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1. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

Author

T. Dumontet, Antoine Martinez, Bruno Ragazzon, Anne-Marie Lefrançois-Martinez, Jean-Christophe Pointud, Nathanaëlle Montanier, Jérôme Bertherat, Igor Tauveron, Florence Roucher-Boulez, Isabelle Sahut-Barnola, Annabel Berthon, Damien Dufour, Pierre Val, Cyril Djari, M. Batisse-Lignier, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’endocrinologie diabétologie et maladies métaboliques, CHU Clermont-Ferrand, CHU Lyon, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d’Endocrinologie Diabète et Maladies Métaboliques [CHU Clermont-Ferrand], Pôle RHEUNNIRS [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, Centre de référence des maladies rares de la surrénale ( CHU Cochin [AP-HP]), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), and Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, MESH: Neoplasm Proteins, MESH: Signal Transduction, MESH: beta Catenin, SUMO protein, MESH: Adrenal Cortex Neoplasms, Biochemistry, MESH: Mice, Knockout, Dexamethasone, MESH: Zona Fasciculata, Mice, 0302 clinical medicine, Cortex (anatomy), PKA, MESH: Animals, Cycloheximide, MESH: Cycloheximide, Wnt Signaling Pathway, beta Catenin, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Adrenal cortex, MESH: Sumoylation, MESH: Wnt Signaling Pathway, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, PIAS3.β-catenin, Cell biology, Neoplasm Proteins, medicine.anatomical_structure, MESH: Dexamethasone, Dactinomycin, Female, Zona Glomerulosa, Signal transduction, Biotechnology, Endocrine gland, Signal Transduction, MESH: Colforsin, MESH: Cell Line, Tumor, MESH: Mice, Transgenic, MESH: Zona Glomerulosa, MESH: Delayed-Action Preparations, Repressor, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Cyclic AMP-Dependent Protein Kinases, Biology, 03 medical and health sciences, MESH: Carney Complex, Adrenocorticotropic Hormone, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Animals, Humans, mouse models, Carney Complex, Molecular Biology, Psychological repression, MESH: Mice, MESH: Adrenocorticotropic Hormone, MESH: Humans, Colforsin, Sumoylation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, endocrine diseases, Cyclic AMP-Dependent Protein Kinases, Adrenal Cortex Neoplasms, MESH: Dactinomycin, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, SENP1/2, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Delayed-Action Preparations, MESH: Protein Processing, Post-Translational, Adrenal Cortex, MESH: Adrenal Cortex, Zona Fasciculata, Protein Processing, Post-Translational, MESH: Female, 030217 neurology & neurosurgery, Homeostasis
Abstract

SUMOylation is a highly conserved and dynamic post-translational mechanism primarily affecting nuclear programs for adapting organisms to stressful challenges. Alteration of SUMOylation cycles leads to severe developmental and homeostatic defects and malignancy, but signals coordinating SUMOylation are still unidentified. The adrenal cortex is a zonated endocrine gland that controls body homeostasis and stress response. Here, we show that in human and in mouse adrenals, SUMOylation follows a decreasing centripetal gradient that mirrors cortical differentiation flow and delimits highly and weakly SUMOylated steroidogenic compartments, overlapping glomerulosa, and fasciculata zones. Activation of PKA signaling by acute hormonal treatment, mouse genetic engineering, or in Carney complex results in repression of small ubiquitin-like modifier (SUMO) conjugation in the inner cortex by coordinating expression of SUMO pathway inducers and repressors. Conversely, genetic activation of canonical wingless-related integration site signaling maintains high SUMOylation potential in the outer neoplastic cortex. Thus, SUMOylation is tightly regulated by signaling pathways that orchestrate adrenal zonation and diseases.-Dumontet, T., Sahut-Barnola, I., Dufour, D., Lefrancois-Martinez, A.-M., Berthon, A., Montanier, N., Ragazzon, B., Djari, C., Pointud, J.-C., Roucher-Boulez, F., Batisse-Lignier, M., Tauveron, I., Bertherat, J., Val, P., Martinez, A. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.

Published
2019

2. Dexamethasone and Recombinant Human Activated Protein C Improve Myocardial Function and Efficiency During Experimental Septic Shock

Author

Bruno Levy, Jérémie Lemarié, Youcef Bouazza, Alice Blet, Ferhat Meziani, Julie Boisramé-Helms, Service de Réanimation Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Traitement des Brûlés, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Service de réanimation Médicale [Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu], and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]

Subjects
Male, Resuscitation, MESH: Myocardial Contraction, medicine.medical_treatment, Critical Care and Intensive Care Medicine, Dexamethasone, MESH: Recombinant Proteins, chemistry.chemical_compound, Anti-Infective Agents, Medicine, MESH: Animals, biology, Heart, Shock, Septic, Recombinant Proteins, 3. Good health, Nitric oxide synthase, Shock (circulatory), MESH: Dexamethasone, Emergency Medicine, Cardiology, Drug Therapy, Combination, medicine.symptom, medicine.drug, medicine.medical_specialty, MESH: Myocardium, MESH: Rats, MESH: Anti-Infective Agents, MESH: Shock, Septic, Nitric oxide, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Animals, Humans, Rats, Wistar, Ligature, Glucocorticoids, MESH: Humans, business.industry, Septic shock, Myocardium, Electron Spin Resonance Spectroscopy, MESH: Rats, Wistar, medicine.disease, Myocardial Contraction, MESH: Male, Rats, MESH: Heart, Disease Models, Animal, Preload, MESH: Drug Therapy, Combination, chemistry, Immunology, biology.protein, MESH: Electron Spin Resonance Spectroscopy, MESH: Disease Models, Animal, business, MESH: Glucocorticoids, Protein C, MESH: Protein C
Abstract

International audience; Corticosteroids have been shown to reduce short-term mortality during septic shock and therefore recommended in the most severe patients as adjuvant therapy. Until recently, recombinant human activated protein C (APC) was also considered in the management of more severe cases. As myocardial depression has long been recognized as a manifestation of organ dysfunction during septic shock, we examined whether corticosteroids (dexamethasone, 150 µg/kg per hour) and/or APC (33 µg/kg per hour) treatments improve sepsis-induced cardiac dysfunction during cecal ligature and puncture-induced septic shock in Wistar rats. All rats received intravenous saline resuscitation (10 mL/kg per hour) and antibiotics. Eighteen hours after surgery, anesthesia was performed (isoflurane), and myocardial function was assessed using a conductance catheter introduced into the left ventricle. Rats were then killed; blood and heart were harvested for biological analysis, including radical oxygen species determination. Cecal ligature and puncture induced hypotension, depression of myocardial systolic performance (demonstrated by significant decreases in dP/dtmax [first derivative of maximal developed pressure during isovolumetric contraction], end-systolic pressure-volume relationship, and preload recruitable stroke work) and alteration of diastolic function (dP/dtmin [first derivative of minimal developed pressure during isovolumetric relaxation]), whereas dexamethasone, APC, and their combination thereof allowed correction of hemodynamic disorders and improved myocardial mechanical efficiency. Cecal ligature and puncture was associated with higher levels of nitric oxide and superoxide anion (O2) in heart (electron paramagnetic resonance studies) and consequently peroxynitrite. Dexamethasone and APC also improved cardiac dysfunction by downregulating the inducible nitric oxide synthase pathway and reducing myocardial oxidative stress.

Published
2014

3. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS

Author

A. El Yamani, Roch Houot, J L Harousseau, Kamal Bouabdallah, Stéphane Courby, M. Ojeda Uribe, Nina Arakelyan, M. Alexis Vigier, Hervé Maisonneuve, Philippe Rodon, Caroline Dartigeas, S. Le Gouill, Remy Gressin, O. Tournilhac, Marie-Pierre Moles, Laurent Sutton, Luc Mathieu Fornecker, D. Assouline, Sylvie Caulet-Maugendre, Christiane Mounier, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hematology, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Department of clinical hematology, CHU Grenoble, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Nantes Angers Le Mans (UNAM), Clinical Haematology, CHU Hôtel-Dieu, Service d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre hospitalier du Mans, Centre Hospitalier Le Mans (CH Le Mans), Service greffe de moelle osseuse, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre hospitalier La Roche-Sur-Yon, Université de Rennes (UR)-Hôpital Pontchaillou, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140

Subjects
Male, Oncology, medicine.medical_treatment, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell, Dexamethasone, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, rituximab, MESH: Aged, 80 and over, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, 0303 health sciences, Bortezomib, bortezomib, Hematology, MESH: Chlorambucil, Boronic Acids, Chemotherapy regimen, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Pyrazines, 030220 oncology & carcinogenesis, MESH: Pyrazines, MESH: Dexamethasone, Female, Rituximab, MESH: Boronic Acids, medicine.drug, medicine.medical_specialty, Vincristine, lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, elderly, Disease-Free Survival, 03 medical and health sciences, MESH: Doxorubicin, Internal medicine, medicine, Humans, MESH: Kaplan-Meier Estimate, Aged, 030304 developmental biology, mantle cell, Chemotherapy, MESH: Humans, Chlorambucil, business.industry, medicine.disease, MESH: Male, Surgery, Regimen, Doxorubicin, MESH: Antibodies, Monoclonal, Murine-Derived, MESH: Disease-Free Survival, Mantle cell lymphoma, MESH: Lymphoma, Mantle-Cell, business, MESH: Female
Abstract

International audience; BACKGROUND: There is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL. PATIENTS AND METHODS: Patients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C. RESULTS: Thirty-nine patients were enrolled. Median age was 72 years (65-80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity. CONCLUSION: The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.

Published
2012

4. Activation of protein kinase A and exchange protein directly activated by cAMP promotes adipocyte differentiation of human mesenchymal stem cells

Author

Bingbing Jia, Reidun K. Kopperud, Gérard Ailhaud, Nathalie Techer, Karsten Kristiansen, Ez-Zoubir Amri, Jinfu Wang, Rasmus Koefoed Petersen, Stein Ove Døskeland, Lise Madsen, Tao Ma, Dept. Biochemistry and Molecular Biology, Odense, University of Southern Denmark (SDU), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Biochemistry and Molecular Biology, Department of Biology [Copenhagen], Faculty of Science [Copenhagen], and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)

Subjects
MESH: Signal Transduction, IBMX, Cellular differentiation, lcsh:Medicine, MESH: Thiazolidinediones, Biochemistry, Dexamethasone, chemistry.chemical_compound, Mice, 0302 clinical medicine, Adipocyte, 1-Methyl-3-isobutylxanthine, Molecular Cell Biology, Adipocytes, Cyclic AMP, MESH: Guanine Nucleotide Exchange Factors, MESH: Obesity, Guanine Nucleotide Exchange Factors, Insulin, MESH: Animals, lcsh:Science, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Cyclic AMP, 0303 health sciences, Multidisciplinary, Stem Cells, MESH: 1-Methyl-3-isobutylxanthine, Cell Differentiation, MESH: Gene Expression Regulation, Lipids, Signaling Cascades, Cell biology, Adipose Tissue, Adipogenesis, MESH: Dexamethasone, 030220 oncology & carcinogenesis, Signal transduction, MESH: Adipose Tissue, Research Article, Signal Transduction, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Insulin, MESH: Cyclic AMP-Dependent Protein Kinases, MESH: Epoprostenol, Biology, Cell Line, Rosiglitazone, MESH: Gene Expression Profiling, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Obesity, Protein kinase A, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Humans, Gene Expression Profiling, Mesenchymal stem cell, lcsh:R, Mesenchymal Stem Cells, Cyclic AMP-Dependent Protein Kinases, Epoprostenol, MESH: Cell Line, MESH: Mesenchymal Stem Cells, Endocrinology, chemistry, Gene Expression Regulation, Cell culture, Thiazolidinediones, lcsh:Q, Developmental Biology
Abstract

Human mesenchymal stem cells are primary multipotent cells capable of differentiating into several cell types including adipocytes when cultured under defined in vitro conditions. In the present study we investigated the role of cAMP signaling and its downstream effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in adipocyte conversion of human mesenchymal stem cells derived from adipose tissue (hMADS). We show that cAMP signaling involving the simultaneous activation of both PKA- and Epac-dependent signaling is critical for this process even in the presence of the strong adipogenic inducers insulin, dexamethasone, and rosiglitazone, thereby clearly distinguishing the hMADS cells from murine preadipocytes cell lines, where rosiglitazone together with dexamethasone and insulin strongly promotes adipocyte differentiation. We further show that prostaglandin I(2) (PGI(2)) may fully substitute for the cAMP-elevating agent isobutylmethylxanthine (IBMX). Moreover, selective activation of Epac-dependent signaling promoted adipocyte differentiation when the Rho-associated kinase (ROCK) was inhibited. Unlike the case for murine preadipocytes cell lines, long-chain fatty acids, like arachidonic acid, did not promote adipocyte differentiation of hMADS cells in the absence of a PPARγ agonist. However, prolonged treatment with the synthetic PPARδ agonist L165041 promoted adipocyte differentiation of hMADS cells in the presence of IBMX. Taken together our results emphasize the need for cAMP signaling in concert with treatment with a PPARγ or PPARδ agonist to secure efficient adipocyte differentiation of human hMADS mesenchymal stem cells.

Published
2012

5. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue

Author

Flora Picard, Carine Valle, P. Barbe, Jason S. Iacovoni, Nathalie Viguerie, Balbine Roussel, Wim H. M. Saris, Gabby B. Hul, Dominique Langin, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Department of Human Biology, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]

Subjects
Male, MESH: Serum Amyloid A Protein, Physiology, Adipose tissue, Dexamethasone, ACTIVATION, 0302 clinical medicine, Mineralocorticoid receptor, Longitudinal Studies, MESH: Longitudinal Studies, GENE-EXPRESSION, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Muscle, Skeletal, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, C-Reactive Protein, medicine.anatomical_structure, Adipose Tissue, MESH: Dexamethasone, medicine.symptom, Glucocorticoid, MESH: Adipose Tissue, medicine.drug, Adult, medicine.medical_specialty, Adipose tissue macrophages, 030209 endocrinology & metabolism, Inflammation, Biology, METABOLISM, 03 medical and health sciences, Downregulation and upregulation, MICROARRAY, INFLAMMATION, Internal medicine, MESH: C-Reactive Protein, Genetics, medicine, gene expression profiling, Humans, GLUCOCORTICOIDS, Muscle, Skeletal, 030304 developmental biology, Serum Amyloid A Protein, MESH: Humans, Skeletal muscle, 3T3-L1 ADIPOCYTES, MESH: Adult, INSULIN-RESISTANT MICE, MESH: Male, Endocrinology, healthy volunteers, SERUM-AMYLOID-A, CELLS, glucocorticoid, MESH: Glucocorticoids
Abstract

Viguerie N, Picard F, Hul G, Roussel B, Barbe P, Iacovoni JS, Valle C, Langin D, Saris WHM. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue. Physiol Genomics 44: 141-151, 2012. First published November 22, 2011; doi:10.1152/physiolgenomics.00032.2011.-Glucocorticoids are frequently prescribed drugs with important side-effects such as glucose intolerance and tissue remodeling. The goal was to explore the molecular basis of the response of skeletal muscle and adipose tissue during a short-term dexamethasone treatment to better understand the induction of side-effects of glucocorticoids on these metabolic tissues. Fifteen healthy male subjects were assigned to a 4-day treatment with dexamethasone at 4 mg/day. The primary outcome measures were changes in gene expression profiling of subcutaneous skeletal muscle and adipose tissue. Urinary cortisol, plasma, and metabolic biochemistry were also assessed. In both tissues the prominent observation was a response to stress and increased inflammatory responses. An upregulation of the serum amyloid A was detected in skeletal muscle, adipose tissue, and plasma, whereas circulating levels of C reactive protein, another acute phase protein, decreased along with a worsened insulin sensitivity index. As tissue-specific features, tissue remodeling was shown in skeletal muscle while the adipose tissue exhibited a decreased energy metabolism. Several limitations might be raised due to the small number of subjects investigated: a possible cross talk with the mineralocorticoid receptor, and a single time point may not identify regulations occurring during longitudinal treatment. In line with the known physiological effect of glucocorticoids the early modulation of stress response genes was observed. An unexpected feature was the upregulation of the inflammatory and immune pathways. The identification of novel impact on two glucocorticoid target tissues provides a molecular basis for the design of more specific glucocorticoids devoid of adverse effects.

Published
2012

6. A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

Author

Hunault-Berger, Mathilde, Leguay, Thibaut, Thomas, Xavier, Legrand, Ollivier, Huguet, Françoise, Bonmati, Caroline, Escoffre-Barbe, Martine, Legros, Laurence, Turlure, Pascal, Chevallier, Patrice, Larosa, Fabrice, Garban, Frederic, Reman, Oumedaly, Rousselot, Philippe, Dhédin, Nathalie, Delannoy, André, Lafage-Pochitaloff, Marina, Béné, Marie Christine, Ifrah, Norbert, Dombret, Hervé, Renseigné, Non, Service des maladies du sang, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'hématologie clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), TheREx, 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)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Hôpital de Jolimont, Haine-Saint-Paul and Cliniques Universitaires St Luc, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Immunologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Hôpital Pontchaillou, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-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 Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-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)-Département de cancérologie et d'hématologie

Subjects
Male, Pharmacology, Gastroenterology, Dexamethasone, Polyethylene Glycols, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cumulative incidence, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, Hematology, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Vincristine, 030220 oncology & carcinogenesis, MESH: Dexamethasone, Toxicity, Female, Original Article, MESH: Neoplasm Recurrence, Local, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide, MESH: Survival Rate, MESH: Vincristine, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, MESH: Doxorubicin, Internal medicine, medicine, Humans, Doxorubicin, Survival rate, Aged, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, MESH: Cyclophosphamide, MESH: Adult, medicine.disease, MESH: Male, MESH: Polyethylene Glycols, Bacteremia, Liposomes, MESH: Liposomes, Neoplasm Recurrence, Local, business, MESH: Female, 030215 immunology
Abstract

International audience; BACKGROUND: The prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia. DESIGN AND METHODS: Sixty patients received either continuous-infusion doxorubicin (12 mg/m(2)/day) and continuous-infusion vincristine (0.4 mg/day) on days 1-4 or pegylated liposomal doxorubicin (40 mg/m(2)) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors. RESULTS: Myelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm. CONCLUSIONS: With the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities.

Published
2011

7. Increased Lipiodol uptake in hepatocellular carcinoma possibly due to increased membrane fluidity by dexamethasone and tamoxifen

Author

Nicolas Lepareur, François Gaboriau, Nicolas Noiret, Odile Sergent, Valérie Ardisson, Jean-Luc Raoul, Stéphanie Becker, Etienne Garin, Sahar Bayat, Bruno Clément, E. Boucher, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis (CRLCC), Microenvironnement et remodelage, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-CRLCC Eugène Marquis (CRLCC), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Modélisation Conceptuelle des Connaissances Biomédicales, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR)-Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-CRLCC Eugène Marquis (CRLCC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)

Subjects
Cancer Research, Lipiodol, Pharmacology, Dexamethasone, Fluidity, MESH: Benzamides, 0302 clinical medicine, Ethiodized Oil, MESH: Liver Neoplasms, Membrane fluidity, Tumor Cells, Cultured, Tissue Distribution, MESH: Animals, MESH: Double-Blind Method, MESH: Carcinoma, Hepatocellular, 0303 health sciences, MESH: Middle Aged, Liver Neoplasms, 3. Good health, Injections, Intra-Arterial, Selective estrogen receptor modulator, 030220 oncology & carcinogenesis, MESH: Dexamethasone, Molecular Medicine, Corticosteroid, MESH: Gastric Emptying, medicine.drug, medicine.medical_specialty, Hepatocarcinoma, Carcinoma, Hepatocellular, MESH: Rats, medicine.drug_class, Membrane Fluidity, MESH: Morpholines, Antineoplastic Agents, 03 medical and health sciences, MESH: Ethiodized Oil, In vivo, Internal medicine, medicine, Animals, Radiology, Nuclear Medicine and imaging, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Tumor Cells, Cultured, MESH: Tissue Distribution, 030304 developmental biology, MESH: Drug Evaluation, MESH: Humans, business.industry, Electron Spin Resonance Spectroscopy, MESH: Adult, Antiestrogen, MESH: Gastrointestinal Agents, MESH: Male, Rats, Tamoxifen, Endocrinology, MESH: Injections, Intra-Arterial, MESH: Antineoplastic Agents, MESH: Electron Spin Resonance Spectroscopy, MESH: Tamoxifen, business, MESH: Membrane Fluidity
Abstract

International audience; INTRODUCTION: Lipiodol is used as a vector for chemoembolization or internal radiotherapy in unresectable hepatocellular carcinomas (HCCs). The aim of this study is to improve the tumoral uptake of Lipiodol by modulating membrane fluidizing agents to optimize the effectiveness of Lipiodol vectorized therapy. METHODS: The effect of dexamethasone and tamoxifen on membrane fluidity was studied in vitro by electron paramagnetic resonance applied to rat hepatocarcinoma cell line N1S1. The tumoral uptake of Lipiodol was studied in vivo on rats with HCC, which had been previously treated by dexamethasone and/or tamoxifen, after intra-arterial administration of (99m)Tc-SSS-Lipiodol. RESULTS: The two molecules studied here exhibit a fluidizing effect in vitro which appears dependent on time and dose, with a maximum fluidity obtained after 1 hr at concentrations of 20 μM for dexamethasone and 200 nM for tamoxifen. In vivo, while the use of dexamethasone or tamoxifen alone tends to lead to increased tumoral uptake of Lipiodol, this effect does not reach levels of significance. On the other hand, there is a significant increase in the tumoral uptake of (99m)Tc-SSS-Lipiodol in rats pretreated by both dexamethasone and tamoxifen, with a tumoral uptake (expressed in % of injected activity per g of tumor) of 13.57 ± 3.65% after treatment, as against 9.45 ± 4.44% without treatment (P

Published
2010

8. 18F-FDG PET/CT in primary non-Hodgkin's lymphoma of the sinonasal tract

Author

Sylvie Boisramé, Christian Berthou, Gerald Valette, Solène Querellou, Adrian Tempescul, Jean-Christophe Ianotto, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Department of Nuclear Medicine, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Department of Odontology, Department of ORL, Université européenne de Bretagne - European University of Brittany (UEB), and Michel, Geneviève

Subjects
medicine.medical_specialty, Pathology, MESH: Remission Induction, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Tomography, Emission-Computed, MESH: Vincristine, MESH: Prognosis, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, MESH: Doxorubicin, 0302 clinical medicine, MESH: Lymphoma, Non-Hodgkin, MESH: Fluorodeoxyglucose F18, Internal medicine, medicine, MESH: Cytarabine, ComputingMilieux_MISCELLANEOUS, MESH: Aged, MESH: Paranasal Sinus Neoplasms, Hematology, MESH: Humans, MESH: Middle Aged, business.industry, MESH: Organoplatinum Compounds, MESH: Cyclophosphamide, General Medicine, Sinonasal Tract, medicine.disease, MESH: Positron-Emission Tomography, Non-Hodgkin's lymphoma, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, MESH: Dexamethasone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Fdg pet ct, Radiology, business, MESH: Paranasal Sinuses, MESH: Prednisone
Abstract

International audience

Published
2010

9. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 Trials

Author

Michel Attal, Nicolas Ketterer, Thierry Lamy, Cyrille Hulin, Hervé Avet-Loiseau, Laurent Voillat, Thierry Facon, Jean-Luc Harousseau, Gerald Marit, Laurent Garderet, Claire Mathiot, François Guilhot, Catherine Charbonnel, Chantal Doyen, Philippe Moreau, Mauricette Michallet, Frédéric Garban, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Thales Alenia Space [Cannes], Thales Alenia Space, Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Claude Huriez [Lille], CHU Lille, Institut Cochin (UMR_S567 / UMR 8104), 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 des maladies du sang, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Poitiers-Institut de Chimie du CNRS (INC), Hématologie et oncologie pédiatrique, Thales Alenia Space [Toulouse] (TAS), THALES [France], Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Université Toulouse III - Paul Sabatier ( UPS ), Thales Alenia Space ( TAS ), THALES, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Chimie des Milieux et Matériaux de Poitiers ( IC2MP ), and Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Oncology, Cancer Research, MESH: Combined Modality Therapy, MESH: Remission Induction, MESH : Antineoplastic Combined Chemotherapy Protocols, medicine.medical_treatment, MESH: Multiple Myeloma, Hematopoietic stem cell transplantation, Dexamethasone, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Multiple myeloma, MESH : Prognosis, MESH: Middle Aged, Remission Induction, Hematopoietic Stem Cell Transplantation, Middle Aged, MESH : Survival Rate, Prognosis, Combined Modality Therapy, MESH: Transplantation, Autologous, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Vincristine, 030220 oncology & carcinogenesis, MESH: Dexamethasone, MESH : Disease-Free Survival, Multiple Myeloma, MESH : Dexamethasone, medicine.drug, MESH : Vincristine, medicine.medical_specialty, MESH : Transplantation, Autologous, MESH: Survival Rate, Context (language use), MESH: Vincristine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transplantation, Autologous, Disease-Free Survival, MESH: Prognosis, 03 medical and health sciences, MESH: Doxorubicin, MESH : Hematopoietic Stem Cell Transplantation, Internal medicine, MESH : Doxorubicin, Humans, MESH : Middle Aged, Survival rate, MESH: Hematopoietic Stem Cell Transplantation, Very Good Partial Response, MESH : Remission Induction, MESH: Humans, business.industry, MESH : Humans, medicine.disease, Surgery, Transplantation, Doxorubicin, MESH: Disease-Free Survival, MESH : Combined Modality Therapy, MESH : Multiple Myeloma, business, 030215 immunology
Abstract

Purpose The prognostic impact of complete response (CR) achievement in multiple myeloma (MM) has been shown mostly in the context of autologous stem-cell transplantation. Other levels of response have been defined because, even with high-dose therapy, CR is a relatively rare event. The purpose of this study was to analyze the prognostic impact of very good partial response (VGPR) in patients treated with high-dose therapy. Patients and Methods All patients were included in the Intergroupe Francophone du Myelome 99-02 and 99-04 trials and treated with vincristine, doxorubicin, and dexamethasone (VAD) induction therapy followed by double autologous stem-cell transplantation (ASCT). Best post-ASCT response assessment was available for 802 patients. Results With a median follow-up of 67 months, median event-free survival (EFS) and 5-year EFS were 42 months and 34%, respectively, for 405 patients who achieved at least VGPR after ASCT versus 32 months and 26% in 288 patients who achieved only partial remission (P = .005). Five-year overall survival (OS) was significantly superior in patients achieving at least VGPR (74% v 61% P = .0017). In multivariate analysis, achievement of less than VGPR was an independent factor predicting shorter EFS and OS. Response to VAD had no impact on EFS and OS. The impact of VGPR achievement on EFS and OS was significant in patients with International Staging System stages 2 to 3 and for patients with poor-risk cytogenetics t(4;14) or del(17p). Conclusion In the context of ASCT, achievement of at least VGPR is a simple prognostic factor that has importance in intermediate and high-risk MM and can be informative in more patients than CR.

Published
2009

10. Stathmin-like 2, a developmentally-associated neuronal marker, is expressed and modulated during osteogenesis of human mesenchymal stem cells

Author

Marcel Scheideler, Christian Dani, Gabriele Grenningloh, Chiara Chiellini, Gérard Ailhaud, Olivia Cochet, Ez-Zoubir Amri, Zlatko Trajanoski, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Center for Psychiatric Neuroscience, Lausanne, Université de Lausanne (UNIL), Institute for Genomics and Bioinformatics, Graz, and Karl-Franzens-Universität [Graz, Autriche]

Subjects
RHOA, Pyridines, MESH: Neurons, Golgi Apparatus, Biochemistry, Dexamethasone, chemistry.chemical_compound, Cytosol, 0302 clinical medicine, MESH: Cytosol, Osteogenesis, Adipocyte, Adipocytes, MESH: Protein Kinase Inhibitors, MESH: Osteogenesis, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Stem cell transplantation for articular cartilage repair, Neurons, rho-Associated Kinases, 0303 health sciences, Adipogenesis, biology, MESH: Bone Marrow Cells, Osteoblast, MESH: Amides, Cell biology, medicine.anatomical_structure, Adipose Tissue, MESH: Dexamethasone, MESH: Membrane Proteins, Stem cell, MESH: rho-Associated Kinases, MESH: Adipose Tissue, medicine.medical_specialty, Biophysics, Bone Marrow Cells, Stathmin, 03 medical and health sciences, MESH: Golgi Apparatus, Internal medicine, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Protein Kinase Inhibitors, Molecular Biology, MESH: Adipocytes, 030304 developmental biology, MESH: RNA, Messenger, MESH: Osteoblasts, Osteoblasts, MESH: Humans, Mesenchymal stem cell, MESH: Pyridines, MESH: Biological Markers, Membrane Proteins, Mesenchymal Stem Cells, Cell Biology, Amides, Endocrinology, MESH: Mesenchymal Stem Cells, chemistry, biology.protein, MESH: Adipogenesis, Biomarkers, 030217 neurology & neurosurgery
Abstract

International audience; Stathmin-like 2 (STMN2) protein, a neuronal protein of the stathmin family, has been implicated in the microtubule regulatory network as a crucial element of cytoskeletal regulation. Herein, we describe that STMN2 expression increases at both mRNA and protein levels during osteogenesis of human mesenchymal stem cells derived from adipose tissue (hMADS cells) and bone marrow (hBMS cells), whereas it decreases to undetectable levels during adipogenesis. STMN2 protein is localized in both Golgi and cytosolic compartments. Its expression appears modulated in osteoblasts by nerve growth factor, dexamethasone or RhoA kinase inhibitor Y-27632 which are known effectors of osteogenesis. Thus STMN2 appears a novel marker of osteogenesis and osteoblast per se, that could play a role in the regulation of the adipocyte/osteoblast balance.

Published
2008

11. Successful heart transplantation following melphalan plus dexamethasone therapy in systemic AL amyloidosis

Author

Jean-Michel Goujon, Frank Bridoux, Frédéric Favreau, Antoine Thierry, Annick Delcourt, Daniel Herpin, Shaida Varnous, Arnaud Jaccard, Aude Mignot, Jean Marc Gombert, Guy Touchard, Myriam Pujo, Service de Néphrologie-Hémodialyse-Transplantation rénale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie [Poitiers], Service d'Hématologie biologique [CHU Limoges], and CHU Limoges

Subjects
Graft Rejection, Male, Melphalan, Nephrotic Syndrome, medicine.medical_treatment, Paraproteinemias, 030204 cardiovascular system & hematology, Gastroenterology, Dexamethasone, 0302 clinical medicine, Autologous stem-cell transplantation, MESH: Paraproteinemias, Secondary Prevention, Medicine, 030212 general & internal medicine, Heart transplantation, MESH: Middle Aged, Peripheral Nervous System Diseases, MESH: Heart Transplantation, Amyloidosis, Hematology, Middle Aged, 3. Good health, surgical procedures, operative, MESH: Dexamethasone, MESH: Immunoglobulin lambda-Chains, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Therapy, Combination, MESH: Peripheral Nervous System Diseases, medicine.drug, medicine.medical_specialty, MESH: Immunoglobulin kappa-Chains, MESH: Graft Rejection, Immunoglobulin kappa-Chains, 03 medical and health sciences, MESH: Melphalan, Immunoglobulin lambda-Chains, Internal medicine, AL amyloidosis, Humans, MESH: Amyloidosis, Heart Failure, MESH: Humans, business.industry, Restrictive cardiomyopathy, medicine.disease, MESH: Male, Surgery, MESH: Recurrence, Transplantation, MESH: Drug Therapy, Combination, Heart failure, MESH: Heart Failure, Heart Transplantation, MESH: Nephrotic Syndrome, business
Abstract

International audience; Recurrence in the allograft and progression in other organs increase mortality after cardiac transplantation in AL amyloidosis. Survival may be improved after suppression of monoclonal light chain (LC) production following high dose melphalan and autologous stem cell transplantation (HDM/ASCT). However, because of high treatment related mortality, this tandem approach is restricted to few patients without significant extra-cardiac involvement. A diagnosis of systemic AL amyloidosis was established in a 45-year old patient with congestive heart failure related to restrictive cardiomyopathy, nephrotic syndrome, peripheral neuropathy, postural hypotension, macroglossia, and lambda LC monoclonal gammopathy. After melphalan and dexamethasone (M-Dex) therapy, which resulted in 80% reduction of serum free lambda LC, he underwent orthotopic cardiac transplantation. Two years later, he remains in a sustained hematologic remission, with no evidence of allograft or extra-cardiac amyloid accumulation. M-Dex should be considered as an alternative therapy in AL amyloid heart transplant recipients ineligible for HDM/ASCT.

Published
2008

12. Proteomics unveil corticoid-induced S100A11 shuttling in keratinocyte differentiation

Author

Xavier Dezitter, Bernadette Masselot, Hervé Drobecq, Thierry Idziorek, Denise Mendy, Fatma Hammoudi, Pierre Formstecher, Jean-Christophe Deloulme, Nicolas Belverge, 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, Transduction du signal : signalisation calcium, phosphorylation et inflammation, 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), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Collaboration, Andrieux, Annie, 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, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé

Subjects
Keratinocytes, Proteomics, Apoptosis, Mitochondrion, Biochemistry, Dexamethasone, MESH: Cell Compartmentation, Protein purification, Cells, Cultured, 0303 health sciences, MESH: Middle Aged, MESH: Proteomics, 030302 biochemistry & molecular biology, S100 Proteins, Cell Differentiation, Middle Aged, MESH: Keratinocytes, Cell biology, medicine.anatomical_structure, MESH: Calcium, MESH: Dexamethasone, Female, Keratinocyte, MESH: S100 Proteins, MESH: Cells, Cultured, Adult, MESH: Cell Differentiation, Biophysics, Active Transport, Cell Nucleus, chemistry.chemical_element, MESH: Active Transport, Cell Nucleus, Calcium, Biology, 03 medical and health sciences, Organelle, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Glucocorticoids, 030304 developmental biology, Calcium metabolism, MESH: Humans, MESH: Apoptosis, Cell Membrane, MESH: Adult, Cell Biology, Cell Compartmentation, chemistry, Cytoplasm, MESH: Glucocorticoids, MESH: Female, MESH: Cell Membrane
Abstract

International audience; Unlike classical protein extraction techniques, proteomic mapping using a selective subcellular extraction kit revealed S100A11 as a new member of the S100 protein family modulated by glucocorticoids in keratinocytes. Glucocorticoids (GC)-induced S100A11 redistribution in the "organelles and membranes" compartment. Microscopic examination indicated that glucocorticoids specifically routed cytoplasmic S100A11 toward perinuclear compartment. Calcium, a key component of skin terminal differentiation, directed S100A11 to the plasma membrane as previously reported. When calcium was added to glucocorticoids, minor change was observed at the proteomic level while confocal microscopy revealed a rapid and dramatic translocation of S100A11 toward plasma membrane. This effect was accompanied by strong nuclear condensation, loss of mitochondrial potential and DNA content, and increased high molecular weight S100A11 immunoreactivity, suggesting corticoids accelerate calcium-induced terminal differentiation. Finally, our results suggest GC-induced S100A11 relocalization could be a key step in both keratinocyte homeostasis and glucocorticoids side effects in human epidermis.

Published
2007

13. Dexamethasone and IL-10 stimulate glucocorticoid-induced leucine zipper synthesis by human mast cells

Author

Véronique Godot, Dominique Emilie, Francis Capel, Ingrid Durand-Gasselin, Marie Liesse Asselin-Labat, Michel Arock, G. Garcia, Marc Humbert, Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-IFR13-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Francis PERRIN (LFP - URA 2453), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre d'étude des environnements terrestre et planétaires (CETP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de géobiologie, biochronologie et paléontologie humaine (LGBPH), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Laboratoire pour l'utilisation du rayonnement électromagnétique (LURE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-MENRT-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Service de microbiologie, immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Physique et Mécanique Textiles (LPMT), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'étude des textures et application aux matériaux (LETAM), Université Paul Verlaine - Metz (UPVM)-Centre National de la Recherche Scientifique (CNRS), ENSITM-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Antoine Béclère [Clamart], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
medicine.medical_specialty, MESH: Interleukin-10, medicine.medical_treatment, Immunology, Biology, Dexamethasone, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Downregulation and upregulation, Internal medicine, medicine, Immunology and Allergy, Humans, Mast Cells, RNA, Messenger, Receptor, Interleukin 5, Interleukin 4, 030304 developmental biology, MESH: RNA, Messenger, 0303 health sciences, MESH: Humans, MESH: Mast Cells, MESH: Transcription Factors, MESH: Interleukin-4, Mast cell, MESH: Interleukin-5, MESH: Gene Expression Regulation, 3. Good health, Cell biology, Interleukin-10, MESH: Cell Line, Interleukin 10, medicine.anatomical_structure, Cytokine, Endocrinology, chemistry, Gene Expression Regulation, MESH: Dexamethasone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin-4, Interleukin-5, Histamine, hormones, hormone substitutes, and hormone antagonists, 030215 immunology, Transcription Factors
Abstract

International audience; BACKGROUND: Glucocorticoids (GCs) decrease tissue mast cell (MC) number and prevent their activation via their high-affinity IgE receptor. Glucocorticoid-induced leucine zipper (GILZ) is one of the GC-induced genes, which inhibits the functions of the transcriptional activators AP-1 and NF-kappaB. GILZ appears to be a critical actor in the anti-inflammatory and immunosuppressive effects of GCs in human T lymphocytes, macrophages and dendritic cells. AIMS OF THE STUDY: We investigated whether GILZ was produced by human MCs and whether GILZ synthesis was stimulated by GCs. We also investigated whether GILZ production was modulated by (i) IL-10, because of its common immunosuppressive properties with GCs, (ii) histamine because of its pro-inflammatory properties and (iii) IL-4 and IL-5 because of their ability to favour MC survival and proliferation with SCF. METHODS: The human MC lines HMC-1 5C6 and LAD-2, and cord blood-derived MCs (CB-MCs) were cultured alone or in the presence of GCs, IL-10, histamine, IL-4 or IL-5. The expression of GILZ was evaluated by using RT-PCR, Western blotting or immunocytochemistry. RESULTS: We found that human MC lines and CB-MCs constitutively produce GILZ. We also show that GCs and IL-10 stimulate GILZ production by human MCs. Our present results indicate that histamine, IL-4 and IL-5 alone or in combination with SCF do not downregulate GILZ production by MCs. CONCLUSIONS: These results show that GCs and IL-10 stimulate GILZ production by human MCs. As GILZ mediates anti-inflammatory effects of GCs in immune cells, we speculate that GILZ could account for the deactivation of MCs by GCs and IL-10.

Published
2006

14. Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma

Author

Guibert, S., Arnaud Jaccard, Bernard, M., Turlure, P., Bordessoule, D., Lamy, T., Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Laboratoire Hubert Curien [Saint Etienne] (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], Université de Limoges (UNILIM), Laboratoire Hubert Curien (LHC), and Institut d'Optique Graduate School (IOGS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Aged, MESH: Middle Aged, MESH: Humans, MESH: Survival Rate, MESH: Male, MESH: Transplantation, Autologous, MESH: Antibodies, Monoclonal, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Cisplatin, MESH: Dexamethasone, MESH: Cytarabine, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Lymphoma, Mantle-Cell, MESH: Female, MESH: Hematopoietic Stem Cell Transplantation
Abstract

International audience; We report on a series of 24 patients with newly diagnosed mantle cell lymphoma treated with four to six courses of DHAP-rituximab followed by autologous stem cell transplantation for patients

Published
2006

15. Inhibition of the anti-adipogenic Hedgehog signaling pathway by cyclopamine does not trigger adipocyte differentiation

Author

Wendy Cousin, Pascal Peraldi, Christian Dani, Peraldi, Pascal, Institut de signalisation, biologie du développement et cancer (ISBDC), 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), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, Time Factors, Lipodystrophy, Cellular differentiation, MESH: Veratrum Alkaloids, Biochemistry, Dexamethasone, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Lipodystrophy, Adipocyte, 1-Methyl-3-isobutylxanthine, Adipocytes, Insulin, MESH: Animals, Oncogene Proteins, 0303 health sciences, biology, MESH: 1-Methyl-3-isobutylxanthine, Veratrum Alkaloids, Cell Differentiation, Hedgehog signaling pathway, Cell biology, Adipogenesis, 030220 oncology & carcinogenesis, MESH: Dexamethasone, Signal Transduction, MESH: Cell Differentiation, medicine.medical_specialty, Indian hedgehog, Cyclopamine, MESH: Trans-Activators, Biophysics, MESH: Insulin, Zinc Finger Protein GLI1, 03 medical and health sciences, MESH: Oncogene Proteins, GLI1, Internal medicine, 3T3-L1 Cells, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Hedgehog Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Hedgehog, MESH: Mice, MESH: Adipocytes, 030304 developmental biology, MESH: Time Factors, Cell Biology, MESH: Hedgehog Proteins, biology.organism_classification, MESH: 3T3-L1 Cells, Endocrinology, chemistry, biology.protein, Trans-Activators
Abstract

International audience; Dysregulation of Hedgehog signaling can lead to several pathologies such as congenital defects and cancer. Here, we show that Hedgehog signaling is active in undifferentiated 3T3-L1 cells and decreases during adipocyte differentiation. Interestingly, this is paralleled by a decrease in Indian Hedgehog expression. We then tested if this down-regulation was sufficient to induce adipocyte differentiation. To this end, we demonstrate that the well-characterized Hedgehog inhibitor cyclopamine induced a decrease in Hedgehog signaling, similar to the one observed during adipocyte differentiation. However, cyclopamine did not induce nor potentiate adipocyte differentiation, as monitored by triglyceride staining and by the expression of several adipocyte markers: aP2, adipsin, C/EBPalpha, and Pref-1. Moreover, cyclopamine cannot substitute for other components of the differentiation medium: insulin, dexamethasone or IBMX. These results indicate that although Hedgehog signaling decreases during adipocyte differentiation, this down-regulation is not sufficient to trigger adipocyte differentiation. This suggests that Hedgehog signaling is an inadequate pharmacological target for patient suffering from syndromes associated with a decrease in fat mass, such as the ones observed in lipodystrophies.

Published
2006

16. Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects

Author

Philippe Quittet, Eric Legouffe, Jean-Pierre Daurès, Valérie Rouille, Marie-Cécile Bozonnat, Bernard Klein, Tarik Kanouni, Jean-François Rossi, Nathalie Fegueux, Carole Exbrayat, Ernesto Lopez, Zhao Yang Lu, John Widjenes, Robert Navarro, Service d'hématologie et oncologie médicale, Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Unité de Thérapie Cellulaire et Génique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Diaclone Research, Frei, Monique, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Melphalan, Male, medicine.medical_treatment, Anti-Inflammatory Agents, Pilot Projects, MESH: Multiple Myeloma, Pharmacology, Dexamethasone, autologous transplantation, MESH: Antibodies, Monoclonal, chemistry.chemical_compound, 0302 clinical medicine, Autologous stem-cell transplantation, Multiple myeloma, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Mucositis, Antibodies, Monoclonal, Hematology, MESH: Pil, Middle Aged, Nitrogen mustard, 3. Good health, multiple myeloma, C-Reactive Protein, 030220 oncology & carcinogenesis, MESH: Dexamethasone, Female, medicine.drug, Adult, Mucositis, medicine.medical_specialty, MESH: Myeloablative Agonists, Transplantation, Autologous, Article, Disease-Free Survival, 03 medical and health sciences, MESH: Melphalan, Internal medicine, MESH: C-Reactive Protein, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Autologous transplantation, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, anti-interleukin-6, 030304 developmental biology, Aged, MESH: Drug Evaluation, Transplantation, Chemotherapy, MESH: Humans, business.industry, Interleukin-6, MESH: Adult, Myeloablative Agonists, medicine.disease, MESH: Interleukin-6, MESH: Male, Endocrinology, chemistry, MESH: Anti-Inflammatory Agents, MESH: Disease-Free Survival, Drug Evaluation, business, MESH: Female, Stem Cell Transplantation
Abstract

International audience; Interleukin-6 (IL-6) is a major survival factor for multiple myeloma (MM) cells preventing apoptosis induced by dexamethasone (DEX) or chemotherapy. In all, 24 consecutive patients with MM in first-line therapy received DEX for 4 days, followed by melphalan (HDM: 140 mg/m2) and autologous stem cell transplantation (ASCT). The anti-IL-6 monoclonal antibody (mAb) (B-E8) was given till haematological recovery, starting 1 day before DEX. Results were historically compared to MM patients treated with HDM 140 and 200 mg/m2. Our results show (1) that B-E8 was able to fully neutralize IL-6 activity in vivo before and after HDM as shown by inhibition of C reactive protein (CRP) production; (2) no haematological toxicity; (3) a significant reduction of mucositis and fever; (4) a median event-free survival of 35 months and an overall survival of 68.2% at 5 years with a median follow-up of 72 months; and (5) the overall daily IL-6 production progressively increased on and after 7 days post-HDM, with the increased serum CRP levels. In the 5/24 patients with uncontrolled CRP production, a large IL-6 production was detected (320 microg/day) that could not possibly be neutralized by B-E8. These data show the feasibility to neutralize IL-6 in vivo with anti-IL-6 mAb in the context of HDM.

Published
2005

17. Dexamethasone impairs muscle energetics, studied by (31)P NMR, in rats

Author

Jean-François Dumas, Gilles Simard, Patrick Ritz, Pierre-Henri Ducluzeau, Jean-Pierre Renou, Damien Roussel, Yves Malthièry, G. Bielicki, Expression des gènes des phosphorylations oxydatives mitochondriales. Maintenance de l'ADN MT, Institut National de la Santé et de la Recherche Médicale (INSERM), Structure tissulaire et intramoléculaire (STIM), Institut National de la Recherche Agronomique (INRA), Financement Mairie d'Angers, INTRA-STIM, and Dumas, Jean-François

Subjects
Leptin, Male, MESH: Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH: Adenine Nucleotides, food restriction, Fatty Acids, Nonesterified, Dexamethasone, Rats, Sprague-Dawley, chemistry.chemical_compound, MESH: 3-Hydroxybutyric Acid, Insulin, MESH: Animals, MESH: Oxygen Consumption, MESH: Muscle, Skeletal, MESH: Fatty Acids, Nonesterified, 3-Hydroxybutyric Acid, Adenine Nucleotides, Energetics, MESH: Energy Metabolism, food and beverages, Hydrogen-Ion Concentration, MESH: Phosp, MESH: Dexamethasone, Corticosteroid, Glucocorticoid, medicine.drug, medicine.medical_specialty, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], medicine.drug_class, oxidative phosphorylation, Oxidative phosphorylation, MESH: Insulin, Biology, Phosphates, Phosphocreatine, Oxygen Consumption, Internal medicine, Internal Medicine, medicine, Animals, Muscle, Skeletal, phosphocreatine, MESH: Magnetic Resonance Spectroscopy, Body Weight, Metabolism, MESH: Leptin, MESH: Male, Rats, MESH: Body Weight, ATP, Steroid hormone, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, chemistry, glucocorticoid, Energy Metabolism, Phosphorus Radioisotopes, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

The original publication is available at www.springerlink.com; AIMS/HYPOTHESIS: Glucocorticoid treatments are associated with increased whole-body oxygen consumption. We hypothesised that an impairment of muscle energy metabolism can participate in this increased energy expenditure. METHODS: To investigate this possibility, we have studied muscle energetics of dexamethasone-treated rats (1.5 mg kg(-1) day(-1) for 6 days), in vivo by (31)P NMR spectroscopy. Results were compared with control and pair-fed (PF) rats before and after overnight fasting. RESULTS: Dexamethasone treatment resulted in decreased phosphocreatine (PCr) concentration and PCr:ATP ratio, increased ADP concentration and higher PCr to gamma-ATP flux but no change in beta-ATP to beta-ADP flux in gastrocnemius muscle. Neither 4 days of food restriction (PF rats) nor 24 h fasting affected high-energy phosphate metabolism. In dexamethasone-treated rats, there was an increase in plasma insulin and non-esterified fatty acid concentration. CONCLUSIONS/INTERPRETATION: We conclude that dexamethasone treatment altered resting in vivo skeletal muscle energy metabolism, by decreasing oxidative phosphorylation, producing ATP at the expense of PCr.

Published
2005

18. The Bcl-2 family member Bfl-1/A1 is strongly repressed in normal and malignant plasma cells but is a potent anti-apoptotic factor for myeloma cells

Author

Tarte, Karin, Jourdan, Michel, Veyrune, Jean-Luc, Berberich, Ingolf, Fiol, Geneviève, Redal, Nicole, Shaughnessy, John, Klein, Bernard, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de Thérapie Cellulaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institute for Virology and Immunology, Julius-Maximilians-Universität Würzburg (JMU), Donna and Donald Lambert Laboratory of Myeloma Genetics, University of Arkansas for Medical Sciences (UAMS)-Myeloma Institute for Research and Therapy, This work was supported by a grant from the Ligue Nationale Contre le Cancer (Equipe Labellisée). I.B. was supported by Forschergruppe 303 der DFG., Frei, Monique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, and Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)

Subjects
MESH: Neoplasm Proteins, B-cell differentiation, Down-Regulation, MESH: Multiple Myeloma, Bfl-1/A1, Dexamethasone, Article, MESH: Down-Regulation, Minor Histocompatibility Antigens, Transduction, Genetic, MESH: Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Tumor Cells, Cultured, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Plasma cells, MESH: Plasma Cells, MESH: Humans, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, MESH: Apoptosis, apoptosis, MESH: Transduction, Genetic, MESH: Interleukin-6, Neoplasm Proteins, myeloma, Proto-Oncogene Proteins c-bcl-2, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Dexamethasone, MESH: Oligonucleotide Array Sequence Analysis, gene expression profile, Multiple Myeloma, MESH: Cells, Cultured
Abstract

International audience; Terminal B-cell differentiation is a multi-step process, from short-lived plasmablasts to mature long-lived plasma cells (PC). The anti-apoptotic Bcl-2 family member Bfl-1/A1 plays a critical role in the survival of mature B cells. However, its potential involvement at the later stages of B-cell development remains highly controversial. Our aim was thus to clarify the place of Bfl-1/A1 in the biology of normal PC and in the pathogenesis of multiple myeloma (MM), the major PC dyscrasia. Using gene expression profiling and quantifiable reverse transcription polymerase chain reaction experiments, we found a similar down-regulation of Bfl-1/A1 in both normal immature plasmablasts and mature PC when compared with B cells. In myeloma cells, the level of Bfl-1/A1 was low and Bfl-1/A1 was not a nuclear factor kappaB-inducible gene. Collectively, these data demonstrate that Bfl-1/A1 is not involved in the prolonged survival of normal mature PC, and that Bfl-1/A1 deregulation is not a common oncogenic event in MM. However, overexpression of Bfl-1/A1 by retroviral transduction promoted autonomous survival of an interleukin-6-dependent myeloma cell line and rendered it less sensitive to dexamethasone. Thus, Bfl-1/A1 transduction could be an interesting tool to obtain myeloma cell lines from primary samples and to favour the in vitro generation of antibody-secreting, long-lived normal PC.

Published
2004

19. Paracrine and Autocrine Signals Promoting Full Chondrogenic Differentiation of a Mesoblastic Cell Line

Author

Michel Huerre, Odile Kellermann, Marie Boucquey, Huot Khun, Morgane Locker, Anne Poliard, Génétique moléculaire et intégration des fonctions cellulaires (GMIFC), Centre National de la Recherche Scientifique (CNRS), Brussels Branch and Cellular Genetics Unit, Ludwig Institute for Cancer Research, and Unité d'Anatomo-pathologie, Institut Pasteur

Subjects
MESH: Extracellular Matrix Proteins, MESH: Signal Transduction, MESH: Osteopontin, Endocrinology, Diabetes and Metabolism, Cellular differentiation, MESH: Bone Morphogenetic Proteins, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Insulin-Like Growth Factor I, MESH: Collagen Type I, SMAD, MESH: Triiodothyronine, Culture Media, Serum-Free, Dexamethasone, Mice, MESH: Transforming Growth Factor beta1, 0302 clinical medicine, MESH: Cell Aggregation, MESH: Aggrecans, Transforming Growth Factor beta, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Up-Regulation, Orthopedics and Sports Medicine, MESH: Animals, Aggrecans, Insulin-Like Growth Factor I, MESH: Sialoglycoproteins, BMP signaling pathway, Cell Aggregation, MESH: Collagen Type X, Extracellular Matrix Proteins, 0303 health sciences, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Reverse Transcriptase Polymerase Chain Reaction, High Mobility Group Proteins, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell Differentiation, SOX9 Transcription Factor, MESH: Gene Expression Regulation, Neoplastic, MESH: Transcription Factors, MESH: Culture Media, Serum-Free, Immunohistochemistry, Up-Regulation, Cell biology, Gene Expression Regulation, Neoplastic, Autocrine Communication, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Dexamethasone, MESH: Proteoglycans, Bone Morphogenetic Proteins, Triiodothyronine, MESH: Pluripotent Stem Cells, Proteoglycans, Signal Transduction, Pluripotent Stem Cells, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Cell Line, Tumor, Sialoglycoproteins, Biology, Bone morphogenetic protein, MESH: Bone Morphogenetic Protein Receptors, Collagen Type I, Chondrocyte, Transforming Growth Factor beta1, 03 medical and health sciences, Paracrine signalling, MESH: SOX9 Transcription Factor, Chondrocytes, Cell Line, Tumor, Internal medicine, MESH: Chondrocytes, Paracrine Communication, MESH: Receptors, Growth Factor, medicine, Animals, MESH: Blotting, Northern, Lectins, C-Type, Receptors, Growth Factor, MESH: Paracrine Communication, Autocrine signalling, Collagen Type II, MESH: Mice, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Immunohistochemistry, Bone Morphogenetic Protein Receptors, MESH: Collagen Type II, Blotting, Northern, Chondrogenesis, MESH: High Mobility Group Proteins, Endocrinology, Osteopontin, MESH: Autocrine Communication, MESH: Lectins, C-Type, Collagen Type X, Transcription Factors
Abstract

The pluripotent mesoblastic C1 cell line was used under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to drive chondrogenesis. Sequential addition of two systemic hormones, dexamethasone and triiodothyronine, permits full chondrogenic differentiation. The cell intrinsic activation of the BMP signaling pathway and Sox9 expression occurring on mesoblastic condensation is insufficient for recruitment of the progenitors. Dexamethasone-dependent Sox9 upregulation is essential for chondrogenesis. Introduction: Differentiation of lineage stem cells relies on cell autonomous regulations modulated by external signals. We used the pluripotent mesoblastic C1 cell line under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to induce differentiation of a precursor clone along the chondrogenic lineage. Materials and Methods: C1 cells, cultured as aggregates, were induced toward chondrogenesis by addition of 10−7 M dexamethasone in serum-free medium. After 30 days, dexamethasone was replaced by 10 nM triiodothyronine to promote final hypertrophic conversion. Mature and hypertrophic phenotypes were characterized by immunocytochemistry using specific antibodies against types II and X collagens, respectively. Type II collagen, bone morphogenetic proteins (BMPs), BMP receptors, Smads, and Sox9 expression were monitored by reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot, and/or Western blot analysis. Results and Conclusions: Once C1 cells have formed nodules, sequential addition of two systemic hormones is sufficient to promote full chondrogenic differentiation. In response to dexamethasone, nearly 100% of the C1 precursors engage in chondrogenesis and convert within 30 days into mature chondrocytes, which triggers a typical cartilage matrix. On day 25, a switch in type II procollagen mRNA splicing acted as a limiting step in the acquisition of the mature chondrocyte phenotype. On day 30, substitution of dexamethasone with triiodothyronine triggers the final differentiation into hypertrophic chondrocytes within a further 15 days. The chondrogenic process is supported by intrinsic expression of Sox9 and BMP family genes. Similarly to the in vivo situation, activation of Sox9 expression and the BMP signaling pathway occurred on mesoblastic condensation. After induction, BMP-activated Smad nuclear translocation persisted throughout the process until the onset of hypertrophy. After dexamethasone addition, Sox9 expression was upregulated. Dexamethasone withdrawal reversed the increase in Sox9 expression and stopped differentiation. Thus, Sox9 seems to be a downstream mediator of dexamethasone action.

Published
2004

20. An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis

Author

Michel Jourdan, Catherine Hertogh, Eric Jourdan, Karène Mahtouk, Jean-François Rossi, John De Vos, Geneviève Fiol, Bernard Klein, Frei, Monique, Immunopathologie des maladies tumorales et autoimmunes, Université Montpellier 1 (UM1)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de thérapie cellulaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Receptor, ErbB-4, Cellular differentiation, medicine.medical_treatment, Lipopolysaccharide Receptors, Apoptosis, Cell Separation, Biochemistry, Dexamethasone, Monocytes, Phosphatidylinositol 3-Kinases, Epidermal growth factor, immune system diseases, hemic and lymphatic diseases, Plasma cell differentiation, Enzyme Inhibitors, Multiple myeloma, Cells, Cultured, Reverse Transcriptase Polymerase Chain Reaction, MESH: Antigens, CD14, MESH: Bone Marrow Cells, Cell Differentiation, Drug Synergism, Hematology, MESH: Antineoplastic Agents, Hormonal, ErbB Receptors, medicine.anatomical_structure, MESH: Dexamethasone, Intercellular Signaling Peptides and Proteins, MESH: Cell Division, Electrophoresis, Polyacrylamide Gel, Multiple Myeloma, hormones, hormone substitutes, and hormone antagonists, Cell Division, Heparin-binding EGF-like Growth Factor, MESH: Cells, Cultured, MESH: Cell Differentiation, Stromal cell, MESH: Cell Line, Tumor, Antineoplastic Agents, Hormonal, Immunology, Blotting, Western, Bone Marrow Cells, Biology, Sensitivity and Specificity, MESH: Cell Separation, Article, MESH: Cell Adhesion, Growth factor receptor, Cell Line, Tumor, medicine, Cell Adhesion, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: Blotting, Western, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epidermal Growth Factor, Interleukin-6, Growth factor, MESH: Apoptosis, Cell Biology, MESH: 1-Phosphatidylinositol 3-Kinase, medicine.disease, Hematopoietic Stem Cells, Cancer research, Leukocytes, Mononuclear, Bone marrow, MESH: Drug
Abstract

We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor–like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti–IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.

Published
2004

21. Effect of hibernation, thyroid hormones and dexamethasone on cytosolic and mitochondrial glycerol-3-phosphate dehydrogenase from jerboa (Jaculus orientalis)

Author

Widad Berrada, Noureddine Bourhim, Abdallah Naya, L'Houcine Ouafik, Faculté des Sciences, Université Hassan II, LABORATOIRE DE CANCEROLOGIE EXPERIMENTALE EA2671, Université de la Méditerranée - Aix-Marseille 2, and Ouafik, L'Houcine

Subjects
Hibernation, Male, Physiology, Adipose tissue, MESH: Rodentia, Mitochondrion, Kidney, Biochemistry, Dexamethasone, Cytosol, Adipose Tissue, Brown, MESH: Cytosol, Brown adipose tissue, MESH: Animals, MESH: Muscle, Skeletal, MESH: Propylthiouracil, biology, Brain, MESH: Glycerolphosphate Dehydrogenase, Mitochondria, medicine.anatomical_structure, Liver, MESH: Dexamethasone, MESH: Hibernation, medicine.medical_specialty, Thyroid Hormones, MESH: Mitochondria, Glycerolphosphate Dehydrogenase, Rodentia, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Adipose Tissue, Brown, MESH: Brain, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Thyroid Hormones, Internal medicine, medicine, Animals, Muscle, Skeletal, Molecular Biology, Jaculus orientalis, Skeletal muscle, MESH: Kidney, biology.organism_classification, Enzyme assay, MESH: Male, Endocrinology, Glycerol-3-phosphate dehydrogenase, Propylthiouracil, biology.protein, MESH: Liver
Abstract

International audience; Tissue distribution of the cytosolic and mitochondrial glycerol-3-phosphate dehydrogenase (cGPDH and mGPDH) activities in jerboa (Jaculus orientalis), a hibernator, shows the highest level of enzyme activity in skeletal muscle and brown adipose tissue, respectively. The effect of hibernation on cGPDH indicates an increase of activity in all tissues examined. In contrast, hibernation decreases mGPDH activity in all tissues, except skeletal muscle. The effect of thyroid hormones on GPDH activity was tissue specific: in kidneys, cGPDH activity doubled in euthermic jerboas treated with T4. In contrast, 6-n-propyl-2-thiouracil treatment provokes an increase of enzyme activity in brown adipose tissue, liver and brain. T4 treatment leads to a 2.7-fold increase in liver mGPDH activity. 6-n-propyl-2-thiouracil treatment decreases mGPDH activity in the skeletal muscle whereas the opposite effect was observed in brain. Dexamethasone stimulates cGPDH in all tissues examined, except skeletal muscle and kidneys. In the case of mGPDH activity, this increase was observed only for brown adipose tissue and brain. Our results suggest that hibernation, thyroid hormones and dexamethasone probably play a role in the regulation of cGPDH and mGPDH activities in jerboa. Our findings confirm that these enzymes are involved in metabolic adaptation to thermal stress in Jaculus orientalis.

Published
2000

22. Characterization and regulation of peptidylglycine alpha-amidating monooxygenase (PAM) expression in H9c2 cardiac myoblasts

Author

Françoise Boudouresque, L'Houcine Ouafik, Béatrice Girard, LABORATOIRE DE CANCEROLOGIE EXPERIMENTALE EA2671, Université de la Méditerranée - Aix-Marseille 2, and Ouafik, L'Houcine

Subjects
Muscle Fibers, Skeletal, MESH: Multienzyme Complexes, MESH: Triiodothyronine, Dexamethasone, Mixed Function Oxygenases, MESH: Animals, In Situ Hybridization, MESH: Muscle Fibers, Skeletal, medicine.diagnostic_test, MESH: Alternative Splicing, MESH: Gene Expression Regulation, Enzymologic, MESH: Mixed Function Oxygenases, Blot, MESH: Dexamethasone, embryonic structures, Triiodothyronine, Peptidylglycine alpha-amidating monooxygenase, Histology, MESH: Myocardium, MESH: Rats, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, In situ hybridization, Biology, Gene Expression Regulation, Enzymologic, Pathology and Forensic Medicine, MESH: In Situ Hybridization, [SDV.CAN] Life Sciences [q-bio]/Cancer, Western blot, stomatognathic system, Multienzyme Complexes, Complementary DNA, parasitic diseases, medicine, Animals, MESH: Blotting, Western, RNA, Messenger, Northern blot, Glucocorticoids, MESH: RNA, Messenger, Messenger RNA, Myocardium, Alternative splicing, MESH: Clone Cells, Cell Biology, Molecular biology, Clone Cells, Rats, Alternative Splicing, MESH: Glucocorticoids
Abstract

International audience; Peptidylglycine alpha-amidating monooxygenase (PAM), which catalazyes the two-step formation of bioactive alpha-amidated peptides from their glycine-extended precursors, has been found in H9c2 myoblasts. The expression of PAM has been evaluated in H9c2 cells. Northern blot analysis and amplification of fragments derived from rat PAM by the reverse transcription/polymerase chain reaction method has demonstrated the presence of rPAM-1, -2, -3, -3a and -3b mRNA transcripts. These forms of PAM mRNA may be generated by alternative splicing. PAM mRNA levels are increased to 160 +/- 12% of control values by treatment with dexamethasone but are unchanged during triiodothyronine incubation of the cells. PAM activity is very low, which is not comparable to the high levels found in adult atrium tissue. Western blot analysis has demonstrated 86-, 76-, and 46-kDa PAM proteins in the particulate fraction. The soluble fraction contains major PAM proteins of 110, 86, and 46 kDa. In situ hybridization studies with 35S-labeled full length RNA antisense transcripts of rat PAM-1 cDNA have localized autoradiographic grains around the nucleus. Our data clearly demonstrate PAM expression in H9c2 rat heart cells, suggesting the ability of these cardiac cells to make bioactive alpha-amidated hormones and/or neuropeptides.

Published
1999

23. Regulation of interleukin-1 receptor expression in mouse brain and pituitary by lipopolysaccharide and glucocorticoids

Author

William Rostène, E. Ban, Gilles Fillion, Alain Sarrieau, F. Fitzpatrick, G. Milon, C. Marquette, F. Haour, Pharmacologie Neuro-Immuno-Endocrinienne, Institut Pasteur [Paris] (IP), Imagerie cellulaire des neurorécepteurs et physiopathologie neuroendocrinienne, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies auto-immunes: génétique, mécanismes et traitements, Institut National de la Santé et de la Recherche Médicale (INSERM), lmmunophysiologie cellulaire, and Institut Pasteur [Paris]

Subjects
Lipopolysaccharides, Pituitary gland, MESH: Hippocampus, Lipopolysaccharide, Endocrinology, Diabetes and Metabolism, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Dexamethasone, Iodine Radioisotopes, Mice, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, MESH: Pituitary Gland, MESH: Animals, MESH: Brain Chemistry, Receptor, MESH: Adrenalectomy, Mice, Inbred C3H, 0303 health sciences, Interleukin, Adrenalectomy, MESH: Stress, Psychological, MESH: Iodine Radioisotopes, medicine.anatomical_structure, Pituitary Gland, MESH: Dexamethasone, Female, Glucocorticoid, medicine.drug, medicine.medical_specialty, Central nervous system, In Vitro Techniques, Interleukin-1 receptor, Biology, MESH: Receptors, Interleukin-1, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Animals, MESH: Mice, Inbred C3H, Glucocorticoids, MESH: Mice, 030304 developmental biology, Brain Chemistry, Endocrine and Autonomic Systems, Receptors, Interleukin-1, chemistry, MESH: Lipopolysaccharides, MESH: Glucocorticoids, human activities, MESH: Female, Stress, Psychological, 030217 neurology & neurosurgery
Abstract

International audience; Interleukin-1 (IL-1) receptors have been characterized in mouse pituitary and brain. Previous studies have demonstrated that IL-1 receptor density is high in the dentate gyrus in the hippocampus and that lipopolysaccharide (LPS) injection caused an 80% decrease in the number of hippocampal IL-1 receptors, while pituitary receptors in the anterior pituitary were unaffected. In order to investigate on the role of glucocorticoids (GC) in the control of IL-1 receptor expression in the brain and pituitary, the effect of stress, exogenous GC administration or adrenalectomy (ADX) on IL-1 receptor density was determined. Assays were achieved under basal and LPS-stimulated conditions by in situ quantitative autoradiography technique using human recombinant 125I-IL-1 alpha as a tracer. An increase of GC concentration in serum, following immobilization stress or dexamethasone (DEX) treatment (short and long term), did not modify, in the hippocampus, the density of IL-1 receptors under basal conditions or after peripheral LPS injection. On the contrary, ADX significantly decreased IL-1 receptor density in LPS-treated animals. In the anterior pituitary, a significant increase in the density of basal IL-1 receptors was observed 6 h following immobilization stress or after 7 days of DEX treatment while short-term DEX treatments are ineffective. In contrast to what was observed in the hippocampus, no changes in pituitary receptor densities were observed in ADX mice. These results indicate that hippocampal and pituitary IL-1 receptor expressions are differentially regulated by GC. Therefore, this report constitutes the first demonstration of an in vivo regulation of IL-2 receptors in the pituitary.

Published
1993

24. Dexamethasone inhibits a heme-independent event necessary for terminal differentiation of murine erythroleukemia cells

Author

Brigitte Hugues, H. Beverley Osborne, Laboratoire de Biologie Moléculaire et Cellulaire (ER199), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Osborne, Howard Beverley

Subjects
Biochemistry, Dexamethasone, chemistry.chemical_compound, Hemoglobins, Mice, hemic and lymphatic diseases, Acetamides, polycyclic compounds, MESH: Animals, Nuclear protein, Heme, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cell Differentiation, MESH: Diamines, MESH: Acetamides, MESH: Gene Expression Regulation, Globins, MESH: Hemoglobins, MESH: Dexamethasone, MESH: Heme, Hemin, MESH: Leukemia, Erythroblastic, Acute, hormones, hormone substitutes, and hormone antagonists, medicine.drug, MESH: Cells, Cultured, MESH: Cell Differentiation, endocrine system, MESH: Hemin, Biophysics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Diamines, Hexamethylene bisacetamide, medicine, MESH: Globins, Animals, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Cell Biology, Molecular biology, Nucleoproteins, chemistry, Gene Expression Regulation, MESH: Nucleoproteins, Hemoglobin, Leukemia, Erythroblastic, Acute
Abstract

Summary The hexamethylene bisacetamide(HMBA) induced differentiation of murine erythroleukemia cells is inhibited by dexamethasone (DEX). We show here that addition of hemin (100 pM) to cells cultured with HMBA (4mM) and DEX (100 μM) leads to an appearance of hemoglobin containing cells. However these cells cultured with HMBA, DEX, and hemin are not reprogrammed to limited growth. DEX does not inhibit the synthesis of the nuclear protein IP25. Hence commitment to terminal differentiation is controlled by at least one heme-independant event (other than the induction of IP25) which is inhibited by DEX.

Published
1981

25. Relationship between ornithine decarboxylase activity and hexamethylene bisacetamide-induced differentiation of murine erythroleukemia cells

Author

Marie-José Moutin, Howard Beverley Osborne, Eliane Meilhoc, Brigitte Hughes Romani, Osborne, Howard Beverley, Biophysique Moleculaire et Cellulaire (UA520), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ornithine, Erythrocytes, genetic structures, Spermidine, Dexamethasone, Ornithine decarboxylase, Mice, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Acetamides, MESH: Animals, MESH: Spermine, MESH: Spermidine, MESH: Putrescine, MESH: Eflornithine, Ornithine decarboxylase antizyme, 0303 health sciences, MESH: Kinetics, MESH: Erythrocytes, Cell Differentiation, MESH: Ornithine, MESH: Acetamides, MESH: Ornithine Decarboxylase, 030220 oncology & carcinogenesis, MESH: Dexamethasone, MESH: Leukemia, Erythroblastic, Acute, Intracellular, MESH: Cell Differentiation, Eflornithine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Ornithine Decarboxylase, Hexamethylene bisacetamide, Cell Line, MESH: Interphase, 03 medical and health sciences, Putrescine, Animals, Interphase, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, fungi, MESH: Clone Cells, Cell Biology, Molecular biology, Clone Cells, MESH: Cell Line, Kinetics, chemistry, Spermine, Leukemia, Erythroblastic, Acute, Polyamine
Abstract

International audience; A transitory increase in ornithine decarboxylase (ODC) activity is shown not to be a prerequisite for the differentiation induced by hexamethylene bisacetamide (HMBA) in murine erythroleukemic (MEL) cells. On the contrary, conditions are described, where inhibition of the ODC activity with alpha-difluoromethyl ornithine (DFMO) stimulated the induced differentiation. Polyamine analysis demonstrated that a reduction in intracellular putrescine and spermidine occurred in MEL cells before commitment to erythrodifferentiation. The presence of DFMO increased the rapidity and the amplitude of these changes. No effect of dexamethasone on these changes in ODC activity or intracellular polyamines was observed.

Published
1986

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