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1. A polygenic risk score for multiple myeloma risk prediction

Author: Angelica Macauda, Matteo Pelosini, Krzysztof Jamroziak, Mario Petrini, Annette Juul Vangsted, Chiara Piredda, Stephane Minvielle, Marek Dudziński, Hervé Avet-Loiseau, Aleksandra Butrym, Ulla Vogel, Niels Abildgaard, Fabienne Lesueur, Waldemar Tomczak, Vibeke Andersen, Herlander Marques, Daniele Campa, Judit Várkonyi, Rui Manuel Reis, Katalin Kadar, Gabriele Buda, Małgorzata Raźny, Charles Dumontet, Juan Sainz, Anna Suska, Enrico Orciuolo, Agnieszka Druzd-Sitek, Marcin Kruszewski, Daria Zawirska, Niels Frost Andersen, Artur Jurczyszyn, Grzegorz Mazur, Marcin Rymko, Federica Gemignani, Edyta Subocz, Federico Canzian, Katia Beider, Jan Maciej Zaucha, Marzena Wątek, Arnon Nagler, Genomic Epidemiology Group [Heidelberg, Germany] (GEP / DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Pisa - Università di Pisa, University Hospital of Cracow/Szpital Uniwersytecki w Krakowie [Poland] (SUK), Aarhus University Hospital, Chaim Sheba Medical Center, Sea Hospital [Gdynia, Poland] (SH), Wroclaw Medical University [Wrocław, Pologne] (WMU), Hospices Civils de Lyon (HCL), Holycross Cancer Center of Kelce, Hematology Clinic, Kielce, Institute of Hematology and Transfusion Medicine [Warsaw, Poland] (IHTM), Centre for Genomics and Oncological Research Pfizer [Granada, Spain] (GENYO), University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], Hospital Universitario Virgen de las Nieves [Granada, Spain] (HUVN), Semmelweis University [Budapest], Odense University Hospital (OUH), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Teaching Hospital No 1 [Rzeszów, Poland] (TH1), University of Copenhagen = Københavns Universitet (KU), Military Institute of Medicine [Warsaw, Poland] (MIM), Rydygier Specialistic Hospital [Cracow, Poland] (RSH), University of Minho [Braga], Jagiellonian University Medical College [Cracow, Poland] (JUMC), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), The National Research Center for Work Environment [Copenhagen, Denmark] (NRCWE), University of Southern Denmark (SDU), ICVS/3B's - PT Government Associate Laboratory [Braga/Guimarães, Portugal] (AL), Barretos Cancer Hospital [São Paulo, Brazil] (BCH), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Bydgoszcz [Bydgoszcz, Poland] (UHB), Medical University of Lublin, N. Copernicus Town Hospital [Torun, Poland] (NCTH), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Bernardo, Elizabeth, Wrocław Medical University, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), 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), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Oncology, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), Multiple myeloma, 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, business.industry, medicine.disease, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Polygenic risk score, Multiple Myeloma, business, Genome-Wide Association Study
Abstract: This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France
Published: 2021

2. LentiRILES, a miRNA-ON sensor system for monitoring the functionality of miRNA in cancer biology and therapy

Author: David Gosset, Loris Roncali, Yoan Laurent, Chantal Pichon, Flora Reverchon, Emmanuel Garcion, Patrick Baril, Audrey Rousseau, Francisco Martin, Patrick Midoux, Claire Loussouarn, Viorel Simion, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre for Genomics and Oncological Research Pfizer [Granada, Spain] (GENYO), University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], Inca : PL-BIO 2014–2020 (consortium Marengo)Ligue Contre le Cancer [Région du Loiret : 2017-2019]ARD 2020 Biopharmaceuticals [RNA cell factory 2017-2020], ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), ANR-19-ENM3-0003,GLIOSILK,Silk-fibroin interventional nano-trap for the treatment of glioblastoma.(2019), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], Bernardo, Elizabeth, Radiopharmaceutiques Innovants en Oncologie et Neurologie - - IRON2011 - ANR-11-LABX-0018 - LABX - VALID, and Silk-fibroin interventional nano-trap for the treatment of glioblastoma. - - GLIOSILK2019 - ANR-19-ENM3-0003 - Euronanomed III - VALID
Subjects: Male, Cell, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biosensing Techniques, Mice, SCID, Computational biology, Biology, Cell therapy, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Genes, Reporter, microRNA, Biomarkers, Tumor, Tumor Cells, Cultured, medicine, Animals, Humans, Luciferase, Molecular Biology, Gene, Cell Proliferation, miRNA, 030304 developmental biology, 0303 health sciences, Technical Paper, Cell Cycle, Lentivirus, glioblastoma, RNA therapeutics, Cell Biology, Middle Aged, molecular imaging, RILES, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Luminescent Measurements, Female, Molecular imaging, Function (biology), Intracellular
Abstract: International audience; A major unresolved challenge in miRNA biology is the capacity to monitor the spatiotemporal activity of miRNAs expressed in animal disease models. We recently reported that the miRNA-ON monitoring system called RILES (RNAi-inducible expression Luciferase system) implanted in lentivirus expression system (LentiRILES) offers opportunity to decipher the kinetics of miRNA activity in vitro, in relation with their intracellular trafficking in glioblastoma cells. In this study we describe in detail the method for production of LentiRILES stable cell lines and employed it in several applications in the field of miRNA biology and therapy. We show that LentiRILES is a robust, highly specific and sensitive miRNA sensor system that can be used in vitro as a single-cell miRNA monitoring method, cell-based screening platform for miRNA therapeutics and as a tool to analyze the structurefunction relationship of the miRNA duplex. Furthermore, we report the kinetic of miRNA activity upon the intracranial delivery of miRNA mimics in an orthotopic animal model of glioblastoma. This information is exploited to evaluate the tumor suppressive function of miRNA-200c as locoregional therapeutic modality to treat glioblastoma. Our data provide evidence that LentiRILES is a robust system, well-suited to resolve the activity of endogenous and exogenously expressed miRNAs for basic research to gene and cell therapy.
Published: 2021

3. Correlation between magnetic resonance, X-ray imaging alterations and histological changes in an ovine model of age-related disc degeneration

Author: Bouhsina, N, Decante, C, Hardel, J, Madec, S, Abadie, J, Hamel, A, Le Visage, C, Lesoeur, J, Guicheux, J, Clouet, J, Fusellier, M, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes - UFR Odontologie, Université de Nantes (UN), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Femme, Enfant, Adolescent [CHU Nantes] (Pôle hospitalo-universitaire PHU5 - FEA), Centre hospitalier universitaire de Nantes (CHU Nantes), Animaux modèles pour la recherche en oncologie comparée (AMaROC), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Ostéo-articulaire - Tête et cou - Odontologie - Neurochirurgie - Neurotraumatologie [CHU Nantes] (Pôle hospitalo-universitaire PHU4 - OTONN), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Santé Publique, Pharmacie et Prévention [CHU Nantes] (Pôle hospitalo-universitaire PHU11 - S3P), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Jehan, Frederic
Subjects: [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], sheep, Lumbar Vertebrae, Magnetic Resonance Spectroscopy, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, RD1-811, X-Rays, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, x-ray imaging, degeneration, Intervertebral Disc Degeneration, Diseases of the musculoskeletal system, histology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, RC925-935, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, magnetic resonance imaging, Female, intervertebral disc, Surgery
Abstract: International audience; Sheep are one of the many animal models used to investigate the pathophysiology of disc degeneration and the regenerative strategies for intervertebral disc (IVD) disease. To date, few studies have thoroughly explored ageing of ovine lumbar IVDs. Hence, the objective of the present study was to concomitantly assess the development of spontaneous age-related lumbar IVD degeneration in sheep using X-ray, magnetic resonance imaging (MRI) as well as histological analyses. 8 young ewes (< 48 months old) and 4 skeletally mature ewes (> 48 months old) were included. Disc height, Pfirrmann and modified Pfirrmann grades as well as T2-wsi and T2 times were assessed by X-ray and MRI. The modified Boos score was also determined using histology sections. Pfirrmann (2 to 3) and modified Pfirrmann (2 to 4) grades as well as Boos scores (7 to 13) gradually increased with ageing, while T2-weighted signal intensity (1.18 to 0.75), T2 relaxation time (114.36 to 70.65 ms) and disc height (4.1 to 3.2 mm) decreased significantly. All the imaging modalities strongly correlated with the histology (p < 0.0001). The present study described the suitability of sheep as a model of age-related IVD degeneration by correlation of histological tissue alterations with the changes observed using X-ray and MRI. Given the structural similarities with humans, the study demonstrated that sheep warrant being considered as a pertinent animal model to investigate IVD regenerative strategies without induction of degeneration.
Published: 2021

4. Advances in the Chemistry of Astatine and Implications for the Development of Radiopharmaceuticals

Author: Gilles Montavon, François Guérard, Jean-François Gestin, Nicolas Galland, Romain Eychenne, Lu Liu, Clémence Maingueneau, Nuclear Oncology (CRCINA-ÉQUIPE 13), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire de physique subatomique et des technologies associées (SUBATECH), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), GIPARRONAX [Saint-Herblain, France], Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), INCa-DGOSInserm_12558, ANR-11-EQPX-0004,ARRONAXPLUS,Nucléaire pour la Santé(2011), ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), ANR-16-IDEX-0007,NExT (I-SITE),NExT (I-SITE)(2016), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Guérard, François, Nucléaire pour la Santé - - ARRONAXPLUS2011 - ANR-11-EQPX-0004 - EQPX - VALID, Radiopharmaceutiques Innovants en Oncologie et Neurologie - - IRON2011 - ANR-11-LABX-0018 - LABX - VALID, and NExT (I-SITE) - - NExT (I-SITE)2016 - ANR-16-IDEX-0007 - IDEX - VALID
Subjects: Halogen bond, 010405 organic chemistry, [SDV]Life Sciences [q-bio], chemistry.chemical_element, General Medicine, General Chemistry, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences, 3. Good health, [SDV] Life Sciences [q-bio], chemistry, 13. Climate action, Computational chemistry, Electrophile, Halogen, Nucleophilic substitution, Fluorine, Molecule, Earth (chemistry), Astatine, ComputingMilieux_MISCELLANEOUS
Abstract: ConspectusAstatine (At) is the rarest on Earth of all naturally occurring elements, situated below iodine in the periodic table. While only short-lived isotopes (t1/2 ≤ 8.1 h) are known, 211At is the object of growing attention due to its emission of high-energy alpha particles. Such radiation is highly efficient to eradicate disseminated tumors, provided that the radionuclide is attached to a cancer-targeting molecule. The interest in applications of 211At in nuclear medicine translates into the increasing number of cyclotrons able to produce it. Yet, many challenges related to the minute amounts of available astatine are to be overcome in order to characterize its physical and chemical properties. This point is of paramount importance to develop synthetic strategies and solve the labeling instability in current approaches that limits the use of 211At-labeled radiopharmaceuticals. Despite its discovery in the 1940s, only the past decade has seen a significant rise in the understanding of astatine's basic chemical and radiochemical properties, thanks to the development of new analytical and computational tools.In this Account, we give a concise summary of recent advances in the determination of the physicochemical properties of astatine, putting in perspective the duality of this element which exhibits the characteristics both of a halogen and of a metal. Striking features were evidenced in the recent determination of its Pourbaix diagram such as the identification of stable cationic species, At+ and AtO+, contrasting with other halogens. Like metals, these species were shown to form complexes with anionic ligands and to exhibit a particular affinity for organic species bearing soft donor atoms. On the other hand, astatine shares many characteristics with other halogen elements. For instance, the At- species exists in water, but with the least range of EH-pH stability in the halogen series. Astatine can form molecular interactions through halogen bonding, and it was only recently identified as the strongest halogen-bond donor. This ability is nonetheless affected by relativistic effects, which translate to other peculiarities for this heavy element. For instance, the spin-orbit coupling boosts astatine's propensity to form charge-shift bonds, catching up with the behavior of the lightest halogens (fluorine, chlorine).All these new data have an impact on the development of radiolabeling strategies to turn 211At into radiopharmaceuticals. Inspired by the chemistry of iodine, the chemical approaches have sparsely evolved over the past decades and have long been limited to electrophilic halodemetalation reactions to form astatoaryl compounds. Conversely, recent developments have favored the use of the more stable At- species including the aromatic nucleophilic substitution with diaryliodonium salts or the copper-catalyzed halodeboronation of arylboron precursors. However, it is clear that new bonding modalities are necessary to improve the in vivo stability of 211At-labeled aryl compounds. The tools and data gathered over the past decade will contribute to instigate original strategies for overcoming the challenges offered by this enigmatic element. Alternatives to the C-At bond such as the B-At and the metal-At bonds are typical examples of exciting new axes of research.
Published: 2021

5. Deciphering the biology of KIR2DL3+ T lymphocytes that are associated to relapse in haploidentical HSCT

Author: Catherine Willem, Zakia Djaoud, Thierry Guillaume, Gaëlle David, Nolwenn Legrand, Patrice Chevallier, Katia Gagne, Alexandre Walencik, Christelle Retière, Pierre Mérieau, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), EFS Centre-Pays de la Loire [Nantes], Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Cyclophosphamide, medicine.medical_treatment, T cell, T-Lymphocytes, Science, Cell, Immunology, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Hematopoietic stem cell transplantation, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immune Reconstitution, [SDV.CAN] Life Sciences [q-bio]/Cancer, Receptors, KIR, Recurrence, immune system diseases, medicine, Humans, Receptor, 030304 developmental biology, Cancer, Interleukin-15, 0303 health sciences, Multidisciplinary, Hematopoietic Stem Cell Transplantation, In vitro, Killer Cells, Natural, medicine.anatomical_structure, Receptors, KIR2DL3, Transplantation, Haploidentical, Medicine, 030215 immunology, medicine.drug
Abstract: KIR are mainly expressed on NK cells and to a lesser extent on T lymphocytes. Although the KIR NK cell repertoire was well explored in haploidentical Hematopoietic Stem Cell Transplantation (HSCT), KIR T cell compartment remains to be investigated in this context. In this study, the investigation of NK receptors on T lymphocytes during immune reconstitution after T-cell-replete haploidentical HSCT with Post-Transplant Cyclophosphamide (PTCy) has shown a significant increase of KIR2DL2/3+T cell frequency at day 25. This was especially observed at day 30 in recipients who relapsed. IL-15 but not IL-12 increased in vitro KIR+T cell expansion suggesting that the raised IL-15 serum concentration observed after PTCy in haploidentical HSCT might increase KIR+T cell frequency. Moreover, investigations from healthy blood donors showed a higher inhibiting effect of KIR2DL3 on CMV specific T cell response against allogeneic than autologous C1+target cells. The association of KIR+T cell subset with relapse may suggest that inhibitory KIR2DL2/3 limit anti-leukemic effect of specific T lymphocytes at this early step of immune reconstitution. Further phenotypic and mechanistic investigations on this cell subset from a broader cohort of HSCT recipients should clarify its potential implication in relapse occurrence. Our results demonstrate that KIR-HLA interactions known to modulate NK cell functions also modulate T cell immune responses in the context of allogeneic HSCT.
Published: 2021

6. Immune checkpoint inhibitors for the treatment of myeloma: novel investigational options

Author: Cyrille Touzeau, Baptiste Le Calvez, Philippe Moreau, Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Site de Recherche Intégrée sur le Cancer [Nantes] (SIRIC), Imaging and Longitudinal Investigations to Ameliorate Decision-making [Nantes] (ILIAD), Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre hospitalier universitaire de Nantes (CHU Nantes), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: PD-L1, Oncology, medicine.medical_specialty, Standard of care, Immune checkpoint inhibitors, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pembrolizumab, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Refractory, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, PD-1, medicine, Animals, Humans, Pharmacology (medical), Molecular Targeted Therapy, Immune Checkpoint Inhibitors, Multiple myeloma, 030304 developmental biology, nivolumab, Pharmacology, 0303 health sciences, biology, business.industry, Drugs, Investigational, General Medicine, Immunotherapy, medicine.disease, 3. Good health, multiple myeloma, Treatment Outcome, pembrolizumab, 030220 oncology & carcinogenesis, Immune checkpoints, biology.protein, Nivolumab, business
Abstract: International audience; Introduction: Multiple myeloma (MM) is still considered incurable and the outcome of patients with triple-class refractory remains very poor. Immunotherapy is considered as a standard of care for the treatment of MM. Among immunotherapeutic approaches, the PD-1/PD-L1 axis is an attractive target because PD-L1 is highly expressed in most myeloma plasma cells. While many types of cancer benefit from checkpoint inhibitor treatment, their relevance in multiple myeloma needs to be defined.Areas covered: The authors evaluate the published data regarding the mechanism of action, safety profile, and clinical efficacy of the immune checkpoint inhibitors (ICI) for the treatment of multiple myeloma.Expert opinion: The use of ICI monotherapy does not offer any clinical benefit in myeloma patients. In combination with immunomodulatory drugs (IMID), ICI failed to demonstrate clinical benefit and were associated with increased toxicity. Given the toxicities of these treatments, predictive markers would be useful to select patients who would benefit most. Clinical studies are necessary to evaluate the safety and efficacy of checkpoint inhibitors in combination with other standards of care such as proteasome inhibitors and monoclonal antibodies. The combination of anti-PD-1 with T-cell engager (TCE) or CAR-T cells seems theoretically attractive and should be explored in clinical trials.
Published: 2021

7. Unsupervised flow cytometry analysis in hematological malignancies: A new paradigm

Author: Anna Porwit, Marie C. Béné, Francis Lacombe, Bernardo, Elizabeth, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Bordeaux [Bordeaux], Lund University [Lund], Skane University Hospital [Lund], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Hematological disorders, Computer science, Clinical Biochemistry, Large array, [SDV.CAN]Life Sciences [q-bio]/Cancer, Field (computer science), Bioconductor, 03 medical and health sciences, 0302 clinical medicine, Data acquisition, Software, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bone Marrow, Cluster Analysis, Humans, Cluster analysis, 030304 developmental biology, 0303 health sciences, business.industry, flow cytometry, unsupervised analysis, Biochemistry (medical), Computational Biology, Hematology, General Medicine, Models, Theoretical, artificial intelligence, Data science, machine learning, Hematologic Neoplasms, 030220 oncology & carcinogenesis, T cell subset, Disease Progression, business, Algorithms, Unsupervised Machine Learning
Abstract: International audience; Ever since hematopoietic cells became "events" enumerated and characterized in suspension by cell counters or flow cytometers, researchers and engineers have strived to refine the acquisition and display of the electronic signals generated. A large array of solutions was then developed to identify at best the numerous cell subsets that can be delineated, notably among hematopoietic cells. As instruments became more and more stable and robust, the focus moved to analytic software. Almost concomitantly, the capacity increased to use large panels (both with mass and classical cytometry) and to apply artificial intelligence/machine learning for their analysis. The combination of these concepts raised new analytical possibilities, opening an unprecedented field of subtle exploration for many conditions, including hematopoiesis and hematological disorders. In this review, the general concepts and progress achieved in the development of new analytical approaches for exploring high-dimensional data sets at the single-cell level will be described as they appeared over the past few years. A larger and more practical part will detail the various steps that need to be mastered, both in data acquisition and in the preanalytical check of data files. Finally, a step-by-step explanation of the solution in development to combine the Bioconductor clustering algorithm FlowSOM and the popular and widely used software Kaluza® (Beckman Coulter) will be presented. The aim of this review was to point out that the day when these progresses will reach routine hematology laboratories does not seem so far away
Published: 2021

8. Small RNA mediated gradual control of lipopolysaccharide biosynthesis affects antibiotic resistance in Helicobacter pylori

Author: Pernitzsch, Sandy, Alzheimer, Mona, Bremer, Belinda, Robbe-Saule, Marie, De Reuse, Hilde, Sharma, Cynthia, University of Würzburg, ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Pathogenèse de Helicobacter / Helicobacter Pathogenesis, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Open Access funding enabled and organized by Projekt DEAL. This publication was supported by the Open Access Publication Fund of the University of Würzburg. The Sharma lab received financial support from the Deutsche Forschungsgemeinschaft (DFG) project Sh580/1-1, the Young Academy program of the Bavarian Academy of Sciences and Humanities (BAdW), and the Bavarian Research Network bayresq.net. The De Reuse’s lab was funded by the Agence National de la Recherche [ANR-12-BSV5-0025-Bactox1] and the Pasteur-Weizmann consortium 'The roles of noncoding RNAs in regulation of microbial life styles and virulence.', ANR-12-BSV5-0025,BacTox1,Rôle des systèmes toxine antitoxine de type I dans la persistence bactérienne(2012), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bernardo, Elizabeth, and BLANC - Rôle des systèmes toxine antitoxine de type I dans la persistence bactérienne - - BacTox12012 - ANR-12-BSV5-0025 - BLANC - VALID
Subjects: Lipopolysaccharides, Bacterial immune evasion, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Salt Stress, Article, Helicobacter Infections, Mice, Bacterial Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bacterial genetics, Drug Resistance, Bacterial, Animals, ddc:610, Polymyxin B, Repetitive Sequences, Nucleic Acid, Helicobacter pylori, Stomach, Small RNAs, O Antigens, Gene Expression Regulation, Bacterial, RNA, Bacterial, RNA, Small Untranslated, Pathogens, 5' Untranslated Regions
Abstract: The small, regulatory RNA RepG (Regulator of polymeric G-repeats) regulates the expression of the chemotaxis receptor TlpB in Helicobacter pylori by targeting a variable G-repeat in the tlpB mRNA leader. Here, we show that RepG additionally controls lipopolysaccharide (LPS) phase variation by also modulating the expression of a gene (hp0102) that is co-transcribed with tlpB. The hp0102 gene encodes a glycosyltransferase required for LPS O-chain biosynthesis and in vivo colonization of the mouse stomach. The G-repeat length defines a gradual (rather than ON/OFF) control of LPS biosynthesis by RepG, and leads to gradual resistance to a membrane-targeting antibiotic. Thus, RepG-mediated modulation of LPS structure might impact host immune recognition and antibiotic sensitivity, thereby helping H. pylori to adapt and persist in the host., The small RNA RepG modulates expression of chemotaxis receptor TlpB in Helicobacter pylori by targeting a length-variable G-repeat in the tlpB mRNA. Here, Pernitzsch et al. show that RepG also gradually controls lipopolysaccharide biosynthesis, antibiotic susceptibility, and in-vivo colonization of the stomach, by regulating a gene that is co-transcribed with tlpB.
Published: 2021

9. Éligibilité des patients aux cellules CAR-T : avis d’experts proposé par la SFGM-TC

Author: Franck Morschhauser, Florence Rabian, Catherine Thieblemont, Marie-Thérèse Rubio, Guillaume Cartron, David Beauvais, Steven Le Gouill, Jacques-Olivier Bay, André Baruchel, Sabine Furst, Gandhi Damaj, Denis Caillot, Emmanuel Bachy, Ibrahim Yakoub-Agha, Université de Lille, Hôpital Claude Huriez [Lille], CHU Lille, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Recherche clinique appliquée à l'hématologie (URP_3518), Université de Paris (UP), Hôpital Robert Debré, CHU Clermont-Ferrand, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut d'Hématologie de Basse-Normandie (IHBN), 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), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris Cité (UPCité), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, CAR T-cells, Leucémie aiguë lymphoblastique B, Lymphoblastic Leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, Marketing authorization, B-cell acute lymphoblastic leukemia, CD19, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, Lymphome diffus à grandes cellules B, biology, business.industry, Diffuse large B-cell lymphoma, Hematology, General Medicine, medicine.disease, Tumor antigen, Chimeric antigen receptor, 3. Good health, Lymphoma, Cellules CAR-T, 030104 developmental biology, Anticancer treatment, 030220 oncology & carcinogenesis, Expert opinion, biology.protein, business
Abstract: International audience; The chimeric antigen receptor T-cells are a new class of anticancer treatment consisting in genetically modifying autologous or allogenic T-cells to make express a CAR directed against a membrane tumor antigen. In Europe, tisagenlecleucel (KymriahTM) has a marketing authorization for the treatment of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia in children and young adults and of R/R diffuse large B-cell lymphoma (DLBCL). The marketing authorization for axicabtagene ciloleucel (YescartaTM) is the treatment of DLBCL and primary R/R mediastinal B-cell lymphoma. The two products are autologous T-cells directed against CD19. This collaborative work, part of a series of expert opinion-based work, aims to give practical advice to help centers in selection of patients for commercially available CAR T-cell treatment.
Published: 2021

10. COVID-19 vaccines: Frequently asked questions and updated answers

Author: B Wyplosz, R Cohen, B Pitard, E Botelho-Nevers, O Epaulard, M Lefebvre, Nicolas Vignier, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infovac-France, Centre Hospitalier Intercommunal de Créteil (CHIC), Centre d'Investigation Clinique [Grenoble] (CIC Grenoble), CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), SPILF Vaccination Prevention group, Bernardo, Elizabeth, CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne)
Subjects: medicine.medical_specialty, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Article, World health, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Pandemic, medicine, Humans, 030212 general & internal medicine, Antiviral treatment, 030304 developmental biology, 0303 health sciences, SARS-CoV-2, business.industry, Frequently asked questions, 3. Good health, Clinical trial, Infectious Diseases, Action (philosophy), Family medicine, Covid-19, business, Vaccine
Abstract: International audience; At the end of December 2019, China notified the World Health Organization about a viral pneumonia epidemic soon to be named Covid-19, of which the infectious agent, SARS-CoV-2, was rapidly identified. Less than one year later, published phase 3 clinical trials underlined the effectiveness of vaccines utilizing hitherto unusual technology consisting in injection of the messenger RNA (m-RNA) of a viral protein. In the meantime, numerous clinical trials had failed to identify a maximally effective antiviral treatment, and mass vaccination came to be considered as the strategy most likely to put an end to the pandemic. The objective of this text is to address and hopefully answer the questions being put forward by healthcare professionals on the different anti-SARS-CoV-2 vaccines as regards their development, their modes of action, their effectiveness, their limits, and their utilization in different situations; we are proposing a report on both today's state of knowledge, and the 14 February 2021 recommendations of the French health authorities.
Published: 2021

11. No survival improvement in patients with high‐risk multiple myeloma harbouring del(17p) and/or t(4;14) over the two past decades

Author: Carole Barin, Lotfi Benboubker, Cyrille Touzeau, Nicolas Vallet, Olivier Theisen, Pascal Godmer, Thomas Chalopin, Hervé Avet-Loiseau, Olivier Herault, Steven Le Gouill, Marlene Ochmann, Philippe Moreau, Mourad Tiab, Emmanuel Gyan, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Université de Bretagne Sud - Vannes (UBS Vannes), Université de Bretagne Sud (UBS), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service d'Hématologie [Nantes], Site de Recherche Intégrée sur le Cancer [Nantes] (SIRIC), Imaging and Longitudinal Investigations to Ameliorate Decision-making [Nantes] (ILIAD), Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours (UT)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Toulouse [Toulouse]-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)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), 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)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), and Bernardo, Elizabeth
Subjects: Adult, Male, Oncology, medicine.medical_specialty, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, In patient, ComputingMilieux_MISCELLANEOUS, Multiple myeloma, Aged, Retrospective Studies, Aged, 80 and over, Chromosome Aberrations, business.industry, Hematology, Middle Aged, Prognosis, medicine.disease, Survival Analysis, 3. Good health, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, business, 030215 immunology
Abstract: International audience; No abstract available
Published: 2021

12. Delivery of cancer therapies by synthetic and bio-inspired nanovectors

Author: Briolay, Tina, Petithomme, Tacien, Fouet, Morgane, Nguyen-Pham, Nelly, Blanquart, Christophe, Boisgerault, Nicolas, Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Drug Carriers, Targeting, Cancer therapy, Genetic Vectors, Vesicle, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Combined Modality Therapy, lcsh:RC254-282, Theranostic Nanomedicine, Virus, Nanoparticle, Drug Delivery Systems, Treatment Outcome, Nanomedicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Vectorization, Drug delivery, Animals, Humans, Nanoparticles, Nanotechnology
Abstract: International audience; Background: As a complement to the clinical development of new anticancer molecules, innovations in therapeutic vectorization aim at solving issues related to tumor specificity and associated toxicities. Nanomedicine is a rapidly evolving field that offers various solutions to increase clinical efficacy and safety. Main: Here are presented the recent advances for different types of nanovectors of chemical and biological nature, to identify the best suited for translational research projects. These nanovectors include different types of chemically engineered nanoparticles that now come in many different flavors of 'smart' drug delivery systems. Alternatives with enhanced biocompatibility and a better adaptability to new types of therapeutic molecules are the cell-derived extracellular vesicles and microorganism derived oncolytic viruses, virus-like particles and bacterial minicells. In the first part of the review, we describe their main physical, chemical and biological properties and their potential for personalized modifications. The second part focuses on presenting the recent literature on the use of the different families of nanovectors to deliver anticancer molecules for chemotherapy, radiotherapy, nucleic acid-based therapy, modulation of the tumor microenvironment and immunotherapy. Conclusion: This review will help the readers to better appreciate the complexity of available nanovectors and to identify the most fitting "type" for efficient and specific delivery of diverse anticancer therapies.
Published: 2021

13. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Author: Hani Hassoun, Jacob P. Laubach, Jan S. Moreb, Sara Thuresson, Paula Rodriguez-Otero, Marcus Thuresson, Michele Cavo, Albert Oriol, Maria-Victoria Mateos, Joan Bladé, John W. Hiemenz, Adrian Alegre, Amitabha Mazumder, Horizon (Op ) Investigators, Kenneth C. Anderson, Omar Nadeem, Johan Harmenberg, Nicolaas A Bakker, Xavier Leleu, Alessandra Larocca, Christopher Maisel, Paul G. Richardson, Agne Paner, Anastasios Raptis, Cyrille Touzeau, Catriona Byrne, Harvard Medical School [Boston] (HMS), Hospital Universitari Germans Trias I Pujol [Badalona], Università degli studi di Torino = University of Turin (UNITO), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Bologna/Università di Bologna, Clínica Universidad de Navarra [Pamplona], Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Florida [Gainesville] (UF), Memorial Sloane Kettering Cancer Center [New York], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA), Université de Nantes (UN), Site de Recherche Intégrée sur le Cancer [Nantes] (SIRIC), Centre hospitalier universitaire de Nantes (CHU Nantes), SIRIC ILIAD [Angers, Nantes], Hospital Universitario Quironsalud, Rush University Medical Center [Chicago], Baylor Scott & White Charles A. Sammons Cancer Center [Dallas, TX, USA], Oncology Institute of Hope and Innovation [Glendale, CA, USA] (OIHI), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Novant Health Forsyth Medical Center [Winston-Salem, NC, USA] (NHFMC), Oncopeptides AB [Stockholm, Sweden], Instituto de Investigación Biomédica de Salamanca [Salamanca, Spain] (IBSAL/CIC), HORIZON (OP-106) Investigators, Bernardo, Elizabeth, Università degli studi di Torino (UNITO), University of Bologna, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Richardson P.G., Oriol A., Larocca A., Blade J., Cavo M., Rodriguez-Otero P., Leleu X., Nadeem O., Hiemenz J.W., Hassoun H., Touzeau C., Alegre A., Paner A., Maisel C., Mazumder A., Raptis A., Moreb J.S., Anderson K.C., Laubach J.P., Thuresson S., Thuresson M., Byrne C., Harmenberg J., Bakker N.A., and Mateos M.-V.
Subjects: Adult, Male, Cancer Research, Time Factors, Time Factor, Phenylalanine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor cells, Drug resistance, Dexamethasone, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Recurrence, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Neoplasm, Progression-free survival, Melphalan, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Antineoplastic Combined Chemotherapy Protocol, business.industry, Refractory Multiple Myeloma, Middle Aged, medicine.disease, Progression-Free Survival, United States, 3. Good health, Europe, Clinical trial, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Disease Progression, Cancer research, Female, Multiple Myeloma, business, Human, Conjugate, medicine.drug
Abstract: PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.
Published: 2021

14. Standardization of 18F-FDG–PET/CT According to Deauville Criteria for Metabolic Complete Response Definition in Newly Diagnosed Multiple Myeloma

Author: Elena Zamagni, Cristina Nanni, Luca Dozza, Thomas Carlier, Clément Bailly, Paola Tacchetti, Annibale Versari, Stephane Chauvie, Andrea Gallamini, Barbara Gamberi, Denis Caillot, Francesca Patriarca, Margaret Macro, Mario Boccadoro, Laurent Garderet, Simona Barbato, Stefano Fanti, Aurore Perrot, Francesca Gay, Peter Sonneveld, Lionel Karlin, Michele Cavo, Caroline Bodet-Milin, Philippe Moreau, Françoise Kraeber-Bodéré, Zamagni E., Nanni C., Dozza L., Carlier T., Bailly C., Tacchetti P., Versari A., Chauvie S., Gallamini A., Gamberi B., Caillot D., Patriarca F., Macro M., Boccadoro M., Garderet L., Barbato S., Fanti S., Perrot A., Gay F., Sonneveld P., Karlin L., Cavo M., Bodet-Milin C., Moreau P., Kraeber-Bodere F., Bernardo, Elizabeth, The Institute of Hematology and Oncology L. and A. Seràgnoli [Bologna, Italy], Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Policlinico S. Orsola-malpighi, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)-Servizio sanitario regionale Emilia-Romagna, Nuclear Oncology (CRCINA-ÉQUIPE 13), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Santa Croce e Carle Hospital [Cuneo, Italy], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Udine - University of Udine [Italie], Laboratoire d'Hématologie Biologique [CHU Caen], 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), Università degli studi di Torino = University of Turin (UNITO), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Università degli Studi di Modena e Reggio Emilia, Università degli studi di Torino (UNITO), and Hematology
Subjects: Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computed tomography, Newly diagnosed, 18F-Fluorodeoxyglucose, FDG, positron emission tomography, PET, computed tomography, CT, minimal residual disease, multiple myeloma, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Deauville Criteria, 18 F-FDG-PET/CT, Medicine, Multiple myeloma, Complete response, 18F-FDG-PET/C, Multiple Myeloma, medicine.diagnostic_test, business.industry, medicine.disease, Standard technique, Minimal residual disease, Oncology, Positron emission tomography, 030220 oncology & carcinogenesis, Fdg pet ct, 18F-FDG, myeloma, Deauville, Nuclear medicine, business, 030215 immunology
Abstract: PURPOSE 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in patients with multiple myeloma (MM). This study aimed to define criteria for PET complete metabolic response after therapy, jointly analyzing a subgroup of newly diagnosed transplantation-eligible patients with MM enrolled in two independent European randomized phase III trials (IFM/DFCI2009 and EMN02/HO95). PATIENTS AND METHODS Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes. RESULTS At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS < 4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively) CONCLUSION FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.
Published: 2021

15. A new cytokine‐based dynamic stratification during induction is highly predictive of survivals in acute myeloid leukemia

Author: Amandine Le Bourgeois, Marion Eveillard, Camille Debord, Joëlle Gaschet, Marie-C. Béné, Cyrille Touzeau, Soraya Wuilleme, Michel Chérel, Thierry Guillaume, Thomas Gastinne, Patrice Chevallier, Philippe Moreau, Catherine Godon, Benoit Tessoulin, Beatrice Mahe, Olivier Theisen, Nicolas Blin, Alice Garnier, Viviane Dubruille, Anne Lok, Pierre Peterlin, Yannick Le Bris, Steven Le Gouill, Nuclear Oncology (CRCINA-ÉQUIPE 13), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre hospitalier universitaire de Nantes (CHU Nantes), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), CRLCC René Gauducheau, Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Response to therapy, medicine.medical_treatment, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, prognostic biomarker, Original Research, Potential impact, biology, Myeloid leukemia, Induction Chemotherapy, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Pathophysiology, 3. Good health, Survival Rate, Leukemia, Myeloid, Acute, Cytokine, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, Induction Phase, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute myeloid leukemia, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Biomarkers, Tumor, Humans, FLT3 ligand, Radiology, Nuclear Medicine and imaging, Interleukin 6, Aged, IL-6, business.industry, Interleukin-6, Clinical Cancer Research, Membrane Proteins, IL‐6, 030104 developmental biology, biology.protein, business, Intermediate risk, Follow-Up Studies
Abstract: The aim of this study was to assess the potential impact of the kinetics of serum levels of seven cytokines during induction in acute myeloid leukemia (AML) patients. Indeed, the role of cytokines, in the pathophysiology and response to therapy of AML patients, remains under investigation. Here, we report on the impact of peripheral levels of two cytokines, the Fms‐like tyrosine kinase 3 ligand (FL) and interleukin‐6 (IL‐6), evaluated during first‐line intensive induction. A new risk stratification can be proposed, which supersedes the ELN 2017 classification to predict survivals in AML patients by examining the kinetic profile of these cytokines during the induction phase. It segregates three groups of, respectively, high‐risk, characterized by a stagnation of low FL levels, intermediate risk, with dynamic increasing FL levels and high IL‐6 at day 22, and favorable risk with increasing FL levels but low IL‐6 at day 22., Here we report on the impact of the peripheral levels of two cytokines, the Fms‐like tyrosine kinase 3 ligand (FL), and interleukin‐6 (IL‐6), evaluated during first‐line intensive induction. Indeed, a new risk stratification can be proposed, which supersedes the ELN 2017 classification to predict survivals in AML patients by examining their profile during the induction phase.
Published: 2021

16. Laparoscopic closure of the pouch of Douglas by a peritoneal running suture. A minimally invasive and prosthetic-free technique to prevent excessive dose delivery to the small bowel during pelvic irradiation for prostate cancer

Author: Martina-Aida Angeles, Ciprian Chira, Pierre Graff-Cailleaud, Bernard Malavaud, Maxime Loo, Elodie Martin, Lucie Piram, Carlos Martínez-Gómez, Gwenael Ferron, Jonathan Khalifa, Laboratoire Joliot Curie, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), 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), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), and CCSD, Accord Elsevier
Subjects: medicine.medical_specialty, Intraoperative Complication, medicine.medical_treatment, [SDV]Life Sciences [q-bio], R895-920, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Prostate cancer, Medical physics. Medical radiology. Nuclear medicine, 0302 clinical medicine, Suture (anatomy), medicine, Radiology, Nuclear Medicine and imaging, Hernia, Laparoscopy, Pelvis, RC254-282, medicine.diagnostic_test, Radiotherapy, business.industry, digestive, oral, and skin physiology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Small bowel, digestive system diseases, 3. Good health, Surgery, [SDV] Life Sciences [q-bio], Radiation therapy, medicine.anatomical_structure, Douglas’ pouch, Oncology, Radiation-induced enteritis, 030220 oncology & carcinogenesis, Pouch, business, Prostatic neoplasm
Abstract: Highlights • The radiation tolerance of the small bowel is limited. • Chronic radiation-induced enteritis affects patients quality of life. • Ectopic small bowel loops trapped in the pelvis may challenge prostate radiotherapy. • A laparoscopic prosthetic-free technique to cordon off bowel loops from the pelvis., Background and purpose Prostate radiotherapy relies on the delivery of high doses that can be obstructed when a small bowel loop descends in the pelvis. We present a laparoscopic minimally invasive prosthetic-free technique closing the Douglas’ pouch with a peritoneal running suture to cordon off the bowel from the pelvis and hence allow optimal irradiation. Materials and methods Prostate cancer patients referred for radiotherapy and whose planning-CT revealed a bowel loop trapped in the pelvis were proposed the procedure, followed by a new planning-CT. This proof-of-concept study reports postoperative follow-up and dosimetric benefits. Results The procedure was performed in ten patients (2016–2020) as a same-day surgery for nine. Median operative time was 34 min (range 22–50) and no relevant intraoperative complication occurred. The third patient of the series presented a small bowel hernia through the peritoneal suture at the 15th postoperative day requiring a laparotomic desincarceration without major consequences. Regarding the small bowel, median D1cc (dose to 1 cc) was 65.5 Gy and 55.5 Gy (p = 0.005) before and after procedure. Median V60 (volume receiving ≥60 Gy) was 10.2 cc and 0.0 cc (p = 0.005). In the immediate vicinity of the small bowel (5 mm), median D1cc was 68.3 Gy and 57.7 Gy (p = 0.005). Radiotherapy was safely delivered to all patients. Conclusion Laparoscopic closure of the Douglas’ pouch by a peritoneal suture is an efficient technique to cordon off inconvenient ectopic small bowel loops. It prevents excessive bowel irradiation and hence facilitates curative prostate radiotherapy. The technique could be applied to other pelvic malignancies.
Published: 2021

17. Covid-19 and blood groups: ABO antibody levels may also matter

Author: Adrien Breiman, Valéry Daubie, Hanane El Kenz, Francis Corazza, Jean-François Fils, Nathalie Ruvoën-Clouet, Marie Deleers, Bhavna Mahadeb, Jacques Jani, Mieke Cannie, Isabelle Barreau, Béatrice Clémenceau, Tatiana Besse, Virginie Doyen, Jacques Le Pendu, Evelyne Maillart, Philippe Van der Linden, Nabil Hayef, Carine Maggetto, Centre Hospitalier Universitaire Brugmann [Bruxelles] (CHU), Université libre de Bruxelles (ULB), Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Ars Statistica [Nivelles, Belgium], Clinical sciences, Supporting clinical sciences, Radiology, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Male, Epitope, Epitopes, 0302 clinical medicine, hemic and lymphatic diseases, 030212 general & internal medicine, Aged, 80 and over, biology, ABO antibody levels, General Medicine, Covid-19 infection risk, Middle Aged, Galactosyltransferases, 3. Good health, medicine.anatomical_structure, Infectious Diseases, Radiology Nuclear Medicine and imaging, Spike Glycoprotein, Coronavirus, Female, Disease Susceptibility, medicine.symptom, Antibody, Microbiology (medical), Adult, Risk, congenital, hereditary, and neonatal diseases and abnormalities, 030106 microbiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Lower risk, Asymptomatic, Article, Antibodies, lcsh:Infectious and parasitic diseases, ABO Blood-Group System, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Polysaccharides, ABO blood group system, Glycosyltransferase, parasitic diseases, medicine, Humans, lcsh:RC109-216, Aged, business.industry, SARS-CoV-2, ABO blood group, COVID-19, Epithelial Cells, Agglutination (biology), Immunoglobulin M, Immunology, biology.protein, ABO antibodies, business, Respiratory tract
Abstract: Highlights • The SARS-CoV-2 spike protein can be tagged with A and/or B blood group antigens. • Upper respiratory tract epithelial cells express A and B antigens. • ABO antibody levels are significantly lower in Covid-19 patients compared to controls. • ABO-related anti-xenoantigen levels do not differ between patients and controls. • People with low levels of ABO antibodies may be at a higher risk of being infected., Background Susceptibility to Covid-19 has been found to be associated with the ABO blood group, with O type individuals being at a lower risk. However, the underlying mechanism has not been elucidated. Here, we aimed to test the hypothesis that Covid-19 patients might have lower levels of ABO antibodies than non-infected individuals as they could offer some degree of protection. Methods After showing that the viral spike protein harbors the ABO glycan epitopes when produced by cells expressing the relevant glycosyltransferases, like upper respiratory tract epithelial cells, we enrolled 290 patients with Covid-19 and 276 asymptomatic controls to compare their levels of natural ABO blood group antibodies. Results We found significantly lower IgM anti-A + anti-B agglutination scores in blood group O patients (76.93 vs 88.29, P-value = 0.034) and lower levels of anti-B (24.93 vs 30.40, P-value = 0.028) and anti-A antibodies (28.56 vs 36.50, P-value = 0.048) in blood group A and blood group B patients, respectively, compared to controls. Conclusion In this study, we showed that ABO antibody levels are significantly lower in Covid-19 patients compared to controls. These findings could indicate that patients with low levels of ABO antibodies are at higher risk of being infected.
Published: 2020

18. Fluorescent Peptide Biosensor for Probing CDK6 Kinase Activity in Lung Cancer Cell Extracts

Author: Mathieu Galibert, Christophe Blanquart, Morgan Pellerano, Karine Puget, Magali Jullian, Sebastien Diot, Jessica Soamalala, May C. Morris, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), GENEPEP [France], Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Genepep SA
Subjects: Cell Extracts, Lung Neoplasms, CDK6, Angiogenesis, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Peptide, Biosensing Techniques, kinase activity, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Humans, Amino Acid Sequence, Kinase activity, Molecular Biology, Fluorescent Dyes, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, Rhodamines, Kinase, Organic Chemistry, technology, industry, and agriculture, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Recombinant Proteins, lung cancer, Spectrometry, Fluorescence, medicine.anatomical_structure, chemistry, Cell culture, mesothelioma, 030220 oncology & carcinogenesis, biology.protein, fluorescent peptide biosensor, Molecular Medicine, Cyclin-dependent kinase 6, Peptides, Biosensor
Abstract: International audience; CDK6 kinase regulates cell cycle progression in G1, together with CDK4, but has cell-, tissue- and developmentally-distinct functions associated with transcription, angiogenesis and metabolism. Although CDK6 constitutes an attractive cancer biomarker and target there are no means of assessing its activity in a complex environment. In this study we describe design, engineering and characterization of a fluorescent peptide biosensor derived from 6-phosphofructokinase that reports on CDK6 kinase activity through sensitive changes in fluorescence intensity. This biosensor can report on CDK6 activity in a dose-dependent fashion, thereby enabling quantification of differences in kinase activity in complex and physiologically-relevant environments. Further implementation of this biosensor in different lung and melanoma cell lines, as well as in mesothelioma cell lines derived from patients together with a CDK4 biosensor highlighted differences in kinase activity between CDK6 and CDK4 kinase. This work demonstrates the utility of these selective tools for monitoring two closely related kinases comparatively and simultaneously in the same samples, thereby offering attractive perspectives for diagnostic and therapeutic purposes.
Published: 2020

19. Mitochondria transfer from tumor-activated stromal cells (TASC) to primary Glioblastoma cells

Author: Fanny Geraldo, Víctor M. Pérez-García, Gabriel F. Calvo, Claire Pecqueur, Juan Belmonte-Beitia, Arturo Álvarez-Arenas, Lisa Oliver, François M. Vallette, Céline Salaud, Catherine Gratas, Delphine Garnier, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), University of Castilla-La Mancha (UCLM), Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universidad de Castilla-La Mancha = University of Castilla-La Mancha (UCLM), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Stromal cell, medicine.medical_treatment, Population, Mesenchymal stromal cells, Biophysics, Brain tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mitochondrion, Biochemistry, Cell Line, Extracellular Vesicles, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tumor Cells, Cultured, Tumor Microenvironment, Organoid, medicine, Humans, education, Molecular Biology, Cell Proliferation, education.field_of_study, Tumor microenvironment, Chemotherapy, Primary GBM cultures, Brain Neoplasms, Chemistry, Mesenchymal stem cell, Mesenchymal Stem Cells, Cell Biology, medicine.disease, Coculture Techniques, Mitochondria, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Glioblastoma, Tunneling nanotubes
Abstract: International audience; The tumor microenvironment (TME) controls many aspects of cancer development but little is known about its effect in Glioblastoma (GBM), the main brain tumor in adults. Tumor-activated stromal cell (TASC) population, a component of TME in GBM, was induced in vitro by incubation of MSCs with culture media conditioned by primary cultures of GBM under 3D/organoid conditions. We observed mito-chondrial transfer by Tunneling Nanotubes (TNT), extracellular vesicles (EV) and cannibalism from the TASC to GBM and analyzed its effect on both proliferation and survival. We created primary cultures of GBM or TASC in which we have eliminated mitochondrial DNA [Rho 0 (r 0) cells]. We found that TASC, as described in other cancers, increased GBM proliferation and resistance to standard treatments (radio-therapy and chemotherapy). We analyzed the incorporation of purified mitochondria by r 0 and r þ cells and a derived mathematical model taught us that r þ cells incorporate more rapidly pure mitochondria than r 0 cells.
Published: 2020

20. Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance

Author: Riad Abes, Kevin Biteau, Alexandre Glémain, Christophe Blanquart, Dominique Costantini, Catherine Ruiz, David Laplaud, Hélène Aublé, Stéphanie Le Bas-Bernardet, E. Sergio Trombetta, Véronique Catros, Gilles Blancho, Isabelle Archambeaud, Sylvie Métairie, Isabelle Girault, Emmanuelle Wilhelm, Masayuki Miyasaka, Jean-François Mosnier, Vanessa Gauttier, Sabrina Pengam, Charlène Trilleaud, Alexandra Garcia, Pierre-Antoine Gouraud, Pierre Duplouye, Bernard Martinet, Géraldine Teppaz, Georgia Porto, Fabienne Haspot, Sarah Bruneau, Aurore Morello, Justine Durand, Caroline Mary, Richard Danger, Sophie Conchon, Nathalie Labarrière, Kerry L. M. Ralph, Virginie Thepenier, Nicolas Vince, Nicolas Poirier, Bernard Vanhove, Virginie Vignard, Mélanie Néel, Safa Dehmani, OSE Immunotherapeutics [Nantes, France], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Boehringer Ingelheim Pharma GmbH & Co. KG, Osaka University, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Nantes (UN), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Institut des maladies de l'appareil digestif [Nantes] (IMAD), BPI EFFI-CLIN PSPC grant,INCA MDSCAN PRT-K15-136, the French Public Bank of Investment and French Institut National du Cancer, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Rennes (UR)-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 de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), and Jonchère, Laurent
Subjects: 0301 basic medicine, T-Lymphocytes, [SDV]Life Sciences [q-bio], T cell, medicine.medical_treatment, Immunology, T cells, Cancer immunotherapy, Therapeutics, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Receptors, Immunologic, Mice, Inbred BALB C, Tumor microenvironment, Chemistry, Macrophages, CD47, Mammary Neoplasms, Experimental, General Medicine, Immune checkpoint, Neoplasm Proteins, 3. Good health, Blockade, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Chemokine secretion, Cancer research, Female, Immunotherapy, Immunologic Memory, Memory T cell, Research Article
Abstract: International audience; T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.
Published: 2020

21. Slower degradation rate of cytarabine in blood samples from acute myeloid leukemia by comparison with control samples

Author: Philippe Guardiola, Sarah Ghamrawi, Séverine Férec, Mathilde Hunault-Berger, Simon Souchet, Chadi Abbara, Guillaume Drevin, Marie Briet, Jean-Baptiste Robin, Aline Schmidt, Département de Pharmacologie-Toxicologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), Service de Génomique Onco-Hématologique [CHU Angers], Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service des maladies du sang [CHU Angers], Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Bernardo, Elizabeth
Subjects: Male, 0301 basic medicine, Cancer Research, Time Factors, medicine.medical_treatment, Toxicology, Gastroenterology, 0302 clinical medicine, Drug Stability, AML, Tandem Mass Spectrometry, hemic and lymphatic diseases, Pharmacology (medical), Chromatography, High Pressure Liquid, Randomized Controlled Trials as Topic, Cytarabine, In vitro degradation, Area under the curve, Myeloid leukemia, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, Oncology, Deamination, 030220 oncology & carcinogenesis, Female, Multiple linear regression analysis, Stability, Half-Life, medicine.drug, Adult, Antimetabolites, Antineoplastic, medicine.medical_specialty, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Clinical pharmacokinetic, Specimen Handling, Young Adult, 03 medical and health sciences, Clinical Trials, Phase II as Topic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cytidine Deaminase, Internal medicine, medicine, Humans, Clinical significance, Pharmacology, Chemotherapy, business.industry, 030104 developmental biology, Clinical Trials, Phase III as Topic, Case-Control Studies, business
Abstract: International audience; Purpose: Cytarabine, a key chemotherapy agent for acute myeloid leukemia (AML) treatment, is deaminated into inactive uracil-arabinoside by cytidine deaminase. This deamination leads to samples stability issues with respect to clinical pharmacokinetic trials. The aim of our study was to study in vitro cytarabine stability in blood samples obtained from AML patients.Methods: Cytarabine quantification was performed using a fully validated LC/MS/MS method. In vitro cytarabine stability was assessed at room temperature over 24 h in samples coming from 14 AML patients and 7 control patients (CTRL) with no hematological malignancy. In vitro concentrations versus time data were analyzed using a noncompartmental approach.Results: Cytarabine in vitro area under the curve (AUCIVlast) was 22-fold higher in AML samples as compared to CTRL samples (AML mean (standard deviation (SD)), 51,829 (27,004) h ng/mL; CTRL mean (SD), 2356 (1250) h ng/mL, p = 0.00019). This increase was associated with a prolonged in vitro degradation half-life (t1/2IVdeg AML mean (SD), 15 (11.8) h; CTRL mean (SD), 0.36 (0.37) h, p = 0.0033). Multiple linear regression analysis showed that AML diagnosis significantly influenced t1/2IVdeg and AUCIVlas relationship.Conclusion: Cytarabine stability is higher in AML than in CTRL samples. The absence of correlation between t1/2IVdeg and AUCIVlast in AML samples suggests that in vitro cytarabine degradation in AML is complex. These results open perspectives including the evaluation of the clinical relevance and the involved molecular mechanisms.
Published: 2020

22. Universal scaling laws rule explosive growth in human cancers

Author: Ángel Acosta Rojas, Esther Hernández-San Miguel, María Pérez-Cano, Gabriel F. Calvo, Lucía Zhu, Ana María García Vicente, Juan Belmonte-Beitia, Juan J. Jiménez, David Albillo, Philippe Schucht, Víctor M. Pérez-García, Pedro García-Gómez, Antonio Francisco Honguero Martínez, François M. Vallette, Manuel Valiente, Jesús J. Bosque, Álvaro Martínez, Julián Pérez-Beteta, David Molina-García, Youness Azimzade, Odelaisy León-Triana, Michael Murek, Pilar Sánchez-Gómez, Ana Ortiz de Mendivil, Rafael Hortigüela, Germán Andrés Jiménez Londoño, Estanislao Arana, Universidad de Castilla-La Mancha (UCLM), Spanish National Cancer Research Center (CNIO), Institute of Health Carlos III, University of Tehran, Sanchinarro University Hospita [HM Hospitales, Madrid], Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Bern University Hospital [Berne] (Inselspital), MD Anderson Cancer Center [Madrid, Spain], Hospital General Universitario de Albacete, Hospital General Universitario de Ciudad Real [Ciudad Real, Spain], Fundación Instituto Valenciano de Oncología [Valencia, Spain], James S. McDonnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer, European Regional Development Fund (ERDF/FEDER), Junta de Comunidades de Castilla-La Mancha, Ministerio de Economia y Competividad (MINECO), Bristol-Myers Squibb, Beug Foundation's Prize for Metastasis Research 2017, Fundacion Ramon Areces, Worldwide Cancer Research, H2020-FETOPEN, Fundacio La Marato de TV3, Clinic and Laboratory Integration Program CRI Award 2018, AECC Coordinated Translational Groups 2017, LAB AECC 2019, La Caixa INPhINIT Fellowship, La Caixa-Severo Ochoa International PhD Program Fellowship, European Molecular Biology Organization Young Investigators programme, Bernardo, Elizabeth, Universidad de Castilla-La Mancha = University of Castilla-La Mancha (UCLM), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Scaling law, Explosive material, Computer science, General Physics and Astronomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, 01 natural sciences, Measure (mathematics), Article, 010305 fluids & plasmas, [SDV.CAN] Life Sciences [q-bio]/Cancer, GENERAL-MODEL, 0103 physical sciences, RATES, Statistical physics, Tissues and Organs (q-bio.TO), 010306 general physics, Set (psychology), Evolutionary dynamics, Mathematical model, TUMOR-GROWTH, Quantitative Biology - Tissues and Organs, Observable, EVOLUTION, PREDICTS, 3. Good health, PET, Oncología matemática, FOS: Biological sciences, SURVIVAL, Biomedicina, Value (mathematics)
Abstract: Most physical and other natural systems are complex entities composed of a large number of interacting individual elements. It is a surprising fact that they often obey the so-called scaling laws relating an observable quantity with a measure of the size of the system. Here we describe the discovery of universal superlinear metabolic scaling laws in human cancers. This dependence underpins increasing tumour aggressiveness, due to evolutionary dynamics, which leads to an explosive growth as the disease progresses. We validated this dynamic using longitudinal volumetric data of different histologies from large cohorts of cancer patients. To explain our observations we put forward increasingly-complex biologically-inspired mathematical models that captured the key processes governing tumor growth. Our models predicted that the emergence of superlinear allometric scaling laws is an inherently three-dimensional phenomenon. Moreover, the scaling laws thereby identified allowed us to define a set of metabolic metrics with prognostic value, thus providing added clinical utility to the base findings. This research has been supported by the James S. McDonnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (collaborative awards 220020560 and 220020450), Ministerio de Economia y Competitividad/FEDER, Spain (grant no. MTM2015-71200-R), Junta de Comunidades de Castilla-La Mancha (grant no. SBPLY/17/180501/000154). Research in the Brain Metastasis Group is supported by MINECO grant MINECO-Retos SAF2017-89643-R (M.V.), Bristol-Myers Squibb Melanoma Research Alliance Young Investigator Award 2017 (498103) (M.V.), Beug Foundation's Prize for Metastasis Research 2017 (M.V.), Fundacion Ramon Areces (CIVP19S8163) (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Fundacio La Marato de tv3 (141), Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), La Caixa INPhINIT Fellowship (LCF/BQ/IN17/11620028) (P.G.-G.), La Caixa-Severo Ochoa International PhD Program Fellowship (LCF/BQ/SO16/52270014) (L.Z.). M.V. is a member of the European Molecular Biology Organization Young Investigators programme (4053). We would like to acknowledge J. Cervera and J. C. Penalver from the IVO Foundation (Valencia, Spain). No
Published: 2020

23. Impact of age at diagnosis of metastatic breast cancer on overall survival in the real-life ESME metastatic breast cancer cohort

Author: Frank, Sophie, Carton, Matthieu, Dubot, Coraline, Campone, Mario, Pistilli, Barbara, Dalenc, Florence, Mailliez, Audrey, Lévy, Christelle, D'Hondt, Veronique, Debled, Marc, Vermeulin, Thomas, Coudert, Benoit, Perrin, Christophe, Gonçalves, Anthony, Uwer, Lionel, Ferrero, Jean-Marc, Eymard, Jean-Christophe, Petit, Thierry, Mouret-Reynier, Marie-Ange, Patsouris, Anne, Guesmia, Tahar, Bachelot, Thomas, Robain, Mathieu, Cottu, Paul, D’Hondt, Véronique, Institut Curie [Paris], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut du Cancer de Montpellier (ICM), Institut Bergonié [Bordeaux], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Centre Eugène Marquis (CRLCC), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Jean Godinot [Reims], Centre Paul Strauss, CRLCC Paul Strauss, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre Léon Bérard [Lyon], Institut Curie [Saint-Cloud], French Breast Cancer Intergroup - UCBG [Paris] (R&D UNICANCER), R&D Unicancer [Paris], Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Département d'Oncologie Médicale [Institut Curie, Paris], Centre de Lutte Contre le Cancer Nantes Atlantique 'René Gauducheau' (CLCC), Université Lille Nord de France (COMUE)-UNICANCER, Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Catholique de Louvain = Catholic University of Louvain (UCL), Service d'Oncologie Médicale, UNICANCER-UNICANCER, Hôpital Charles Nicolle [Tunis], Département d'oncologie médicale [Rennes], CRLCC Eugène Marquis (CRLCC), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de recherche translationnelle, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPC), Université Côte d'Azur (UCA)-UNICANCER, and Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA)
Subjects: Adult, Oncology, medicine.medical_specialty, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Age at diagnosis, Breast Neoplasms, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Cohort Studies, Metastatic disease, 03 medical and health sciences, Age Distribution, Breast cancer, Age, 0302 clinical medicine, Internal medicine, Overall survival, Humans, Medicine, 030212 general & internal medicine, Stage (cooking), skin and connective tissue diseases, Early Detection of Cancer, Retrospective Studies, business.industry, Cancer, General Medicine, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Survival Analysis, Metastatic breast cancer, Real-world data, 3. Good health, Young age, 030220 oncology & carcinogenesis, Cohort, Original Article, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Surgery, France, business
Abstract: Background Young age is a poor prognostic factor in early stage breast cancer (BC) but its value is less established in metastatic BC (MBC). We evaluated the impact of age at MBC diagnosis on overall survival (OS) across three age groups ( 60 years(y)). Methods ESME MBC database is a national cohort, collecting retrospective data from 18 participating French cancer centers between January 01, 2008 and December 31, 2014. Results Among 14 403 women included, 1077 (7.5%), 6436 (44.7%) and 6890 (47.8%) pts were 60 y respectively. Pts 60y) and triple negative subtypes (27.4 vs 14.6% in >60y), and more frequent visceral involvement (36.3 vs 29.8% in >60y). At a median follow-up of 48 months, median OS differed across age groups: 38.8, 38.4 and 35.6 months for pts 60y, respectively (p 60y, respectively (p, Highlights • Young age is a poor prognosis factor in early stage breast cancer. • Young age is associated with an aggressive presentation in metastatic breast cancer. • Young age had no impact on overall survivall in metastatic breast cancer. • Oppositely, older women (>60y) had a stightly poorer prognosis at the metastatic stage.
Published: 2020

24. Reply to: Oncolytic Viral Therapy for Malignant Pleural Mesothelioma

Author: Clément Meiller, Nicolas Boisgerault, Tiphaine Delaunay, Marc Grégoire, Marion Grard, Stefano Caruso, Jean-François Fonteneau, Jaafar Bennouna, Didier Jean, Frédéric Tangy, Emanuela Felley-Bosco, Christophe Blanquart, 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), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), University hospital of Zurich [Zurich], Service de pneumologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), ANR-16-CE18-0016,OncoMeVax,Un virus de la rougeole modifié pour traiter le cancer(2016), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Un virus de la rougeole modifié pour traiter le cancer - - OncoMeVax2016 - ANR-16-CE18-0016 - AAPG2016 - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, 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), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Zurich, Jean, Didier, and École Pratique des Hautes Études (EPHE)
Subjects: Mesothelioma, Pulmonary and Respiratory Medicine, Lung Neoplasms, 10255 Clinic for Thoracic Surgery, Pleural Neoplasms, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, Measles virus, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Oncolytic immunotherapy, Humans, Medicine, Viral therapy, ComputingMilieux_MISCELLANEOUS, Sequence Deletion, 030304 developmental biology, 0303 health sciences, MESH: Type I interferon, MESH: Mesothelioma, biology, business.industry, Pleural mesothelioma, Homozygote, MESH: Gene homozygous deletion, biology.organism_classification, Oncolytic virus, Oncolytic Viruses, Oncology, 2740 Pulmonary and Respiratory Medicine, 030220 oncology & carcinogenesis, Interferon Type I, Cancer research, 2730 Oncology, business, MESH: Measles virus, Interferon type I, medicine.drug
Abstract: International audience
Published: 2020

25. Biomarkers of tumor invasiveness in proteomics (Review)

Author: Catherine Guette, Alice Boissard, Daniel Pouliquen, Olivier Coqueret, Bernardo, Elizabeth, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: proteomics biomarkers, Proteomics, 0301 basic medicine, Cancer Research, Quantitative proteomics, [SDV.CAN]Life Sciences [q-bio]/Cancer, membrane proteins, Computational biology, Biology, nuclear proteins, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Neoplasms, extracellular matrix remodeling, Biomarkers, Tumor, medicine, Animals, Humans, Neoplasm Invasiveness, Oncogene, Cancer, Articles, Cell cycle, medicine.disease, cytoskeletal proteins, Molecular medicine, 3. Good health, endoplasmic reticulum, Disease Models, Animal, 030104 developmental biology, Oncology, mitochondrial proteins, 030220 oncology & carcinogenesis, Proteome, cytoplasmic enzymes, tumor invasiveness, plasma proteins
Abstract: International audience; Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of references involving studies on the cancer metastatic process has doubled since 2010, while the last 5 years have seen the development of novel technologies combining deep proteome coverage capabilities with quantitative consistency and accuracy. To highlight key findings within this huge amount of information, the present review identified a list of tumor inva-sive biomarkers based on both the literature and data collected on a biocollection of experimental cell lines, tumor models of increasing invasiveness and tumor samples from patients with colorectal or breast cancer. Crossing these different data sources led to 76 proteins of interest out of 1,245 mentioned in the literature. Information on these proteins can potentially be translated into clinical prospects, since they represent potential targets for the development and evaluation of innovative therapies , alone or in combination. Herein, a systematical review of the biology of each of these proteins, including their specific subcellular/extracellular or multiple localizations is presented. Finally, as an important advantage of quantitative proteomics is the ability to provide data on all these molecules simultaneously in cell pellets, body fluids or paraffin-embedded sections of tumors/invaded tissues, the significance of some of their interconnections is discussed.
Published: 2020

26. Rifampicin and clarithromycin (extended release) versus rifampicin and streptomycin for limited Buruli ulcer lesions

Author: Alan Knell, Thomas Berko, Linda Lehman, Tuah Wilson, Sarah Eyangoh, Kingsley Asiedu, Ernest Opoku, Kristien Velding, Edwin Ampadu, Jérôme Robert, Estelle Marion, Bright Osei-Wusu, Annick Chauty, Edward Sarpong, William Faber, Anastasia Nsiah, Ambroise Adeye, Yaw Ampem Amoako, Marie Françoise Ardent, William Thompson, George Amofa, Richard Phillips, Line Ganlonon, John M Macdonald, Elliot Koranteng Tannor, Till F. Omansen, Raymond Omollo, Terry Treadwell, Justice Abotsi, Albert Paintsil, Nanaa Francisca Sarpong, Samuel Osei Mireku, Maxime Kiki, Raoul Saizonou, David Ofori-Adjei, Bernadette Agbavor, Godfred Sarpong, Espoir Sodjinou, Michael Ochieng Otieno, Fred Stephen Sarfo, Paul Saunderson, Aloysius Dzibordzi Loglo, Martial Kindjinou, Justice K. Boakye-Appiah, Beatrice Konadu, Arnaud Yamadjako, Didier Agossadou, Mark Forson, Tjip S. van der Werf, Sally-Ann Ohene, Elizabeth Ofori, Mathias Ndogyele, Ymkje Stienstra, Thaddaeus Egondi, Richard Asamoah-Frimpong, Joseph Ken Adu Poku, Mabel Sarpong-Duah, Joyce Mensah-Bonsu, Felicity Aboagye, Thierry Gateau, Michael Frimpong, Joseph Ofori Nyarko, Mark Wansbrough-Jones, Kabiru Mohamed Abass, Clémence Guegnard, Alexandre Tiendrebeogo, Akpolan, Jacques H. Grosset, Sandor-Adrian Klis, Naomi Adanmado Gersande, Bernardo, Elizabeth, Identification and development of vaccine candidates for Buruli Ulcer Disease - BURULIVAC - - EC:FP7:HEALTH2010-03-01 - 2013-05-31 - 241500 - VALID, Kwame Nkrumah University of Science and Technology [GHANA] (KNUST), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Agogo Presbyterian Hospital [GHANA], NkawieToaso Government Hospital [GHANA], Centre de diagnostic et de traitement de la lèpre et de l’Ulcère de Buruli Madeleine et Raoul Follereau [Pobè, Bénin], Drugs for Neglected Diseases initiative [Nairobi, Kenya] (ARO), Africa Regional Office [Nairobi, Kenya], National Buruli ulcer Control Programme [Accra, Ghana] (GHS), Ghana Health Service [Accra, Ghana], Programme National de Lutte contre la lèpre et l’Ulcère de Buruli [Cotonou, Benin], ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), St George's, University of London, Johns Hopkins University (JHU), University of Miami Leonard M. Miller School of Medicine (UMMSM), Institute for Advanced Wound Care [Montgomery, AL, USA], American Leprosy Missions [Greenville, SC, USA], Korle-BU Teaching Hospital [Accra, Ghana], WHO, Country Office for Benin [Cotonou, Benin], WHO, Regional Office for Africa [Brazzaville, Republic of the Congo], WHO, Country Office for Ghana [Accra, Ghana], University Medical Center Groningen [Groningen] (UMCG), Department of Neglected Tropical Diseases, WHO [Geneva, Switzerland], WHO sponsored the study with additional support in cash or kindprovided by MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, SanofiPasteur France, and BuruliVac (EU FP7-241500)., European Project: 241500,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,BURULIVAC(2010), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Microbes in Health and Disease (MHD), and Kwame Nkrumah University of Science and Technology (KNUST)
Subjects: Male, Buruli ulcer, Administration, Oral, 030204 cardiovascular system & hematology, Ghana, DISEASE, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Clarithromycin, INFECTION, Clinical endpoint, Benin, Medicine, EPIDEMIOLOGY, 030212 general & internal medicine, Child, Buruli Ulcer, education.field_of_study, biology, General Medicine, Anti-Bacterial Agents, 3. Good health, Tolerability, Mycobacterium ulcerans, Streptomycin, MYCOBACTERIUM-ULCERANS, Drug Therapy, Combination, Female, Rifampin, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, education, COMBINATION, Wound Healing, business.industry, medicine.disease, biology.organism_classification, EFFICACY, Regimen, Delayed-Action Preparations, business
Abstract: BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans infection that damages the skin and subcutis. It is most prevalent in western and central Africa and Australia. Standard antimicrobial treatment with oral rifampicin 10 mg/kg plus intramuscular streptomycin 15 mg/kg once daily for 8 weeks (RS8) is highly effective, but streptomycin injections are painful and potentially harmful. We aimed to compare the efficacy and tolerability of fully oral rifampicin 10 mg/kg plus clarithromycin 15 mg/kg extended release once daily for 8 weeks (RC8) with that of RS8 for treatment of early Buruli ulcer lesions.METHODS: We did an open-label, non-inferiority, randomised (1:1 with blocks of six), multicentre, phase 3 clinical trial comparing fully oral RC8 with RS8 in patients with early, limited Buruli ulcer lesions. There were four trial sites in hospitals in Ghana (Agogo, Tepa, Nkawie, Dunkwa) and one in Benin (Pobè). Participants were included if they were aged 5 years or older and had typical Buruli ulcer with no more than one lesion (caterories I and II) no larger than 10 cm in diameter. The trial was open label, and neither the investigators who took measurements of the lesions nor the attending doctors were masked to treatment assignment. The primary clinical endpoint was lesion healing (ie, full epithelialisation or stable scar) without recurrence at 52 weeks after start of antimicrobial therapy. The primary endpoint and safety were assessed in the intention-to-treat population. A sample size of 332 participants was calculated to detect inferiority of RC8 by a margin of 12%. This study was registered with ClinicalTrials.gov, NCT01659437.FINDINGS: Between Jan 1, 2013, and Dec 31, 2017, participants were recruited to the trial. We stopped recruitment after 310 participants. Median age of participants was 14 years (IQR 10-29) and 153 (52%) were female. 297 patients had PCR-confirmed Buruli ulcer; 151 (51%) were assigned to RS8 treatment, and 146 (49%) received oral RC8 treatment. In the RS8 group, lesions healed in 144 (95%, 95% CI 91 to 98) of 151 patients, whereas lesions healed in 140 (96%, 91 to 99) of 146 patients in the RC8 group. The difference in proportion, -0·5% (-5·2 to 4·2), was not significantly greater than zero (p=0·59), showing that RC8 treatment is non-inferior to RS8 treatment for lesion healing at 52 weeks. Treatment-related adverse events were recorded in 20 (13%) patients receiving RS8 and in nine (7%) patients receiving RC8. Most adverse events were grade 1-2, but one (1%) patient receiving RS8 developed serious ototoxicity and ended treatment after 6 weeks. No patients needed surgical resection. Four patients (two in each study group) had skin grafts.INTERPRETATION: Fully oral RC8 regimen was non-inferior to RS8 for treatment of early, limited Buruli ulcer and was associated with fewer adverse events. Therefore, we propose that fully oral RC8 should be the preferred therapy for early, limited lesions of Buruli ulcer.FUNDING: WHO with additional support from MAP International, American Leprosy Missions, Fondation Raoul Follereau France, Buruli ulcer Groningen Foundation, Sanofi-Pasteur, and BuruliVac.
Published: 2020

27. Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma

Author: Serge Lebecque, Sylvie Lantuejoul, Kathrin Weber, Yann Estornes, Marc Grégoire, Toufic Renno, Olivier Micheau, Thomas Daunizeau, Audrey Ziverec, Marion Delphin, Béatrice Vanbervliet-Defrance, Tiphaine Delaunay, Leila Djemal, Christophe Blanquart, Karene Mahtouk, Jean-François Fonteneau, Vahan Kepenekian, Guillaume Passot, Olivier Glehen, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEX IGO Immunothérapie Grand Ouest, Service de Chirurgie Viscérale et Oncologique (Centre Hospitalier Lyon Sud [CHU - HCL] CHLS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Biopathology and Translation Research and Innovation [Centre Léon Bérard, Lyon], Centre Léon Bérard [Lyon], Synergie Lyon Cancer [Lyon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service D'Anatomie Pathologique (Centre Hospitalier Lyon Sud [CHU - HCL] CHLS ), Bernardo, Elizabeth, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), and 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
Subjects: Mesothelioma, 0301 basic medicine, Cancer Research, Programmed cell death, Lung Neoplasms, viruses, Cell, CASP8 and FADD-Like Apoptosis Regulating Protein, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Downregulation and upregulation, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Cell Proliferation, Inflammation, Cisplatin, Caspase 8, Chemistry, Mesothelioma, Malignant, hemic and immune systems, medicine.disease, Toll-Like Receptor 3, 3. Good health, Gene Expression Regulation, Neoplastic, Poly I-C, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Immune receptor, TLR3, Cancer research, Peritoneal mesothelioma, Therapy, Signal Transduction, medicine.drug
Abstract: International audience; Toll-like receptor 3 (TLR3) is an immune receptor that behaves like a death receptor in tumor cells, thereby providing an original target for cancer therapy. The therapeutic potential of TLR3 targeting in malignant mesothelioma, an aggressive and incurable neoplasia of the pleura and peritoneum, has so far not been addressed. We investigated TLR3 expression and sensitivity of human mesothelioma cell lines to the synthetic dsRNA Poly (I:C), alone or in combination with cisplatin, the gold standard chemotherapy in mesothelioma. Activation of TLR3 by Poly(I:C) induced apoptosis of 4/8 TLR3-positive cell lines but not of TLR3-negative cell lines. The combined cisplatin/Poly(I:C) treatment enhanced apoptosis of 3/4 Poly(I:C)-sensitive cell lines and overcame resistance to Poly(I:C) or cisplatin alone in 2/4 cell lines. Efficacy of the combined treatment relied on cisplatininduced downregulation of c-FLIP, the main regulator of the extrinsic apoptotic pathway, leading to an enhanced caspase-8-mediated pathway. Of note, 6/6 primary cell samples isolated from patients with peritoneal mesothelioma expressed TLR3. Patient-derived cells were sensitive to Poly(I:C) alone while the combined cisplatin/Poly(I:C) treatment induced dramatic cell death. Our findings demonstrate that TLR3 targeting in combination with cisplatin presents an innovative therapeutic strategy in mesothelioma.
Published: 2020

28. Novel MS vital sign: multi‐sensor captures upper and lower limb dysfunction

Author: Alireza Akhbardeh, Bardia Nourbakhsh, Jennifer Graves, Pierre-Antoine Gourraud, Jennifer Arjona, Kristen M. Krysko, Johns Hopkins University School of Medicine [Baltimore], University of California [San Francisco] (UC San Francisco), University of California (UC), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), University of California [San Diego] (UC San Diego), Le Bihan, Sylvie, University of California [San Francisco] (UCSF), University of California, Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Multiple Sclerosis, Intraclass correlation, [SDV]Life Sciences [q-bio], Diagnostic Techniques, Neurological, Neurosciences. Biological psychiatry. Neuropsychiatry, Motor Activity, Severity of Illness Index, Spearman's rank correlation coefficient, Fingers, Wearable Electronic Devices, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Accelerometry, Partial least squares regression, medicine, Humans, Generalizability theory, RC346-429, Research Articles, Reproducibility, Electromyography, Foot, Vital Signs, business.industry, General Neuroscience, Signal Processing, Computer-Assisted, Gold standard (test), Middle Aged, Regression, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, Treatment Outcome, 030104 developmental biology, Female, Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery, Research Article, RC321-571, Sign (mathematics)
Abstract: International audience; OBJECTIVE:To create a novel neurological vital sign and reliably capture MS-related limb disability in less than 5 min.METHODS:Consecutive patients meeting the 2010 MS diagnostic criteria and healthy controls were offered enrollment. Participants completed finger and foot taps wearing the MYO-band© (accelerometer, gyroscope, and surface electromyogram sensors). Signal processing was performed to extract spatiotemporal features from raw sensor data. Intraclass correlation coefficients (ICC) assessed intertest reproducibility. Spearman correlation and multivariable regression methods compared extracted features to physician- and patient-reported disability outcomes. Partial least squares regression identified the most informative extracted textural features.RESULTS:Baseline data for 117 participants with MS (EDSS 1.0-7.0) and 30 healthy controls were analyzed. ICCs for final selected features ranged from 0.80 to 0.87. Time-based features distinguished cases from controls (P = 0.002). The most informative combination of extracted features from all three sensors strongly correlated with physician EDSS (finger taps rs = 0.77, P < 0.0001; foot taps rs = 0.82, P < 0.0001) and had equally strong associations with patient-reported outcomes (WHODAS, finger taps rs = 0.82, P < 0.0001; foot taps rs = 0.82, P < 0.0001). Associations remained with multivariable modeling adjusted for age and sex.CONCLUSIONS:Extracted features from the multi-sensor demonstrate striking correlations with gold standard outcomes. Ideal for future generalizability, the assessments take only a few minutes, can be performed by nonclinical personnel, and wearing the band is nondisruptive to routine practice. This novel paradigm holds promise as a new neurological vital sign.
Published: 2020

29. The role of exposome in acne: results from an international patient survey: The role of exposome in acne

Author: Brigitte Dréno, Anne Bouloc, Jason Shourick, Delphine Kerob, Charles Taieb, Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Bio Informatics/statistics (Université Paris-Sud ), Université Paris-Sud - Paris 11 (UP11), Les laboratoires Vichy [Levallois Perret], Private Practice [Paris], European Market Maintenance Assessment [Fontenay-sous-Bois] (EMMA ), Santé Publique ( CHU Necker - Enfants Malades [AP-HP]), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and The study was financially supported by Laboratoires Vichy France.
Subjects: Adult, Exposome, Adolescent, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, mechanical factors, stress, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Environmental health, Acne Vulgaris, Prevalence, medicine, pollution, Humans, Statistical analysis, Young adult, Acne, biology, business.industry, medicine.disease, biology.organism_classification, Response to treatment, 3. Good health, nutrition, Infectious Diseases, 030220 oncology & carcinogenesis, Patient survey, Dairy Products, Cannabis, business
Abstract: International audience; BACKGROUND:Acne severity and its response to treatment may be influenced by internal and external factors: the exposome.OBJECTIVES:The aim of this international real-life survey was to assess the most involved exposome factors in acne.METHODS:11000 individuals, aged between 15 and 39 years, with clinically confirmed acne or without acne, defined by age, gender and prevalence, were invited to participate in an internet survey of 63 questions in order to assess the frequency of identified acne exposome factors.RESULTS:Data from 6679 questionnaires were used for statistical analysis purposes: 2826 from the acne group and 3853 from the control group. Nibbling, consumption of dairy products, sweets, alcohol, or whey proteins, as well as exposure to pollution, stress, certain mechanical factors and humid or hot weather or sun exposure, were significantly (all P≤0.05) more frequently reported for the acne group than for the control group. This was not the case for tobacco consumption. Data regarding the impact of cannabis consumption were insufficient for drawing any conclusions.CONCLUSIONS:Data from this international, anonymized internet questionnaire conducted with more than almost 6700 participants add new arguments to assumptions made that certain exposome factors have an impact on acne. Nutrition, pollution, stress and harsh skin care, as well as climate and sun exposure may be considered the most frequent factors related to acne.
Published: 2020

30. Cell-free circulating epimarks in cancer monitoring

Author: Gwenola Bougras-Cartron, Dominique Heymann, Jean-Sebastien Frenel, François M. Vallette, Pierre-François Cartron, Joséphine Briand, Manon Duforestel, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Niches & Epigenetics of Tumors Network [Nantes] (Cancéropôle Grand Ouest), Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], Service d'Oncologie Médicale Thoracique et Digestive [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, M Duforestel was supported by a fellowship from EpiSAVMEN/REGION PAYS DE LA LOIRE. J Briand was supported by a fellowship from EpiSAVMEN/REGION PAYS DE LA LOIRE and ‘EN AVANT LA VIE’, a French association that fights against glioma., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), and Bernardo, Elizabeth
Subjects: Cancer Research, RNA, Untranslated, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell free, Drug resistance, Biology, Circulating Tumor DNA, Epigenesis, Genetic, cfc-DNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Blood circulating, Neoplasms, Biomarkers, Tumor, Genetics, Extracellular, medicine, Humans, cancer, Epigenetics, Analysis method, 030304 developmental biology, 0303 health sciences, epigenetics, biomarkers, Cancer, DNA Methylation, cfc-ncRNA, medicine.disease, cfc-nucleosomes, Nucleosomes, 3. Good health, Histone Code, 030220 oncology & carcinogenesis, Cancer research, Cell-Free Nucleic Acids, Intracellular
Abstract: International audience; Cancer numbers increasing, cases heterogeneity and the drug resistance emergence have pushed scientists to search for innovative solutions for patients and epimutations can be one. Methylated DNA, modified nucleosomes and noncoding RNAs are found in all cells, including tumor cells. They are intracellular actors but also have intercellular communication roles, being released in extracellular environment and in different body fluids. Here, we reviewed current literature on the use of these blood circulating epimarks in cancer monitoring. What stands out is that epimarkers must be considered as 'real time' images of the tumor, and can be isolated without invasive methods. In the future, the real challenge lies in the development of specific, sensitive, fast and clinically applicable detection and analysis methods of epimarkers.
Published: 2020

31. Epigenetic protein complexes: the adequate candidates for the use of a new generation of epidrugs in personalized and precision medicine in cancer

Author: Laurent Bretaudeau, Mathilde Cheray, Pierre-François Cartron, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Epigénétique - Santé - AgroAlimentaire - Végétal - Mer - Environnement - Nutrition [Nantes] (EpiSAVMEN), Consortium de la Recherche en Epigénétique de la Région Pays de la Loire [Nantes], LabEX IGO Immunothérapie Grand Ouest, Niches & Epigenetics of Tumors Network [Nantes] (Cancéropôle Grand Ouest), Toxicology Unit [Stockholm, Sweden] (Institute of Environmental Medicine), Karolinska Institutet [Stockholm], LB4 Biotech [Nantes, France], Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Nantes Université (Nantes Univ)
Subjects: 0301 basic medicine, Cancer Research, high resolution DNA methylation, (epigenetic player/protein-X disruptor), [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, protein–protein interactions, Biology, Bioinformatics, Epigenesis, Genetic, Protein–protein interaction, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Genetics, medicine, Humans, high selective drug, Epigenetics, epidrugs, Precision Medicine, epigenetics, business.industry, Cancer, personalized medicine, DNA Methylation, Precision medicine, medicine.disease, Response to treatment, 3. Good health, DNMT inhibitors, 030104 developmental biology, Mechanism of action, Drug development, Multiprotein Complexes, 030220 oncology & carcinogenesis, Personalized medicine, medicine.symptom, business
Abstract: International audience; Until recently, drug development in oncology was focused on treating most patients for a specific cancer type without taking in account the heterogeneity between these patients in term of response to treatment. Therefore, this type of broad treatment approach excludes the treatment of patient not responding to disease-specific common drugs. In this review, we focus on the different types of epigenetic drugs currently used as DNA methylation inhibitor agents and their limits in patient care due to their lack of specificity. We also highlight the emergence of a new type of epidrug with higher target specificity due to their original mechanism of action: the disruption of protein complexes involved in the epigenetic modifications.
Published: 2020

32. hnRNP-A1 binds to the IRES of MELOE-1 antigen to promote its translation in stressed melanoma cells

Author: Charpentier, Maud, Dupré, Emilie, Fortun, Agnès, Briand, Floriane, Maillasson, Mike, Com, Emmanuelle, Pineau, Charles, Labarrière, Nathalie, Rabu, Catherine, Lang, François, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Plateforme IMPACT Nantes (CRCINA-IMPACT), Institut de recherche en santé, environnement et travail (Irset), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Proteomics Core Facility (Protim), Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®, Ligue Contre le Cancer, Conseil Régional de Bretagne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), 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 ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®, and Jonchère, Laurent
Subjects: [SDV] Life Sciences [q-bio], tumor antigens, IRES, [SDV]Life Sciences [q-bio], long non coding RNA, melanoma, ER stress, ITAF
Abstract: International audience; The major challenge in antigen-specific immunotherapy of cancer is to select the most relevant tumor antigens to target. To this aim, understanding their mode of expression by tumor cells is critical. We previously identified a melanoma-specific antigen, melanoma-overexpressed antigen 1 (MELOE-1) - coded for by a long non-coding RNA - whose internal ribosomal entry sequence (IRES)-dependent translation is restricted to tumor cells. This restricted expression is associated with the presence of a broad specific T cell repertoire that is involved in tumor immunosurveillance in melanoma patients. In the present work, we explored the translation control of MELOE-1 and provide evidence that heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) binds to the MELOE-1 IRES and acts as an IRES trans-activating factor (ITAF) to promote the translation of MELOE-1 in melanoma cells. In addition, we showed that endoplasmic reticulum (ER) stress induced by thapsigargin, which promotes hnRNP-A1 cytoplasmic translocation, enhances MELOE-1 translation and recognition of melanoma cells by a MELOE-1-specific T cell clone. These findings suggest that pharmacological stimulation of stress pathways may enhance the efficacy of immunotherapies targeting stress-induced tumor antigens such as MELOE-1.
Published: 2022

33. A partially demineralized allogeneic bone graft: in vitro osteogenic potential and preclinical evaluation in two different intramembranous bone healing models

Author: Pierre Corre, Christophe Blanquart, Arnaud Paré, Julie Lesoeur, Pierre Weiss, Caroline Vignes, Pierre Tournier, Joëlle Veziers, Thibaut Blondy, Alexis Gaudin, Aymeric Maltezeanu, Valérie Geoffroy, Manon André, Ana G. Barbeito, Jérôme Guicheux, Raphaël Bardonnet, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), BioBank SAS [Lieusaint, France], Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Jehan, Frederic
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Cell biology, Bone Regeneration, medicine.medical_treatment, Science, Immunology, Bone Matrix, Calvaria, Bone healing, Stem cells, Bone grafting, Article, Monocytes, 03 medical and health sciences, 0302 clinical medicine, Medical research, In vivo, Osteogenesis, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Bone regeneration, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Wound Healing, Multidisciplinary, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Mesenchymal stem cell, Bone Cements, Mesenchymal Stem Cells, 030206 dentistry, In vitro, Rats, 030104 developmental biology, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rats, Inbred Lew, Intramembranous ossification, Bone Substitutes, Medicine, business
Abstract: In skeletal surgical procedures, bone regeneration in irregular and hard-to-reach areas may present clinical challenges. In order to overcome the limitations of traditional autologous bone grafts and bone substitutes, an extrudable and easy-to-handle innovative partially demineralized allogenic bone graft in the form of a paste has been developed. In this study, the regenerative potential of this paste was assessed and compared to its clinically used precursor form allogenic bone particles. Compared to the particular bone graft, the bone paste allowed better attachment of human mesenchymal stromal cells and their commitment towards the osteoblastic lineage, and it induced a pro-regenerative phenotype of human monocytes/macrophages. The bone paste also supported bone healing in vivo in a guide bone regeneration model and, more interestingly, exhibited a substantial bone-forming ability when implanted in a critical-size defect model in rat calvaria. Thus, these findings indicate that this novel partially demineralized allogeneic bone paste that combines substantial bone healing properties and rapid and ease-of-use may be a promising alternative to allogeneic bone grafts for bone regeneration in several clinical contexts of oral and maxillofacial bone grafting.
Published: 2021

34. The von Willebrand Factor stamps Plasmatic Extracellular Vesicles from Glioblastoma Patients

Author: Emmanuel Jouglar, Gwennan André-Grégoire, Quentin Sabbagh, Jean-Sebastien Frenel, Nicolas Bidère, Carolina Alves-Nicolau, Aurélien Dupont, Laetitia Guevel, Julie Gavard, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCI2NA / Eq 6), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Gavard, Julie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Male, Cell biology, Proteome, Science, [SDV]Life Sciences [q-bio], Tumor burden, Extracellular vesicles, Article, Extracellular Vesicles, 03 medical and health sciences, 0302 clinical medicine, Individual health, Von Willebrand factor, von Willebrand Factor, Biomarkers, Tumor, Tumor Microenvironment, Humans, Medicine, Aged, Cancer, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Tumor microenvironment, Multidisciplinary, biology, Brain Neoplasms, business.industry, Extracellular vesicle, Middle Aged, Prognosis, medicine.disease, [SDV] Life Sciences [q-bio], Case-Control Studies, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, Glioblastoma, business, Homeostasis, Follow-Up Studies
Abstract: Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.
Published: 2021

35. Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma

Author: Ophelie Renoult, François Paris, Gabriel Alzial, Claire Pecqueur, Anne Clavreul, Catherine Gratas, Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre hospitalier universitaire de Nantes (CHU Nantes), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Cancer Research, Cell biology, Mutant, Brain tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, medicine, Molecular Biology, neoplasms, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Cancer stem cells, Wild type, medicine.disease, 3. Good health, CNS cancer, Enzyme, Isocitrate dehydrogenase, chemistry, Tumor progression, 030220 oncology & carcinogenesis, Cancer research, Good prognosis, Glioblastoma
Abstract: Brain tumors actively reprogram their cellular metabolism to survive and proliferate, thus offering potential therapeutic opportunities. Over the past decade, extensive research has been done on mutant IDH enzymes as markers of good prognosis in glioblastoma, a highly aggressive brain tumor in adults with dismal prognosis. Yet, 95% of glioblastoma are IDH wild-type. Here, we review current knowledge about IDH wild-type enzymes and their putative role in mechanisms driving tumor progression. After a brief overview on tumor metabolic adaptation, we present the diverse metabolic function of IDH enzymes and their roles in glioblastoma initiation, progression and response to treatments. Finally, we will discuss wild-type IDH targeting in primary glioblastoma.
Published: 2021

36. Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies

Author: Stéphane J.C. Mancini, Karl Balabanian, Isabelle Corre, Julie Gavard, Gwendal Lazennec, Marie-Caroline Le Bousse-Kerdilès, Fawzia Louache, Véronique Maguer-Satta, Nathalie M. Mazure, Fatima Mechta-Grigoriou, Jean-François Peyron, Valérie Trichet, Olivier Herault, Microenvironnement des niches tumorales [UNIV Tours] (CNRS GDR 3697 MicroNiT), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang Bretagne, EFS, Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Carnot, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Intégré d'Oncologie Nantes/Angers, Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Interactions cellules souches-niches : physiologie, tumeurs et réparation tissulaire, Service de Santé des Armées-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), 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)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Université de Tours (UT)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CNRS GDR 3697 MicroNiT, Centre National de la Recherche Scientifique (CNRS), CNRS UMR9005, Université de Rennes (UR)-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 ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCI2NA / Eq 6), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), 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), Université de Tours (UT), Lazennec, Gwendal, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), and Université de Tours (UT)-Université de Tours (UT)
Subjects: Stromal cell, endothelial plasticity, Angiogenesis, Mini Review, [SDV]Life Sciences [q-bio], Niche, Immunology, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, cytokines and chemokines, Biology, cancer-associated fibroblasts (CAFs), 03 medical and health sciences, angiogenesis, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer-Associated Fibroblasts, Cancer stem cell, Neoplasms, medicine, Tumor Microenvironment, Immunology and Allergy, Animals, Humans, 030304 developmental biology, 0303 health sciences, Neovascularization, Pathologic, energy/oxidative metabolism, Mesenchymal stem cell, mitochondrial transfer, Mesenchymal Stem Cells, RC581-607, microenvironment, 3. Good health, Haematopoiesis, medicine.anatomical_structure, mesenchymal stem/stromal cells (MSCs), 030220 oncology & carcinogenesis, Cancer research, Cytokines, Bone marrow, Endothelium, Vascular, Immunologic diseases. Allergy
Abstract: International audience; Knowledge about the hematopoietic niche has evolved considerably in recent years, in particular through in vitro analyzes, mouse models and the use of xenografts. Its complexity in the human bone marrow, in particular in a context of hematological malignancy, is more difficult to decipher by these strategies and could benefit from the knowledge acquired on the niches of solid tumors. Indeed, some common features can be suspected, since the bone marrow is a frequent site of solid tumor metastases. Recent research on solid tumors has provided very interesting information on the interactions between tumoral cells and their microenvironment, composed notably of mesenchymal, endothelial and immune cells. This review thus focuses on recent discoveries on tumor niches that could help in understanding hematopoietic niches, with special attention to 4 particular points: i) the heterogeneity of carcinoma/cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs), ii) niche cytokines and chemokines, iii) the energy/oxidative metabolism and communication, especially mitochondrial transfer, and iv) the vascular niche through angiogenesis and endothelial plasticity. The elements highlighted in this review identify actors and/or pathways of the microenvironment that are broadly and often involved in cancer processes. This would open avenues for innovative therapeutic opportunities targeting not only cancer stem cells but also their regulatory tumor niche(s), in order to improve current antitumor therapies.
Published: 2021

37. Functional pre-therapeutic evaluation by genome editing of variants of uncertain significance of essential tumor suppressor genes

Author: Jean-Sébastien Frenel, Alain Morel, Amandine Billaud, Christophe Passot, Mario Campone, Paule Augereau, Louise-Marie Chevalier, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Functional testing, QH426-470, law.invention, 0302 clinical medicine, Genome editing, law, Genes, Tumor Suppressor, Variants of uncertain significance, Genetics (clinical), Cancer, Gene Editing, Ovarian Neoplasms, 0303 health sciences, BRCA1 Protein, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, POLE, RNA splicing, PARP inhibitor, Medicine, Molecular Medicine, Female, Systems biology, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Poly(ADP-ribose) Polymerase Inhibitors, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, Molecular Biology, Gene, Retrospective Studies, 030304 developmental biology, BRCA2 Protein, Research, Genetic Variation, BRCA1, BRCA2, Human genetics, Theranostic, Suppressor, CRISPR-Cas Systems
Abstract: BackgroundTargeted therapies in oncology are promising but variants of uncertain significance (VUS) limit their use for clinical management and necessitate functional testing in vitro. UsingBRCA1andBRCA2variants, which have consequences on PARP inhibitor sensitivity, andPOLEvariants, potential biomarkers of immunotherapy response, we developed a rapid functional assay based on CRISPR-Cas9 genome editing to determine the functional consequences of these variants having potentially direct implications on patients’ access to targeted therapies.MethodsWe first evaluated the functional impact of 26BRCA1and 7BRCA2variants by editing and comparing NGS results between the variant of interest and a silent control variant. Ten of these variants had already been classified as benign or pathogenic and were used as controls. Finally, we extended this method to the characterization ofPOLEVUS.ResultsFor the 23 variants that were unclassified or for which conflicting interpretations had been reported, 15 were classified as functionally normal and 6 as functionally abnormal. Another two variants were found to have intermediate consequences, both with potential impacts on splicing. We then compared these scores to the patients’ responses to PARP inhibitors when possible. Finally, to prove the application of our method to the classification of variants from other tumor suppressor genes, we exemplified with threePOLEVUS. Among them, two were classified with an intermediate functional impact and one was functionally abnormal. Eventually, fourPOLEvariants previously classified in databases were also evaluated. However, we found evidence of a discordance with the classification, variant p.Leu424Val being found here functionally normal.ConclusionsOur new rapid functional assay can be used to characterize the functional implication ofBRCA1andBRCA2variants, giving patients whose variants were evaluated as functionally abnormal access to PARP inhibitor treatment. Retrospective analysis of patients’ responses to PARP inhibitors, where accessible, was consistent with our functional score evaluation and confirmed the accuracy of our protocol. This method could potentially be extended to the classification of VUS from all essential tumor suppressor genes and can be performed within a timeframe compatible with clinical applications, thereby having a direct theranostic impact.
Published: 2021

38. Voluntary Wheel Running Does Not Enhance Radiotherapy Efficiency in a Preclinical Model of Prostate Cancer: The Importance of Physical Activity Modalities?

Author: Suzanne, Dufresne, Cindy, Richard, Arthur, Dieumegard, Luz, Orfila, Gregory, Delpon, Sophie, Chiavassa, Brice, Martin, Laurent, Rouvière, Jean-Michel, Escoffre, Edward, Oujagir, Baudouin, Denis de Senneville, Ayache, Bouakaz, Nathalie, Rioux-Leclercq, Vincent, Potiron, Amélie, Rébillard, Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Modélisation Mathématique pour l'Oncologie (MONC), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Escoffre, Jean-Michel, Laboratoire Mouvement Sport Santé (M2S), Université de Rennes (UR)-École normale supérieure - Rennes (ENS Rennes)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Institut de Recherche Mathématique de Rennes (IRMAR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest, 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), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], 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 (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 de Biologie des Cancers et de Théranostic (LabCT), UNICANCER-UNICANCER, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), This research was funded by la Ligue Contre le Cancer Comité Départemental 35, Comité Départemental 72, Comité Départemental 85, and the Fondation ARC., École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC René Gauducheau, AGROCAMPUS OUEST, 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)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), UMR 1253 IBrain Imagerie & Cerveau Equipe 3 'Imagerie, Biomarqueurs & Thérapie' (IBT), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Chimie de la Matière Condensée de Bordeaux (ICMCB), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), 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 ), ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: exercise, vascularization, [SDV.CAN] Life Sciences [q-bio]/Cancer, proliferation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, physical activity, [SDV.CAN]Life Sciences [q-bio]/Cancer, prostate cancer, radiation therapy, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, RC254-282, Article, radiotherapy
Abstract: Simple Summary Physical activity is increasingly incorporated in cancer patient health care as a strategy to improve survival outcomes. However, its effects on treatment efficiency remains unclear. The aim of our preclinical study is to evaluate whether access to a running wheel could enhance the response to radiotherapy in mice with prostate cancer. We observed that voluntary wheel running (VWR) did not slow down tumor growth but appeared to modulate some parameters related to tumor perfusion. However, this did not result in enhanced response to radiotherapy. To investigate whether the lack of benefits on tumor growth observed with VWR could be attributed to the choice of physical activity modality, we conducted additional experiments comparing the effects of treadmill running versus VWR in two different preclinical models of prostate cancer. Only treadmill running was able to slow down tumor growth. Hence, the anti-cancer effects of physical activity seem dependent on its modalities. Abstract Physical activity is increasingly recognized as a strategy able to improve cancer patient outcome, and its potential to enhance treatment response is promising, despite being unclear. In our study we used a preclinical model of prostate cancer to investigate whether voluntary wheel running (VWR) could improve tumor perfusion and enhance radiotherapy (RT) efficiency. Nude athymic mice were injected with PC-3 cancer cells and either remained inactive or were housed with running wheels. Apparent microbubble transport was enhanced with VWR, which we hypothesized could improve the RT response. When repeating the experiments and adding RT, however, we observed that VWR did not influence RT efficiency. These findings contrasted with previous results and prompted us to evaluate if the lack of effects observed on tumor growth could be attributable to the physical activity modality used. Using PC-3 and PPC-1 xenografts, we randomized mice to either inactive controls, VWR, or treadmill running (TR). In both models, TR (but not VWR) slowed down tumor growth, suggesting that the anti-cancer effects of physical activity are dependent on its modalities. Providing a better understanding of which activity type should be recommended to cancer patients thus appears essential to improve treatment outcomes.
Published: 2021

39. Microvalve bioprinting as a biofabrication tool to decipher tumor and endothelial cell crosstalk: Application to a simplified glioblastoma model

Author: Chantal Medina, Baptiste Henri, Hugo Oliveira, Jean-Christophe Fricain, Marie-Laure Stachowicz, François Paris, Nathalie Dusserre, Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Accélérateur de Recherche Technologique BioPrint [Bordeaux] (ART BioPrint/U1026 Inserm/UBS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Unité Mixte de Génomique du Cancer [ICO, Saint Herblain] (Site René Gauducheau), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER-Hôpital Guillaume-et-René-Laennec [Saint-Herblain]-Hôpital Laennec, Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0303 health sciences, Tumor microenvironment, Radiotherapy, Chemistry, Cell growth, Endothelial cells, Biomedical Engineering, Crosstalk Oxidative stress, Glioblastoma cells, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Computer Science Applications, Cell biology, Endothelial stem cell, Extracellular matrix, 03 medical and health sciences, Crosstalk (biology), 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, Cancer cell, Tumor Expansion, Microvalve-based bioprinting, 030304 developmental biology, Biotechnology
Abstract: International audience; Bioprinting technologies are powerful new bioengineering tools that can spatially reproduce multiple microenvironmental cues in a highly controlled, tunable, and precise manner. In this study, microvalve bioprinting technology was successfully used to print in close proximity endothelial and tumor cells at higher concentrations than previously thought possible, while preserving their viability. We propose that the resulting multicellular models, bioprinted in a controlled extracellular matrix microenvironment, are well-suited to study endothelial and cancer cell crosstalk within a cancer niche. As proof of concept, microvalve bioprinting was applied to the bioengineering of a simplified glioblastoma model in which biological processes involved in tumor expansion, such as tumor cell invasion patterns, cell proliferation, and senescence could be easily visualized and quantified. In this model, U251 glioblastoma cells and primary human umbilical vein endothelial cells (HUVECs) exhibited good printability and high viability after printing. U251 cells formed physiologically relevant clusters and invasion margins, while HUVECs generated vascular-like networks when primary fibroblasts were added to the model. An oxidative stress mimicking the one encountered within a tumor microenvironment during radiotherapy or genotoxic chemotherapy was shown to both diminish endothelial cells proliferation and to increase their senescence. Results also suggested that stressed glioblastoma cells may alter normal endothelial cell proliferation but not impact their senescence. This data demonstrates the potential of microvalve bioprinting to fabricate in vitro models that can help decipher endothelial and tumor cell crosstalk, within controlled and modulable microenvironments, and can then be used to address critical questions in the context of cancer recurrence.
Published: 2021

40. The Necroptosis Effector MLKL drives Small Extracellular Vesicle Release and Tumour Growth in Glioblastoma

Author: Gwennan André-Grégoire, Kathryn A Jacobs, Kilian Trillet, Ignacio Busnelli, Tiphaine Douanne, An Thys, Cyndie Ballu, Jacky G. Goetz, Vincent Hyenne, Clément Maghe, Julie Gavard, Nicolas Bidère, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Gavard, Julie, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0303 health sciences, Programmed cell death, Endosome, Chemistry, Effector, Necroptosis, [SDV]Life Sciences [q-bio], Regulator, Extracellular vesicle, In vitro, Cell biology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Biogenesis, 030304 developmental biology
Abstract: Extracellular vesicles (EVs) are lipid-based nano-sized particles that convey biological material from donor to recipient cells. They play key roles in tumour progression, notably in glioblastoma in which the subpopulation of Glioblastoma Stem-like Cells (GSCs) might represent a meaningful source of tumour-derived EVs. However, the mechanisms involved in the production and release of EVs by GSCs are still poorly understood. Here, we report the identification of MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of small EVs from GSCs. The targeting of MLKL by genetic, protein depletion or chemical approaches alters endosomal trafficking and EV release and reduces GSC expansion in vitro. This function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL triggers a reduction of both the tumour burden in xenografted mice and of the level of plasmatic EVs. This work reinforces the idea of a non-deadly role for MLKL in endosomal trafficking and suggests that interfering with EV biogenesis is a promising therapeutic option to sensitize glioblastoma cells to death.
Published: 2021

41. Targeted alpha particle therapy remodels the tumor microenvironment and improves efficacy of immunotherapy

Author: E Donnadieu, Alfred Morgenstern, Nicolas Chouin, Yannick Guilloux, Joëlle Gaschet, Marisa Capitao, Sébastien Gouard, Justine Perrin, Frank Bruchertseifer, M Allard, Michel Chérel, Cédric Louvet, Séverine Marionneau-Lambot, Nuclear Oncology (CRCINA-ÉQUIPE 13), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), 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), European Commission - Joint Research Centre [Karlsruhe] (JRC), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Bernardo, Elizabeth
Subjects: Cancer Research, Adoptive cell transfer, Chemokine, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Tumor Microenvironment, Medicine, Animals, Radiology, Nuclear Medicine and imaging, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Radiation, biology, business.industry, Immunotherapy, Alpha Particles, Cytokine, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Antibody, business, Ex vivo
Abstract: The tumor microenvironment (TME) can severely impair immunotherapy efficacy by repressing the immune system. In a multiple myeloma (MM) murine model, we investigated the impact of targeted alpha particle therapy (TAT) on the immune TME. TAT was combined with an adoptive cell transfer of CD8 T cells (ACT), and the mechanisms of action of this combination were assessed at the tumor site.This combination treatment was conducted in a syngeneic MM murine model grafted subcutaneously. TAT was delivered by intravenous injection of a bismuth-213 radiolabeled anti-CD138 antibody. To strengthen antitumor immune response, TAT was combined with an ACT of tumor-specific CD8+ OT-1 T-cells. The tumors were collected and the immune TME analyzed by flow cytometry, immunohistochemistry, and ex vivo T-cell motility assay on tumor slices. The chemokine and cytokine productions were also assessed by quantitative reverse transcription polymerase chain reaction.Tumor-specific CD8+ OT-1 T cells infiltrated the tumors after ACT. However, only treatment with TAT resulted in regulatory CD4 T-cell drop and transient increased production of interleukin-2, CCL-5, and interferon-γ within the tumor. Moreover, OT-1 T-cell recruitment and motility were increased on tumor slices from TAT-treated mice, as observed via ex vivo time lapse, contributing to a more homogeneous distribution of OT-1 T cells in the tumor. Subsequently, the tumor cells increased PD-L1 expression, antitumor cytokine production decreased, and OT-1 T-cells overexpressed exhaustion markers, suggesting an exhaustion of the immune response.Combining TAT and ACT seems to transiently remodel the cold TME, improving ACT efficiency. The immune response then leads to the establishment of other tumor cell resistance mechanisms.
Published: 2021

42. Interaction Between Modern Radiotherapy and Immunotherapy for Metastatic Prostate Cancer

Author: Luc Ollivier, Maureen Labbé, Delphine Fradin, Vincent Potiron, Stéphane Supiot, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Région Pays de Loire : EpiSAVMENLigue Contre le Cancer : Comités 16, 22, 29, 35, 44, 49 and 56Cancéropole Grand Ouest : CGO Structurant 2018 ExomiRTransports LoizeauDe Graet consultingAstra- ZenecaMs. Suzanne Saulnier, Fradin, Delphine, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Cancer Research, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Disease, Metastasis, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunogenic tumor, metastasis, Medicine, RC254-282, radiotherapy, 030304 developmental biology, 0303 health sciences, business.industry, treatment combination, Potent inducer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, Immunotherapy, prostate cancer, medicine.disease, 3. Good health, Radiation therapy, Oncology, 030220 oncology & carcinogenesis, Cancer research, immunotherapy, business
Abstract: International audience; Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. In recent decades, the development of immunotherapies has resulted in great promise to cure metastatic disease. However, prostate cancer has failed to show any significant response, presumably due to its immunosuppressive microenvironment. There is therefore growing interest in combining immunotherapy with other therapies able to relieve the immunosuppressive microenvironment. Radiation therapy remains the mainstay treatment for prostate cancer patients, is known to exhibit immunomodulatory effects, depending on the dose, and is a potent inducer of immunogenic tumor cell death. Optimal doses of radiotherapy are thus expected to unleash the full potential of immunotherapy, improving primary target destruction with further hope of inducing immune-cell-mediated elimination of metastases at distance from the irradiated site. In this review, we summarize the current knowledge on both the tumor immune microenvironment in prostate cancer and the effects of radiotherapy on it, as well as on the use of immunotherapy. In addition, we discuss the utility to combine immunotherapy and radiotherapy to treat oligometastatic metastatic prostate cancer.
Published: 2021

43. U-Net 3D par patchs et régularisation spatiale avec CRF pour l'extraction de cerveau sur IRM de porcelet

Author: COUPEAU, Patty, Fasquel, Jean-Baptiste, Mazerand, Edouard, Montero-Menei, Claudia, Menei, Philippe, Dinomais, Mickael, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de neurochirurgie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre National de la Recherche Scientifique [CNRS], Sciencesconf.org, CCSD, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Net, IRM du porcelet, [INFO.INFO-CV] Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Extraction de cerveau, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], [INFO]Computer Science [cs], CRF, [INFO] Computer Science [cs], Patchs, Paralysie cérébrale
Abstract: International audience; Du fait de ses similarités morphologiques avec le cerveau de l’enfant, le porcelet est un modèle prisé. Il est notamment utilisé dans l’étude de la paralysie cérébrale afin de quantifier l’impact de la lésion précoce sur le neurodéveloppement en particulier sur des IRM que nous considérons dans ces travaux. Pour disposer d’une évaluation objective, il est nécessaire de développer des algorithmes automatiques de segmentation des différentes structures et tissus . L’étape préliminaire cruciale consiste à extraire le cerveau. Nous proposons ici une méthode d’extraction entièrement automatique du cerveau du porcelet combinant un réseau U-Net 3D par patchs et l’utilisation de champs aléatoires conditionnels (CRF) pour la régularisation spatiale finale. Notre méthode est entraînée et évaluée à partir de 15 IRM T1 de porcelets âgés de 15 jours et comparée à l’outil BET, standard pour le cerveau humain. L’influence de la taille et de la distribution des patchs utilisés lors de l’apprentissage profond est étudiée tout comme les bénéfices de la régularisation spatiale. Les premiers résultats montrent que notre approche est prometteuse en terme de DICE moyen (0.954) et de distance d’Hausdorff (7.73), surpassant les performances de BET (DICE de 0.754 et distance d’Hausdorff de 24.31)
Published: 2021

44. Highlight selection of radiochemistry and radiopharmacy developments by editorial board

Author: Jun Toyohara, Mohammed Al-Qahtani, Ya-Yao Huang, Emiliano Cazzola, Sergio Todde, Shozo Furumoto, Renata Mikolajczak, Clemens Decristoforo, Nic Gillings, Min Yang, Raymond Reilly, Adriano Duatti, Antonia Denkova, Ralf Schirrmacher, Giuseppe Carlucci, Yann Seimbille, Zhaofei Liu, Beverley Ellis, Bart T. Cornelissen, Klaus Kopka, Emerson Bernardes, University of Coimbra [Portugal] (UC), University Medical Center Groningen [Groningen] (UMCG), IRCCS Sacro Cuore Don Calabria Hospital [Vérone, Italie], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Technische Universiteit Delft (TU Delft), University of Wisconsin-Madison, Nuclear Oncology (CRCINA-ÉQUIPE 13), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, International Atomic Energy Agency [Vienna] (IAEA), Paul Scherrer Institute (PSI), Radioisotope Centre POLATOM [Otwock, Pologne] (POLATOM), Helmholtz-Zentrum Dresden-Rossendorf (HZDR), DDRC SRL Diagnostics [Kerala, India] (Molecular Group of Companies), University of Toronto, Stellenbosch University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Groningen [Groningen], National Institutes of Health [Bethesda] (NIH), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Radiopharmaceutical Sciences, R895-920, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chemistry, Medicinal, Review, RM1-950, RADIONUCLIDE THERAPY, Analytical Chemistry, Medical physics. Medical radiology. Nuclear medicine, Highlight Articles, [SDV.CAN] Life Sciences [q-bio]/Cancer, Radiopharmacy, Chemistry, Inorganic & Nuclear, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Highlight articles, Pharmacology & Pharmacy, Pharmacology, Science & Technology, Radiochemistry, Radiology, Nuclear Medicine & Medical Imaging, Chemistry, Trends in radiopharmaceutical sciences, PET, Nuclear medicine, ANTIBODIES, Physical Sciences, Trends in Radiopharmaceutical Sciences, Highlight selection, Therapeutics. Pharmacology, Nuclear Medicine, Life Sciences & Biomedicine
Abstract: Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field, and include new PET-labelling methods for 11C and 18F, the importance of choosing the proper chelator for a given radioactive metal ion, implications of total body PET on use of radiopharmaceuticals, legislation issues and radionuclide therapy including the emerging role of 161Tb.
Published: 2021

45. Activation Status Dictates the Function of Unlicensed Natural Killer Cells

Author: Aguilar, Ethan, Dunai, Cordelia, J Judge, Sean, Elston Zamora, Anthony, T Khuat, Lam, V Vick, Logan, P Collins, Craig, M Stoffel, Kevin, Alvarez, Maite, Barao, Isabel, S Miller, Jeffrey, Blazar, Bruce Robert, Chevallier, Patrice, Retiere, Christelle, J Canter, Robert, J Murphy, William, UC Davis School Of Medicine [Sacramento, CA, USA] (UC-DSOM), University of California [Davis] (UC Davis), University of California (UC), Medical College of Wisconsin [Milwaukee] (MCW), Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), EFS, RETIERE, Christelle, University of California, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract: International audience; Natural Killer (NK) cells are involved in innate defense against viral infection and cancer. NK cells can be divided into subsets based on the ability of different receptors to bind to major histocompatibility (MHC) class I molecules resulting in differential responses upon activation in a process called "licensing" or "arming". NK cells expressing receptors that bind self-MHC are considered licensed due to augmented effector lytic function capability compared to unlicensed subsets. However, we demonstrated unlicensed NK subsets instead positively regulate the adaptive T cell response during viral infections due to localization and cytokine production. We demonstrate here that the differential effects of the two types of NK subsets is contingent on the environment using viral infection and hematopoietic stem cell transplantation (HSCT) models. Infection of mice with high-dose (HD) MCMV leads to a loss of licensing-associated differences as compared to mice with low-dose infection, as the unlicensed NK subset no longer localized in lymph nodes (LN), but instead remained at the site of infection. Similarly, the patterns observed during HD infection paralleled with the phenotypes of both human and mouse NK cells in a HSCT setting where NK cells exhibit an activated phenotype. However, in contrast to effects of subset depletion in T-replete models, the licensed NK cell subsets still dominated anti-viral responses post-HSCT. Overall, our results highlight the intricate tuning of the NK cells and how it impacts overall immune responses with regard to licensing patterns, as it is dependent on the level of stimulation and their activation status.
Published: 2021

46. Chromatin accessibility combined with enhancer clusters activation mediates heterogeneous response to dexamethasone in myeloma cells

Author: Loïc Campion, Catherine Guérin-Charbonnel, Stephane Minvielle, Victor Gaborit, Jennifer Derrien, Jérémie Bourdon, P. Moreau, Carl Herrmann, Nathalie Roi, Jonathan Cruard, Elise Douillard, Florence Magrangeas, Magali Devic, Jean-Baptiste Alberge, Frank Westermann, Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire des Sciences du Numérique de Nantes (LS2N), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Heidelberg, Medical Faculty, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), and Bernardo, Elizabeth
Subjects: 0303 health sciences, Chemistry, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, 3. Good health, Cell biology, Chromatin, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, [SDV.CAN] Life Sciences [q-bio]/Cancer, Regulatory sequence, medicine, Binding site, Enhancer, Receptor, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics
Abstract: Glucocorticoids (GC) effects occur through binding to the GC receptor (GR) which, once translocated to the nucleus, binds to GC response elements (GREs) to activate or repress target genes. Among GCs, dexamethasone (Dex) is widely used in treatment of multiple myeloma (MM), mainly in combination regimens. However, despite a definite benefit, all patients relapse. Moreover, while GC efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive.To determine the functional role of GR binding in myeloma cells, we generated bulk and single cell multi-omic data and high-resolution contact maps of active enhancers and target genes. We show that a minority (6%) of GR binding sites are associated with enhancer activity gains and increased interaction loops. We find that enhancers contribute to regulate gene activity through combinatorial assembly of large stretches of enhancers and/or enhancer cliques. Furthermore, one enhancer, proximal to GR-responsive genes, is predominantly associated with increased chromatin accessibility and higher H3K27ac occupancy. Finally, we show that Dex exposure leads to co-accessibility changes between predominant enhancer and other regulatory regions of the interaction network. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity. As consequences, BIM critical for GR-induced apoptosis and CXCR4 protective from chemotherapy-induced apoptosis are rather upregulated in different cells.In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.
Published: 2021

47. The glycoprotein GP130 governs the surface presentation of the G protein-coupled receptor APLNR

Author: Julie Gavard, Kathryn A Jacobs, Jonathan Cruard, Nicolas Bidère, Clément Maghe, Stephane Minvielle, Kilian Trillet, An Thys, Gwennan André-Grégoire, Guillaume Montagnac, Sara Gonzalez Diest, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Intégré d'Oncologie Nantes/Angers, Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Gavard, Julie
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], APELIN, ANGIOGENESIS, ACTIVATION, 0302 clinical medicine, Cytokine Receptor gp130, Receptor, Apelin Receptors, ADP-Ribosylation Factors, Brain Neoplasms, GTPase-Activating Proteins, 3. Good health, Apelin, Cell biology, FAMILY, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, Neoplastic Stem Cells, GROWTH, Female, Life Sciences & Biomedicine, Signal Transduction, endocrine system, Biology, 03 medical and health sciences, Stroma, Cancer stem cell, Spheroids, Cellular, GAPS, medicine, Humans, PROMOTES TUMORIGENESIS, Transport Vesicles, G protein-coupled receptor, Aged, Cell Proliferation, Science & Technology, GLIOBLASTOMA STEM-CELLS, IDENTIFICATION, fungi, Cancer, Endothelial Cells, Biological Transport, Mesenchymal Stem Cells, Cell Biology, Glycoprotein 130, medicine.disease, Survival Analysis, 030104 developmental biology, HEK293 Cells, GTPASES, Glioblastoma, 030217 neurology & neurosurgery, Ex vivo
Abstract: Glioblastoma is one of the most lethal forms of adult cancer, with a median survival of ∼15 mo. Targeting glioblastoma stem-like cells (GSCs) at the origin of tumor formation and relapse may prove beneficial. In situ, GSCs are nested within the vascular bed in tight interaction with brain endothelial cells, which positively control their expansion. Because GSCs are notably addicted to apelin (APLN), sourced from the surrounding endothelial stroma, the APLN/APLNR nexus has emerged as a druggable network. However, how this signaling axis operates in gliomagenesis remains underestimated. Here, we find that the glycoprotein GP130 interacts with APLNR at the plasma membrane of GSCs and arbitrates its availability at the surface via ELMOD1, which may further impact on ARF-mediated endovesicular trafficking. From a functional standpoint, interfering with GP130 thwarts APLNR-mediated self-renewal of GSCs ex vivo. Thus, GP130 emerges as an unexpected cicerone to the G protein-coupled APLN receptor, opening new therapeutic perspectives toward the targeting of cancer stem cells. ispartof: JOURNAL OF CELL BIOLOGY vol:220 issue:9 ispartof: location:United States status: published
Published: 2021

48. Safety and antibody response after one and/or two doses of BNT162b2 Anti‐SARS‐CoV‐2 mRNA vaccine in patients treated by CAR T cells therapy

Author: Anne Lok, Pierre Peterlin, Viviane Dubruille, Steven Le Gouill, Sophie Vanthygem, Marianne Coste-Burel, Patrice Chevallier, Benoit Tessoulin, Berthe-Marie Imbert, Marie C. Béné, Nicolas Blin, Philippe Moreau, Thomas Drumel, Alice Garnier, Thierry Guillaume, Amandine Le Bourgeois, Beatrice Mahe, Maxime Jullien, Thomas Gastinne, Cyrille Touzeau, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Male, Antibodies, Viral, Immunotherapy, Adoptive, Immunogenicity, Vaccine, 0302 clinical medicine, vaccine, Antineoplastic Combined Chemotherapy Protocols, Medicine, CAR‐T cells, 030212 general & internal medicine, Antigens, Viral, ComputingMilieux_MISCELLANEOUS, Receptors, Chimeric Antigen, Lymphoma, Non-Hodgkin, Vaccination, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, SARS-CoV-2 mRNA, Combined Modality Therapy, 3. Good health, 030220 oncology & carcinogenesis, Spike Glycoprotein, Coronavirus, Female, Car t cells, COVID 19, Adult, 2019-20 coronavirus outbreak, Fever, Coronavirus disease 2019 (COVID-19), CAR-T cells, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunization, Secondary, Receptors, Antigen, T-Cell, Pain, [SDV.CAN]Life Sciences [q-bio]/Cancer, SARS‐CoV‐2 mRNA, Immunocompromised Host, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Correspondence, Humans, In patient, BNT162 Vaccine, Aged, Biological Products, Messenger RNA, SARS-CoV-2, business.industry, COVID-19, Virology, Antibody response, Immunoglobulin G, BNT162b2, business
Abstract: International audience; No abstract available
Published: 2021

49. Treatment-induced shrinking of tumour aggregates: a nonlinear volume-filling chemotactic approach

Author: Luis Almeida, Lisa Oliver, Diane Peurichard, François M. Vallette, Alexandre Poulain, Gissell Estrada-Rodriguez, Universitat Politècnica de Catalunya. Departament de Matemàtiques, Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), This research was funded by the Plan Cancer/ITMO HTE (tumor heterogeneity and ecosystem) program (MoGlimaging)., Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Poulain, Alexandre, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: FOS: Physical sciences, Pattern Formation and Solitons (nlin.PS), 03 medical and health sciences, 0302 clinical medicine, [NLIN.NLIN-PS]Nonlinear Sciences [physics]/Pattern Formation and Solitons [nlin.PS], Neoplasms, Quimiotaxi, [NLIN.NLIN-PS] Nonlinear Sciences [physics]/Pattern Formation and Solitons [nlin.PS], Cell Behavior (q-bio.CB), Extracellular, Organoid, medicine, Tumor Microenvironment, Humans, [MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP], [MATH.MATH-AP] Mathematics [math]/Analysis of PDEs [math.AP], 030304 developmental biology, 0303 health sciences, Partial differential equation, Física [Àrees temàtiques de la UPC], Chemistry, Cell growth, Applied Mathematics, Physics, Chemotaxis, Aggregate (data warehouse), Volume-filling approach, Matemàtiques i estadística [Àrees temàtiques de la UPC], Stability analysis, Física, medicine.disease, Agricultural and Biological Sciences (miscellaneous), Nonlinear Sciences - Pattern Formation and Solitons, Nonlinear system, FOS: Biological sciences, Modeling and Simulation, Biophysics, Quantitative Biology - Cell Behavior, Glioblastoma, Matemàtica, 030217 neurology & neurosurgery, Mathematics
Abstract: International audience; Motivated by experimental observations in 3D/organoid cultures derived from glioblastoma, we develop a mathematical model where tumour aggregate formation is obtained as the result of nutrient-limited cell proliferation coupled with chemotaxis-based cell movement. The introduction of a chemotherapeutic treatment induces mechanical changes at the cell level, with cells undergoing a transition from rigid bodies to semi-elastic entities. We analyse the influence of these individual mechanical changes on the properties of the aggregates obtained at the population level by introducing a nonlinear volume-filling chemotactic system of partial differential equations. The elastic properties of the cells are taken into account through the so-called squeezing probability, which allows us to change the packing capacity of the aggregates, depending on the concentration of the treatment in the extracellular microenvironment. We explore two scenarios for the effect of the treatment: firstly, the treatment acts only on the mechanical properties of the cells and, secondly, we assume it also prevents cell proliferation. A linear stability analysis enables us to study the ability of the system to create patterns. We provide numerical simulations in 1D and 2D that illustrate the shrinking of the aggregates due to the presence of the treatment.
Published: 2021

50. Macrophages: Checking Toxicity of Fungal Metabolites in the Colon

Author: Jean-Paul Latge, Michael Blatzer, Nicolas Papon, Yves Delneste, Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Colon, Chemistry, [SDV]Life Sciences [q-bio], Macrophages, Microbiota, Endocrinology, Diabetes and Metabolism, Fungal Toxins, Epithelial Cells, 030209 endocrinology & metabolism, Absorption (skin), 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Biochemistry, Sense (molecular biology), Toxicity, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Homeostasis
Abstract: It is well known that the intestine absorbs nutrients, electrolytes, and water. Chikina et al. recently demonstrated that it is also able to sense, recognize, and block the absorption of toxins through a very sophisticated interactive cellular cooperation between novel subpopulations of macrophages and epithelial cells.
Published: 2021

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