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9 results on '"Ecole de Médecine [CHRU Lille]"'

1. Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs

Author

Chmielewski, Alexandra, Hubert, Thomas, Descamps, Amandine, Mazur, Daniele, Daoudi, Mehdi, Ciofi, Philippe, FONTAINE, Christian, Caiazzo, Robert, Pattou, François, Prevot, Vincent, Pigeyre, Marie, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, This work was supported by grants from the Fond Français de l’Alimentation (FFA), the Société Française de Nutrition (SFN), the Institut Benjamin Delessert, the Diamenord Association, and the Agence Nationale de la Recherche (ANR‐15‐CE14‐0025, Glioshuttles4metabolism, Distalz)., ANR-15-CE14-0025,GlioShuttles4Metabolism,Les tanycytes transportent la leptine dans le cerveau: identification des mécanismes et rôle dans la physiopathologie de l'obésité et du diabète(2015), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Prevot, Vincent, and Les tanycytes transportent la leptine dans le cerveau: identification des mécanismes et rôle dans la physiopathologie de l'obésité et du diabète - - GlioShuttles4Metabolism2015 - ANR-15-CE14-0025 - AAPG2015 - VALID

Subjects
Leptin, Male, Swine, digestive, oral, and skin physiology, Original Articles, Diet, High-Fat, Animals, Humans, Swine, Miniature, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Original Article, Obesity Biology and Integrated Physiology, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Obesity, hormones, hormone substitutes, and hormone antagonists, Cerebrospinal Fluid
Abstract

International audience; Objective: A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high-fat diet (HFD) compared with standard diet.Methods: Serum and cerebrospinal fluid (CSF) leptin concentrations during 10 weeks of HFD versus standard diet and exogenous leptin-induced STAT3 phosphorylation in the hypothalamus of minipigs were assessed, and the hypothalamic leptin-sensitive cells were characterized by immunofluorescence.Results: The efficiency of the passage of endogenous blood-borne leptin into the CSF (measured as the log [CSF:serum leptin ratio]) decreased over time in minipigs fed a HFD (β = -0.04 ± 0.005 per kilogram of weight gain in HFD; P < 0.0001), while it remained stable in minipigs fed a standard diet. However, the ability of peripherally administered leptin to activate its receptor in hypothalamic neurons was preserved in obese minipigs at 10 weeks of HFD.Conclusions: Together, these data are consistent with the existence of an early-onset tranport deficiency for endogenous circulating leptin into the brain in individuals developing obesity, preceding the acquisition of hypothalamic leptin resistance. Although additional studies are required to identify the underlying mechanisms, our study paves the way for the development of new preclinical pharmacological models targeting the restoration of the shuttling of peripheral leptin into the central nervous system to manage obesity.

Published
2019
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2. Nitric oxide signalling in the brain and its control of bodily functions

Author

Vincent Prevot, Konstantina Chachlaki, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FHU 1,000 Days for Health [Lille], Université de Lille, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), ANR-17-CE16-0015,GRAND,Vieillissement et démence: un rôle hormonal?(2017), Prevot, Vincent, and Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC))

Subjects
Neurons, 0301 basic medicine, Pharmacology, Brain, Sensory system, Biology, Nitric Oxide, TARGETING THE NITRIC OXIDE (NO)‐cGMP PATHWAY: THERAPEUTIC OPPORTUNITIES IN THE 21ST CENTURY, Nitric oxide, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Signalling, chemistry, Animals, Homeostasis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, Control (linguistics), Neuroscience, 030217 neurology & neurosurgery, Function (biology), Signal Transduction
Abstract

International audience; Nitric oxide (NO) is a versatile molecule that plays key roles in the development and survival of mammalian species by endowing brain neuronal networks with the ability to make continual adjustments to function in response to moment-to-moment changes in physiological input. Here, we summarize the progress in the field and argue that NO-synthetizing neurons and NO signalling in the brain provide a core hub for integrating sensory- and homeostatic-related cues, control key bodily functions, and provide a potential target for new therapeutic opportunities against several neuroendocrine and behavioural abnormalities.

Published
2020
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3. Should a Multigene Signature be Used in all Luminal Early Breast Cancers

Author

Nawale Hajjaji, Yves Marie Robin, Jacques Bonneterre, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Lille Nord de France (COMUE)-UNICANCER, and SALZET, Michel

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Mitotic index, [SDV]Life Sciences [q-bio], Concordance, medicine.medical_treatment, Disease, lcsh:RC254-282, clinical risk, risk of recurrence, 03 medical and health sciences, luminal breast cancer, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, PAM50, Original Research, Chemotherapy, business.industry, Genomic signature, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, multigene signature, business, Clinical risk factor
Abstract

International audience; Background: Multigene signatures refine the risk of recurrence and guide adjuvant chemotherapy decision in luminal breast cancers. The decision to perform the assay is highly variable among oncologists. In order to guide the appropriate clinical group in whom to perform a genomic signature, our study analyzed in a homogeneous cohort which clinical risk groups triggered the use of the PAM50-based signature and their concordance with the genomic risk. Methods: A real life cohort of 222 early breast cancer patients with hormone receptor positive and HER2 negative disease had a commercial PAM50-based assay (Prosigna®) performed at our institution. The assay provided the risk group, the 10-year risk of distant recurrence and the intrinsic molecular subtype of breast cancer. Results: Based on nodal involvement, Ki67, tumor grade, mitotic index, and tumor size, no clinical pattern could identify a specific genomic risk group. The discordance with the genomic risk was high in patients with clinical low risk tumors, both in node negative and node positive patients. Up to 60% of them had a 10% or more risk of distant recurrence. Moreover, we identified a subgroup of luminal A tumors with a high genomic risk of recurrence. Genomic risk and intrinsic subtype were strong determinants of chemotherapy decision. Conclusions: Clinical profiles could not reliably identify genomic risk groups and guide the decision to use a multigene signature. Significant discordance with the genomic risk was observed within low clinical risk and luminal A tumors.

Published
2019
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4. Prognostic and predictive factors for angiosarcoma patients receiving paclitaxel once weekly plus or minus bevacizumab: an ancillary study derived from a randomized clinical trial

Author

Thomas Ryckewaert, Axel Le Cesne, Yves Toiron, Olivier Mir, Luc Camoin, Emmanuelle Tresch-Bruneel, François Bertucci, Isabelle Ray-Coquard, Emmanuelle Bompas, Nicolas Penel, Marie-Cécile Le Deley, Antoine Italiano, Jean-Yves Blay, Loïc Lebellec, Anthony Gonçalves, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département d’Oncologie Médicale [IPC, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Direction de la recherche et de l'innovation [Lille] (Centre Oscar Lambret), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Département d'Oncologie Médicale [Lyon] ( Centre Léon Bérard), Centre Léon Bérard [Lyon], Sarcome, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département d'oncologie médicale [ICO, Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Département d'oncologie médicale, Institut Bergonié [Bordeaux], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris-Sud - Paris 11 (UP11), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], This work was supported by the French National Cancer Institute (INCa) [PHRC 2010] and ROCHE [grant number 0906-EPPA153667-G]., Bodescot, Myriam, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, CHU Lille, Université de Lille, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Department of Medical Oncology [Lyon], Institut Gustave Roussy [IGR], CRLCC René Gauducheau, Centre René Gauducheau, Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], Université Paris-Sud - Paris 11 [UP11], and Université Paris-Saclay

Subjects
0301 basic medicine, Oncology, Vascular Endothelial Growth Factor A, Cancer Research, Multivariate analysis, Weekly paclitaxel, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Surgical oncology, Angiosarcoma, Aged, 80 and over, Univariate analysis, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, 3. Good health, Bevacizumab, Paclitaxel, 030220 oncology & carcinogenesis, Female, medicine.drug, Research Article, Adult, medicine.medical_specialty, Hemangiosarcoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Genetics, medicine, Biomarkers, Tumor, Humans, Aged, Placenta Growth Factor, Proportional hazards model, business.industry, Radiation-induced angiosarcoma, Antineoplastic Agents, Phytogenic, 030104 developmental biology, chemistry, Biomarkers, business
Abstract

Background We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel. Methods Circulating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables. Results Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (

Published
2018
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5. Efficacy and safety of regorafenib compared to placebo and to post-cross-over regorafenib in advanced non-adipocytic soft tissue sarcoma

Author

Desmedt, Christine, Salgado, Roberto, Fornili, Marco, Pruneri, Giancarlo, van den Eynden, Gert, Zoppoli, Gabriele, Rothé, Françoise, Buisseret, Laurence, Garaud, Soizic, Willard-Gallo, Karen, Brown, David, Bareche, Yacine, Rouas, Ghizlane, Galant, Christine, Loi, Sherene, Viale, Giuseppe, Di Leo, Angelo, Green, Andrew, Ellis, Ian, Rakha, Emad, Larsimont, Denis, Biganzoli, Elia, Sotiriou, Christos, Brodowicz, Thomas, Mir, Olivier, Wallet, Jennifer, Italiano, Antoine, Blay, Jean-Yves, Bertucci, François, Eisterer, Wolfgang, Chevreau, Christine, Piperno-Neumann, Sophie, Bompas, Emmanuelle, Ryckewaert, Thomas, Liegl-Antzwager, Bernadette, Thery, Julien, Penel, Nicolas, Le Cesne, Axel, Le Deley, Marie-Cécile, Breast Cancer Translational Research Laboratory, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), University of Pisa - Università di Pisa, European Institute of Oncology [Milan] (ESMO), IRCCS Ospedale Policlinico San Martino [Genoa, Italy], Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Institut des Matériaux Jean Rouxel (IMN), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cliniques Universitaires Saint-Luc [Bruxelles], Division of Pathology and Laboratory Medicine, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), Translational Research Unit c/o Department of Oncology, Hospital of Prato, Istituto Toscano Tumori, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Université médicale de Vienne, Autriche, Sarcome, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Bergonié [Bordeaux], UNICANCER, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Département d'oncologie médicale [ICO, Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Département d'oncologie médicale, Ecole de Médecine [CHRU Lille], Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), 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 d'Etudes Médiévales de Montpellier (CEMM), and Université Paul-Valéry - Montpellier 3 (UPVM)

Subjects
0301 basic medicine, Leiomyosarcoma, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Pyridines, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Kaplan-Meier Estimate, Placebo, Placebos, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Double-Blind Method, Internal medicine, Regorafenib, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Cross-Over Studies, Proportional hazards model, business.industry, Soft tissue sarcoma, Phenylurea Compounds, Hazard ratio, Sarcoma, Middle Aged, medicine.disease, Synovial sarcoma, Progression-Free Survival, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Disease Progression, Female, business, Follow-Up Studies
Abstract

The placebo-controlled phase-2 REGOSARC trial demonstrated the efficacy of regorafenib in patients with leiomyosarcoma, synovial sarcoma and other non-adipocytic sarcoma but not in liposarcoma. Patients initially allocated to placebo were allowed to receive regorafenib after progression. We report here an updated analysis of the trial including evaluation of regorafenib activity after cross-over.From June 2013 to December 2014, 139 patients were enrolled in the non-adipocytic sarcoma cohorts. Median follow-up is now 32.4 months. Benefit of regorafenib versus placebo in terms of progression-free survival (PFS) and overall survival (OS) from randomisation was estimated by hazard ratio (HR) in Cox models. In the placebo arm, intra-patient benefit of regorafenib after cross-over was evaluated by the growth modulation index (GMI) (GMI was here, for each patient, PFS after cross-over regorafenib divided by PFS with placebo). Furthermore, the activity of delayed (after cross-over) versus early (at study entry) regorafenib was evaluated by comparing PFS after cross-over to regorafenib to PFS after randomisation in the regorafenib arm.PFS benefit of regorafenib as compared to placebo was confirmed with longer follow-up (HR = 0.50; 95% CI: 0.35-0.71; p .0001). OS was not statistically significant different (HR = 0.78; 0.54-1.12; p = .18). This finding may partially be explained by the fact that 55/68 patients who progressed on placebo (81%) received cross-over Regorafenib after progression: 59% of them had a GMI ≥ 1.3 (95% CI, 45-71%). Delayed start of regorafenib was associated with a statistically non-significant shorter PFS as compared to early treatment (HR = 1.21; 0.84-1.73; p = .30) without impact on OS.Observed PFS confirms that regorafenib warrants further clinical investigation in refractory non-adipocytic sarcomas.

Published
2018
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6. Impact of Trabectedin Interruption and Subsequent Rechallenge on Progression in Patients With Advanced Soft Tissue Sarcoma

Author

Kotecki, Nuria, Le Cesne, Axel, Tresch-Bruneel, Emmanuelle, Ray-Coquard, Isabelle, Chevreau, Christine, Bertucci, François, Bogart, Emilie, Mir, Olivier, Pautier, Patricia, Decoupigny, Emilie, Clisant, Stéphanie, Blay, Jean-Yves, Penel, Nicolas, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Sarcome, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Direction de la recherche et de l'innovation [Lille] (Centre Oscar Lambret), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Département d'Oncologie Médicale [Lyon] ( Centre Léon Bérard), Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-UNICANCER, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Ecole de Médecine [CHRU Lille], and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
[SDV.CAN]Life Sciences [q-bio]/Cancer, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018
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7. Molecular targeted therapies (MTT) in advanced chordoma (AC) patients (pts)

Author

Nicolas Penel, Loïc Lebellec, Michel Fabbro, Georges Noël, Loïc Feuvret, Emmanuelle Bompas, Didier Cupissol, Bruno Chauffert, Axel Le Cesne, François Bertucci, Olivier Mir, Alice Bonneville-Levard, Jacques-Olivier Bay, Jean-Yves Blay, Esma Saada, Christine Chevreau, Florence Duffaud, Elodie Vauleon, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Sarcome, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut Claudius Regaud, CRLCC René Gauducheau, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Institute of Developmental Biology and Cancer (IBDC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Medical Oncology Unit, S. Camillo-Forlanini Hospital, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Paul Strauss, CRLCC Paul Strauss, CHU Amiens-Picardie, CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), and Université de Picardie Jules Verne (UPJV)

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], education, Molecular Targeted Therapies, Retrospective cohort study, macromolecular substances, medicine.disease, carbohydrates (lipids), stomatognathic diseases, Internal medicine, otorhinolaryngologic diseases, medicine, bacteria, Chordoma, Sarcoma, business, health care economics and organizations
Abstract

11020Background: The data about the clinical benefit of MTT in AC pts are spare. Methods: Retrospective study of 74 AC pts treated between January 2004 and August 2015 in 12 major French sarcoma or...

Published
2016
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8. SEMA3A, a Gene Involved in Axonal Pathfinding, Is Mutated in Patients with Kallmann Syndrome

Author

Michel Pugeat, Charlotte Vanacker, Christine Cortet-Rudelli, Vincent Meyer, Corinne Fouveaut, Céline Campagne, Catherine Dodé, Chrystel Leroy, Stéphanie Baron, Gérard Chabrier, Jyoti Parkash, Alfons Garcia-Piñero, Vincent Prevot, Paolo Giacobini, Ksenija Gersak, Chantal Metz, Francis Collier, Cécile Espy, Jacques Young, J.-P. Hardelin, Didier Dewailly, Pierre Lhuillier, Naresh Kumar Hanchate, Corinne Cruaud, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Lille Nord de France, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Roger Salengro [Lille], Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), 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), Universitat de Barcelona (UB), Service Endocrinologie, diabétologie, maladies métaboliques et nutrition (LILLE - Endocrino), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Nouvel Hôpital Civil de Strasbourg, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service d'Endocrinologie (LILLE - Endocrino), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Prevot, Vincent

Subjects
Male, Cancer Research, Kallmann syndrome, Gonadotropin-releasing hormone, medicine.disease_cause, Gonadotropin-Releasing Hormone, Mice, Endocrinology, 0302 clinical medicine, Missense mutation, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Oligogenic Inheritance, Phenotype, 3. Good health, Medicine, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, Mice, 129 Strain, lcsh:QH426-470, Nose, Biology, Frameshift mutation, Molecular Genetics, 03 medical and health sciences, Fetus, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Semaphorin-3A, Human Genetics, Kallmann Syndrome, Neuroendocrinology, Embryo, Mammalian, medicine.disease, Axons, Neuropilin-1, Mice, Inbred C57BL, Disease Models, Animal, lcsh:Genetics, Genetics of Disease, 030217 neurology & neurosurgery
Abstract

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1 sema/sema mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS–like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder., Author Summary Kallmann syndrome is a hereditary developmental disease that affects both the hormonal reproductive axis and the sense of smell. There is a developmental link between the reproductive and olfactory disorders: neuroendocrine cells producing the gonadotropin-releasing hormone that is deficient in the patients normally migrate from the nose to the forebrain along olfactory nerve fibers during embryonic life, and they fail to do so in the patients. Affected individuals usually do not undergo spontaneous puberty. Hormone replacement therapy is the treatment to initiate virilization in males or breast development in females and later to develop fertility in both sexes. This is a genetically heterogeneous disease. Mutations in any of eight causative genes identified so far have been found in approximately 30% of the affected individuals, thus indicating that other genes remain to be discovered. We report on the identification, in 6% of the KS patients, of various loss-of-function mutations in the gene coding for semaphorin-3A, a secreted protein involved in the navigation of olfactory nerve fibers during embryogenesis. The fact that many of these mutations were also detected in clinically unaffected individuals indicates that they must combine with other genetic defects to produce the disease phenotype.

Published
2012
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9. Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

Author

Xavier d'Anglemont de Tassigny, William H. Colledge, Danièle Mazur, Naresh Kumar Hanchate, Jyoti Parkash, Nicole Bellefontaine, Vincent Prevot, Prevot, Vincent, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine predictive et de recherche thérapeutique (IMPRT), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Cambridge [UK] (CAM), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], and Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Ovulation, medicine.medical_specialty, endocrine system, media_common.quotation_subject, Hypothalamus, Enzyme-Linked Immunosorbent Assay, Estrous Cycle, Nitric Oxide Synthase Type I, Biology, Inhibitory postsynaptic potential, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, 0302 clinical medicine, Kisspeptin, Internal medicine, medicine, Animals, Premovement neuronal activity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Enzyme Inhibitors, Phosphorylation, Receptor, PI3K/AKT/mTOR pathway, 030304 developmental biology, media_common, Mice, Knockout, Neurons, Analysis of Variance, Kisspeptins, 0303 health sciences, General Neuroscience, Articles, Luteinizing Hormone, Cell biology, Mice, Inbred C57BL, Endocrinology, Gene Expression Regulation, nervous system, Female, Steroids, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Receptors, Kisspeptin-1, Signal Transduction
Abstract

Reproduction is controlled in the brain by a neural network that drives the secretion of gonadotropin-releasing hormone (GnRH). Various permissive homeostatic signals must be integrated to achieve ovulation in mammals. However, the neural events controlling the timely activation of GnRH neurons are not completely understood. Here we show that kisspeptin, a potent activator of GnRH neuronal activity, directly communicates with neurons that synthesize the gaseous transmitter nitric oxide (NO) in the preoptic region to coordinate the progression of the ovarian cycle. Using a transgenicGpr54-null IRES-LacZ knock-in mouse model, we demonstrate that neurons containing neuronal NO synthase (nNOS), which are morphologically associated with kisspeptin fibers, express the kisspeptin receptor GPR54 in the preoptic region, but not in the tuberal region of the hypothalamus. The activation of kisspeptin signaling in preoptic neurons promotes the activation of nNOS through its phosphorylation on serine 1412 via the AKT pathway and mimics the positive feedback effects of estrogens. Finally, we show that while NO release restrains the reproductive axis at stages of the ovarian cycle during which estrogens exert their inhibitory feedback, it is required for the kisspeptin-dependent preovulatory activation of GnRH neurons. Thus, interactions between kisspeptin and nNOS neurons may play a central role in regulating the hypothalamic–pituitary–gonadal axisin vivo.

Published
2012
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