Peritoneal metastasis (PM) is considered as the terminal stage of metastatic colon cancer, with still poor median survival rate even with the best recent chemotherapy (Chem) treatment suggesting the need for advanced methods to assist with the early diagnosis and treatment. However, the newest methods combine cytoreductive surgery with hyperthermic intraperitoneal Chem (HIPEC), which uses mild hyperthermia (Hyp) by circulation of a hot fluid to boost the diffusion and cytotoxic effect of drugs. A recent development in patients with unresectable PM is pressurized intraperitoneal aerosol Chem (PIPAC) that combines a diagnostic laparoscopy with locoregional administration of Chem as an aerosol. Non-selective biodistribution, low bioavailability, high drug concentrations, limited drug circulation time, and various side-effects limit the utilisation of HIPEC and PIPAC. Innovative drug delivery system with the controlled drug release at tumour site can enhance the therapeutic efficacy. Utilisation of nanoparticles (NPs) as carriers to deliver drugs with the possibility of tagging them with targeting agents will overcome the off-site toxicity. Cyto/hemocompatible magnetic hybrid NPs (Silver sulphide-Iron oxide) with luminescence in the near-infrared region for combinational therapy of peritoneal metastasis (SANTE) project aims to develop multimodal therapy approach for diagnosis and treatment of PM. It intends to enhance the efficacy of PM treatment using a combination of image guided remotely activated nanoHyp coupled with targeted Chem. Tumour targeted Ag2S will allow preoperative detection of microscopic or residual tumours to improve resection before Chem/Hyp. Iron oxide, targeting agent(cetuximab), and the chemotherapeutic drug(cisplatin) are all clinically used for the treatment of various type of cancers. The result of this fellowship will enable scientists in the PM field to translate the novel diagnostic and therapeutic methods into clinical practice and market.a

Rare diseases are a major public health topic because of the difficulty of their management, both in terms of diagnosis and treatment. Composed of a large and heterogeneous group of pathologies, they are individually rare but collectively frequent, with more than 350 million people affected worldwide, including 3 million in France. It is estimated that 80% of them are of genetic origin, 65% are severe and disabling and 50% develop in childhood. But above all, 95% of them have no curative treatment. There is a real need for diagnosis: 25% of patients suffering from these conditions are forced to wait 5 years or more for a diagnosis. This diagnostic wandering delays the implementation of an adapted medical follow-up, the prevention of complications, the development of personalized therapeutic strategies and genetic counseling. Created in 2007 as a scientific cooperation foundation with AP-HP, Inserm, the University of Paris, the AFM, the Fondation Hôpitaux de Paris-Hôpitaux de France and the City of Paris as founding members, the Imagine Institute for Genetic Diseases is a research and care institute, an international leader in the field of rare genetic diseases. It was awarded the IHU label in 2011 in recognition of its translational research activities, and the Carnot Institute label in 2020 in recognition of its commitment to strongly develop its partnership research activities with industry. Located on the campus of the Hôpital Necker (Paris), Imagine is a unique place, bringing together a range of multidisciplinary and multi-professional skills, experts in care, teaching and research, patients and patient associations, all committed to the fight against rare genetic diseases. As part of its societal mission, the Imagine Institute wishes to continue its openness and explore concrete actions of mediation and communication with the general public, and more particularly with young people, on genetic diseases and the advances and hopes brought about by research. It has thus set itself 4 ambitious societal missions: - Disseminate knowledge about rare genetic diseases - To share with as many people as possible the challenges, methods and results of research. - To stimulate vocations as doctors and researchers, particularly among young people. - To work on the social inclusion of patients suffering from rare genetic diseases. In this context, the institute is carrying out various communication and mediation actions for the general public (conferences, visits, etc.), patient associations (annual FAIR forum), as well as school group (visits, mediation workshops, development of new playful formats). These formats take shape both in person and remote, throughout the year, regularly punctuated by regional and national highlights (Fête de la Science, Rare Disease Days, etc.). The researchers are literally the actors of these events, together with the communication service and the person in charge of Science and Society programs. One example is the Bourse de Diffusion Scientifique program, dedicated to doctoral students at the Institut Imagine. Through this program, students have the opportunity to contribute to societal issues related to rare genetic diseases, with an educational and inclusive purpose. SAPS-CSTI-AAPG18/19 call for proposals concerns a maximum of 5 innovative projects of the institute for which we propose 3 main approaches of communication and scientific mediation: inclusion of dedicated contents within the next Forum of patient associations, development of a ludic mediation format under the format of an Escape Game, construction of transdisciplinary "Regards Croisés" conferences around the innovations and approaches of these projects.

The pathophysiological mechanisms for most primary antibody deficiencies (PADs) are not well understood in contrast to those underlying other primary immunodeficiencies. Lymphoproliferation, chronic diarrhea, autoimmune cytopenia and increased incidence of lymphomas are the main clinical complications associated to PADs. Our project is based on the hypothesis that most PADs have underlying genetic defects. For pediatric cases of PADs we assume that they are more frequently related to monogenic causes. PADs diagnosed in adulthood have also likely underlying genetic defects, however, the late disease onset and diagnosis in these patients could be explained due to further genetic modifying, epigenetic and environmental factors. The genetic delineation of PADs is essential to enable precise diagnosis, better treatment and follow-up und thus improve the quality of life of chronically affected patients and their families. By combining clinical, immunological, histopathological, functional and genetic data analysis, we aim to establish new diagnosis biomarkers, identify new therapeutic targets and decipher novel pathophysiological mechanisms for PADs. Exploration of PAD pathogenesis and validation of genetic defects will be performed by in-depth characterization of patients' cells and generation of in vitro cellular models. This project will contribute to a better understanding of the fundamental mechanisms underlying human antibody mediated immune responses and will improve the diagnosis and care of PAD patients.

The stated goal of RHAPSODY is to define a molecular taxonomy of type 2 diabetes mellitus (T2D) that will support patient segmentation, inform clinical trial design, and the establishment of regulatory paths for the adoption of novel strategies for diabetes prevention and treatment. To address these goals, RHAPSODY will bring together prominent European experts, including the leaders of the diabetes-relevant IMI1 projects to identify, validate and characterize causal biomarkers for T2D subtypes and progression. Our plans are built upon: (a) access to large European cohorts with comprehensive genetic analyses and rich longitudinal clinical and biochemical data and samples; (b) detailed multi-omic maps of key T2D-relevant tissues and organs; (c) large expertise in the development and use of novel genetic, epigenetic, biochemical and physiological experimental approaches; (d) the ability to combine existing and novel data sets through effective data federation and use of these datasets in systems biology approaches towards precision medicine; and (e) expertise in regulatory approval, health economics and patient engagement. These activities will lead to the discovery of novel biomarkers for improved T2D taxonomy, to support development of pharmaceutical activities, and for use in precision medicine to improve health in Europe and worldwide.

Mastocytosis is a heterogeneous disease characterized by an accumulation of mast cells (MCs) in the skin or various organs. The systemic form includes indolent and aggressive forms such as mast cell leukemia. Somatic mutations activating the KIT receptor tyrosine kinase (TK) are found in 90% of cases, but several arguments indicate that other genetic events are necessary to trigger the disease. We have recently demonstrated the synergistic cooperation between germline GLI3 hedgehog (Hh) mutations and somatic KIT mutations in mastocytosis onset, and have proposed a new therapeutic strategy combining anti-Hh and anti-TKs for patients overexpressing Hh genes. Seeking other genetic events, we recently identified mastocytosis patients carrying germline mutations (stop codon FASR250X and missense FASLGH122N) in the FAS-FASLG apoptotic pathway. The deficiency of this pathway is known to be the main driver of autoimmune lymphoproliferative syndrome (ALPS) but has never been studied in mastocytosis. We also found that MCs from patients with aggressive mastocytosis express very low levels of FAS at the membrane, indicating that deregulation of FAS is involved in the pathophysiology of the disease via resistance to apoptosis. Interestingly, 75% of ALPS patients carry germline mutations in FAS gene with variable expressivity. Mutations induce partial or total inhibition of FAS, or production of a dominant negative form that blocks apoptosis. Among the patients, 15% develop urticaria and/or severe allergies indicating that MCs are activated in this pathophysiological context. Here, we propose to study post-transcriptional defects of FAS expression resulting from pathogenic mutations or splicing dysregulation in mastocytosis and ALPS diseases. Moreover, our collaborative work will shed light on the contribution of mast cells in ALPS.