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290 results on '"Ligue Nationale Contre le Cancer (LNCC)"'

51. The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice

Author: Laurence Desrues, Marie Lange, Ludovic Galas, Florence Joly, Hélène Castel, Martine Dubois, C. Nicola, Damien Schapman, T. Al Sagheer, Cynthia Campart, Lebon, Alexis, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Ligue Nationale Contre le Cancer (LNCC)-Cancéropole Nord-Ouest, Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de recherche clinique [Centre François Baclesse], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, metastatic resistant prostate cancer, [SDV]Life Sciences [q-bio], Substantia nigra, abiraterone acetate/prednisone, Article, Androgen deprivation therapy, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Internal medicine, medicine, Enzalutamide, RC254-282, enzalutamide, business.industry, Pars compacta, behavior, Dopaminergic, Abiraterone acetate, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, dopaminergic pathways, aged castrated mice, medicine.disease, [SDV] Life Sciences [q-bio], Ventral tegmental area, medicine.anatomical_structure, chemistry, Dopaminergic pathways, 030220 oncology & carcinogenesis, business, 030217 neurology & neurosurgery
Abstract: Simple Summary Cognitive side effects and fatigue after cancer treatment now constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next-generation therapies improving metastatic castration-resistant prostate cancer (mCRPC) patient survival, but also associated with neurological disturbances. We developed a behavioral 17 months-aged and castrated mouse model receiving AAP or ENZ for 5 days per week for six weeks. We establish that ENZ impacts locomotor and explorative behaviors, and strength capacity likely by preventing binding of central synthetized androgens to androgen receptors expressed by dopamine neurons of the Substantia Nigra and the Ventral Tegmentum. ENZ also reduces the cognitive score, associated with less neuronal activity in dorsal hippocampal areas. This demonstrates ENZ-specific consequences on motivation to exploration and cognition, being of particular importance for future management of elderly prostate cancer patients and their quality of life. Abstract Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients.
Published: 2021

52. Mitotic memories of gene activity

Author: Inma Gonzalez, Pablo Navarro, Amandine Molliex, Epigénomique, Prolifération et Identité Cellulaire - Epigenomics, Proliferation and the Identity of Cells (EPIC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Work in P.N laboratory is supported by recurrent funding from the Institut Pasteur, the CNRS and Revive, as well as by funding obtained from the Agence Nationale de la Recherche (ANR 16 CE120004 01 MITMAT), the Ligue Nationale Contre le Cancer (LNCC EL2018 NAVARRO), and the European Research Council (ERC-CoG-2017 BIND)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-16-CE12-0004,MitMAT,Mémoire mitotique de l'activité transcriptionnelle dans les cellules ES(2016), European Project: 773083,ERC-CoG-2017,BIND(2018), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Cell division, Mitosis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Biology, Cell identity, Chromatin, Chromosomes, Cell biology, Structure and function, 03 medical and health sciences, 0302 clinical medicine, Gene Expression Regulation, Gene expression, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene activity, Transcription factor, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: International audience; When cells enter mitosis, they undergo series of dramatic changes in their structure and function that severely hamper gene regulatory processes and gene transcription. This raises the question of how daughter cells efficiently recapitulate the gene expression profile of their mother such that cell identity can be preserved. Here, we review recent evidence supporting the view that distinct chromatin-associated mechanisms of gene-regulatory inheritance assist daughter cells in the postmitotic reestablishment of gene activity with increased fidelity.
Published: 2021

53. Host genetic control of natural killer cell diversity revealed in the Collaborative Cross

Author: James P. Di Santo, Nicolas Serafini, Solenne Marie, Christian A. J. Vosshenrich, Xavier Montagutelli, Magali S. J. Dupont, Pascal Campagne, Vincent Guillemot, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris] (IP), M.S.J.D. was supported by the French Ministry of Higher Education, Research and Innovation. J.P.D. was supported by grants from the Institut Pasteur, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Ligue Nationale Contre le Cancer (LNCC -Équipe labélisée Ligue Contre le Cancer)., Vosshenrich, Christian, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Candidate gene, Quantitative Trait Loci, Population, Mice, Inbred Strains, NK cells, Biology, Polymorphism, Single Nucleotide, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Collaborative Cross, Natural killer cell, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Animals, Antigens, Ly, Cytotoxic T cell, Quantitative trait locus mapping, education, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Crosses, Genetic, Innate immunity, Genetics, education.field_of_study, Genetic diversity, Multidisciplinary, Innate immune system, Natural Cytotoxicity Triggering Receptor 1, Biological Sciences, Phenotype, Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, NK Cell Lectin-Like Receptor Subfamily D, 030215 immunology
Abstract: International audience; Natural Killer (NK) cells are innate effectors armed with cytotoxic and cytokine-secreting capacities whose spontaneous anti-tumor activity is key to numerous immunotherapeutic strategies. However, current mouse models fail to mirror the extensive human immune system variation that exists in the normal population which may impact on NK cell-based therapies. We performed a comprehensive profiling of NK cells in the Collaborative Cross (CC), a collection of novel recombinant inbred mouse strains whose genetic diversity matches that of humans, thereby providing a unique and highly diverse small animal model for the study of immune variation. We demonstrate that NK cells from CC lines displayed a breadth of phenotypic and functional variation reminiscent of that reported for humans with regards to cell numbers, key marker expression and functional capacities. We took advantage of the vast genetic diversity of the CC and identified 9 genomic loci through quantitative trait locus mapping driving these phenotypic variations. SNP haplotype-patterns and variant effect analyses identified candidate genes associated with lung NK cell numbers, frequencies of CD94+NK cells, and expression levels of NKp46. Thus, we demonstrate that the CC represents an outstanding resource to study NK cell diversity and its regulation by hostgenetics.
Published: 2021

54. Targeting Redox Metabolism in Pancreatic Cancer

Author: Abdel Hadi, Nadine, Reyes-Castellanos, Gabriela, Carrier, Alice, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, and Fondation ARC pour la Recherche sur le Cancer (PJA 20151203544 and PJA 20181208207). NAH was supported by Association AZM et Saade (Lebanon), and GR-C by the CONACYT (Mexico, grant 339091/471717) and la Ligue Nationale Contre le Cancer (LNCC), and CARRIER, Alice
Subjects: mitochondrial metabolism, [SDV]Life Sciences [q-bio], Drug Evaluation, Preclinical, pancreatic ductal adenocarcinoma, cancer metabolism, Antineoplastic Agents, Review, Antioxidants, lcsh:Chemistry, Biomarkers, Tumor, Animals, Humans, oxidative stress, Molecular Targeted Therapy, cancer therapeutic strategy, lcsh:QH301-705.5, redox metabolism, Clinical Studies as Topic, Disease Management, ROS, Pancreatic Neoplasms, [SDV] Life Sciences [q-bio], mitochondria, Treatment Outcome, lcsh:Biology (General), lcsh:QD1-999, Disease Susceptibility, Energy Metabolism, Reactive Oxygen Species, Oxidation-Reduction, Signal Transduction
Abstract: International audience; Cell metabolism is reprogrammed in cancer cells to meet their high bioenergetics and biosynthetic demands. This metabolic reprogramming is accompanied by alterations in redox metabolism, characterized by accumulation of reactive oxygen species (ROS). Elevated production of ROS, mostly by mitochondrial respiration, is counteracted by higher production of antioxidant defenses (mainly glutathione and antioxidant enzymes). Cancer cells are adapted to a high concentration of ROS, which contributes to tumorigenesis, metastasis formation, resistance to therapy and relapse. Frequent genetic alterations observed in pancreatic ductal adenocarcinoma (PDAC) affect KRAS and p53 proteins, which have a role in ROS production and control, respectively. These observations led to the proposal of the use of antioxidants to prevent PDAC development and relapse. In this review, we focus on the therapeutic strategies to further increase ROS level to induce PDAC cell death. Combining the promotion of ROS production and inhibition of antioxidant capacity is a promising avenue for pancreatic cancer therapy in the clinic.
Published: 2021

55. Le sommeil dans les cancers non-cérébraux : revue de la littérature, mécanismes potentiels et perspectives pour mieux comprendre les troubles cognitifs associés

Author: PERRIER, Joy, Duivon, Mylène, Rauchs, Géraldine, Giffard, Bénédicte, Neuropsychologie et imagerie de la mémoire humaine (NIMH), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: [SCCO]Cognitive science, Breast cancer, Cognition, Cancer du sein Actimétrie, Polysomnographie, Polysomnography, Sommeil, Sleep, Actigraphy, Fatigue
Abstract: International audience; Breast cancer patients have frequent complaints of sleep disturbances. Sleep plays a major role in cognitive functioning, especially in executive functions, such as planning or flexibility, and also in memory consolidation. These cognitive functions are among the most frequently impaired in breast cancer. However, the influence of sleep on cognitive performance in patients treated for breast cancer has been little investigated. In addition, the physio-pathological mechanisms associated with sleep disturbances in breast cancer patients are not clear for now. The objective of this non-exhaustive review is to describe sleep alterations encountered in breast cancer, their potential mechanisms and to link these alterations with cognitive difficulties of patients. The studies conducted until now revealed the existence of a sleep complaint, with mainly insomnia symptoms, in breast cancer patients. These results are in accordance with those of studies using actigraphy after chemotherapy. Polysomnography (PSG) studies also suggest alterations in sleep architecture, but these studies are scarce and suffer from several limitations. Sleep alterations have mainly been studied in the context of chemotherapy. However, sleep alterations are little studied in case of other treatments, such as hormonal therapy, or even in the absence of treatment. Recent studies have highlighted the potential role of sleep–wake cycle alterations and sleep apnea in breast cancer occurrence and survival; however, this association still needs to be more deeply evaluated. Finally, the links between objective sleep alterations and cognition are still little explored. A better understanding of sleep disorders in breast cancer will allow adapting the treatment in order to improve patients’ quality of life.; Les patientes atteintes d’un cancer du sein se plaignent fréquemment d’une altération de leur sommeil. Ce dernier joue un rôle crucial dans le fonctionnement cognitif, notamment dans les fonctions exécutives telles que la planification ou la flexibilité, ou encore dans la consolidation des souvenirs en mémoire à long terme. Ces fonctions cognitives sont fréquemment altérées dans le cancer du sein. Cependant, l’influence du sommeil sur les performances cognitives reste peu documentée dans cette pathologie. En outre, les mécanismes physiopathologiques associés aux troubles du sommeil dans le cancer du sein sont, actuellement, mal compris. L’objectif de cette mise au point est de faire un état de l’art des altérations du sommeil rencontrées dans le cancer du sein, de décrire les potentiels mécanismes impliqués et de mettre en lien ces altérations avec les troubles cognitifs. Les études réalisées jusqu’ici auprès de patientes atteintes d’un cancer du sein révèlent l’existence d’une plainte de sommeil, avec principalement des symptômes évocateurs d’insomnie. Ces résultats sont en accord avec les données obtenues en actimétrie après chimiothérapie. Les études en polysomnographie (PSG) suggèrent également des altérations de l’architecture du sommeil, mais ces études sont encore peu nombreuses et souffrent de plusieurs limites. Les altérations du sommeil ont été majoritairement décrites chez des patientes traitées par chimiothérapie. En revanche, elles sont peu étudiées dans le cadre d’autres traitements, tels que l’hormonothérapie, ou même en dehors des traitements. Des études récentes mettent en avant les effets potentiellement carcinogènes des altérations du rythme activité–repos et des apnées, mais la causalité de ces effets doit être confirmée. Enfin, les liens existant entre les altérations du sommeil et la cognition sont encore peu explorés, notamment à l’aide de mesures objectives du sommeil. Une meilleure compréhension des troubles du sommeil dans le cancer du sein permettra d’adapter la prise en charge afin d’améliorer, à terme, la qualité de vie des patientes.
Published: 2021

56. Prognostic value of the PrPC-ILK-IDO1 axis in the mesenchymal colorectal cancer subtype

Author: Ghazi, Alexandre, Le Corre, Delphine, Pilati, Camilla, Taieb, Julien, Aparicio, Thomas, Didelot, Audrey, Dedhar, Shoukat, Mulot, Claire, Le Malicot, Karine, Djouadi, Fatima, De Reynies, Aurélien, Launay, Jean-Marie, Laurent-Puig, Pierre, Mouillet-Richard, Sophie, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), BC Cancer Agency (BCCRC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, HAL-SU, Gestionnaire, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Ligue Nationnale Contre le Cancer, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord
Subjects: integrin-linked kinase, animal diseases, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, RC581-607, colorectal cancer molecular classification, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, nervous system diseases, IDO, Prion protein, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], mental disorders, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Immunologic diseases. Allergy, Kynurenine pathway, RC254-282
Abstract: International audience; The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrP C is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrP C downstream pathways that may underlie its role in CMS4 CRC. By combining gene set enrichment analyses and gain and loss of function approaches in CRC cell lines, we identify the integrin-linked kinase ILK as a proximal effector of PrP C that mediates its control on the CMS4 phenotype. We further leveraged three independent large CRC cohorts to assess correlations in gene expression pattern with patient outcomes and found that ILK is overexpressed in CMS4 mesenchymal tumors and confers a poor prognosis, especially when combined with high expression of the PrP C encoding gene PRNP. Of note, we discovered that the PrP C-ILK signaling axis controls the expression and activity of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase IDO1, a key player in immune tolerance. In addition, we monitored alterations in the levels of tryptophan and its metabolites of the kynurenine pathway in the plasma of metastatic CRC patients (n = 325) and we highlight their prognostic value in combination with plasma PrP C levels. Thus, the PrP C-ILK-IDO1 axis plays a key role in the mesenchymal subtype of CRC. PrP C and IDO1-targeted strategies may represent new avenues for patient stratification and treatment in CRC.
Published: 2021

57. A global database of Holocene paleotemperature records

Author: Marcela Sandra Tonello, Vincent Montade, Walter Finsinger, Karen J. Taylor, Manuel Chevalier, Isabelle Larocque-Tobler, Philipp Sommer, Nicholas P. McKay, Mateusz Płóciennik, Snezhana Zhilich, David F. Porinchu, Andrei Andreev, Markus Heinrichs, Tomi P. Luoto, Elena A. Ilyashuk, Anson W. Mackay, Deborah Khider, Stephen J. Roberts, Cody C. Routson, Les C. Cwynar, Samuel L Jaccard, Naomi Holmes, Kira Rehfeld, Aaron P. Potito, Emma J. Pearson, Steve Juggins, Anais Orsi, Louise C. Foster, Angela Self, Sakari Salonen, Basil A. S. Davis, Boris K. Biskaborn, Christoph Dätwyler, Sebastien Bertrand, Anne de Vernal, Jeannine Marie St-Jacques, Angelica Feurdean, Janet M. Wilmshurst, Lukas Jonkers, Heikki Seppä, Stephen J. Brooks, Elizabeth K. Thomas, Sonja Hausmann, Peter G. Langdon, Steven B. Malevich, Larisa Nazarova, Shyhrete Shala, Enikö Magyari, Matthew Peros, Scott A. Reinemann, Krystyna M. Saunders, Elena Novenko, Barbara Stenni, Yarrow Axford, Liudmila Syrykh, Julien Emile-Geay, Nicolas Rolland, Bryan G. Mark, Jianyong Li, Andria Dawson, Mathew Fox, André F. Lotter, Jessica E. Tierney, Oliver Heiri, Stefan Engels, Ian R. Walker, Andrew P. Rees, Pol Tarrats, Valerie van den Bos, Konrad Gajewski, Brian M. Chase, Eugene R. Wahl, Martin Grosjean, Boris P. Ilyashuk, Thomas Brussel, Mónika Tóth, Enlou Zhang, Darrell S. Kaufman, Olivier Cartapanis, Magaly Caniupán, Julieta Massaferro, Reinhard Pienitz, John M. Fegyveresi, Manuel Bringué, Carrie Morrill, Gaute Velle, M. P. Erb, Marie Claude Fortin, Petr Pařil, Karin A. Koinig, Richard S. Vachula, Paola Moffa-Sanchez, Jeremiah Marsicek, Northern Arizona University [Flagstaff], Institute of Earth Surface Dynamics [Lausanne], Université de Lausanne (UNIL), Utrecht University Palaeoecology, Laboratory of Palaeobotany and Palynology (UTRECHT UNIVERSITY), Utrecht University [Utrecht], Oeschger Centre for Climate Change Research (OCCR), University of Bern, University of Arizona, Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Collège de France (CdF (institution))-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Mount Royal University, Centre de recherche sur la dynamique du système Terre (GEOTOP), Université de Montréal (UdeM)-McGill University = Université McGill [Montréal, Canada]-École Polytechnique de Montréal (EPM)-Concordia University [Montreal]-Université du Québec à Rimouski (UQAR)-Université du Québec à Montréal = University of Québec in Montréal (UQAM)-Université du Québec en Abitibi-Témiscamingue (UQAT), Center for Marine Environmental Sciences [Bremen] (MARUM), Universität Bremen, Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institute of Environmental Physics [Heidelberg] (IUP), Universität Heidelberg [Heidelberg], Programme CIT, Ligue Nationale Contre le Cancer, Snecma Propulsion Solide (SPS), SAFRAN Group, University of Southern California (USC), Senckenberg biodiversität und klima forschungszentrum (BIK-F), Forschungsinstitut Senckenberg (SGN), Université d'Ottawa [Ontario] (uOttawa), Faculty of Biological and Environmental Sciences [Helsinki], University of Helsinki, Department of Environmental and Landscape Geography, Eötvös Loránd University (ELTE), MTA-MTM-ELTE Research Group for Paleontology, Eötvös Loránd University (ELTE)-Hungarian Academy of Sciences (MTA), GINOP Sustainable Ecosystem Research Group, MTA Centre for Ecological Research [Tihany], Hungarian Academy of Sciences (MTA)-Hungarian Academy of Sciences (MTA), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Centre d'Etudes Nordiques (CEN), Université Laval [Québec] (ULaval), British Antarctic Survey (BAS), Natural Environment Research Council (NERC), Department of Geosciences and Geography [Helsinki], Falculty of Science [Helsinki], University of Helsinki-University of Helsinki, Departemanto di Scienze Ambientali Informatica e Statistica (DAIS), University of Ca’ Foscari [Venice, Italy], Uni Research Environment, Uni Research Ltd, University of Bath [Bath], Université de Lausanne = University of Lausanne (UNIL), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), École Polytechnique de Montréal (EPM)-McGill University = Université McGill [Montréal, Canada]-Université de Montréal (UdeM)-Université du Québec en Abitibi-Témiscamingue (UQAT)-Université du Québec à Rimouski (UQAR)-Concordia University [Montreal]-Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg] = Heidelberg University, Ligue Nationale Contre le Cancer (LNCC), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Faculty of Biological and Environmental Sciences, and Department of Geosciences and Geography
Subjects: Peat, 010504 meteorology & atmospheric sciences, 580 Plants (Botany), computer.software_genre, 01 natural sciences, MILLENNIAL-SCALE CHANGES, Proxy (climate), purl.org/becyt/ford/1 [https], purl.org/becyt/ford/1.5 [https], INTERTROPICAL CONVERGENCE ZONE, HOLOCENE, 910 Geography & travel, lcsh:Science, Holocene, LAKE VUOLEP-NJAKAJAURE, geography.geographical_feature_category, Database, EASTERN TIBETAN PLATEAU, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Computer Science Applications, LATE-QUATERNARY VEGETATION, [SDU.STU.CL]Sciences of the Universe [physics]/Earth Sciences/Climatology, SEA-SURFACE TEMPERATURE, PROXIES, Statistics, Probability and Uncertainty, geog, Geology, Information Systems, Statistics and Probability, 1171 Geosciences, 010506 paleontology, NORTHERN NORTH-ATLANTIC, DATABASE, PALEOTEMPERATURE, [SDE.MCG]Environmental Sciences/Global Changes, education, Library and Information Sciences, Education, Paleoclimatology, SOUTH CHINA SEA, [SDU.ENVI]Sciences of the Universe [physics]/Continental interfaces, environment, Southern Hemisphere, 1172 Environmental sciences, POLLEN-BASED RECONSTRUCTION, 550 Earth sciences & geology, 0105 earth and related environmental sciences, geography, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Intertropical Convergence Zone, Glacier, 15. Life on land, WESTERN EQUATORIAL PACIFIC, Sea surface temperature, 13. Climate action, Settore GEO/08 - Geochimica e Vulcanologia, Earth and Environmental Sciences, lcsh:Q, computer
Abstract: A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format. Fil: Kaufman, Darrell. Northern Arizona University.; Estados Unidos Fil: McKay, Nicholas. Northern Arizona University.; Estados Unidos Fil: Routson, Cody. Northern Arizona University.; Estados Unidos Fil: Erb, Michael. Northern Arizona University.; Estados Unidos Fil: Davis, Basil. University Of Lausanne; Suiza Fil: Heiri, Oliver. University Of Basel; Suiza Fil: Jaccard, Samuel. University Of Bern; Suiza Fil: Tierney, Jessica. University of Arizona; Estados Unidos Fil: Dätwyler, Christoph. University Of Bern; Suiza Fil: Axford, Yarrow. Northwestern University; Estados Unidos Fil: Brussel, Thomas. University of Utah; Estados Unidos Fil: Cartapanis, Olivier. University Of Bern; Suiza Fil: Chase, Brian. Universite de Montpellier; Francia Fil: Dawson, Andria. Mount Royal University; Canadá Fil: de Vernal, Anne. Université du Québec a Montreal; Canadá Fil: Engels, Stefan. University of London; Reino Unido Fil: Jonkers, Lukas. University Of Bremen; Alemania Fil: Marsicek, Jeremiah. University of Wisconsin-Madison; Estados Unidos Fil: Moffa Sánchez, Paola. University of Durham; Reino Unido Fil: Morrill, Carrie. University of Colorado; Estados Unidos Fil: Orsi, Anais. Université Paris-Saclay; Francia Fil: Rehfeld, Kira. Heidelberg University; Alemania Fil: Saunders, Krystyna. Australian Nuclear Science And Technology Organisation; Australia Fil: Sommer, Philipp. University Of Lausanne; Suiza Fil: Thomas, Elizabeth. University At Buffalo; Estados Unidos Fil: Tonello, Marcela Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Tóth, Mónika. Balaton Limnological Institute; Hungría Fil: Vachula, Richard. Brown University; Estados Unidos Fil: Andreev, Andrei. Alfred Wegener Institut Helmholtz Centre for Polar and Marine Research; Alemania Fil: Bertrand, Sebastien. Ghent University; Bélgica Fil: Massaferro, Julieta. Administración de Parques Nacionales. Parque Nacional "Nahuel Huapi"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Published: 2020

58. Genetic determinism of spontaneous masculinisation in XX female rainbow trout: new insights using medium throughput genotyping and whole-genome sequencing

Author: Charles Poncet, Florent Petitprez, Maria Bernard, Edwige Quillet, Chris Hoze, Nicolas Dechamp, Philippe Hocdé, Anastasia Bestin, Céline Ciobotaru, Yann Guiguen, Pierrick Haffray, Marine Milhes, Florence Phocas, Olivier Bouchez, Jérôme Lluch, Clémence Fraslin, Mathieu Charles, Francine Krieg, Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Edinburgh, Syndicat des Sélectionneurs Avicoles et Aquacoles Français (SYSAAF), Système d'Information des GENomes des Animaux d'Elevage (SIGENAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Allice, Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Génome et Transcriptome - Plateforme Génomique ( GeT-PlaGe), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique Diversité et Ecophysiologie des Céréales (GDEC), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Pisciculture Charles Murgat, Laboratoire de Physiologie et Génomique des Poissons (LPGP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), European Maritime and Fisheries Fund and France Agrimer co-funded this work (NeoBio project, n° RFEA470016FA1000008), Ligue Nationnale Contre le Cancer, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse)
Subjects: 0106 biological sciences, 0301 basic medicine, Male, Candidate gene, QTL, animal diseases, [SDV]Life Sciences [q-bio], Masculinisation des poissons, Genome-wide association study, heritability, 01 natural sciences, Genome-wide association studies, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, biology, Reproduction, 04 agricultural and veterinary sciences, Genomics, Poisson, Trout, Phenotype, Oncorhynchus mykiss, maleness, Medicine, Female, Sex, Maleness, Heterogametic sex, endocrine system, animal structures, Genotype, Science, Population, Quantitative trait locus, Déterminisme génétique du sexe, 010603 evolutionary biology, Article, Heritability, 03 medical and health sciences, Salmonide, Genetic variation, sex, Animals, 14. Life underwater, education, 030304 developmental biology, Genetic association, Animal breeding, fish, Whole Genome Sequencing, urogenital system, Truite arc-en-ciel, 0402 animal and dairy science, Sex Determination Processes, biology.organism_classification, 040201 dairy & animal science, 030104 developmental biology, Fish, Rainbow trout, Sequençage
Abstract: Rainbow trout has a male heterogametic (XY) sex determination system controlled by a major sex-determining gene, sdY. Unexpectedly, a few phenotypically masculinised fish are regularly observed in all-female farmed trout stocks. To better understand the genetic determinism underlying spontaneous maleness in XX-rainbow trout, we recorded the phenotypic sex of 20,210 XX-rainbow trout from a French farm population at 10 and 15 months post-hatching. The overall masculinisation rate was 1.45%. We performed two genome-wide association studies (GWAS) on a subsample of 1139 individuals classified as females, intersex or males using either medium-throughput genotyping (31,811 SNPs) or whole-genome sequencing (WGS, 8.7 million SNPs). The genomic heritability of maleness ranged between 0.48 and 0.62 depending on the method and the number of SNPs used for the estimation. At the 31K SNPs level, we detected four QTL on three chromosomes (Omy1, Omy12 and Omy20). Using WGS information, we narrowed down the positions of the two QTL detected on Omy1 to 96 kb and 347 kb respectively, with the second QTL explaining up to 14% of the total genetic variance of maleness. Within this QTL, we detected three putative candidate genes, fgfa8, cyp17a1 and an uncharacterised protein (LOC110527930), which might be involved in spontaneous maleness of XX-female rainbow trout.
Published: 2020

59. The epigenetic regulator RINF (CXXC5) maintains SMAD7 expression in human immature erythroid cells and sustains red blood cell expansion

Author: Astori, Audrey, Matherat, Gabriel, Munoz, Isabelle, Gautier, Emilie-Fleur, Surdez, Didier, Zermati, Yaël, Verdier, Frédérique, Zaidi, Sakina, Feuillet, Vincent, Kadi, Amir, LAURET, Evelyne, Delattre, Olivier, Lefèvre, Carine, Fontenay, Michaela, Ségal-Bendirdjian, Evelyne, Dusanter-Fourt, Isabelle, Bouscary, Didier, Hermine, Olivier, Mayeux, Patrick, Pendino, Frédéric, Princess Margaret Hospital, University of Toronto, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes et Recherches en Thermique, Environnement et Systèmes [Créteil] (CERTES EA 3481), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was supported by INSERM, Paris-Descartes University, the Ligue Nationale Contre le Cancer (LNCC), the Cochin Institute, and the Laboratory of Excellence GR-EX. AA was supported by LNCC, Société Française d'Hématologie, Fondation pour la Recherche Médicale, and Boehringer Society (travel grant). GM was supported by a fellowship grant from the Ministère de l’Enseignement Supérieur et de la Recherche and Société Française d’Hématologie. ES-B is supported by the National Center for Scientific Research (CNRS) and her team was supported by LNCC and Fondation de France. We are also grateful for support from the French-Norwegian exchange program (Aurora to FP)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Zurich, and Pendino, Frédéric
Subjects: hemic and lymphatic diseases, [SDV]Life Sciences [q-bio], 2720 Hematology, RINF maintenance of SMAD7 sustains human erythropoiesis 244. Figures: 7. Tables: 1. All supplementary data (Supplementary Methods, 610 Medicine & health, 10046 Balgrist University Hospital, Swiss Spinal Cord Injury Center, Tables (1), and References, Legends, and Figures (7)) are included into a single PDF document
Abstract: International audience; The gene CXXC5, encoding a retinoid-inducible nuclear factor (RINF), is located within a region at 5q31.2 commonly deleted in myelodysplastic syndrome and adult acute myeloid leukemia. RINF may act as an epigenetic regulator and has been proposed as a tumor suppressor in hematopoietic malignancies. However, functional studies in normal hematopoiesis are lacking, and its mechanism of action is unknown. Here, we evaluated the consequences of RINF silencing on cytokine-induced erythroid differentiation of human primary CD34+ progenitors. We found that RINF is expressed in immature erythroid cells and that RINF-knockdown accelerated erythropoietin-driven maturation, leading to a significant reduction (~45%) in the number of red blood cells, without affecting cell viability. The phenotype induced by RINF-silencing was dependent on tumor growth factor b (TGFb) and mediated by SMAD7, a TGFb-signaling inhibitor. RINF upregulates SMAD7 expression by direct binding to its promoter and we found a close correlation between RINF and SMAD7 mRNA levels both in CD34+ cells isolated from bone marrow of healthy donors and myelodysplastic syndrome patients with del(5q). Importantly, RINF knockdown attenuated SMAD7 expression in primary cells and ectopic SMAD7 expression was sufficient to prevent the RINF knockdown-dependent erythroid phenotype. Finally, RINF silencing affects 5’-hydroxymethylation of human erythroblasts, in agreement with its recently described role as a TET2-anchoring platform in mouse. Collectively, our data bring insight into how the epigenetic factor RINF, as a transcriptional regulator of SMAD7, may fine-tune cell sensitivity to TGFb superfamily cytokines and thus play an important role in both normal and pathological erythropoiesis.
Published: 2020

60. Living Labs et autres approches participatives appliqués à la recherche sur les multi-expositions environnementales et les risques chroniques : le projet LILAS

Author: Olivier Laurent, Yara Carrejo Gironza, Sophie Ancelet, Olivier Armant, Denis Bard, Katia Baumgartner, Sylvie Bortoli, Céline Boudet, Philippe Chamaret, Michel Chartier, Stéphanie Cormier, Arthur David, Hélène Desqueyroux, Christine Fassert, Mariette Gerber, Rodolphe Gilbin, Stephane Grison, Lionel Larqué, Christian Mougin, Laurence Gamet-Payrastre, Sylvie Platel, Alain Rannou, Pascale Scanff, Arnaud Vanzemberg, Simon Schraub, Sylvie Supervil, Eric Thybaud, Brigitte Trousse, Sylvie Charron, PSE-SANTE/SESANE/LEPID, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), PSE-ENV/SRTE/LECO, Société Francophone de Santé Environnement (SFSE), France Nature Environnement (FNE), INSERM UMRS 1124 - Université de Paris., INSERM - Université de Paris. (INSERM UMRS 1124 - Université de Paris.), Institut National de l'Environnement Industriel et des Risques (INERIS), Institut Ecocitoyen [Fos-sur-Mer] (IECP), PSE-ENV/SEREN, Centre Permanent d'Initiatives pour l'Environnement des Pays de l'Aisne (CPIE des Pays de l'Aisne), ADEME, PSN-SRDS/SHOT/LSHS, Association nationale des comités et commissions locales d'information [Teteghem] (ANCCLI), PSE-ENV/SRTE, PSE-SANTE/SESANE/LRTOX, ALLISS, INRAE, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), PSE-SANTE, DTR/D3NSI/SVDDA, DST/SP3In, Ligue Nationale Contre le Cancer, DRP, Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria), DST/SPOS, and Ligue Nationale Contre le Cancer (LNCC)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Contexte Les recherches participatives en santé-environnement restent peu développées en France. Les objectifs poursuivis par les recherches en santé-environnement (estimer des expositions, évaluer des effets, tester des actions préventives) et méthodes employées sont variés. Les opportunités d’une plus grande implication de la société civile et défis associés diffèrent à chaque étape de ces recherches. Ces aspects demandent à être mieux appréhendés collectivement. LILAS vise, en amont du développement de futurs projets de recherches participatives sur les multi-expositions environnementales, à 1) co-construire, entre chercheurs institutionnels, académiques et représentants de la société civile, une bonne compréhension commune des principales problématiques et méthodes de recherche en santé-environnement, de leurs enjeux, prérequis, forces et limites 2) identifier les bénéfices et points de vigilance liés à l’introduction de plus fortes dimensions participatives dans ces recherches. Méthode LILAS a rassemblé des chercheurs institutionnels, académiques et représentants de la société civile intéressés par les multi-expositions (chimiques, radiologiques). Une recherche bibliographique a été initiée pour tirer le retour d’expérience de projets de recherches participatives à l’international. Plusieurs réunions ont permis d’identifier collectivement différents types d’études et de réfléchir sur les apports, limites et précautions méthodologiques relatifs à l’introduction de différents degrés de participation dans celles-ci. Une matrice d’analyse a été co-construite puis alimentée par les participants, en s’inspirant des approches Living Lab.Résultats Pour différents types d’études (évaluations d’expositions, identification de déterminants, tests d’interventions, développement de capteurs, évaluations de risques sanitaires, études épidémiologiques, recherches expérimentales, études sur la santé humaine et des écosystèmes…), la matrice liste les bénéfices attendus pour différentes catégories de parties prenantes, les conditions méthodologiques et contraintes associées, les avantages et limites relatifs à l’emploi d’approches participatives voire “classiques”.Conclusion LILAS a permis, par acculturation croisée, de poser des bases consolidées pour la co-construction de futurs projets de recherches participatives sur les multi-expositions environnementales.
Published: 2020

61. Le projet LILAS : Living Labs et autres approches participatives appliquées à la recherche sur les multi-expositions environnementales et les risques chroniques

Author: Laurent, Olivier, Gironza, Yara Carrejo, Ancelet, Sophie, Armant, Olivier, Bard, Denis, Baumgartner, Katia, Bortoli, Sylvie, Boudet, Céline, Chamaret, Philippe, Chartier, Michel, Cormier, Stéphanie, David, Arthur, Desqueyroux, Hélène, Gerber, Mariette, Gilbin, Rodolphe, Grimbuhler, Sonia, Grison, Stéphane, Larqué, Lionel, Laurier, Dominique, Mougin, Christian, Gamet-Payrastre, Laurence, Platel, Sylvie, Rannou, Alain, Scanff, Pascale, Vanzemberg, Arnaud, Schraub, Simon, Supervil, Sylvie, Thybaud, Eric, Trousse, Brigitte, Charron, Sylvie, PSE-SANTE/SESANE/LEPID, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), PSE-ENV/SRTE/LECO, Société francophone de santé environnement (SFSE), France Nature Environnement (FNE), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de l'Environnement Industriel et des Risques (INERIS), Institut Ecocitoyen pour la Connaissance des Pollutions [Fos-sur-Mer], PSE-ENV/SEREN, CPIE des Pays de l'Aisne, EHESP-Irset (EHESP-Irset), École des Hautes Études en Santé Publique [EHESP] (EHESP), Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), ANCCLI, PSE-ENV/SRTE, Information – Technologies – Analyse Environnementale – Procédés Agricoles (UMR ITAP), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), PSE-SANTE/SESANE/LRTOX, ALLISS Sciences Sociétés [Paris], PSE-SANTE/SESANE, Ecologie fonctionnelle et écotoxicologie des agroécosystèmes (ECOSYS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), PSE-SANTE, DTR/D3NSI/SVDDA, DST/SP3In, Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, DRP, Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria), DST/SPOS, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d épidémiologie des rayonnements ionisants (IRSN/PSE-SANTE/SESANE/LEPID), Service de recherche sur les effets biologiques et Sanitaires des rayonnements ionisants (IRSN/PSE-SANTE/SESANE), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'écotoxicologie des radionucléides (IRSN/PSE-ENV/SRTE/LECO), Service de recherche sur les transferts et les effets des radionucléides sur les écosystèmes (IRSN/PSE-ENV/SRTE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service d'expertise et d'étude en radioprotection des populations et de la radioactivité dans l'environnement (IRSN/PSE-ENV/SEREN), Laboratoire d'étude et de recherche en environnement et santé (LERES), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro - Montpellier SupAgro, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Laboratoire de radiotoxicologie et radiobiologie expérimentale (IRSN/PSE-SANTE/SESANE/LRTOX), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Pôle Santé Environnement - Direction Santé (IRSN/PSE-SANTE), Service Valorisation des Données et Développement des Applications (IRSN/DTR/D3NSI/SVDDA), Direction Déléguée Développement numérique et aux systèmes d’information (IRSN/DTR/D3NSI), Service de la programmation, des partenariats, de la prospective et de l’appui à l’innovation (IRSN/DST/SP3IN), Direction de la Stratégie (IRSN/DST), Ligue Nationale Contre le Cancer (LNCC), Direction des Risques et de la Performance (IRSN/DRP), Service des politiques d’ouverture à la société (IRSN/DST/SPOS), Trousse, Brigitte, and Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan)
Subjects: [SDV] Life Sciences [q-bio], méthodes, [SHS.STAT]Humanities and Social Sciences/Methods and statistics, [SDV]Life Sciences [q-bio], [SHS.STAT] Humanities and Social Sciences/Methods and statistics, santé environnementale, sciences participatives, [SDE.ES] Environmental Sciences/Environmental and Society, Multi-expositions, co-construction, [SDE.ES]Environmental Sciences/Environmental and Society
Abstract: National audience; Contexte :Les sciences participatives en santé environnementale restent peu développées en France. Les objectifs poursuivis par les recherches en santé environnement (ex: estimer des expositions, évaluer des risques, tester des actions préventives) et méthodes employées sont variés. Les opportunités de plus grandes implications de la société civile et défis associés peuvent également différer à chaque étape de ces recherches. Ces aspects demandent à être mieux appréhendés collectivement. LILAS vise, en amont du développement de futurs projets de recherches participatives sur les multi-expositions environnementales, à 1) co-construire, entre chercheurs institutionnels et représentants de la société civile, une bonne compréhension commune des principales problématiques et méthodes de recherche en santé environnementale, de leurs enjeux, prérequis, forces et limites 2) identifier les bénéfices et points de vigilance liés à l’introduction de plus fortes dimensions participatives dans ces recherches. Méthode :LILAS a rassemblé une vingtaine de chercheurs institutionnels, académiques et représentants de la société civile intéressés par de multiples expositions environnementales (chimiques, radiologiques). Une recherche bibliographique a été initiée pour tirer le retour d’expérience de projets de sciences participatives à l’international. Plusieurs réunions ont permis d’identifier collectivement différents types d’études et de réfléchir sur les apports, limites et précautions méthodologiques relatifs à l’introduction de différents degrés de participation dans celles-ci. Une matrice d’analyse a été co-construite puis alimentée par les participants.Résultats :Pour différents types d’études (évaluations d’expositions multiples, identification de déterminants, tests d’interventions, développement de capteurs et applications, évaluations de risques sanitaires, études épidémiologiques, recherches expérimentales, études sur la santé des écosystèmes…), la matrice liste les bénéfices attendus pour différentes catégories de parties prenantes, les conditions méthodologiques (ex : contrôle des biais, puissance statistique) et contraintes associées, les avantages et limites relatives à l’emploi d’approches participatives ou plus “classiques”.Conclusion :LILAS a permis, par acculturation croisée, de poser des bases consolidées pour la co-construction de futurs projets de recherches participatives sur les multi-expositions environnementales.
Published: 2020

62. ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

Author: Rozenn Riou, Meriem Ladli, Sabine Gerbal-Chaloin, Pascale Bossard, Angélique Gougelet, Cécile Godard, Robin Loesch, Isabelle Lagoutte, Franck Lager, Julien Calderaro, Alexandre Dos Santos, Zhong Wang, Frédérique Verdier, Sabine Colnot, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Paul Brousse, Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Université Paris-Est Créteil Val-de-Marne - Institut de formation en ergothérapie (UPEC IFE), GOUGELET, Angélique, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Bossard, Pascale
Subjects: Adult, Male, Mouse, QH301-705.5, Science, [SDV]Life Sciences [q-bio], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, chromatin remodeling, Mice, epo transcription, hemic and lymphatic diseases, Animals, Humans, Erythropoiesis, Biology (General), Erythropoietin, Wnt Signaling Pathway, In Situ Hybridization, beta Catenin, ComputingMilieux_MISCELLANEOUS, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Chromosomes and Gene Expression, Wnt signaling, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Hepatocytes, Medicine, Female, Research Article, Developmental Biology, liver physiopathology, Human, Transcription Factors
Abstract: International audience; Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice, genetically invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating b-catenin signaling increased binding of Tcf4/b-catenin complex and upregulated its enhancer function. The loss of Arid1a together with b-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.
Published: 2020

63. Chimiothérapie et autres modèles animaux

Author: Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: [SCCO]Cognitive science, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2020

64. Basal‐like and classical cells coexist in pancreatic cancer revealed by single‐cell analysis on biopsy‐derived pancreatic cancer organoids from the classical subtype

Author: Odile Gayet, Martin Bigonnet, Natalia Juiz, Rémy Nicolle, Julie Roques, Nelson Dusetti, Abdessamad El-Kaoutari, Juan L. Iovanna, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Ligue Nationale Contre le Cancer (LNCC)
Subjects: 0301 basic medicine, MESH: Signal Transduction, Stromal cell, Biopsy, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Organoids, Biochemistry, Transcriptome, 03 medical and health sciences, transcriptomics, MESH: Biopsy, 0302 clinical medicine, Single-cell analysis, Pancreatic cancer, Genetics, medicine, Humans, single-cell analysis, RNA-Seq, MESH: RNA-Seq, Molecular Biology, MESH: Humans, medicine.diagnostic_test, MESH: Carcinoma, Pancreatic Ductal, intra-tumor heterogeneity, medicine.disease, Phenotype, Organoids, Pancreatic Neoplasms, combinational barcoding, 030104 developmental biology, medicine.anatomical_structure, Cancer cell, Cancer research, MESH: Pancreatic Neoplasms, 030217 neurology & neurosurgery, Biotechnology, Carcinoma, Pancreatic Ductal, Signal Transduction, MESH: Single-Cell Analysis
Abstract: International audience; Pancreatic ductal adenocarcinoma (PDAC) is composed of stromal, immune, and cancerous epithelial cells. Transcriptomic analysis of the epithelial compartment allows classification into different phenotypic subtypes as classical and basal-like. However, little is known about the intra-tumor heterogeneity particularly in the epithelial compartment. Growing evidences suggest that this phenotypic segregation is not so precise and different cancerous cell types may coexist in a single tumor. To test this hypothesis, we performed single-cell transcriptomic analyses using combinational barcoding exclusively on epithelial cells from six different classical PDAC patients obtained by Endoscopic Ultrasound (EUS) with Fine Needle Aspiration (FNA). To purify the epithelial compartment, PDAC were grown as biopsy-derived pancreatic cancer organoids. Single-cell transcriptomic analysis allowed the identification of four main cell clusters present in different proportions in all tumors. Remarkably, although all these tumors were classified as classical, one cluster present in all corresponded to a basal-like phenotype. These results reveal an unanticipated high heterogeneity of pancreatic cancers and demonstrate that basal-like cells, which have a highly aggressive phenotype, are more widespread than expected.
Published: 2020

65. Tissue Adaptation to Environmental Cues by Symmetric and Asymmetric Division Modes of Intestinal Stem Cells

Author: Raphaël Rousset, Aurélia Joly, Institut Sophia Agrobiotech (ISA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Recherche Agronomique (INRA), 'Ligue nationale contre le cancer' (LNCC doctoral grant 2018), Centre National de la Recherche Scientifique (CNRS), Fondation ARC pour la Recherche sur le Cancer 20171206145, PNR-EST ANSES & ECOPHYTO II (2017), and ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015)
Subjects: Regulator, Review, lcsh:Chemistry, stress, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Homeostasis, Intestinal Mucosa, lcsh:QH301-705.5, Spectroscopy, 0303 health sciences, symmetric, symmetric/asymmetric divisions, Stem Cells, 030302 biochemistry & molecular biology, General Medicine, asymmetric divisions, Adaptation, Physiological, Computer Science Applications, Cell biology, Drosophila, adaptive growth, gut, Cues, Stem cell, Signal transduction, Cell Division, Signal Transduction, Adult stem cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Stress, Physiological, Animals, Humans, Physical and Theoretical Chemistry, Molecular Biology, mouse, 030304 developmental biology, Innate immune system, Abiotic stress, Regeneration (biology), Asymmetric Cell Division, Organic Chemistry, fungi, aging, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, Diet, stem cell, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Stem cell division, lcsh:Biology (General), lcsh:QD1-999, regeneration, JNK, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: International audience; Tissues must adapt to the different external stimuli so that organisms can survive in their environments. The intestine is a vital organ involved in food processing and absorption, as well as in innate immune response. Its adaptation to environmental cues such as diet and biotic/abiotic stress involves regulation of the proliferative rate and a switch of division mode (asymmetric versus symmetric) of intestinal stem cells (ISC). In this review, we outline the current comprehension of the physiological and molecular mechanisms implicated in stem cell division modes in the adultDrosophilamidgut. We present the signaling pathways and polarity cues that control the mitotic spindle orientation, which is the terminal determinant ensuring execution of the division mode. We review these events during gut homeostasis, as well as during its response to nutrient availability, bacterial infection, chemical damage, and aging. JNK signaling acts as a central player, being involved in each of these conditions as a direct regulator of spindle orientation. The studies of the mechanisms regulating ISC divisions allow a better understanding of how adult stem cells integrate different signals to control tissue plasticity, and of how various diseases, notably cancers, arise from their alterations.
Published: 2020

66. Pharmacologic Normalization of Pancreatic Cancer-Associated Fibroblast Secretome Impairs Prometastatic Cross-Talk With Macrophages

Author: Ilaria Cascone, Marjorie Fanjul, Véronique Gigoux, Marie Pierre Bousquet, Christine Jean, Jerome Raffenne, Stéphane Pyronnet, Julia Rochotte, Rémy Nicolle, Matteo Ponzo, Herbert A. Schmid, Cindy Neuzillet, Yvan Martineau, Richard Tomasini, Thibault Douché, Stéphanie Cassant-Sourdy, Jérôme Cros, Jérémy Nigri, Camille Duluc, Alexia Brunel, Corinne Bousquet, Aurélie Perraud, Ivan Bièche, Muriel Mathonnet, Gilles Carpentier, Rémi Samain, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Limoges (UNILIM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche sur la croissance cellulaire, la réparation et la régénération tissulaires (LRCCRRT), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Novartis Pharmaceutical Corporation, Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Ligue Nationale Contre le Cancer, the Labex Toucan, the French Institut National du Cancer INCa (PLBIO15-115, PAIR18-080, PAIR18-082), Association pour la Recherche sur le Cancer ARC (20191209786), and the Plan Cancer 3R. Also supported by a fellowship from the Fondation pour la Recherche Médicale (FRM40493) (R.S. and T.D.), and a fellowship from the Ligue Nationale Contrele Cancer (C.J. and A.B.)., ANR-11-LABX-0068,TOUCAN,Analyse intégrée de la résistance dans les cancers hématologiques(2011), Ligue Nationnale Contre le Cancer, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Douché, Thibaut, and Analyse intégrée de la résistance dans les cancers hématologiques - - TOUCAN2011 - ANR-11-LABX-0068 - LABX - VALID
Subjects: 0301 basic medicine, Male, WT, wild type, Myeloid, medicine.medical_treatment, RC799-869, Metastasis, Mice, 0302 clinical medicine, PCR, polymerase chain reaction, Cancer-Associated Fibroblasts, GSEA, gene set enrichment analysis, Pancreatic Adenocarcinoma, GBSS, Grey’s balanced salt solution, Secretome, Original Research, Aged, 80 and over, sst1, somatostatin receptor subtype 1, mTOR, mechanistic target of rapamycin, PSC, pancreatic stellate cell, Gastroenterology, Stromal Cell Cross-Talk, KOsst1, Knock-out, LNR, lymph node ratio, ELISA, enzyme-linked immunosorbent assay, PDA, pancreatic ductal adenocarcinoma, Diseases of the digestive system. Gastroenterology, Middle Aged, LAR, long-acting release, mRNA, messenger RNA, 3. Good health, ECM, extracellular matrix, MS, mass-spectrometry, FFPE, formalin-fixed paraffin-embedded, medicine.anatomical_structure, Adenocarcinoma, 030211 gastroenterology & hepatology, Female, RNAseq, RNA sequencing, TAM, tumor-associated macrophage, αSMA, α smooth muscle actin, Somatostatin, Stroma Normalization, Carcinoma, Pancreatic Ductal, Stromal cell, education, KPC, Pdx-1-Cre, PBS, phosphate-buffered saline, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, Transgenic, CSF-1-R, colony stimulating factor 1 receptor, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Stroma, Pancreatic cancer, medicine, Animals, Humans, PDX, patient-derived xenograft, Aged, CAF, cancer-associated fibroblast, Hepatology, CSF-1, colony stimulating factor 1, business.industry, Growth factor, Macrophages, LSL-KrasG12D/+, LSL-Trp53R172H/+, Antimetastatic Therapy, medicine.disease, Hormones, Mice, Inbred C57BL, Pancreatic Neoplasms, CAFhTERT, human Telomerase reverse transcriptase, 030104 developmental biology, Somatostatin Receptor, Cancer research, BSA, bovine serum albumin, GPCR, G-protein–coupled receptor subtype, business
Abstract: Background & Aims Cancer-associated fibroblasts (CAFs) from pancreatic adenocarcinoma (PDA) present high protein synthesis rates. CAFs express the G-protein–coupled somatostatin receptor sst1. The sst1 agonist SOM230 blocks CAF protumoral features in vitro and in immunocompromised mice. We have explored here the therapeutic potential of SOM230, and underlying mechanisms, in immunocompetent models of murine PDA mimicking the heavy fibrotic and immunosuppressive stroma observed in patient tumors. Methods Large-scale mass spectrometry analyses were performed on media conditioned from 9 patient PDA-derived CAF primary cultures. Spontaneous transgenic and experimental (orthotopic co-graft of tumor cells plus CAFs) PDA-bearing mice were longitudinally ultrasound-monitored for tumor and metastatic progression. Histopathology and flow cytometry analyses were performed on primary tumors and metastases. Stromal signatures were functionally validated through bioinformatics using several published, and 1 original, PDA database. Results Proteomics on the CAF secretome showed that SOM230 controls stromal activities including inflammatory responses. Among the identified secreted proteins, we validated that colony-stimulating factor 1 (CSF-1) (a macrophage growth factor) was reduced by SOM230 in the tumor and plasma of PDA-harboring mice, alongside intratumor stromal normalization (reduced CAF and macrophage activities), and dramatic metastasis reduction. In transgenic mice, these SOM230 benefits alleviate the chemotherapy-induced (gemcitabine) immunosuppressive stroma reshaping. Mechanistically, SOM230 acts in vivo on CAFs through sst1 to disrupt prometastatic CAF production of CSF-1 and cross-talk with macrophages. We found that in patients, stromal CSF-1 was associated with aggressive PDA forms. Conclusions We propose SOM230 as an antimetastatic therapy in PDA for its capacity to remodel the fibrotic and immunosuppressive myeloid stroma. This pharmacotherapy should benefit PDA patients treated with chemotherapies., Graphical abstract
Published: 2020

67. The Set1 N-terminal domain and Swd2 interact with RNA polymerase II CTD to recruit COMPASS

Author: Marion Dubarry, Jongcheol Jeon, Vincent Géli, Luis M. Soares, Hyun Jin Bae, Stephen Buratowski, Catherine Dargemont, Jae-Hoon Kim, Harvard Medical School [Boston] (HMS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Korea Advanced Institute of Science and Technology (KAIST), Foghorn Therapeutics [Cambridge, MA, États-Unis], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), H.B. was supported by a postdoctoral fellowship from the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2015R1A6A3A03017730). This work was supported by grants from the National Research Foundation of Korea (NRF-2019R1A2C2090830) to J.K., from 'Ligue Nationale Contre le Cancer' (LNCC) (Equipe labellisée) to M.D. and V.G., and grants GM046498 and GM056663 from the U.S. National Institutes of Health to S.B., Bodescot, Myriam, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, Molecular biology, [SDV]Life Sciences [q-bio], General Physics and Astronomy, RNA polymerase II, Biochemistry, environment and public health, Histones, 0302 clinical medicine, Histone methylation, Histone post-translational modifications, lcsh:Science, Regulation of gene expression, Multidisciplinary, biology, Chemistry, RNA-Binding Proteins, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Chromatin, Cell biology, Chromatin Immunoprecipitation Sequencing, RNA Polymerase II, Transcription, Protein Binding, Histone H3 Lysine 4, Saccharomyces cerevisiae Proteins, animal structures, Science, Saccharomyces cerevisiae, Methylation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Histone H3, Protein Domains, Histone H2B, Point Mutation, Lysine, Ubiquitination, Histone-Lysine N-Methyltransferase, General Chemistry, 030104 developmental biology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], biology.protein, lcsh:Q, CTD, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract: Methylation of histone H3 lysine 4 (H3K4) by Set1/COMPASS occurs co-transcriptionally, and is important for gene regulation. Set1/COMPASS associates with the RNA polymerase II C-terminal domain (CTD) to establish proper levels and distribution of H3K4 methylations. However, details of CTD association remain unclear. Here we report that the Set1 N-terminal region and the COMPASS subunit Swd2, which interact with each other, are both needed for efficient CTD binding in Saccharomyces cerevisiae. Moreover, a single point mutation in Swd2 that affects its interaction with Set1 also impairs COMPASS recruitment to chromatin and H3K4 methylation. A CTD interaction domain (CID) from the protein Nrd1 can partially substitute for the Set1 N-terminal region to restore CTD interactions and histone methylation. However, even when Set1/COMPASS is recruited via the Nrd1 CID, histone H2B ubiquitylation is still required for efficient H3K4 methylation, indicating that H2Bub acts after the initial recruitment of COMPASS to chromatin., Methylation of histone H3 lysine 4 (H3K4) by Set1/COMPASS occurs co-transcriptionally, and is important for gene regulation. Here the authors provide evidence that the Set1 N-terminal region and the COMPASS subunit Swd2 interact with RNA polymerase II CTD to recruit COMPASS in budding yeast.
Published: 2020

68. Tertiary Lymphoid Structures and B cells: Clinical impact and therapeutic modulation in cancer

Author: Marco Moreira, Catherine Sautès-Fridman, Florent Petitprez, Wolf H. Fridman, Tom Wei-Wu Chen, Cheng-Ming Sun, Johanna Verneau, Maxime Meylan, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), National Taiwan University [Taiwan] (NTU), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Ligue Nationale Contre le Cancer (LNCC), and Gestionnaire, HAL Sorbonne Université 5
Subjects: 0301 basic medicine, medicine.medical_treatment, T-Lymphocytes, Immunology, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biomarkers, Pharmacological, Metastasis, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Biomarkers, Tumor, Tumor Microenvironment, Immunology and Allergy, Medicine, Cytotoxic T cell, Animals, Humans, B-Lymphocytes, B cells, business.industry, Clinical outcome, Cancer, Immunotherapy, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, Cytokine, Lymphatic system, Adaptive anti-tumor response, 030220 oncology & carcinogenesis, Cancer research, medicine.symptom, business, Tertiary lymphoid structures
Abstract: International audience; Tumors progression is under the control of a heterogeneous microenvironment composed of immune cells, fibroblasts, blood and lymphatic vessels, in which T cells have been demonstrated to be major actors, through their cytotoxic and cytokine producing effector functions and their long term memory that protects against metastasis. In this scenario, lessons from mouse models taught that B cells exert a protumoral role, via macrophage-dependent activation of inflammation. However, it became progressively evident from studies in patients with human cancers that the anti-tumor responses can be generated and controlled in tertiary lymphoid structures (TLS) that concentrate most of the intratumoral B cells and where B cells can differentiate into plasma cells and memory cells. Furthermore, recent studies demonstrated that the presence in tumors of B cells and TLS are associated with favorable outcome in patients treated by immunotherapy, unraveling TLS as a new predictive marker of anti-tumor response human cancers. This review encompasses the characteristics and functions of TLS and of B cells in human tumors, their prognostic and theranostic impact and summarizes the mouse models used to induce TLS neogenesis in tumors.
Published: 2020

69. Autres modèles animaux et chimiothérapies

Author: Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: [SDV]Life Sciences [q-bio], [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2020

70. Expression plasticity of chemotactic GPCRs and signalling commutators controls glioblastoma invasion and survival

Author: Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2020

71. TET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2α-Driven Mesenchymal Transition

Author: Morin, Aurélie, Goncalves, Judith, Moog, Sophie, Castro-Vega, Luis-Jaime, Job, Sylvie, Buffet, Alexandre, Fontenille, Marie-Joséphine, Woszczyk, Justine, Gimenez-Roqueplo, Anne-Paule, Letouzé, Eric, Favier, Judith, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ligue Nationale Contre le Cancer (LNCC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and HAL-SU, Gestionnaire
Subjects: [SDV] Life Sciences [q-bio], paraganglioma, hypoxia, [SDV]Life Sciences [q-bio], hydroxymethylation, SDH, methylation, epithelial-to-mesenchymal transition, succinate dehydrogenase, SDHB, pheochromocytoma
Abstract: International audience; Loss-of-function mutations in the SDHB subunit of succinate dehydrogenase predispose patients to aggressive tumors characterized by pseudohypoxic and hypermethylator phenotypes. The mechanisms leading to DNA hypermethylation and its contribution to SDH-deficient cancers remain undemonstrated. We examine the genome-wide distribution of 5-methylcytosine and 5-hydroxymethylcytosine and their correlation with RNA expression in SDHB-deficient tumors and murine Sdhb−/− cells. We report that DNA hypermethylation results from TET inhibition. Although it preferentially affects PRC2 targets and known developmental genes, PRC2 activity does not contribute to the DNA hypermethylator phenotype. We also prove, in vitro and in vivo, that TET silencing, although recapitulating the methylation profile of Sdhb−/− cells, is not sufficient to drive their EMT-like phenotype, which requires additional HIF2α activation. Altogether, our findings reveal synergistic roles of TET repression and pseudohypoxia in the acquisition of metastatic traits, providing a rationale for targeting HIF2α and DNA methylation in SDH-associated malignancies.
Published: 2020

72. Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox

Author: Gaëlle Legube, Sérgio F. de Almeida, Pablo Huertas, Alexandra C Vítor, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Repositório da Universidade de Lisboa, Fundação para a Ciência e a Tecnologia (Portugal), European Commission, Programa Operacional do Potencial Humano (Portugal), European Research Council, Agence Nationale de la Recherche (France), Ligue Nationale contre le Cancer (France), Institut National du Cancer (France), Universidad de Sevilla. Departamento de Genética, [Vítor,AC, de Almeida,SF] Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. [Huertas,P] Department of Genetics, University of Seville, Seville, Spain. [Huertas,P] Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain. [Legube,G] LBCMCP, Centre de Biologie Integrative (CBI), CNRS, Université de Toulouse, Toulouse, France., Work in the SA lab was funded by PTDC/BIM-ONC/0016/2014 and PTDC/BIA-MOL/30438/2017 from Fundação para a Ciência e a Tecnologia (FCT), Portugal, by LISBOA-01-0145-FEDER-007391, project co-funded by FEDER through POR Lisboa, Portugal 2020–Programa Operacional Regional de Lisboa, and FCT, and and by the IMM-Laço Fund. The GL laboratory was funded by grants from the European Research Council (ERC-2014-CoG 647344), Agence Nationale pour la Recherche (ANR-18-CE12-0015-02), the Institut National contre le Cancer (INCA), and the Ligue Nationale contre le Cancer (LNCC).
Subjects: 0301 basic medicine, Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Repair [Medical Subject Headings], Non-homologous DNA end joining, Cell cycle checkpoint, DNA damage, DNA repair, [SDV]Life Sciences [q-bio], ComputingMilieux_LEGALASPECTSOFCOMPUTING, Review, Computational biology, Biology, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle::Cell Cycle Checkpoints [Medical Subject Headings], Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Cromatina, homologous recombination (HR), 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Damage::DNA Breaks::DNA Breaks, Double-Stranded [Medical Subject Headings], Recombinación homóloga, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Recombination, Genetic::Homologous Recombination [Medical Subject Headings], Roturas del ADN de doble cadena, Reparación del ADN por unión de extremidades, Molecular Biosciences, Molecular Biology, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Chromosome Structures::Chromatin [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Damage [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Repair::DNA End-Joining Repair [Medical Subject Headings], Double Strand Break Repair, Chromatin, 3. Good health, 030104 developmental biology, Daño del ADN, chemistry, lcsh:Biology (General), Homologous recombination (HR), 030220 oncology & carcinogenesis, Reparación del ADN, chromatin, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::DNA [Medical Subject Headings], DNA, non-homologous DNA end joining
Abstract: To ward off against the catastrophic consequences of persistent DNA double-strand breaks (DSBs), eukaryotic cells have developed a set of complex signaling networks that detect these DNA lesions, orchestrate cell cycle checkpoints and ultimately lead to their repair. Collectively, these signaling networks comprise the DNA damage response (DDR). The current knowledge of the molecular determinants and mechanistic details of the DDR owes greatly to the continuous development of ground-breaking experimental tools that couple the controlled induction of DSBs at distinct genomic positions with assays and reporters to investigate DNA repair pathways, their impact on other DNA-templated processes and the specific contribution of the chromatin environment. In this review, we present these tools, discuss their pros and cons and illustrate their contribution to our current understanding of the DDR., Work in the SA lab was funded by PTDC/BIM-ONC/0016/2014 and PTDC/BIA-MOL/30438/2017 from Fundação para a Ciência e a Tecnologia (FCT), Portugal; by LISBOA-01-0145-FEDER-007391, project co-funded by FEDER through POR Lisboa, Portugal 2020–Programa Operacional Regional de Lisboa, and FCT; and by the IMM-Laço Fund. The GL laboratory was funded by grants from the European Research Council (ERC-2014-CoG 647344), Agence Nationale pour la Recherche (ANR-18-CE12-0015-02), the Institut National contre le Cancer (INCA), and the Ligue Nationale contre le Cancer (LNCC).
Published: 2020

73. Protecting effects of Panax quinquefolius on chemotherapy-induced fatigue symptoms associated with systemic normalization of IL-6 in mice

Author: Parment, Renaud, Dubois, Martine, Desrues, Laurence, Joly, Florence, Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC), Service d'Oncologie médicale [Caen], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), and Normandie Université (NU)
Subjects: [SCCO]Cognitive science, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

74. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1

Author: Caroline Imbert, Stéphane Carpentier, Nathalie Andrieu-Abadie, Marlène Marcellin, Marine Fraisse, Pierre Brousset, Florie Bertrand, Elodie Martin, Céline Colacios, Bruno Ségui, Philippe Rochaix, Odile Burlet-Schiltz, Nicolas Meyer, Virginie Garcia, Thierry Levade, Anne Montfort, Laurence Lamant, Anne Gonzalez de Peredo, Elie Marcheteau, Julia Gilhodes, Thomas Filleron, Florent Puisset, Sophie Tartare-Deckert, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Équipe labellisée Ligue Nationale Contre le Cancer [Toulouse], Ligue Nationale Contre le Cancer [Paris] (LNCC), Université Fédérale Toulouse Midi-Pyrénées, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], This work was supported by INSERM, Paul Sabatier University, Ligue Nationale Contre le Cancer (LNCC, Equipe Labellisée 2013), INSERM Transfert, Cancéropôle Grand Sud-Ouest, ROTARY Toulouse clubs, Fondation Toulouse Cancer Santé and Fondation ARC (IMMUSPHINX project). The research leading to these results has received funding from the Transcan-2 Research Program, which is a transnational R&D program jointly funded by national funding organizations within the framework of the ERA-NET Transcan-2. C.I. is a recipient of a fellowship from LNCC and Fondation pour la Recherche Médicale (FRM). The IBiSA Toulouse Proteomics facility is supported by the following institutions: Région Midi-Pyrénées, Fonds Européens de Développement Régional, Toulouse Métropole, and the French Ministry of Research with the ‘Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program’ (Proteomics French Infrastructure project, ANR-10-INBS-08). P.B. is supported by the LABEX TOUCAN., ANR-10-INBS-08-01/10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-11-IDEX-0002-02/11-LABX-0068,TOUCAN,Analyse intégrée de la résistance dans les cancers hématologiques(2011), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-11-IDEX-0002,UNITI,Université Fédérale de Toulouse(2011), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Bodescot, Myriam, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Initiative d'excellence - Université Fédérale de Toulouse - - UNITI2011 - ANR-11-IDEX-0002 - IDEX - VALID
Subjects: 0301 basic medicine, Male, Skin Neoplasms, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Melanoma, Experimental, General Physics and Astronomy, Cancer immunotherapy, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Tumour biomarkers, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, polycyclic compounds, Molecular Targeted Therapy, lcsh:Science, Melanoma, Mice, Inbred BALB C, Multidisciplinary, biology, Middle Aged, Cancer metabolism, 3. Good health, Gene Expression Regulation, Neoplastic, Survival Rate, Phosphotransferases (Alcohol Group Acceptor), medicine.anatomical_structure, Nivolumab, Sphingosine kinase 1, 030220 oncology & carcinogenesis, Veterinary medicine and animal Health, Female, hormones, hormone substitutes, and hormone antagonists, Regulatory T cell, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biotechnologies, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Antibodies, Monoclonal, Humanized, General Biochemistry, Genetics and Molecular Biology, Gene Expression Regulation, Enzymologic, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Gene silencing, Animals, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Aged, Tumor microenvironment, Sphingosine, business.industry, General Chemistry, Immunotherapy, medicine.disease, Médecine vétérinaire et santé animal, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Cancer cell, Cancer research, biology.protein, Tumor Escape, lcsh:Q, business
Abstract: Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy., There are many patients who do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Here, the authors show a significant negative correlation between sphingosine kinase-1 (SK1) expression and survival for ICI-treated melanoma patients, and further show that targeting SK1 improves response to ICI in mouse cancer models.
Published: 2020

75. Cancer-associated fibroblasts: Accomplices in the tumor immune evasion

Author: Marc Hilmi, Rémy Nicolle, Cindy Neuzillet, Corinne Bousquet, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Cooperator Multidisciplinary Oncology Group (GERCOR), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, UMR1037, Cancer Research Center of Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UVSQ, Équipe, and Ligue Nationale Contre le Cancer (LNCC)
Subjects: 0301 basic medicine, Cancer Research, Cell signaling, Myeloid, medicine.medical_treatment, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Biology, lcsh:RC254-282, immunology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cancer immunotherapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Tumor microenvironment, cell communication, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Cancer-Associated Fibroblasts, cancer-associated fibroblasts
Abstract: Simple Summary A growing number of studies suggest that cancer-associated fibroblasts (CAFs) modulate both myeloid and lymphoid cells through secretion of molecules (i.e., chemical function) and production of the extracellular matrix (ECM), i.e., physical function. Even though targeting functions CAFs is a relevant strategy, published clinical trials solely aimed at targeting the stroma showed disappointing results, despite being based on solid preclinical evidence. Our review dissects the interactions between CAFs and immune cells and explains how a deeper understanding of CAF subpopulations is the cornerstone to propose relevant therapies that will ultimately improve survival of patients with cancer. Abstract Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy.
Published: 2020

76. Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

Author: Renaud Pourpre, Hélène Bierne, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AgroParisTech, Université Paris-Saclay, and Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE) - French Ligue Nationale Contre le Cancer (LNCC) - iXcore Research Foundation
Subjects: Transcription, Genetic, Virulence Factors, Listeria, Health, Toxicology and Mutagenesis, lcsh:Medicine, Review, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Toxicology, medicine.disease_cause, Legionella pneumophila, Epigenesis, Genetic, nucleomodulin, 03 medical and health sciences, Shigella flexneri, Bacterial Proteins, medicine, Ehrlichia chaffeensis, Animals, Humans, Secretion, 030304 developmental biology, Cell Nucleus, 0303 health sciences, biology, Bacteria, epigenetics, 030306 microbiology, Effector, lcsh:R, nucleus, Pathogenic bacteria, pathogens, Gene Expression Regulation, Bacterial, biology.organism_classification, Chromatin Assembly and Disassembly, 3. Good health, Cell biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Host-Pathogen Interactions, Ankyrin repeat, Protein Processing, Post-Translational, Signal Transduction, effectors
Abstract: Pathogenic bacteria secrete a variety of proteins that manipulate host cell function by targeting components of the plasma membrane, cytosol, or organelles. In the last decade, several studies identified bacterial factors acting within the nucleus on gene expression or other nuclear processes, which has led to the emergence of a new family of effectors called “nucleomodulins”. In human and animal pathogens, Listeria monocytogenes for Gram-positive bacteria and Anaplasma phagocytophilum, Ehrlichia chaffeensis, Chlamydia trachomatis, Legionella pneumophila, Shigella flexneri, and Escherichia coli for Gram-negative bacteria, have led to pioneering discoveries. In this review, we present these paradigms and detail various mechanisms and core elements (e.g., DNA, histones, epigenetic regulators, transcription or splicing factors, signaling proteins) targeted by nucleomodulins. We particularly focus on nucleomodulins interacting with epifactors, such as LntA of Listeria and ankyrin repeat- or tandem repeat-containing effectors of Rickettsiales, and nucleomodulins from various bacterial species acting as post-translational modification enzymes. The study of bacterial nucleomodulins not only generates important knowledge about the control of host responses by microbes but also creates new tools to decipher the dynamic regulations that occur in the nucleus. This research also has potential applications in the field of biotechnology. Finally, this raises questions about the epigenetic effects of infectious diseases.
Published: 2020

77. Direct observation of helicase-topoisomerase coupling within reverse gyrase

Author: Hélène Débat, Xi Yang, Marc Nadal, Terence R. Strick, Florence Garnier, Institut de biologie de l'Ecole Normale Supérieure (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Jacques Monod (IJM (UMR_7592)), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, HAL UVSQ, Équipe, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Ligue Nationale Contre le Cancer (LNCC)
Subjects: DNA, Bacterial, Models, Molecular, Magnetic tweezers, Protein Conformation, [SDV.CAN]Life Sciences [q-bio]/Cancer, single molecule, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, 0302 clinical medicine, Protein Domains, [SDV.CAN] Life Sciences [q-bio]/Cancer, Nucleotide, Thermus, DNA topoisomerase, 030304 developmental biology, Writhe, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, biology, Topoisomerase, DNA Helicases, Helicase, DNA, Biological Sciences, DNA-Binding Proteins, Biophysics and Computational Biology, helicase, DNA Topoisomerases, Type I, Catalytic cycle, chemistry, biology.protein, Biophysics, DNA supercoil, magnetic tweezers, DNA Topoisomerases, 030217 neurology & neurosurgery
Abstract: Significance Collaboration between RecQ helicase and type IA topoisomerase has been found in organisms representing all levels of complexity, including the well-known BLM helicase–Top3α combination found in humans and capable of dissolving DNA double-Holliday junctions. Uniquely, hyperthermophiles have fused these functional units into a chimeric enzyme known as reverse gyrase (RG), which is capable of positively supercoiling DNA using ATP hydrolysis. Single-molecule experimentation allows us to observe at single-molecule resolution the helicase–topoisomerase coupling in RG that leads to the catalytic transitions that make up a complete ATP cycle. Subunit collaboration in RG serves as an entry point to fully understanding the universal cooperation between RecQ and Top IA., Reverse gyrases (RGs) are the only topoisomerases capable of generating positive supercoils in DNA. Members of the type IA family, they do so by generating a single-strand break in substrate DNA and then manipulating the two single strands to generate positive topology. Here, we use single-molecule experimentation to reveal the obligatory succession of steps that make up the catalytic cycle of RG. In the initial state, RG binds to DNA and unwinds ∼2 turns of the double helix in an ATP-independent fashion. Upon nucleotide binding, RG then rewinds ∼1 turn of DNA. Nucleotide hydrolysis and/or product release leads to an increase of 2 units of DNA writhe and resetting of the enzyme, for a net change of topology of +1 turn per cycle. Final dissociation of RG from DNA results in rewinding of the 2 turns of DNA that were initially disrupted. These results show how tight coupling of the helicase and topoisomerase activities allows for induction of positive supercoiling despite opposing torque.
Published: 2020

78. The clinical role of the TME in solid cancer

Author: Rafael Sanchez-Salas, Yann Vano, Nicolas A. Giraldo, J David Peske, Catherine Sautès-Fridman, Wolf H. Fridman, Alexandre Ingels, Florent Petitprez, Pierre Validire, Etienne Becht, Xavier Cathelineau, Gestionnaire, Hal Sorbonne Université, Johns Hopkins University School of Medicine [Baltimore], Service d'urologie [Institut Mutualiste Montsouris], Institut Mutualiste de Montsouris (IMM), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Métabolisme et physiologie rénale (CRC - UMR_S 1138), Centre National de la Recherche Scientifique (CNRS)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Sorbonne Université (SU), Agency for science, technology and research [Singapore] (A*STAR), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), and Ligue Nationnale Contre le Cancer
Subjects: Cancer microenvironment, Cancer Research, Colorectal cancer, [SDV]Life Sciences [q-bio], Cell, Cancer immunotherapy, Review Article, Prognostic markers, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cancer-Associated Fibroblasts, Immunity, Neoplasms, Tumor Microenvironment, medicine, Humans, Cytotoxic T cell, Neoplasm Invasiveness, Clinical significance, Cell Proliferation, business.industry, Melanoma, Immunosurveillance, Endothelial Cells, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, business, T-Lymphocytes, Cytotoxic
Abstract: International audience; The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.
Published: 2018

79. Beyond the on/off chip trade-off: A reversibly sealed microfluidic platform for 3D tumor microtissue analysis

Author: Valérie Taly, Antoine Riaud, Gabriele Pitingolo, Philippe Nizard, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe labellisée Ligue contre le Cancer, This work was supported by the Ministère de l’Enseignement Supérieur et de la Recherche, the Université Paris-Descartes, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Institut National du Cancer (INCA) and canceropole Ile-de-France (no. 2016-1-EMERG-54-UP 5-1), the SIRIC CARPEM, the Fondation de la Recherche Medicale (SPF20160936257) and the ligue nationale contre le cancer (LNCC, Program 'Equipe labelisée LIGUE', no. EL2016.LNCC/VaT). The authors acknowledges the financial support of HTE Program-HetColi network, INSERM Physicancer program (no. PC201423) and the SIRIC CARPEM. Financial supports from CAMPUS FRANCE (n° 39525QJ) and Università Italo-Francese (n° G18_208) are gratefully acknowledged. The authors would like to thank Saksham Sharma for his important contribution to the development of the numerical models. This work has benefited from the facility and expertise of the electron microscopy facility of Institut de Biologie Paris-Seine (IBPS/FR3631 - UPMC/CNRS- Paris, France). This work was carried out with the support of the Pierre-Gilles de Gennes Institute equipment ('Investissements d’Avenir' program, reference: ANR 10-NANO 0207)., and TALY, Valerie
Subjects: 0301 basic medicine, Materials science, Growth kinetics, [SDV]Life Sciences [q-bio], Microfluidics, Nanotechnology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 02 engineering and technology, Fluorescence, SEM analysis, 03 medical and health sciences, 3D cell culture, Tumor microtissue, Materials Chemistry, Drug response, Electrical and Electronic Engineering, Modular chip, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Instrumentation, Fluorescence staining, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Metals and Alloys, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Chip, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, [SDV] Life Sciences [q-bio], Spheroid, 030104 developmental biology, Microfluidic chip, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology
Abstract: International audience; Nowadays, microfluidic 3D cell culture is widely used to mimic complex microtissue and dynamic environment, performing more realistic in vitro assays for drug testing. Herein, we developed a novel microfluidic platform for tumor microtissue culture, drug response analysis and versatile microscopic characterization. By reversibly bonding the chip, we go beyond the on/off chip tradeoff, which allows us to perform both fluorescence and SEM characterization of tumor microtissues on a simple platform. The microfluidic chip consists of spherical microwells connected via microchannels, bonded through a magnetic system. Colorectal cancer HT-29 cells were cultured as spherical microtissues on chip and their growth kinetics monitored. The cytotoxic activity of Camptothecin was evaluated by in situ live/dead fluorescence staining and quantification of morphology parameters. Finally, we demonstrated the possibility to collect the 3D tumor microtissues and characterize their surface damaged by the drug using scanning electron microscopy. This reversibly sealed microfluidic platform thus enables to grow sets of 3D tumor microtissues in a controlled dynamic microenvinroment, and subsequently to retrieve the 3D tumor microtissues after chemotherapeutic treatment for in-depth analysis.
Published: 2018

80. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma

Author: Job, Sylvie, Rapoud, Delphine, dos Santos, Alexandre, Gonzalez, Patrick, Desterke, Christophe, Pascal, Gérard, Elarouci, Nabila, Ayadi, Mira, Adam, René, Azoulay, Daniel, Denis, Castaing, Vibert, Eric, Cherqui, Daniel, Samuel, Didier, Sa Cuhna, Antonio, Marchio, Agnès, Pineau, Pascal, Guettier, Catherine, de Reyniès, Aurélien, Faivre, Jamila, Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Nationale Contre le Cancer (LNCC), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and MARCHIO, Agnes
Subjects: Male, Tumor heterogeneity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunophenotyping, Cholangiocarcinoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Discovery, Hepatobiliary Malignancies, Humans, Immune Checkpoint Inhibitors, Inflammation, Immunity, Original Articles, Middle Aged, Tumor infiltrating leukocytes (TILs), Prognosis, Immunohistochemistry, Immune Stratification, Bile Ducts, Intrahepatic, Cancer Immunology, Bile Duct Neoplasms, Tumor microenvironment, Original Article, Female, sense organs, Transcriptome, Signal Transduction
Abstract: Background and Aims Intrahepatic cholangiocarcinoma (ICC) is a severe malignant tumor in which the standard therapies are mostly ineffective. The biological significance of the desmoplastic tumor microenvironment (TME) of ICC has been stressed but was insufficiently taken into account in the search for classifications of ICC adapted to clinical trial design. We investigated the heterogeneous tumor stroma composition and built a TME‐based classification of ICC tumors that detects potentially targetable ICC subtypes. Approach and Results We established the bulk gene expression profiles of 78 ICCs. Epithelial and stromal compartments of 23 ICCs were laser microdissected. We quantified 14 gene expression signatures of the TME and those of 3 functional indicators (liver activity, inflammation, immune resistance). The cell population abundances were quantified using the microenvironment cell population‐counter package and compared with immunohistochemistry. We performed an unsupervised TME‐based classification of 198 ICCs (training set) and 368 ICCs (validation set). We determined immune response and signaling features of the different immune subtypes by functional annotations. We showed that a set of 198 ICCs could be classified into 4 TME‐based subtypes related to distinct immune escape mechanisms and patient outcomes. The validity of these immune subtypes was confirmed over an independent set of 368 ICCs and by immunohistochemical analysis of 64 ICC tissue samples. About 45% of ICCs displayed an immune desert phenotype. The other subtypes differed in nature (lymphoid, myeloid, mesenchymal) and abundance of tumor‐infiltrating cells. The inflamed subtype (11%) presented a massive T lymphocyte infiltration, an activation of inflammatory and immune checkpoint pathways, and was associated with the longest patient survival. Conclusion We showed the existence of an inflamed ICC subtype, which is potentially treatable with checkpoint blockade immunotherapy.
Published: 2019

81. Cancer, Fatigue and Cognition: a major translational power of preclinical models to understand, identify biomarkers and test prevention

Author: Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2019

82. Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors

Author: Martine Dubois, Florence Joly, Janette L. Vardy, M.B. de Ruiter, Gordon Winocur, Tim A. Ahles, Laure Tron, Marie Lange, Hélène Castel, CASTEL, Hélène, Centre de recherche clinique [CHU Caen] (CRC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Ligue Nationale Contre le Cancer (LNCC)-Cancéropole Nord-Ouest, Service d'Oncologie médicale [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), University of New South Wales [Sydney] (UNSW), Memorial Sloane Kettering Cancer Center [New York], Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rotman Research Institute at the Baycrest Centre (RRI), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), and Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Neurogenesis, Reviews, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Disease, Catechol O-Methyltransferase, [SCCO]Cognitive science, 03 medical and health sciences, 0302 clinical medicine, Apolipoproteins E, Cognition, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer Survivors, Internal medicine, Neoplasms, medicine, Humans, Cognitive Dysfunction, Cognitive rehabilitation therapy, Exercise, Polymorphism, Genetic, business.industry, Brain-Derived Neurotrophic Factor, Neuropsychology, Cancer, [SCCO] Cognitive science, Hematology, Executive functions, medicine.disease, Chemotherapy regimen, Cognitive training, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Quality of Life, Cytokines, business
Abstract: Background Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. However, cancer-related cognitive impairment (CRCI) is frequently reported in patients treated for non-central nervous system cancers, particularly during and after chemotherapy. Design This review provides an update of the state of the art based on PubMed searches between 2012 and March 2019 on ‘cognition’, ‘cancer’, ‘antineoplastic agents’ or ‘chemotherapy’. It includes the most recent clinical, imaging and pre-clinical data and reports management strategies of CRCI. Results Evidence obtained primarily from studies on breast cancer patients highlight memory, processing speed, attention and executive functions as the most cognitive domains impaired post-chemotherapy. Recent investigations established that other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits. Knowledge regarding predisposing factors, biological markers or brain functions associated with CRCI has improved. Factors such as age and genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF may predispose individuals to a higher risk of cognitive impairment. Poor performance on neuropsychological tests were associated with volume reduction in grey matter, less connectivity and activation after chemotherapy. In animals, hippocampus-based memory and executive functions, mediated by the frontal lobes, were shown to be particularly susceptible to the effects of chemotherapy. It involves altered neurogenesis, mitochondrial dysfunction or brain cytokine response. An important next step is to identify strategies for managing cognitive difficulties, with primary studies to assess cognitive training and physical exercise regimens. Conclusions CRCI is not limited to chemotherapy. A multidisciplinary approach has improved our knowledge of the complex mechanisms involved. Nowadays, studies evaluating cognitive rehabilitation programmes are encouraged to help patients cope with cognitive difficulties and improve quality of life during and after cancer.
Published: 2019

83. Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated With Outcome During Pazopanib Therapy in the Metastatic Setting

Author: Annelies Verbiest, Nathalie Rioux-Leclercq, Benoit Beuselinck, Steven Joniau, Aurélien de Reyniès, Laure Caruana, Brigitte Laguerre, Kathleen Van den Eynde, Gabrielle Couchy, Hendrik Van Poppel, Jessica Zucman-Rossi, Evelyne Lerut, Agnieszka Wozniak, Sylvie Job, Raymond Oyen, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, University Hospitals Leuven [Leuven], Département d'oncologie médicale [Rennes], CRLCC Eugène Marquis (CRLCC), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ligue Nationale Contre le Cancer (LNCC), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Indazoles, Urology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Predictive, Pazopanib, 03 medical and health sciences, 0302 clinical medicine, Molecular classification, Renal cell carcinoma, Internal medicine, Biomarkers, Tumor, Humans, Medicine, Prospective Studies, Neoplasm Metastasis, Carcinoma, Renal Cell, Vascular endothelial growth factor receptor tyrosine kinase inhibitor, Aged, Retrospective Studies, Aged, 80 and over, Sulfonamides, Univariate analysis, Tumor size, business.industry, Sunitinib, Biomarker, Middle Aged, medicine.disease, Kidney Neoplasms, Progression-Free Survival, Gene expression profiling, 3. Good health, Clear cell renal cell carcinoma, Pyrimidines, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, business, medicine.drug
Abstract: International audience; Background: We previously described 4 molecular subtypes of metastatic clear cell renal cell carcinoma (mccRCC), named ccrcc1-4 (Beuselinck et al, 2015). These have both prognostic and predictive value for patients treated with first-line sunitinib, with distinctive objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The ccrcc2 and ccrcc3 tumors have the best outcomes, followed by ccrcc1 and then ccrcc4. We hypothesized that these molecular subtypes would show similar outcomes with first-line pazopanib treatment.Patients and methods: We classified 28 mccRCC tumors treated with pazopanib as first-line therapy, as described previously. The primary endpoints were PFS and OS from the start of pazopanib. A secondary endpoint was ORR. Because there were only 2 ccrcc3 tumors, they were pooled with the ccrcc2 tumors for outcome analysis.Results: PFS was 9 months for the ccrcc2 and ccrcc3 tumors, 5 months for ccrcc1 tumors, and 3 months for the ccrcc4 tumors (P = .011). The corresponding OS duration was 69, 19, and 5 months (P = .003). The corresponding ORR was 50%, 33%, and 0%. The corresponding mean tumor size decreased by 34%, 6%, and 2% (P = .032). The ccrcc1-4 classification was a stronger predictor of outcome than the International Metastatic Renal Cell Carcinoma Database Consortium score on univariate analysis (P = .011 vs. P = .094 for PFS and P = .003 vs. .013 for OS). Both remained independent on bivariate analysis.Conclusion: The molecular subtypes of mccRCC are associated with outcome on pazopanib as first-line therapy. The prognostic and predictive value of the ccrcc1-4 molecular classification requires validation in prospective trials.
Published: 2018

84. Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes

Author: Angela Mathison, Huihuang Yan, Odile Gayet, Benjamin Bian, Laetitia Marisa, Véronique Secq, Jean Robert Delpero, Mohamed Gasmi, Vincent Moutardier, Gavin R. Oliver, Rémy Nicolle, Nelson Dusetti, Lucile Armenoult, Zhifu Sun, Philippe Grandval, Pauline Duconseil, Nabila Elarouci, Gwen Lomberk, Marine Gilabert, Martin Bigonnet, Eric W. Klee, Krutika S. Gaonkar, Stéphane Garcia, Aurélien de Reyniès, Mira Ayadi, Yuna Blum, Juan L. Iovanna, Asha Nair, Marc Giovannini, Raul Urrutia, Olivier Turrini, Jeong Heon Lee, Tamas Ordog, Medical College of Wisconsin, Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Ultrasound Research Laboratory, Translational Epigenomics Program, Mayo Clinic-Center for Individualized Medicine (CIM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département de Gastro-Entérologie [Hôpital de La Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Service De Gastroenterologie, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Ligue Nationale Contre le Cancer (LNCC), and Bidaut, Ghislain
Subjects: 0301 basic medicine, Male, Epigenomics, endocrine system diseases, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Datasets as Topic, Regulatory Sequences, Nucleic Acid, Epigenesis, Genetic, Histones, Mice, lcsh:Science, Epigenesis, Cancer, Regulation of gene expression, Aged, 80 and over, Multidisciplinary, biology, Middle Aged, 3. Good health, Chromatin, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, Histone, DNA methylation, Female, Carcinoma, Pancreatic Ductal, Chromatin Immunoprecipitation, Science, Mice, Nude, Computational biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Pancreatic cancer, Cell Line, Tumor, medicine, Biomarkers, Tumor, Animals, Humans, Epigenetics, Aged, Sequence Analysis, RNA, General Chemistry, DNA Methylation, medicine.disease, Xenograft Model Antitumor Assays, digestive system diseases, Pancreatic Neoplasms, 030104 developmental biology, biology.protein, lcsh:Q
Abstract: Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets., Pancreatic ductal adenocarcinoma (PDAC) is a complex disease and its underlying epigenomic heterogeneity is not fully understood. Here, the authors utilize patient-derived PDAC xenografts to define the epigenomic landscape of PDAC, highlighting chromatin states linked to differing disease aggressiveness and survival.
Published: 2018

85. New tumor suppressor microRNAs target glypican-3 in human liver cancer

Author: Nathalie Dugot-Senant, Flora Cartier, Sarah Lesjean, Justine Charpentier, Amani Ghousein, Emilie Indersie, Martin Hagedorn, Angélique Desplat, Véronique Trézéguet, Christophe Grosset, Katarzyna B. Hooks, Francis Sagliocco, Grosset, Christophe, Initiative d'excellence de l'Université de Bordeaux - - IDEX BORDEAUX2010 - ANR-10-IDEX-0003 - IDEX - VALID, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Biothérapies des maladies génétiques et cancers, TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the French National Cancer Institute (grants INCa_5828/INCa_ PLBIO_2012_110 and INCa_TRANSLA_2013_209) to CFG and VT, the French Ministry of Health (grant n°DGOS/PF4/0013/105) to CFG, the Fondation pour la Recherche Médicale (FRM, grant n°DBI20131228566) to CFG, the Ligue Nationale contre le Cancer (LNCC) to CFG and VT, the Cancéropôle Grand Sud-Ouest to CFG and VT, the French State in the frame of the 'Investments for the future' Programme IdEx Bordeaux (grant ANR10-IDEX-03-02) to KBH and the charity associations Eva Pour La Vie, Aidons Marina, Fondation Flavien and E.S.CA.PE to MH and CFG., ANR-10-IDEX-0003,IDEX BORDEAUX,Initiative d'excellence de l'Université de Bordeaux(2010), Flow Cytometry Facility / TransBioMed Core [Bordeaux] (INSERM US005 - CNRS UMS 3427 - UB), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), and ANR-10-IDEX-0003-02/10-IDEX-0003,IDEX BORDEAUX,IdEx Bordeaux(2010)
Subjects: Adult, Male, 0301 basic medicine, Hepatoblastoma, Pathology, medicine.medical_specialty, Carcinoma, Hepatocellular, Adolescent, [SDV]Life Sciences [q-bio], Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, liver, Glypican 3, Young Adult, 03 medical and health sciences, Glypicans, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, microRNA, medicine, Humans, cancer, Genes, Tumor Suppressor, Aged, Cell Proliferation, Oncogene, Liver Neoplasms, Wnt signaling pathway, Cancer, hepatocellular carcinoma, Middle Aged, medicine.disease, glypican-3, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, 030104 developmental biology, Oncology, Cancer research, Female, Signal transduction, Liver cancer, Research Paper
Abstract: International audience; Glypican-3 (GPC3) is an oncogene, frequently upregulated in liver malignancies such as hepatocellular carcinoma (HCC) and hepatoblastoma and constitutes a potential molecular target for therapy in liver cancer. Using a functional screening system, we identified 10 new microRNAs controlling GPC3 expression in malignant liver cells, five of them e.g. miR-4510, miR-203a-3p, miR-548aa, miR-376b-3p and miR-548v reduce GPC3 expression. These 5 microRNAs were significantly downregulated in tumoral compared to non-tumoral liver and inhibited tumor cell proliferation. Interestingly, miR-4510 inversely correlated with GPC3 mRNA and protein in HCC samples. This microRNA also induced apoptosis of hepatoma cells and blocked tumor growth in vivo in the chick chorioallantoic membrane model. We further show that the tumor suppressive effect of miR-4510 is mediated through direct targeting of GPC3 mRNA and inactivation of Wnt/β-catenin transcriptional activity and signaling pathway. Moreover, miR-4510 up-regulated the expression of several tumor suppressor genes while reducing the expression of other pro-oncogenes. In summary, we uncovered several new microRNAs targeting the oncogenic functions of GPC3. We provided strong molecular, cellular and in vivo evidences for the tumor suppressive activities of miR-4510 bringing to the fore the potential value of this microRNA in HCC therapy.
Published: 2017

86. Endosomal recycling driving glioblastoma cell invasion depends on the core autophagy protein ATG9A

Author: Campisi, Daniele, Coly, Pierre-Mickaël, Castel, Hélène, Gandolfo, Pierrick, Morin, Fabrice, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Ligue Nationale Contre le Cancer (LNCC)-Cancéropole Nord-Ouest
Subjects: [SDV]Life Sciences [q-bio], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2019

87. Travaux et expertise de l’équipe Astrocyte et Niche Vasculaire en NeuroOncoTherapeutic

Author: Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: TheoryofComputation_MISCELLANEOUS, [SDV]Life Sciences [q-bio], ComputingMilieux_COMPUTERSANDEDUCATION, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, GeneralLiterature_MISCELLANEOUS, ComputingMilieux_MISCELLANEOUS
Abstract: Invited lecture; National audience
Published: 2019

88. Glioblastoma cell invasion: Filamin(s)-A in the role of engine and chemokine G-protein coupled receptor

Author: Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: TheoryofComputation_MISCELLANEOUS, [SDV]Life Sciences [q-bio], ComputingMilieux_COMPUTERSANDEDUCATION, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, GeneralLiterature_MISCELLANEOUS, ComputingMilieux_MISCELLANEOUS
Abstract: Invited lecture; International audience
Published: 2019

89. Glioblastoma migration along constraints with different geometries: how to mimick brain parenchyma invasion?

Author: Mehmet Çagatay Tarhan, Mutel, A., Desrues, L., Collard, D., Castel, H., Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Yncrea Hauts de France, Bio-Micro-Electro-Mechanical Systems - IEMN (BIOMEMS - IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer and Cognition Platform, Ligue Nationale contre le cancer,14000Caen, France, Laboratory for Integrated Micro Mechatronics Systems (LIMMS), The University of Tokyo (UTokyo)-Centre National de la Recherche Scientifique (CNRS), Yncréa Hauts-de-France, Université catholique de Lille (UCL), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Ligue Nationale Contre le Cancer (LNCC)-Cancéropole Nord-Ouest
Subjects: [SDV]Life Sciences [q-bio], Microfluidics, Mechanical constraints, Cell migration, [SDV.CAN]Life Sciences [q-bio]/Cancer, [MATH]Mathematics [math], Glioblastoma
Abstract: International audience; A microfluidic device is demonstrated to analyze glioblastoma migration along constraints with precisely designed geometries. This in-vitro model reveals physiologically relevant glioma invasion scenarios: full migration along constraints, suspended motion by extreme constriction, and limited migration associated with the ejection of plasma membrane particles due to the continuing extension.
Published: 2019

90. Cancer-induced cognitive impairment: from mechanisms to biomarkers

Author: Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Ligue Nationale Contre le Cancer (LNCC)-Cancéropole Nord-Ouest
Subjects: TheoryofComputation_MISCELLANEOUS, [SCCO]Cognitive science, [SDV]Life Sciences [q-bio], [SCCO.NEUR]Cognitive science/Neuroscience, ComputingMilieux_COMPUTERSANDEDUCATION, GeneralLiterature_MISCELLANEOUS, ComputingMilieux_MISCELLANEOUS
Abstract: Invited lecture; International audience
Published: 2019

91. Evidences of early astroglial reactivity associated with glioma invasion in a preclinical model of glioblastoma

Author: Lemercier, Quentin, Desrues, Laurence, Godefroy, David, Gandolfo, Pierrick, Castel, Hélène, Chever, Oana, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC)
Subjects: [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

92. Chemoattraction of glioma cells and immune activation

Author: Laillet de Montullé, Emmanuel, Dubois, Martine, Ferracci François, Xavier, Mutel, Alexandre, Dembele Kleouforo, Paul, Desrues, Laurence, Langlois, Olivier, Derrey, Sophie, Morin, Fabrice, Gandolfo, Pierrick, Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU), Service de neurochirurgie [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Service Anesthésie et soins intensifs [CHU Rouen], and Normandie Université (NU)-Normandie Université (NU)
Subjects: TheoryofComputation_MISCELLANEOUS, [SDV]Life Sciences [q-bio], TheoryofComputation_GENERAL, ComputingMethodologies_GENERAL, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: Price for poster presentation; International audience
Published: 2019

93. Magnetic nanocarriers for the specific delivery of siRNA: Contribution of breast cancer cells active targeting for down-regulation efficiency

Author: S. Ben Djemaa, Emilie Allard-Vannier, S. Eljack, Hervé Marchais, Nicolas Aubrey, Katel Hervé-Aubert, Zineb Lakhrif, J. Bruniaux, Stephanie David, Igor Chourpa, Nanomédicaments et Nanosondes, EA 6295 (NMNS), Université de Tours (UT), Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Institut National du Cancer (INCa), France, Institut National du Cancer (INCA) France, Fondation ARC, France, Ligue Nationale Contre le Cancer (LNCC), France [ARC_INCa_LNCC_7636], 'Region Centre-Val de Loire' (NCIS Project), France, 'Canceropole Grand Ouest', France, French Higher Education and Research ministry under the program 'Investissements d'avenir'French National Research Agency (ANR) [LabEx MAbImprove ANR-10-LABX-53-01], Université de Tours, and Institut National de la Recherche Agronomique (INRA)-Université de Tours
Subjects: Small interfering RNA, animal structures, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Receptor, ErbB-2, media_common.quotation_subject, small interfering rna (sirna), Green Fluorescent Proteins, Pharmaceutical Science, scfv anti-her2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, survivin, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, Survivin, medicine, Humans, RNA, Small Interfering, Internalization, skin and connective tissue diseases, media_common, Chemistry, Magnetic Phenomena, Cancer, 021001 nanoscience & nanotechnology, medicine.disease, superparamagnetic iron oxide nanoparticles (spion), Coculture Techniques, 3. Good health, Cell culture, Cancer research, Nanoparticles, Breast cancer cells, Nanocarriers, 0210 nano-technology, Single-Chain Antibodies
Abstract: Section spéciale du Meeting SFNano 2018 : Nanomedicine- from particle design to applications (2018/12/03_2018/12/05, Montpellier, FRA), edited by Nathalie Mignet, Chantal Pichon et Marie-Pierre Rols; International audience; The association between superparamagnetic iron oxide nanoparticles (SPION), carrying small interfering RNA (siRNA) as therapeutic agents and humanized anti- human epidermal growth factor receptor-2 (HER2) single-chain antibody fragments (scFv) for the active delivery into HER2-overexpressing cells appears as an interesting approach for patients with HER2-overexpressing advanced breast cancer. The obtained Targeted Stealth Magnetic siRNA Nanovectors (TS-MSN) are formulated by combining: (i) the synthesis protocol of Targeted Stealth Fluorescent Particles (T-SFP) which form the core of TS-MSN and (ii) the formulation protocol allowing the loading of T-SFP with polyplexes (siRNA and cationic polymers). TS-MSN have suitable physico-chemical characteristics for intravenous administration and protect siRNA against enzymatic degradation up to 24 h. The presence of HER2-targeting scFv on TS-MSN allowed an improved internalization (3-4 times more compared to untargeted S-MSN) in HER2-overexpressing breast cancer cells (BT-474). Furthermore, anti-survivin siRNA delivered by TS-MSN in HER2-negative breast-cancer control cells (MDA-MB-231) allowed significant down-regulation of the targeted anti-apoptotic protein of about 70%. This protein down-regulation increased in HER2 + cells to about 90% (compared to 70% with S-MSN in both cell lines) indicating the contribution of the HER2-active targeting. In conclusion, TS-MSN are promising nanocarriers for the specific and efficient delivery of siRNA to HER2-overexpressing breast cancer cells.
Published: 2019

94. Effet du Panax quinquefolius et/ou de la vitamine C sur les altérations comportementales et neurobiologiques induites par la chimiothérapie au 5-Fluorouracile chez la souris

Author: Feger, Céline, Parment, Renaud, Dubois, Martine, Desrues, Laurence, Tron, L, Joly, Florence, Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Ligue Nationale Contre le Cancer (LNCC)-Cancéropole Nord-Ouest, Service d'Oncologie médicale [Caen], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)
Subjects: [SCCO]Cognitive science, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2019

95. Urantide Improves Cardiac Function, Modulates Systemic Cytokine Response, and Increases Survival in A Murine Model of Endotoxic Shock

Author: Emmanuel Besnier, Mohamad El Amki, Hélène Castel, Laurence Desrues, Thomas Clavier, Martine Dubois, Julie Maucotel, Vincent Compère, Nicolas Perzo, Fabienne Tamion, Arnaud Arabo, Vincent Richard, Pierrick Gandolfo, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Service de soins intensifs [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC), Service Anesthésie et soins intensifs [CHU Rouen], and Normandie Université (NU)-Normandie Université (NU)
Subjects: Cardiac function curve, Lipopolysaccharides, Male, medicine.medical_specialty, Cardiac output, Lipopolysaccharide, [SDV]Life Sciences [q-bio], Urotensins, 030204 cardiovascular system & hematology, Urotensin-II receptor, Critical Care and Intensive Care Medicine, Systemic inflammation, Receptors, G-Protein-Coupled, 03 medical and health sciences, chemistry.chemical_compound, Mice, Random Allocation, 0302 clinical medicine, Internal medicine, medicine, Animals, Survival rate, ComputingMilieux_MISCELLANEOUS, Kidney, business.industry, NF-kappa B, Transcription Factor RelA, 030208 emergency & critical care medicine, Shock, Septic, Peptide Fragments, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, chemistry, Emergency Medicine, Cytokines, medicine.symptom, Urotensin-II, business
Abstract: INTRODUCTION Urotensin II is a potent vasoactive peptide activating the the G protein-coupled urotensin II receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation, and cardiac function during endotoxic shock. METHODS C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6, and 9 h (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. RESULTS Urantide treatment improved survival (88.9% vs. 30% on day 6, P
Published: 2019

96. Sialic acid mediated mechanical activation of β 2 adrenergic receptors by bacterial pili

Author: Virion, Zoé, Doly, Stéphane, Saha, Kusumika, Lambert, Mireille, Guillonneau, Francois, Bied, Camille, Duke, Rebecca, Rudd, Pauline, Robbe-Masselot, Catherine, Nassif, Xavier, Coureuil, Mathieu, Marullo, Stefano, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Ligue Nationnale Contre le Cancer, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; Meningococcus utilizes β-arrestin selective activation of endothelial cell β 2 adrenergic receptor (β 2 AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that β 2 AR activation requires two asparagine-branched glycan chains with terminally exposed N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues located at a specific distance in its N-terminus, while being independent of surrounding amino-acid residues. Meningococcus triggers receptor signaling by exerting direct and hemodynamic-promoted traction forces on β 2 AR glycans. Similar activation is recapitulated with beads coated with Neu5Ac-binding lectins, submitted to mechanical stimulation. This previously unknown glycan-dependent mode of allosteric mechanical activation of a G protein-coupled receptor contributes to meningococcal species selectivity, since Neu5Ac is only abundant in humans due to the loss of CMAH, the enzyme converting Neu5Ac into N-glycolyl-neuraminic acid in other mammals. It represents an additional mechanism of evolutionary adaptation of a pathogen to its host.
Published: 2019

97. Improvement of survival and cognitive functions by means of a local hydrogel trap in a mouse model of glioblastoma resection

Author: Laillet de Montullé, Emmanuel, Dubois, Martine, Ferracci, François-Xavier, Mutel, Alexandre, Dembele K., Paul, Desrues, Laurence, Langlois, Olivier, Durrey, S, Morin, Fabrice, Gandolfo, Pierrick, Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

98. Plasma clearance of RAS mutation under therapeutic pressure is a rare event in metastatic colorectal cancer

Author: Moati, Emilie, Blons, Hélène, Taly, Valérie, Garlan, Fanny, Wang‐renault, Shu‐fang, Pietrasz, Daniel, Didelot, Audrey, Garrigou, Sonia, Saint, Angélique, Pernot, Simon, Taïeb, Julien, Laurent‐puig, Pierre, Zaanan, Aziz, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département de gastro-entérologie et d'oncologie digestive [HEGP - APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Service de Biologie [Hôpital Européen Georges Pompidou, APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), This work was supported by the Ministère de l’Enseignement Supérieur et de la Recherche, the Université Paris-Descartes, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Institut National du Cancer (INCA, n° 2009-1-RT-03-US-1 and 2009-RT-03-UP5-1), the Association pour la recherche contre le cancer (ARC, no. SL220100601375), the Agence Nationale de la Recherche (ANR Nanobiotechnologies, no. ANR-10-NANO-0002-09), the SIRIC CARPEM, the ligue nationale contre le cancer (LNCC, Program 'Equipe labelisée LIGUE', no. EL2016.LNCC/VaT) and Advanced Merieux Research Grant (PLP and VT) and canceropole funding (no. 2011-1-LABEL-UP5-2)., and TALY, Valerie
Subjects: circulating tumor DNA, next generation sequencing, [SDV] Life Sciences [q-bio], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, droplet-based digital PCR, [SDV.CAN] Life Sciences [q-bio]/Cancer, metastatic colorectal cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, RAS mutations, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; In metastatic colorectal cancer (mCRC), circulating tumor DNA (ctDNA) monitoring can be used to genotype tumors and track clonal evolution. We investigated the clearance of RAS mutated clones under chemotherapy pressure by ctDNA analysis in patients with a RAS mutated mCRC. Patients with a RAS mutated tumor included in the prospective PLACOL study, were monitored for ctDNA. Analyzes were based on optimized targeted next generation sequencing and/or droplet-based digital PCR (ddPCR). For plasma samples without detectable mutations at progression disease, we tested the methylation status of WIF1 and NPY genes using methylation-ddPCR (met-ddPCR) to validate the presence of ctDNA. Among the 36 patients with positive plasma samples for RAS mutations at inclusion, 28 (77.8%) remained RAS positive at disease progression, and 8 (22.2%) became negative. Subsequent met-ddPCR for methylated markers showed that only 2 out of the 8 patients with RAS negative plasma had detectable ctDNA at progression. Therefore, only two samples among 36 were confirmed for clearance of RAS mutation in our series. In conclusion, this study suggests that the clearance of RAS mutations in patients treated by chemotherapy for a RAS mutated mCRC is a rare event. Monitoring tumor mutations in plasma samples should be combined with a strict control of the presence of ctDNA. The therapeutic impacts of RAS clearance need to be further explored. This article is protected by copyright. All rights reserved.
Published: 2019

99. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial

Author: Pivot, Xavier, Romieu, Gilles, Debled, Marc, Pierga, Jean-Yves, Kerbrat, Pierre, Bachelot, Thomas, Lortholary, Alain, Espié, Marc, Fumoleau, Pierre, Serin, Daniel, Jacquin, Jean-Philippe, Jouannaud, Christelle, Rios, Maria, Abadie-Lacourtoisie, Sophie, Venat-Bouvet, Laurence, Cany, Laurent, Catala, Stéphanie, Khayat, David, Gambotti, Laetitia, Pauporté, Iris, Faure-Mercier, Céline, Paget-Bailly, Sophie, Henriques, Julie, Grouin, Jean Marie, Centre Paul Strauss, CRLCC Paul Strauss, CRLCC Val d'Aurelle - Paul Lamarque, Institut Bergonié [Bordeaux], UNICANCER, Institut Curie [Paris], Université Paris Descartes - Paris 5 (UPD5), CRLCC Eugène Marquis (CRLCC), Centre Léon Bérard [Lyon], Centre Catherine-de-Sienne [Nantes] (CCS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Sainte Catherine [Avignon], Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, CRLCC Jean Godinot, Institut Jean Godinot [Reims], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), CHU Limoges, Clinique Francheville [Périgueux], CHU Saint-Pierre, Clinique Bizet [Pais], Institut national du cancer [Boulogne] (INCA), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Unité de biostatistiques [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The French National Cancer Institute, PHARE trial investigators: C Piprot, L Cals, L Chaigneau, F Demarchi, T N'Guyen, U Stein, C Villanueva, J L Bréau, A K Chouahnia, P Saintigny, F Boué, P deSaint-Hilaire, I Guimont, N Grossat, B Valenza, E Lévy, J Médioni, C Delbaldo, J Grenier, D Pouessel, S Lavau-Denès, C Falandry, C Fournel-Fédérico, G Freyer, S Tartas, V Trillet-Lenoir, F Bons, G Auclerc, S Chièze, N Raban, C Tournigand, S Trager-Maury, G Bousquet, C Cuvier, S Giacchetti, A Hocini, C LeMaignan, J L Misset, D Avenin, C Beerblock, J Gligorov, P Rivera, H Roché, P Bougnoux, N Hajjaji, O Capitain, R Delva, P Maillart, P Soulié, H Bonnefoi, M Durand, N Madranges, L Mauriac, P Chollet, A F Dillies, X Durando, J P Ferrière, C Mouret-Reynier, J M Nabholtz, I Van Praagh, P Cottu, V Diéras, A Durieux, M Galotte, V Girre, S Henry, I Iurisci, M Jouve, V Laurence, L Mignot, S Piperno-Neumann, P Tresca, B Coudert, E Ferrant, F Mayer, A C Vanneuville, J Bonneterre, V Servent, L Vanlemmens, P Vennin, J P Guastalla, P Biron, L Dupuy-Brousseau, L Lancry, I Ray-Coquard, P Rebattu, O Trédan, J M Extra, F Rousseau, C Tarpin, M Fabbro, E Luporsi, L Uwer, B Weber, D Berton-Rigaud, E Bourbouloux, M Campone, J M Ferrero, P Follana, R Largillier, V Mari, B Costa, H Curé, J C Eymard, N Jovenin, D Lebrun, J Meunier, G Yazbek, D Gedoin, B Laguerre, C Lefeuvre, E Vauléon, A Chevrier, C Guillemet, M Leheurteur, O Rigal, I Tennevet, C Veyret, E Brain, M Guiterrez, F Mefti-Lacheraf, T Petit, F Dalenc, L Gladieff, H Roché, F André, S Delaloge, J Domont, J Ezenfis, M Spielmann, P Guillet, V Boulanger, J Provençal, L Stefani, C Alliot, D Ré, C Bellaiche-Miccio, G Boutan-Laroze, R Vanica, P Dion, A Hocini, G Sadki-Benaoudia, A Marti, A L Villing, B Slama, J L Dutel, S Nguyen, R Saad, O Arsène, Z Merad-Boudia, H Orfeuvre, J Egreteau, M J Goudier, R Lamy, B Leduc, C Sarda, B Salles, C Agostini, I Cauvin, A Dufresne, M Mangold, S Lebouvier-Sadot, B Audhuy, J C Barats, S Cluet-Dennetière, D Zylberait, G Netter, L Gautier-Felizot, I Cojean-Zelek, A Plantade, S Vignot, E Guardiola, P Marti, I deHartingh, R Diab, A Dietmann, S Ruck, C Portois, E Guardiola, S Oddou-Lagranière, F Campos-Gazeau, A Bourcier, F Priou, J F Geay, D Mayeur, P Gabez, R ElAmarti, M Combe, J Ezenfis, P Raichon-Patru, P Amsalhem, J Dauba, D Paraiso, F Guinet, B Duvert, M Litor, F Kara-Slimane, A Bichoffe, N Denizon, J Meunier, P Soyer, F Morvan, S Van-Hulst, L Vincent, C Alleaume, P Ibanez-Martin, A Youssef, Z Tadrist, E Carola, C Pourny, J F Toccanier, N Al-Aukla, K Mahour-Bacha, J Salvat, L Cals, P Nouyrigat, S Clippe, M C Gouttebel, L Vedrine, G Clavreul, O Collard, D Mille, Y Goubely, J Grenier, R Hervé, S Kirscher, F Plat, V Delecroix, V Ligeza-Poisson, D Coeffic, L Dupuy-Brousseau, D Fric, C Garnier, C Leyronnas, T Kreitman, R Largillier, E Teissier, P Martin, S Rohart deCordoue, C ElKouri, J F Ramée, C Laporte, O Bernard, T Altwegg, A Darut-Jouve, J P Dujols, F Darloy, C Giraud, V Pottier-Kyndt, N Achour, S Drony, M Moriceau, C Sarrazin, J C Legueul, J Mandet, D Besson, A C Hardy-Bessard, J Cretin, P Houyau, E Achille, D Genêt, H Thévenot, A Moran-Ribon, J M Pavlovitch, P Ardisson, I Moullet, B Couderc, V Fichet, F Burki, A Auliard, C B Levaché, G Auclerc, P Cailleux, F Schaeffer, N Albin, D Sévin-Robiche, J Domas, S Ellis, P Montcuquet, G A Baumont, M Bégue, S Gréget, J L Ratoanina, A Vanoli, C Bielsa, M Bonichon-Lamichhane, D Jaubert, H Laharie-Mineur, L Alcaraz, J Cretin, E Legouffe, H Bourgeois, G Cartron, F Denis, O Dupuis, G Ganem, S Roche-Forestier, L Delzenne, E Chirat, J L Baticle, E Béguier, S Jacquot, E Janssen, H Lauché, A LeRol, J P Chantelard, G A L'Helgoualc'h, E C Antoine, A Kanoui, J F Llory, J M Vannetzel, J Vignoud, C Bruna, T Facchini, K Moutel-Corviole, A Voloch, A Ghoul, D Loiseau, K Mahour-Bacha, N Barbet, N Dohollou, K Yakendji, CCSD, Accord Elsevier, and Ligue Nationnale Contre le Cancer
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, skin and connective tissue diseases
Abstract: International audience; Background: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events.Methods: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901.Findings: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group.Interpretation: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months.
Published: 2019

100. Re-expression of the neurodevelopmental protein filamin A in glioblastoma enhance tumor proliferation and invasiveness

Author: Mutel, Alexandre, Lecointre, Céline, Dembele K., Paul, Guichet, Pierre-Olivier, Mouchard, L., Desrues, Laurence, Langlois, Olivier, Laquérriere, Annie, Marguet, Florent, Gandolfo, Pierrick, Prézeau, Laurent, Morin, Fabrice, Castel, Hélène, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Equipe Traitement de l'information en Biologie Santé (TIBS - LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Department of Pathology, Rouen University Hospital, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Plateforme Cancer et Cognition, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Cancéropole Nord-Ouest-Ligue Nationale Contre le Cancer (LNCC), and CASTEL, Hélène
Subjects: [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

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