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1. Exposure to a mixture of non-persistent environmental chemicals and neonatal thyroid function in a cohort with improved exposure assessment

Author

Ophélie Coiffier, Dorothy Nakiwala, Matthieu Rolland, Andres Malatesta, Sarah Lyon-Caen, Benoît Chovelon, Patrice Faure, Anne Sophie Gauchez, Dorra Guergour, Amrit K. Sakhi, Azemira Sabaredzovic, Cathrine Thomsen, Isabelle Pin, Rémy Slama, Christelle Corne, Claire Philippat, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Norwegian Institute of Public Health [Oslo] (NIPH), Centre Hospitalier Universitaire [Grenoble] (CHU), and Coiffier, Ophélie

Subjects
[SDE] Environmental Sciences, Phthalates, Thyroid hormones, [SDE]Environmental Sciences, Mixture, Parabens, Bisphenols, DINCH, Heel-prick blood spot, General Environmental Science
Abstract

International audience; Background: In vitro and toxicological studies have shown that non-persistent environmental chemicals can perturb thyroid hormone homeostasis. Epidemiological studies with improved exposure assessment (i.e., repeated urine samples) are needed to evaluate effects of these compounds, individually or as a mixture, in humans. We studied the associations between prenatal exposure to non-persistent environmental chemicals and neonatal thyroid hormones.Methods: The study population consisted of 442 mother–child pairs from the French SEPAGES mother–child cohort recruited between July 2014 and July 2017. For each participant, four parabens, five bisphenols, tri- closan, triclocarban, benzophenone-3 as well as metabolites of phthalates and of di(isononyl)cyclohexane-1,2- dicarboxylate were assessed in two pools of repeated urine samples (median: 21 spot urines per pool), collected in the 2nd and 3rd trimesters of pregnancy, respectively. Thyroid stimulating hormone (TSH) and total thyroxine (T4) levels were determined in newborns from a heel-prick blood spot. Maternal iodine and selenium were assessed in urine and serum, respectively. Adjusted linear regression (uni-pollutant model) and Bayesian Kernel Machine Regression (BKMR, mixture model) were applied to study overall and sex-stratified associations between chemicals and hormone concentrations.Results: Interaction with child sex was detected for several compounds. Triclosan, three parabens, and one phthalate metabolite (OH-MPHP) were negatively associated with T4 among girls in the uni-pollutant model. BKMR also suggested a negative association between the mixture and T4 in girls, whereas in boys the association was positive. The mixture was not linked to TSH levels, and for this hormone the uni-pollutant model revealed associations with only a few compounds.Conclusion: Our study, based on repeated urine samples to assess exposure, showed that prenatal exposure to some phenols and phthalates disturb thyroid hormone homeostasis at birth. Furthermore, both uni-pollutant and mixture models, suggested effect modification by child sex, while, to date underlying mechanisms for such sex-differences are not well understood.

Published
2023
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2. Laser-induced breakdown spectroscopy imaging for material and biomedical applications: recent advances and future perspectives

Author

Vincent Gardette, Vincent Motto-Ros, César Alvarez-Llamas, Lucie Sancey, Ludovic Duponchel, Benoit Busser, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 (LASIRE), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), ANR-17-CE18-0028,MEDI-LIBS,Analyse multi-élémentaire de pathologies pulmonaires par spectroscopie laser(2017), ANR-20-CE17-0021,dIAg-EM,Diagnostique médical par intelligence artificielle appliquée à la microscopie LIBS élémentaire(2020), BUSSER, Benoit, Analyse multi-élémentaire de pathologies pulmonaires par spectroscopie laser - - MEDI-LIBS2017 - ANR-17-CE18-0028 - AAPG2017 - VALID, and Diagnostique médical par intelligence artificielle appliquée à la microscopie LIBS élémentaire - - dIAg-EM2020 - ANR-20-CE17-0021 - AAPG2020 - VALID

Subjects
[SDE] Environmental Sciences, [PHYS]Physics [physics], Libs, [SPI] Engineering Sciences [physics], [SDV]Life Sciences [q-bio], Geology, Laser induced breakdown spectroscopy, Tissue imaging, [PHYS] Physics [physics], [SDV] Life Sciences [q-bio], [SPI]Engineering Sciences [physics], [CHIM] Chemical Sciences, [SDE]Environmental Sciences, Medicine, [CHIM]Chemical Sciences, Chemometrics, Analytical chemistry
Abstract

International audience; No abstract available

Published
2023
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3. Impact of Type 2 Diabetes on the Accuracy of Noninvasive Tests of Liver Fibrosis With Resulting Clinical Implications

Author

Jérôme, Boursier, Clémence M, Canivet, Charlotte, Costentin, Adrien, Lannes, Adèle, Delamarre, Nathalie, Sturm, Brigitte, Le Bail, Sophie, Michalak, Frédéric, Oberti, Marie-Noelle, Hilleret, Marie, Irles-Depé, Isabelle, Fouchard, Paul, Hermabessiere, Justine, Barthelon, Paul, Calès, Bertrand, Cariou, Victor, de Ledinghen, Marine, Roux, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Département d'hépatologie (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), CHU Grenoble, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), 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), and BOURGEAIS, Véronique

Subjects
Type 2 Diabetes Mellitus, [SDV] Life Sciences [q-bio], Hepatology, NAFLD, [SDV]Life Sciences [q-bio], Gastroenterology, Noninvasive Tests, Fibrosis
Abstract

International audience; Background & aims: Noninvasive tests (NITs) of liver fibrosis have been suggested to be less accurate in type 2 diabetes mellitus (T2DM). We aimed to compare the accuracy of 6 NITs between patients with or without T2DM, explain any differences, and adapt diagnostic algorithms for clinical practice accordingly.Methods: We included 1051 patients with nonalcoholic fatty liver disease with liver biopsy, blood fibrosis tests (Nonalcoholic Fatty Liver Disease Fibrosis Score, FIB4, Fibrotest, FibroMeter), vibration-controlled transient elastography (VCTE), and the combinatory elasto-blood test FibroMeterVCTE. The study endpoint was advanced fibrosis on liver biopsy.Results: NIT areas under the receiver operating characteristic curve were significantly lower in patients with T2DM, mostly because of a decrease in specificity. For FIB4, this decrease in specificity was only related to the higher age of patients with T2DM enrolled. For Fibrotest, FibroMeter, and FibroMeterVCTE, the decrease in specificity was related to age but also to higher alpha2-macroglobulin level, which is known to increase in T2DM. Sensitivity was unaffected by T2DM, but it masked a doubled raw number of false negatives because of the 2-fold higher prevalence of advanced fibrosis in that setting. The sequential algorithm FIB4-vibration-controlled transient elastography had 90.3% accuracy in patients without T2DM vs 79.0% in those with (P < .001). Algorithms using first-line specialized tests maintained a low rate of false negatives and false positives in T2DM.Conclusions: The decrease in NIT accuracy observed in T2DM is partly biased by the different characteristics of the groups studied, but also linked to T2DM itself through modification of the levels of some NIT biomarkers. Specialized tests should be used first-line to diagnose advanced liver fibrosis in T2DM.

Published
2023
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4. Utility of macrophages in an antitumor strategy based on the vectorization of iron oxide nanoparticles

Author

Catherine Aude-Garcia, Solveig Reymond, Bastien Dalzon, Véronique Collin-Faure, Josiane Arnaud, Julien Vollaire, Thierry Rabilloud, Olivier Proux, Daphna Fenel, Mélanie Guidetti, Isabelle Testard, Marie Carrière, Denis Testemale, Guy Schoehn, Véronique Josserand, Protéomique, Métaux et Différenciation (ProMD ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Matériaux, Rayonnements, Structure (NEEL - MRS), Institut Néel (NEEL), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Observatoire des Sciences de l'Univers de Grenoble (OSUG ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Rabilloud, Thierry, Protéomique, Métaux et Différenciation (ProMD), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institute for Advanced Biosciences (IAB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), MRS - Matériaux, Rayonnements, Structure, Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Rayonnement Synchrotron et Recherche Medicale (RSRM), Université Joseph Fourier - Grenoble 1 (UJF)-European Synchrotron Radiation Facility (ESRF)-Institut National de la Santé et de la Recherche Médicale (INSERM), équipe FAME, Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie et de Pathologie - IBP [CHU Grenoble], Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Platefome de Microscopie électronique IBS/ISBG, ANR-10-INSB-05-01,FRISBI,French Infrastructure for Integrated Structural Biology, ANR-10- LABX-49-01,Labex GRAL,Labex GRAL, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Matériaux, Rayonnements, Structure (MRS), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_treatment, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, chemistry.chemical_compound, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer stem cell, medicine, General Materials Science, education, Intravascular injection, education.field_of_study, Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, 021001 nanoscience & nanotechnology, medicine.disease, 0104 chemical sciences, Radiation therapy, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], chemistry, Physical Barrier, Cancer cell, Cancer research, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, 0210 nano-technology, Iron oxide nanoparticles
Abstract

International audience; Utility of macrophages in an antitumor strategy based on the vectorization of iron oxide nanoparticles This Trojan horse strategy aims at specifi cally killing tumor cells. To achieve this goal, High-Z-element nanoparticles brought by macrophages are stimulated using low doses of X-ray radiation. The nanoparticles (namely FERINJECT®) liberate toxic photoelectrons in situ without damaging the surrounding healthy tissues. With its specifi c targeting of cancer cells, this promising anticancer strategy could greatly improve the effi ciency of current radiotherapy. Many solid tumors and their metastases are still resistant to current cancer treatments such as chemo-and radiotherapy. The presence of a small population of Cancer Stem Cells in tumors is held responsible for relapses. Moreover, the various physical barriers of the organism (e.g. blood-brain barrier) prevent many drugs from reaching the target cells. In order to alleviate this constraint, we suggest a Trojan horse strategy consisting of intravascular injection of macrophages loaded with therapeutic nanoparticles (an iron nanoparticle-based solution marketed under the name of FERINJECT®) to bring a high quantity of the latter to the tumor. The aim of this article is to assess the response of primary macrophages to FERINJECT® via functional assays in order to ensure that the macrophages loaded with these nano-particles are still relevant for our strategy. Following this first step, we demonstrate that the loaded macro-phages injected into the bloodstream are able to migrate to the tumor site using small-animal imaging. Finally, using synchrotron radiation, we validate an improvement of the radiotherapeutic effect when FERINJECT®-laden macrophages are deposited at the vicinity of cancer cells and irradiated.

Published
2019
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5. Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility

Author

Gérald Le Gac, Yann Fichou, Chandran Ka, Charles Coutton, Emmanuel Dulioust, Graciane Petre, Marie Bidart, Denis Dacheux, Raoudha Zouari, Nicolas Thierry-Mieg, Isabelle Gourlaouen, Julie Beurois, Mélanie Bonhivers, Guillaume Martinez, Derrick R. Robinson, Véronique Satre, Zine-Eddine Kherraf, Pierre F. Ray, Caroline Cazin, Christophe Arnoult, Aminata Touré, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Microbiologie Fondamentale et Pathogénicité (MFP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut Polytechnique de Bordeaux (Bordeaux INP), Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Etablissement français du sang [Rennes] (EFS Bretagne), Institut Brestois Santé Agro Matière (IBSAM), Hôpital Morvan [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205] (Brain Tech Lab ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Polyclinique les Jasmins [Tunis], Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), ANR-12-BSV1-0011,MUCOFERTIL,La protéine TAT1 (SLC26A8), partenaire et activateur de CFTR dans le spermatozoïde, au carrefour des infertilités masculines et de la mucoviscidose.(2012), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), TOURE, Aminata, BLANC - La protéine TAT1 (SLC26A8), partenaire et activateur de CFTR dans le spermatozoïde, au carrefour des infertilités masculines et de la mucoviscidose. - - MUCOFERTIL2012 - ANR-12-BSV1-0011 - BLANC - VALID, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Institut de Biologie et de Pathologie - IBP [CHU Grenoble], Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Computationnelle et Modélisation (TIMC-BCM ), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, Gene knockdown, 030219 obstetrics & reproductive medicine, [SDV]Life Sciences [q-bio], Flagellum, Biology, medicine.disease, Asthenozoospermia, Molecular biology, Sperm, Male infertility, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, molecular genetics, medicine, genetics, Gene, Genetics (clinical), Sperm motility, Immunostaining, reproductive medicine
Abstract

BackgroundMultiple morphological abnormalities of the flagella (MMAF) consistently lead to male infertility due to a reduced or absent sperm motility defined as asthenozoospermia. Despite numerous genes recently described to be recurrently associated with MMAF, more than half of the cases analysed remain unresolved, suggesting that many yet uncharacterised gene defects account for this phenotypeMethodsExome sequencing was performed on 167 infertile men with an MMAF phenotype. Immunostaining and transmission electron microscopy (TEM) in sperm cells from affected individuals were performed to characterise the ultrastructural sperm defects. Gene inactivation using RNA interference (RNAi) was subsequently performed in Trypanosoma.ResultsWe identified six unrelated affected patients carrying a homozygous deleterious variants in MAATS1, a gene encoding CFAP91, a calmodulin-associated and spoke-associated complex (CSC) protein. TEM and immunostaining experiments in sperm cells showed severe central pair complex (CPC) and radial spokes defects. Moreover, we confirmed that the WDR66 protein is a physical and functional partner of CFAP91 into the CSC. Study of Trypanosoma MAATS1’s orthologue (TbCFAP91) highlighted high sequence and structural analogies with the human protein and confirmed the axonemal localisation of the protein. Knockdown of TbCFAP91 using RNAi impaired flagellar movement led to CPC defects in Trypanosoma as observed in humans.ConclusionsWe showed that CFAP91 is essential for normal sperm flagellum structure and function in human and Trypanosoma and that biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility.

Published
2020
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6. Tularemia: A Case Series of Patients Diagnosed at the National Reference Center for Rickettsioses From 2008 to 2017

Author

Darmon-Curti, Anne, Darmon, François, Edouard, Sophie, HENNEBIQUE, Aurélie, Guimard, Thomas, Martin-Blondel, Guillaume, Klopfenstein, Timothée, Talarmin, Jean-Philippe, Raoult, Didier, Maurin, Max, Fournier, Pierre-Edouard, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), École des Ponts ParisTech (ENPC), Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Centre National de Référence des Francisella [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), CHU La Roche sur Yon, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), 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), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), service de maladies infectieuses CHU J Minjoz Besancon, Centre Hospitalier Intercommunal de Cornouaille [Quimper] (CHI Cornouaille [Quimper]), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut de Biologie et de Pathologie - IBP [CHU Grenoble], 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), Service des maladies infectieuses et tropicales [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), and HENNEBIQUE, Aurélie

Subjects
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, AcademicSubjects/MED00290, diagnosis, case series, France, Francisella tularensis, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, ComputingMilieux_MISCELLANEOUS, Major Articles, tularemia
Abstract

Background We describe the epidemiological, clinical, and prognostic aspects of 177 tularemia cases diagnosed at the National Reference Center for rickettsioses, coxiellosis, and bartonelloses between 2008 and 2017. Methods All patients with a microbiological diagnosis of tularemia made in the laboratory were included. Clinical and epidemiological data were collected retrospectively from clinicians in charge of patients using a standardized questionnaire. Diagnostic methods used were indirect immunofluorescence serology, real-time polymerase chain reaction (PCR), and universal PCR targeting the 16S ribosomal ribonucleic acid gene. Results The series included 54 females and 123 males (sex ratio, 2.28; mean age, 47.38 years). Eighty-nine (50.2%) were confirmed as having tularemia on the basis of a positive Francisella tularensis PCR or seroconversion, and 88 (49.8%) were considered as probable due to a single positive serum. The regions of France that were most affected included Pays de la Loire (22% of cases), Nouvelle Aquitaine (18.6% of cases), and Grand Est (12.4% of cases). Patients became infected mainly through contact with rodents or game (38 cases, 21.4%), through tick-bites (23 cases, 12.9%), or during outdoor leisure activities (37 cases, 20.9%). Glandular and ulceroglandular forms were the most frequent (109 cases, 61.5%). Two aortitis, an infectious endocarditis, a myocarditis, an osteoarticular infection, and a splenic hematoma were also diagnosed. Tularemia was discovered incidentally in 54.8% of cases. Seventy-eight patients were hospitalized, and no deaths were reported. Conclusions Our data suggest that in an endemic area and/or in certain epidemiological contexts, tularemia should be sought to allow an optimized antibiotic therapy and a faster recovery., This case series presents 177 patients with tularemia in France between 2008 and 2017: glandular and ulceroglandular forms were the most frequent. Two aortitis, an infectious endocarditis, a myocarditis, an osteoarticular infection, and a splenic hematoma were diagnosed.

Published
2020
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7. AKR1B10, One of the Triggers of Cytokine Storm in SARS-CoV2 Severe Acute Respiratory Syndrome

Author

Clovis Chabert, Anne-Laure Vitte, Domenico Iuso, Florent Chuffart, Candice Trocme, Marlyse Buisson, Pascal Poignard, Benjamin Lardinois, Régis Debois, Sophie Rousseaux, Jean-Louis Pepin, Jean-Benoit Martinot, Saadi Khochbin, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), CHU Grenoble, CHU UCL Namur, Hypoxie et PhysioPathologie (HP2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université Catholique de Louvain = Catholic University of Louvain (UCL), SALAS, Danielle, UCL - (MGD) Service de pneumologie, UCL - (MGD) Laboratoire de biologie clinique, and UCL - SSS/IREC/MONT - Pôle Mont Godinne

Subjects
QH301-705.5, Cells, [SDV]Life Sciences [q-bio], Aldo-Keto Reductases, Catalysis, Inorganic Chemistry, Mice, Animals, Humans, Enzyme Inhibitors, Biology (General), Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Cells, Cultured, Spectroscopy, Respiratory Distress Syndrome, Cultured, SARS-CoV-2, Macrophages, Organic Chemistry, Patient Acuity, COVID-19, drug treatment, General Medicine, cytokines, inflammation, Case-Control Studies, Cytokine Release Syndrome, Cytokines, RAW 264.7 Cells, Transcriptome, Computer Science Applications, [SDV] Life Sciences [q-bio], Chemistry
Abstract

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1β, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.

Published
2022
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8. Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations

Author

Rikke S. Møller, Giuseppe Plazzi, Fabienne Picard, Edouard Hirsch, Elena Gardella, Jamel Chelly, Lino Nobili, Manuela Bramerio, Richard A. Prayson, Jean Boutonnat, Guido Rubboli, Philippe Kahane, Leanne M. Dibbens, Stéphanie Baulac, The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Copenhagen = Københavns Universitet (UCPH), University of Bologna/Università di Bologna, Institute of Neurological Sciences (CNR), National Research Council [Italy] (CNR), Geneva University Hospitals and Geneva University, Niguarda Hospital [Milan, Italy], Hôpital de Hautepierre [Strasbourg], Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nouvel Hôpital Civil de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Cleveland Clinic, Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Université Grenoble Alpes (UGA), CHU Grenoble, University of South Australia [Adelaide], University of Southern Denmark (SDU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, Rubboli G., Plazzi G., Picard F., Nobili L., Hirsch E., Chelly J., Prayson R.A., Boutonnat J., Bramerio M., Kahane P., Dibbens L.M., Gardella E., Baulac S., Moller R.S., Rubboli, Guido, Plazzi, Giuseppe, Picard, Fabienne, Nobili, Lino, Hirsch, Edouard, Chelly, Jamel, Prayson, Richard A, Boutonnat, Jean, Bramerio, Manuela, Kahane, Philippe, Dibbens, Leanne M, Gardella, Elena, Baulac, Stephanie, and Moller, Rikke S

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, KCNT1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Epilepsy surgery, gene mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, sleep-related hypermotor epilepsy, business.industry, General Neuroscience, Periventricular Nodular Heterotopia, Cortical dysplasia, medicine.disease, Malformation of cortical development, Sleep in non-human animals, 3. Good health, ddc:616.8, 030104 developmental biology, epilepsy, Neurology (clinical), business, cortical dysplasia, electroencephalography, 030217 neurology & neurosurgery
Abstract

Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. Mutations in the sodium-activated potassium channel gene KCNT1 have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies. Refereed/Peer-reviewed

Published
2018
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9. [uPA/PAI-1, Oncotype DX™, MammaPrint(®). Prognosis and predictive values for clinical utility in breast cancer management]

Author

Pierre-Jean Lamy, Anne-Gaëlle Le Corroller, Diana Kassab-Chahmi, Laetitia Verdoni, Julia Bonastre, Elisabeth Luporsi, Valérie Mazeau-Woynar, Frédéric Fina, Chafika Mazouni, Patricia de Cremoux, Jérôme Barrière, J. P. Peyrat, Jean-Pierre Bellocq, Pierre-Marie Martin, Gilles Romieu, Jérôme Chetritt, Anne-Sophie Gauchez, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Service d'Anatomie Pathologique Générale [CHU Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Gustave Roussy (IGR), Institut d'Histopathologie [Nantes], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Plateforme de radioactivité [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut National du Cancer [Boulogne Billancourt] (INC), L'Institut national du cancer a reçu le soutien financier d'Unicancer pour la conduite de ce projet., Université Côte d'Azur (UCA)-UNICANCER, Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Université Lille Nord de France (COMUE)-UNICANCER, and Dupuis, Christine

Subjects
Cancer Research, Predictive value, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medicine, Radiology, Nuclear Medicine and imaging, skin and connective tissue diseases, Cancer du sein, Niveaux de preuve, 030304 developmental biology, Biomarqueurs, 0303 health sciences, business.industry, Valeur pronostique, Hematology, General Medicine, Prognosis, Valeur prédictive, 3. Good health, Levels of evidence, Oncology, Radiology Nuclear Medicine and imaging, 030220 oncology & carcinogenesis, business, Biomarkers
Abstract

CONTEXT AND AIMS:Breast cancer prognosis and predictive biomarkers development would allow sparing some patients from chemotherapy or identifying patients for whom chemotherapy would be indicated. In this context, in 2009, the French National Cancer Institute, a National Health and Science Agency dedicated to cancer, in collaboration with the French society of senology and breast pathology (SFSPM) published a report on the assessment of the prognostic and the predictive clinical validity of tissular biomarkers, uPA/PAI-1, Oncotype DX™ and MammaPrint(®), in breast cancer management. They concluded that only the uPA/PAI-1 prognosis value reached the highest level of evidence (LOE I according to Hayes 1998 classification). In 2012, it was decided to update this report since new data have emerged and because information disparities among clinicians have been identified. This article aims to present the main conclusions together with the levels of evidence associated with those conclusions.METHODS:The updating process was based on literature published since 2009 appraisal and on multidisciplinary and independent experts' opinion. The levels of evidence (LOE) used are those of the classification defined by Simon in 2009 (updated Hayes 1998 classification): LOE IA and LOE IB: high level of evidence; LOE IIB and LOE IIC: intermediate level of evidence; LOE IIIC and LOE IV-VD: low level of evidence.CONCLUSIONS:Among patients without lymph-node involvement, uPA/PAI-1, invasion process biomarkers, reach the highest level of evidence for 10 years recurrence free survival prognosis (LOE IA according to Simon). The predictive value to anthracyclins chemotherapy remains to be confirmed. Oncotype DX™ and MammaPrint(®) prognosis and predictive value do not reach the LOE I level. This updating' process confirms the 2009 levels of evidence for all the three biomarkers prognosis value. Besides, concerning Oncotype DX™ and MammaPrint(®), new data do not allow to conclude neither to their complementary clinical information to other clinicopathological existing biomarkers nor to a favorable cost-efficiency ratio in therapeutic decision making and this because of the methodological weakness and uncertainty that are identified in the selected studies. Practically, beyond the prognosis and predictive biomarkers validity, the clinical utility of a new biomarker for chemotherapy indication depends on its clinical added information with regard to validated biomarkers (HR, HER2 and Ki67) and to clinicopathological parameters. Since they are the sole validated biomarkers of the invasion process, uPA/PAI-1 could complete clinical information of other clinicopathological factors and consequently could confer an added clinical value. However, data concerning the impact of this information on chemotherapy clinical indication are lacking.Copyright © 2014. Published by Elsevier Masson SAS., IntroductionDans le cancer du sein, le développement des marqueurs biologiques pronostiques ou prédictifs a pour objectif de mieux identifier les patientes pour lesquelles un traitement par chimiothérapie pourrait être évité ou a contrario indiqué. Dans ce contexte, en 2009, l’Institut national du cancer (INCa), agence sanitaire et scientifique de l’État chargée de coordonner les actions de lutte contre le cancer, avait publié en partenariat avec la Société française de sénologie et de pathologie mammaire un rapport sur l’état des connaissances relatives aux biomarqueurs uPA/PAI-1, Oncotype DX™ et MammaPrint® dans la prise en charge du cancer du sein. Ce rapport avait montré que seule la valeur pronostique d’uPA/PAI-1 atteignait le plus haut niveau de preuve (LOE I selon la grille de Hayes 1998). En 2012, devant la parution de nouvelles publications et la divergence des messages diffusés sur les signatures moléculaires, il a été décidé d’actualiser le rapport de 2009. Cet article présente les principales conclusions accompagnées de leurs niveaux de preuve.MéthodeLe processus de mise à jour s’est appuyé sur l’analyse des données publiées depuis la recherche bibliographique de 2009, complétée par l’avis d’un groupe de travail multidisciplinaire indépendant. Les niveaux de preuve employés sont ceux de la classification définie par Simon en 2009 (grille de Hayes 1998 après mise à jour) : LOE IA et LOE IB : niveau de preuve élevé ; LOE IIB and LOE IIC : niveau de preuve intermédiaire ; LOE IIIC and LOE IV-VD : niveau de preuve faible.ConclusionsChez les patientes sans envahissement ganglionnaire (pN0), uPA/PAI-1, marqueurs d’invasion, ont un niveau de preuve élevé (LOE IA selon Simon) pour la valeur pronostique de la survie sans récidive à 10 ans. Il reste à confirmer leur valeur prédictive de réponse aux anthracyclines. Pour Oncotype DX™ et MammaPrint®, les valeurs pronostique et prédictive n’ont pas atteint à ce jour le niveau de preuve LOE I. Ce travail confirme les niveaux de preuve précédemment établis dans le rapport de 2009. Par ailleurs, les données ne permettent pas de conclure à une valeur ajoutée de Oncotype DX™ et MammaPrint® par rapport aux outils existants. Les données médico-économiques ne permettent pas de statuer sur le rapport coût/efficacité des stratégies utilisant ces tests dans la décision thérapeutique compte tenu d’un niveau de qualité insuffisant pour la plupart des études et d’une forte incertitude mise en évidence par les quelques études bien menées. En pratique, au-delà des niveaux de preuve attribuables à la valeur pronostique et prédictive d’un biomarqueur, l’utilité clinique d’un nouveau marqueur dans l’aide à la prescription d’une chimiothérapie repose sur sa valeur ajoutée par rapport aux marqueurs validés (RH, HER2 et les marqueurs de prolifération comme Ki67) et aux critères anatomo-cliniques. Puisqu’ils sont les seuls marqueurs validés à témoigner du processus d’invasion, uPA/PAI-1 peuvent apporter une information complémentaire et donc avoir une valeur ajoutée par rapport aux marqueurs existants. Les données de la littérature manquent pour apprécier le poids de cette valeur ajoutée dans la décision de prescrire ou non une chimiothérapie.

Published
2015
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10. Dosage de la thyroglobuline dans les liquides de rinçage d’aiguille de cytoponction ganglionnaire : influence des conditions pré-analytiques [Thyroglobulin assay in fluids from lymph node fine needle-aspiration washout: influence of pre-analytical conditions]

Author

Boux de Casson, Florence, Moal, Valérie, Gauchez, Anne-Sophie, Moineau, Marie-Pierre, Sault, Corinne, Schlageter, Marie-Hélène, Massart, Catherine, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Plateforme de radioactivité [Grenoble], Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unite de Biologie Cellulaire (Biol Cell - ST LOUIS - PARIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
washout, [SDV]Life Sciences [q-bio], differentiated thyroid cancer, non-specific adsorption, fine-needle-aspiration, thyroglobulin
Abstract

International audience; The aim of this study was to evaluate the pre-analytical factors contributing to uncertainty in thyroglobulin measurement in fluids from fine-needle aspiration (FNA) washout of cervical lymph nodes. We studied pre-analytical stability, in different conditions, of 41 samples prepared with concentrated solutions of thyroglobulin (FNA washout or certified standard) diluted in physiological saline solution or buffer containing 6% albumin. In this buffer, over time, no changes in thyroglobulin concentrations were observed in all storage conditions tested. In albumin free saline solution, thyroglobulin recovery rates depended on initial sample concentrations and on modalities of their conservation (in conventional storage tubes, recovery mean was 56% after 3 hours-storage at room temperature and 19% after 24 hours-storage for concentrations ranged from 2 to 183 μg/L; recovery was 95%, after 3 hours or 24 hours-storage at room temperature, for a concentration of 5,656 μg/L). We show here that these results are due to non-specific adsorption of thyroglobulin in storage tubes, which depends on sample protein concentrations. We also show that possible contamination of fluids from FNA washout by plasma proteins do not always adequately prevent this adsorption. In conclusion, non-specific adsorption in storage tubes strongly contributes to uncertainty in thyroglobulin measurement in physiological saline solution. It is therefore recommended, for FNA washout, to use a buffer containing proteins provided by the laboratory.

Published
2017
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11. Association between iron level, glucose impairment and increased DNA damage during pregnancy

Author

Samar Rachidi, Khawla Cheikh-Ali, Salam Zein, Jean-Marc Moulis, Jean-Marc Ayoubi, Iman Sharara, Nadine Shami, Pascale Salameh, Isabelle Hininger-Favier, Anne-Sophie Gauchez, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Clinical Pharmacy Department [Beirut, Lebanon], Lebanese University [Beirut] (LU), Department of Gynecology and Obstetrics [Beirut, Lebanon], Bahman Hospital [Beirut, Lebanon], Plateforme de radioactivité [Grenoble], Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Hôpital Foch [Suresnes], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), This study was partly sup-ported by the Rectorat of the Lebanese University, Beirut-Lebanon(Project number 4/2217) and I. Hininger-Favier and J-M. Moulisthank the support of the ANR-13- CESA 0008 Program., ANR-13-CESA-0008,CADMIDIA,Cadmium et Diabète(2013), Dupuis, Christine, Contaminants et Environnements : Santé, Adaptabilité, Comportements et Usages - Cadmium et Diabète - - CADMIDIA2013 - ANR-13-CESA-0008 - CESA - VALID, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP)

Subjects
0301 basic medicine, Adult, Blood Glucose, medicine.medical_specialty, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, medicine.medical_treatment, Iron, 030209 endocrinology & metabolism, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.disease_cause, Gestational diabetes mellitus, Biochemistry, Inorganic Chemistry, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Internal medicine, medicine, Humans, Free-radical theory of aging, 2. Zero hunger, Ferritin, biology, Insulin, Glucose Tolerance Test, medicine.disease, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, Gestational diabetes, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Diabetes, Gestational, Oxidative Stress, 030104 developmental biology, Endocrinology, Ferritins, biology.protein, Molecular Medicine, Gestation, Female, Lipid Peroxidation, Oxidative stress, Blood sampling, DNA Damage
Abstract

International audience; Elevated circulating ferritin has been reported to increase the risk of gestational diabetes mellitus (GDM). When high ferritin translates into high iron stores, iron excess is also a condition leading to free radical damage. We aimed to evaluate the relationship between oxidative stress (OS) induced by iron status and GDM risk in non iron-supplemented pregnant women. Methods: This was a pilot observational study conducted on 93 non-anemic pregnant women. Iron status was assessed at the first trimester of gestation. Blood sampling was done at 24–28 weeks' gestation for oral glucose tolerance test (OGTT), insulin and biological markers of oxidative damage tests. Results: A significant increase in DNA damage was found in patients who developed GDM. Women with elevated DNA damage had a six-fold increased risk of developing GDM (Exp (B) = 6.851, P = 0.038; 95% CI [1.108–42.375]). The serum ferritin levels at first trimester were significantly correlated to lipid per-oxidation (rho = 0.24, p = 0.012). The stratified analysis suggests that ferritin is a modifying factor for the correlation of oxidative stress (OS) and glucose intolerance. Conclusion: Moderate ferritin levels due to iron intake without iron-supplement, at early pregnancy is a modifying factor for the correlation of oxidative damage and glucose intolerance in pregnant women. Larger studies to evaluate the risk of food iron intake induced increased oxidative damage in offspring are warranted to propose nutrition advice regarding iron intake in women with a high risk of GDM.

Published
2016
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12. Middle Iron-Enriched Fructose Diet on Gestational Diabetes Risk and on Oxidative Stress in Offspring Rats

Author

Samar Rachidi, Mireille Osman, Josiane Arnaud, Cécile Batandier, Salam Zein, Karine Couturier, Isabelle Hininger-Favier, Anne-Sophie Gauchez, Farida Sitti, Clinical Pharmacy Department [Beirut, Lebanon], Lebanese University [Beirut] (LU), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Faculty of Medicine [Jakarta, Indonesia], Universitas Indonesia [Jakarta, Indonesia], Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire de Biologie Médicale [CHU Grenoble] (Plateforme de Radioactivité), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut de Biologie et de Pathologie - IBP [CHU Grenoble], We would like to thank the Rectorat of the Lebanese University, Beirut-Lebanon, to support this work., Dupuis, Christine, Universitas Indonesia (UI ), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP)

Subjects
Male, 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Medicine, Gestational diabetes, 2. Zero hunger, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Female, medicine.medical_specialty, Offspring, Iron, 030209 endocrinology & metabolism, Fructose, Hypoglycemia, Inorganic Chemistry, 03 medical and health sciences, Insulin resistance, Internal medicine, Animals, Rats, Wistar, Glycemic, business.industry, Insulin, Biochemistry (medical), nutritional and metabolic diseases, medicine.disease, High fructose diet, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Rats, Diabetes, Gestational, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Oxidative stress, business
Abstract

International audience; Gestational diabetes mellitus (GDM) is associated with increased insulin resistance and a heightened level of oxidative stress (OS). Additionally, high iron consumption could also increase insulin resistance and OS, which could aggravate GDM risk. The aim of this study is to evaluate a high fructose diet (F) as an alternative experimental model of GDM on rats. We also have evaluated the worst effect of a fructose iron-enriched diet (FI) on glucose tolerance and OS status during pregnancy. Anthropometric parameters, plasma glucose levels, insulin, and lipid profile were assessed after delivery in rats fed an F diet. The effects observed in mothers (hyperglycemia, and hyperlipidemia) and on pups (macrosomia and hypoglycemia) are similar to those observed in women with GDM. Therefore, the fructose diet could be proposed as an experimental model of GDM. In this way, we can compare the effect of an iron-enriched diet on the metabolic and redox status of mother rats and their pups. The mothers' glycemic was similar in the F and FI groups, whereas the glycemic was significantly different in the newborn. In rat pups born to mothers fed on an FI diet, the activities of the antioxidant enzyme glutathione peroxidase (GPx) and glutathione-S-transferase in livers and GPx in brains were altered and the gender analysis showed significant differences. Thus, alterations in the glycemic and redox status in newborns suggest that fetuses are more sensitive than their mothers to the effect of an iron-enriched diet in the case of GDM pregnancy. This study proposed a novel experimental model for GDM and provided insights on the effect of a moderate iron intake in adding to the risk of glucose disorder and oxidative damage on newborns.

Published
2016
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13. Protocadherin-12 Cleavage Is a Regulated Process Mediated by ADAM10 Protein

Author

Emmanuelle Tillet, Anne-Sophie Gauchez, Francine Cand, Stéphanie Bouillot, Marie-Hélène Prandini, Philippe Huber, Pascale Hoffmann, Nadia Alfaidy, Guillaume Carmona, Alfaidy, Nadia, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plateforme de radioactivité [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), and Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes)

Subjects
0303 health sciences, Cadherin, ADAM10, Protocadherin, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Biology, Biochemistry, Molecular biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Downregulation and upregulation, Cell–cell interaction, medicine, Signal transduction, Cell adhesion, Molecular Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

International audience; Protocadherins are a group of transmembrane proteins with homophilic binding activity, members of the cadherin superfamily. Apart from their role in adhesion, the cellular functions of protocadherins are essentially unknown. Protocadherin (PCDH)12 was previously identified in invasive trophoblasts and endothelial and mesangial cells in the mouse. Invalidation studies revealed that the protein was required for optimal placental development. In this article, we show that its human homolog is abundantly expressed in various trophoblast subtypes of the human placenta and at lower levels in endothelial cells. We demonstrate that PCDH12 is shed at high rates in vitro. The shedding mechanism depends on ADAM10 and results in reduced cellular adhesion in a cell migration assay. PCDH12 is subsequently cleaved by the γ-secretase complex, and its cytoplasmic domain is rapidly degraded by the proteasome. PCDH12 shedding is regulated by interlinked intracellular pathways, including those involving protein kinase C, PI3K, and cAMP, that either increase or inhibit cleavage. In endothelial cells, VEGF, prostaglandin E(2), or histamine regulates PCDH12 shedding. The extracellular domain of PCDH12 was also detected in human serum and urine, thus providing evidence of PCDH12 shedding in vivo. Importantly, we observed an increase in circulating PCDH12 in pregnant women who later developed a pre-eclampsia, a frequent pregnancy syndrome and a major cause of maternal and fetal morbidity and mortality. In conclusion, we speculate that, like in mice, PCDH12 may play an important role in human placental development and that proteolytic cleavage in response to external factors, such as cytokines and pathological settings, regulates its activity.

Published
2011
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14. [uPA/PAI-1, Oncotype DX™, MammaPrint(®). Prognosis and predictive values for clinical utility in breast cancer management]

Author

Anne-Sophie Gauchez, P. de Cremoux, Pierre-Marie Martin, Valérie Mazeau-Woynar, J. P. Peyrat, A.-G. Le Corroller, Gilles Romieu, Jérôme Barrière, Elisabeth Luporsi, Diana Kassab-Chahmi, Jérôme Chetritt, P-J Lamy, Laetitia Verdoni, Jean-Pierre Bellocq, Chafika Mazouni, Julia Bonastre, Frédéric Fina, Service d'Anatomie Pathologique Générale [CHU Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Gustave Roussy (IGR), Institut d'Histopathologie [Nantes], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Plateforme de radioactivité [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Institut National du Cancer [Boulogne Billancourt] (INC), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Université Lille Nord de France (COMUE)-UNICANCER, L'Institut national du cancer a reçu le soutien financier d'Unicancer pour la conduite de ce projet., and Dupuis, Christine

Subjects
Cost-Benefit Analysis, Predictive value, Antineoplastic Agents, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Real-Time Polymerase Chain Reaction, Disease-Free Survival, Receptors, Urokinase Plasminogen Activator, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Predictive Value of Tests, Plasminogen Activator Inhibitor 1, Biomarkers, Tumor, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Cancer du sein, Niveaux de preuve, Biomarqueurs, Gene Expression Profiling, Philosophy, Valeur pronostique, Reproducibility of Results, Prognosis, Urokinase-Type Plasminogen Activator, Valeur prédictive, Neoplasm Proteins, Oncology, Levels of evidence, Chemotherapy, Adjuvant, Female, France, Lymph Nodes, Humanities, Biomarkers
Abstract

International audience; CONTEXT AND AIMS:Breast cancer prognosis and predictive biomarkers development would allow sparing some patients from chemotherapy or identifying patients for whom chemotherapy would be indicated. In this context, in 2009, the French National Cancer Institute, a National Health and Science Agency dedicated to cancer, in collaboration with the French society of senology and breast pathology (SFSPM) published a report on the assessment of the prognostic and the predictive clinical validity of tissular biomarkers, uPA/PAI-1, Oncotype DX™ and MammaPrint(®), in breast cancer management. They concluded that only the uPA/PAI-1 prognosis value reached the highest level of evidence (LOE I according to Hayes 1998 classification). In 2012, it was decided to update this report since new data have emerged and because information disparities among clinicians have been identified. This article aims to present the main conclusions together with the levels of evidence associated with those conclusions.METHODS:The updating process was based on literature published since 2009 appraisal and on multidisciplinary and independent experts' opinion. The levels of evidence (LOE) used are those of the classification defined by Simon in 2009 (updated Hayes 1998 classification): LOE IA and LOE IB: high level of evidence; LOE IIB and LOE IIC: intermediate level of evidence; LOE IIIC and LOE IV-VD: low level of evidence.CONCLUSIONS:Among patients without lymph-node involvement, uPA/PAI-1, invasion process biomarkers, reach the highest level of evidence for 10 years recurrence free survival prognosis (LOE IA according to Simon). The predictive value to anthracyclins chemotherapy remains to be confirmed. Oncotype DX™ and MammaPrint(®) prognosis and predictive value do not reach the LOE I level. This updating' process confirms the 2009 levels of evidence for all the three biomarkers prognosis value. Besides, concerning Oncotype DX™ and MammaPrint(®), new data do not allow to conclude neither to their complementary clinical information to other clinicopathological existing biomarkers nor to a favorable cost-efficiency ratio in therapeutic decision making and this because of the methodological weakness and uncertainty that are identified in the selected studies. Practically, beyond the prognosis and predictive biomarkers validity, the clinical utility of a new biomarker for chemotherapy indication depends on its clinical added information with regard to validated biomarkers (HR, HER2 and Ki67) and to clinicopathological parameters. Since they are the sole validated biomarkers of the invasion process, uPA/PAI-1 could complete clinical information of other clinicopathological factors and consequently could confer an added clinical value. However, data concerning the impact of this information on chemotherapy clinical indication are lacking.Copyright © 2014. Published by Elsevier Masson SAS.; IntroductionDans le cancer du sein, le développement des marqueurs biologiques pronostiques ou prédictifs a pour objectif de mieux identifier les patientes pour lesquelles un traitement par chimiothérapie pourrait être évité ou a contrario indiqué. Dans ce contexte, en 2009, l’Institut national du cancer (INCa), agence sanitaire et scientifique de l’État chargée de coordonner les actions de lutte contre le cancer, avait publié en partenariat avec la Société française de sénologie et de pathologie mammaire un rapport sur l’état des connaissances relatives aux biomarqueurs uPA/PAI-1, Oncotype DX™ et MammaPrint® dans la prise en charge du cancer du sein. Ce rapport avait montré que seule la valeur pronostique d’uPA/PAI-1 atteignait le plus haut niveau de preuve (LOE I selon la grille de Hayes 1998). En 2012, devant la parution de nouvelles publications et la divergence des messages diffusés sur les signatures moléculaires, il a été décidé d’actualiser le rapport de 2009. Cet article présente les principales conclusions accompagnées de leurs niveaux de preuve.MéthodeLe processus de mise à jour s’est appuyé sur l’analyse des données publiées depuis la recherche bibliographique de 2009, complétée par l’avis d’un groupe de travail multidisciplinaire indépendant. Les niveaux de preuve employés sont ceux de la classification définie par Simon en 2009 (grille de Hayes 1998 après mise à jour) : LOE IA et LOE IB : niveau de preuve élevé ; LOE IIB and LOE IIC : niveau de preuve intermédiaire ; LOE IIIC and LOE IV-VD : niveau de preuve faible.ConclusionsChez les patientes sans envahissement ganglionnaire (pN0), uPA/PAI-1, marqueurs d’invasion, ont un niveau de preuve élevé (LOE IA selon Simon) pour la valeur pronostique de la survie sans récidive à 10 ans. Il reste à confirmer leur valeur prédictive de réponse aux anthracyclines. Pour Oncotype DX™ et MammaPrint®, les valeurs pronostique et prédictive n’ont pas atteint à ce jour le niveau de preuve LOE I. Ce travail confirme les niveaux de preuve précédemment établis dans le rapport de 2009. Par ailleurs, les données ne permettent pas de conclure à une valeur ajoutée de Oncotype DX™ et MammaPrint® par rapport aux outils existants. Les données médico-économiques ne permettent pas de statuer sur le rapport coût/efficacité des stratégies utilisant ces tests dans la décision thérapeutique compte tenu d’un niveau de qualité insuffisant pour la plupart des études et d’une forte incertitude mise en évidence par les quelques études bien menées. En pratique, au-delà des niveaux de preuve attribuables à la valeur pronostique et prédictive d’un biomarqueur, l’utilité clinique d’un nouveau marqueur dans l’aide à la prescription d’une chimiothérapie repose sur sa valeur ajoutée par rapport aux marqueurs validés (RH, HER2 et les marqueurs de prolifération comme Ki67) et aux critères anatomo-cliniques. Puisqu’ils sont les seuls marqueurs validés à témoigner du processus d’invasion, uPA/PAI-1 peuvent apporter une information complémentaire et donc avoir une valeur ajoutée par rapport aux marqueurs existants. Les données de la littérature manquent pour apprécier le poids de cette valeur ajoutée dans la décision de prescrire ou non une chimiothérapie.

Published
2014
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15. The Severity of Nocturnal Hypoxia but Not Abdominal Adiposity Is Associated with Insulin Resistance in Non-Obese Men with Sleep Apnea

Author

Anne-Laure Borel, Patrick Levy, Serge Halimi, Jean-Louis Pépin, Jean-Philippe Baguet, Denis Monneret, Patrice Faure, Renaud Tamisier, Service d'Endocrinologie (GRENOBLE - Endocrino), CHU Grenoble, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie Métabolique [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 Pierre et Marie Curie - Paris 6 (UPMC), Service Physiologie, sommeil et exercice, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU de Grenoble chirurgie cardiaque, Ministère de la santé, Laboratoire de Biologie Médicale [CHU Grenoble] (Plateforme de Radioactivité), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut de Biologie et de Pathologie - IBP [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), HAL UPMC, Gestionnaire, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Pulmonology, Epidemiology, medicine.medical_treatment, lcsh:Medicine, Polysomnography, 030204 cardiovascular system & hematology, Body Mass Index, Endocrinology, 0302 clinical medicine, Risk Factors, Insulin, Hypoxia, lcsh:Science, Adiposity, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glucose tolerance test, Multidisciplinary, medicine.diagnostic_test, Sleep apnea, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Body Composition, Cardiology, Medicine, medicine.symptom, Research Article, Adult, medicine.medical_specialty, Clinical Research Design, Abdominal Fat, 030209 endocrinology & metabolism, 03 medical and health sciences, Sleep Apnea Syndromes, Insulin resistance, Internal medicine, medicine, Humans, Obesity, Biology, Nutrition, Diabetic Endocrinology, Population Biology, Endocrine Physiology, business.industry, lcsh:R, Diabetes Mellitus Type 2, Glucose Tolerance Test, Hypoxia (medical), medicine.disease, Sleep and Ventilation Disorders, lcsh:Q, Insulin Resistance, business, Body mass index
Abstract

International audience; Background: Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients.Methods: The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference.Results: Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2). In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (r = −0.43, p = 0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance.Conclusion: Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.

Published
2013
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