project aims at the advancement of knowledge in cytotoxicology to implement strengthen and validate cytotoxicity assays and flow the information to available innovative high throughput platforms. The research group has extensive experience in "in vitro" systems on 2D or 3D cell models where to perform advanced cytotoxicity assays, redox signaling, efficacy assessment and cellular response. Implementation of "in vitro" cytotoxicity testing and validation of highly innovative systems could provide a data set to be extrapolated for training an AI bioinformatics system. |
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