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1. Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines

Author: Lionel Cazin, Françoise Fauvel-Lafève, Linda-Louise Pritchard, He Lu, Rémi Varin, Marc Laurent, Claudine Soria, Ulrich Joimel, Catherine Buquet, Jean-Pierre Vannier, Caroline Gest, Hong Li, P. Mirshahi, Jeannette Soria, Limin Huang, Charlène Dulong, Alexandre Petit, Chaoquan Hu, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique moléculaire et destin cellulaire (FRE 3377), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hemostase, Endothelium, Angiogenese (UMR_S_553), Unité Fonctionnelle d' oncologie médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, This work was supported by the Groupement des Entreprises Francaises dans la Lutte contre le Cancer de Rouen (GEFLUC of Rouen), and the Ligue Regionale de Haute Normandie de Lutte contre le Cancer. Caroline Gest is a recipient of grant from Ministère de l'enseignement supérieur et de la recherche., BMC, Ed., Départment d'onco-hématologie, Université Paris Descartes - Paris 5 (UPD5)-UMRS 872-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Micro-Environnement et Régulation Cellulaire Intégrée ( MERCI ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique moléculaire et destin cellulaire ( FRE 3377 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -UMRS 872-Centre National de la Recherche Scientifique ( CNRS ), Hemostase, Endothelium, Angiogenese, and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu
Subjects: Cancer Research, RHOA, Time Factors, Apoptosis, NF-κB, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Breast cancer, Cell Movement, Extracellular Signal-Regulated MAP Kinases, Rac3 GTPases, 0303 health sciences, biology, NF-kappa B, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, rac GTP-Binding Proteins, ERK, Oncology, Matrix Metalloproteinase 9, 030220 oncology & carcinogenesis, MCF-7 Cells, Cytokines, Female, RNA Interference, Collagen, Research Article, Signal Transduction, Cell signaling, Cell Survival, RAC1, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transfection, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Genetics, Cell Adhesion, Humans, Neoplasm Invasiveness, Cell Shape, 030304 developmental biology, Tumor Necrosis Factor-alpha, Cancer, medicine.disease, MCF-7, Cancer cell, biology.protein, Cancer research, Cancer aggressiveness, Cytokine secretion, rhoA GTP-Binding Protein
Abstract: Background Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood. Methods This work was conducted to analyze the implication of Rac3 in the aggressiveness of two breast cancer cell lines, MDA-MB-231 and MCF-7: both express Rac3, but MDA-MB-231 expresses more activated RhoA. The effect of Rac3 in cancer cells was also compared with its effect on the non-tumorigenic mammary epithelial cells MCF-10A. We analyzed the consequences of Rac3 depletion by anti-Rac3 siRNA. Results Firstly, we analyzed the effects of Rac3 depletion on the breast cancer cells’ aggressiveness. In the invasive MDA-MB-231 cells, Rac3 inhibition caused a marked reduction of both invasion (40%) and cell adhesion to collagen (84%), accompanied by an increase in TNF-induced apoptosis (72%). This indicates that Rac3 is involved in the cancer cells’ aggressiveness. Secondly, we investigated the effects of Rac3 inhibition on the expression and activation of related signaling molecules, including NF-κB and ERK. Cytokine secretion profiles were also analyzed. In the non-invasive MCF-7 line; Rac3 did not influence any of the parameters of aggressiveness. Conclusions This discrepancy between the effects of Rac3 knockdown in the two cell lines could be explained as follows: in the MDA-MB-231 line, the Rac3-dependent aggressiveness of the cancer cells is due to the Rac3/ERK-2/NF-κB signaling pathway, which is responsible for MMP-9, interleukin-6, -8 and GRO secretion, as well as the resistance to TNF-induced apoptosis, whereas in the MCF-7 line, this pathway is not functional because of the low expression of NF-κB subunits in these cells. Rac3 may be a potent target for inhibiting aggressive breast cancer.
Published: 2013
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2. Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate

Author: Linda-Louise Pritchard, Ulrich Joimel, Hong Li, Rémi Varin, Emmanuel Blot, Claudine Soria, Lionel Cazin, Caroline Gest, Marc Laurent, Jeannette Soria, Jean-Pierre Vannier, Jérôme Alexandre, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire d'Oncologie Médicale, Université Paris Descartes - Paris 5 (UPD5)-Hôtel Dieu de Paris, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique fonctionnelle de la prolifération et différenciation cellulaire, Université Paris-Sud - Paris 11 (UP11)-Institut André Lwoff (IAL)-Centre National de la Recherche Scientifique (CNRS), We are grateful to the comité de l'Eure de la Ligue contre le Cancer and to the Association Ti'toine, for financing the fellowship of Ulrich Joimel. We thank the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC) Rouen Normandie and the comité de Seine-Maritime de la Ligue contre le Cancer, who generously supported this work by a program grant from the Cancer Research Campaign., Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BMC, Ed., Micro-Environnement et Régulation Cellulaire Intégrée ( MERCI ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Paris Descartes - Paris 5 ( UPD5 ) -Hôtel Dieu de Paris, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut André Lwoff (IAL)-Centre National de la Recherche Scientifique ( CNRS )
Subjects: Lipopolysaccharides, Chemokine, Cancer Research, MESH : Coculture Techniques, Angiogenesis, MESH : Cytokines, medicine.medical_treatment, Fluorescent Antibody Technique, Angiogenesis Inhibitors, Apoptosis, Chick Embryo, MESH : Lipopolysaccharides, MESH : Breast Neoplasms, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Chick Embryo, MESH : Female, Interferon gamma, MESH: Animals, MESH : Culture Media, Conditioned, MESH: Fluorescent Antibody Technique, Cells, Cultured, MESH : Macrophages, MESH: Angiogenesis Inhibitors, MESH: Molybdenum, 0303 health sciences, MESH: Cytokines, biology, Neovascularization, Pathologic, MESH: Culture Media, Conditioned, MESH: Enzyme-Linked Immunosorbent Assay, hemic and immune systems, MESH: Chick Embryo, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, MESH: Chemokines, MESH : Enzyme-Linked Immunosorbent Assay, Recombinant Proteins, MESH : Molybdenum, Endothelial stem cell, MESH: Interferon-gamma, Recombinant, Interleukin 10, Cytokine, Oncology, 030220 oncology & carcinogenesis, Cytokines, Tumor necrosis factor alpha, Female, Chemokines, medicine.drug, Research Article, MESH: Cells, Cultured, Macrophage colony-stimulating factor, Breast Neoplasms, Enzyme-Linked Immunosorbent Assay, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, MESH: Coculture Techniques, 03 medical and health sciences, Interferon-gamma, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Cells, Cultured, MESH : Angiogenesis Inhibitors, medicine, Genetics, Animals, Humans, MESH : Chemokines, 030304 developmental biology, Molybdenum, MESH : Interferon-gamma, Recombinant, MESH: Humans, business.industry, Macrophages, MESH: Apoptosis, MESH : Humans, MESH : Neovascularization, Pathologic, MESH: Macrophages, Coculture Techniques, MESH : Fluorescent Antibody Technique, Culture Media, Conditioned, Immunology, Cancer research, biology.protein, MESH : Animals, MESH: Lipopolysaccharides, business, MESH: Neovascularization, Pathologic, MESH: Female, MESH : Apoptosis, MESH: Breast Neoplasms
Abstract: Background Infiltration by macrophages (Mφ) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mφ and aggressive breast cancer cells (MDA-MB-231) induces angiogenesis; 2) to examine the effect of tetrathiomolybdate (TM) on this angiogenic activity. Methods Mφ coincubated with MDA-MB-231 were used as a model to mimic the inflammatory microenvironment. Angiogenesis induced by the culture media was tested in the chick chorioallantoic membrane (CAM). Mφ phenotype was evaluated by 1) expression of the M1 marker CD80, and secretion of interleukin 10 (IL-10), an M2 marker; 2) capacity to secrete Tumour Necrosis Factor α (TNFα) when stimulated by lipopolysaccharide/interferon γ (LPS/IFNγ); 3) ability to induce MDA-MB-231 apoptosis. To explore the molecular mechanisms involved, cytokine profiles of conditioned media from MDA-MB-231, Mφ and the coculture were characterised by an antibody cytokine array. All experiments were carried out both in presence and in absence of TM. Results Incubation of Mφ with MDA-MB-231 induced a pro-angiogenic effect in the CAM. It emerged that the angiogenic activity of the coculture is due to the capacity of Mφ to switch from M1 Mφ towards M2, probably due to an increase in Macrophage Colony Stimulating Factor. This M1-M2 switch was shown by a decreased expression of CD80 upon LPS/IFNγ stimulation, an increased secretion of IL-10, a decreased secretion of TNFα in response to LPS/IFNγ and an inability to potentiate apoptosis. At the molecular level, the angiogenic activity of the coculture medium can be explained by the secretion of CXC chemokines/ELR+ and CC chemokines. Although TM did not modify either the M2 phenotype in the coculture or the profile of the secreted chemokines, it did decrease the angiogenic activity of the coculture medium, suggesting that TM inhibited angiogenic activity by interfering with the endothelial cell signalling induced by these chemokines. Conclusions Cooperation between Mφ and MDA-MB-231 transformed M1 Mφ to an angiogenic, M2 phenotype, attested by secretion of CXC chemokines/ELR+ and CC chemokines. TM inhibited this coculture-induced increase in angiogenic activity, without affecting either Mφ phenotype or cytokine secretion profiles.
Published: 2010
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3. Assessment of adherence to disease-modifying anti-rheumatic drugs in rheumatoid arthritis

Author: Sophie Pouplin, Rémi Varin, Clélia Monchablon, Olivier Vittecoq, Thierry Lequerré, Henri Gondé, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Disease, Medication Adherence, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Diabetes mellitus, Internal medicine, medicine, Humans, In patient, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Aged, 030203 arthritis & rheumatology, business.industry, Anti rheumatic drugs, General Medicine, Middle Aged, medicine.disease, 3. Good health, Medication possession ratio, Cross-Sectional Studies, Antirheumatic Agents, Concomitant, Rheumatoid arthritis, Female, Self Report, business
Abstract: This work aimed to assess treatment adherence in rheumatoid arthritis patients with several tools and to identify factors associated with poor adherence.Between February and December 2015, 183 patients were included in this cross-sectional study. A homemade 23-item self-questionnaire was filled by patients during an outpatient consultation or a day hospitalization stay. Morisky Medication Adherence Scale (MMAS)-4, MMAS-8 and Girerd scores were extracted from this homemade questionnaire. Medication possession ratio (MPR) was then calculated. For identification of factors associated with nonadherence, patients were divided in two groups according to MMAS-8 results differentiating patients with good or bad adherence to treatments.Of the 183 patients, 59% received a combination of biologic and conventional synthetic disease-modifying drugs, 22% a biological treatment alone, and 19% a conventional DMARD alone. Respectively, 3%, 10%, and 7% were considered as low adherent according to MMAS-4, MMAS-8, and Girerd scores. MPR was calculated for 84/183 patients; 23% were low adherent. The need for a help in preparing the drugs (p = 0.05; OR = 6.12; 95% CI: 0.86 to 268.90) and concomitant diabetes (p0.001; OR = 0.045, 95% CI: 0.001 to 0.299) was higher in patients with good adherence. Presence of a patient's relative reminding to take medications was associated with low adherence (p = 0.002; OR = 4.32, 95% CI: 1.41 to 13.11).This study highlighted the difficulty of assessing treatment adherence in rheumatoid arthritis patients despite four different tools. Objective measures by MPR indicated a higher proportion of poor adherent patients than self-questionnaires.Key Points• Proportion of patients considered as low adherent ranged from 3 to 27% according to the method of evaluation.• The use of a pillbox and/or the preparation of drugs by a patient's relative was associated with good adherence.• The presence of a patient's relative reminding to take medication was associated with low adherence.
Published: 2019
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4. Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France

Author: Eliane Gluckman, Yves Bertrand, Karima Yakouben, Isabelle Thuret, Charlotte Jubert, Bénédicte Neven, Felipe Suarez, F. Bernaudin, Sébastien Maury, Catherine Paillard, Patrick Lutz, Société Française de Greffe de Moelle et de Thérapie Cellulaire, Jacques-Olivier Bay, Catherine Poirot, M. Kuentz, Claire Galambrun, Dominique Bories, Marie Robin, Jean-Paul Vernant, Pierre Rohrlich, Gérard Socié, Nicole Raus, Corinne Pondarré, Jean-Hugues Dalle, Régis Peffault de Latour, Jean-Pierre Vannier, Nathalie Dhedin, Centre Hospitalier Intercommunal de Créteil (CHIC), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), CHI Créteil, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Nice (CHU Nice), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hématologie moléculaire [CHU Mondor], CHU Henri Mondor, Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Hôpital Civil, Hopital Civil, Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Service de Greffe de Moelle - Unité AJA, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinical Research Unit, Biology of Reproduction Unit, Paris, France, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Hemolytic anemia, medicine.medical_specialty, Transplantation Conditioning, Anemia, [SDV]Life Sciences [q-bio], Graft vs Host Disease, Anemia, Sickle Cell, Gastroenterology, Chimerism, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Progression-free survival, Red Cell Biology & its Disorders, ComputingMilieux_MISCELLANEOUS, Aged, business.industry, Siblings, Hazard ratio, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Sickle cell anemia, Progression-Free Survival, 3. Good health, Transplantation, Fertility, 030220 oncology & carcinogenesis, France, business, Busulfan, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology, medicine.drug
Abstract: Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG)]. Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells 15 years (hazard ratio=4.37; P=0.002) and lower (5-15 vs. 20 mg/kg) ATG dose (hazard ratio=4.55; P=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells
Published: 2020
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5. Impact of collaborative pharmaceutical care on in-patients’ medication safety: study protocol for a stepped wedge cluster randomized trial (MEDREV study)

Author: Géraldine Leguelinel-Blache, Christel Castelli, Clarisse Roux-Marson, Sophie Bouvet, Sandrine Andrieu, Philippe Cestac, Rémy Collomp, Paul Landais, Bertrice Loulière, Christelle Mouchoux, Rémi Varin, Benoit Allenet, MEDREV Working Group, Pierrick Bedouch, Jean-Marie Kinowski, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM), BESPIM, 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), Institut du Vieillissement, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud, Centre Hospitalier Universitaire de Nice, Hopital de Nice, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), 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 Grenoble Alpes [2016-2019] (UGA [2016-2019])-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 Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie [CHU Nîmes] (BESPIM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon (HCL), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and roussel, pascale
Subjects: Male, Health Knowledge, Attitudes, Practice, Time Factors, [SDV]Life Sciences [q-bio], Hospital pharmacist, Psychological intervention, Medicine (miscellaneous), Collaborative Care, [SHS.PSY]Humanities and Social Sciences/Psychology, Inappropriate Prescribing, Pharmacists, 030226 pharmacology & pharmacy, law.invention, Hospitals, University, Study Protocol, 0302 clinical medicine, Randomized controlled trial, law, Risk Factors, Health care, Medicine, Multicenter Studies as Topic, Pharmacology (medical), Drug Interactions, 030212 general & internal medicine, Cluster randomised controlled trial, Hospital pharmacy, Cooperative Behavior, Drug safety, Randomized Controlled Trials as Topic, lcsh:R5-920, 3. Good health, [SDV] Life Sciences [q-bio], Female, Medical emergency, Hospitalpharmacist, France, Patient Safety, Pharmacy Service, Hospital, lcsh:Medicine (General), Medication review, Drug-Related Side Effects and Adverse Reactions, Attitude of Health Personnel, Medication Therapy Management, [SHS.EDU]Humanities and Social Sciences/Education, Risk Assessment, 03 medical and health sciences, Pharmaceutical care, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Drug-related problem, Humans, Aged, Patient Care Team, Inpatients, business.industry, medicine.disease, Clinical pharmacy, Medication reconciliation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Interdisciplinary Communication, business, Stepped wedge study
Abstract: Background Clinical pharmaceutical care has long played an important role in the improvement of healthcare safety. Pharmaceutical care is a collaborative care approach, implicating all the actors of the medication circuit in order to prevent and correct drug-related problems that can lead to adverse drug events. The collaborative pharmaceutical care performed during patients’ hospitalization requires two mutually reinforcing activities: medication reconciliation and medication review. Until now, the impact of the association of these two activities has not been clearly studied. Methods This is a multicentric stepped wedge randomized study involving six care units from six French University Hospitals (each unit corresponding to a cluster) over seven consecutive 14-day periods. Each hospital unit will start with a control period and switch to an experimental period after a randomized number of 14-day periods. Patients aged at least 65 years hospitalized in one of the participating care units and having given their consent to be called for a 30-day and 90-day follow-up can be enrolled. For each 14-day period, 15 patients will be recruited in each care unit to obtain a total of 630 patients enrolled in all centers. Patients with a hospital stay of more than 21 days will be excluded. During the control period, there will be no clinical pharmacist in the care unit, whereas during the experimental period a clinical pharmacist will perform medication reconciliation and review with the healthcare team. The primary outcome will assess the impact of collaborative pharmaceutical care on preventable medication error rate. The secondary outcomes will evaluate the clinical impact of the strategy, the acceptance rate of pharmaceutical interventions, the induced and avoided costs of the strategy (cost-consequence analysis), and the healthcare team’s satisfaction. Discussion This study will assess the impact of collaborative pharmaceutical care associating medication reconciliation and review at patient admission to hospital in terms of preventable medication error rate and costs. This activity will prevent and correct medication errors arising earlier in the hospitalization. Trial registration ClinicalTrials.gov, NCT02598115. Registered on 4 November 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2412-7) contains supplementary material, which is available to authorized users.
Published: 2018
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6. Fibrinogen αC domain: Its importance in physiopathology

Author: Rémi Varin, Massoud Mirshahi, Claudine Soria, Linda L. Pritchard, Shahsoltan Mirshahi, Sam Qiumars Mirshahi, Jeannette Soria, Départment d'onco-hématologie, Université Paris Descartes - Paris 5 (UPD5)-UMRS 872-Centre National de la Recherche Scientifique (CNRS), Pharmacie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Epigenetique et Cancer, Centre National de la Recherche Scientifique (CNRS), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Normandie Université (NU)-Normandie Université (NU), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Pharmacie [CHU Rouen]
Subjects: Amyloid beta, [SDV]Life Sciences [q-bio], Review Article, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, Fibrinogen, Hemorrhagic disorder, Fibrin, Frameshift mutation, 03 medical and health sciences, fibrinogen αC domain, renal amyloidosis, 0302 clinical medicine, medicine, Dysfibrinogenemia, Review Articles, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, Chemistry, Point mutation, Hematology, dysfibrinogenemia, medicine.disease, Molecular biology, Coagulation, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, fibrinogen, Alzheimer’s disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Essentials The C‐terminal domain of the fibrinogen α chain (αC domain) is implicated in different severe diseases via clotting abnormalities or amyloid deposits.Certain anomalies of the fibrinogen molecule lead to amyloid deposits in the kidney, inducing renal insufficiency.In contrast, in Alzheimer's disease, fibrinogen is normal, but due to an inflammatory process, fibrinogen crosses into the brain and interacts with Aβ, leading to formation of pathological deposits. Abstract Fibrinogen, involved in coagulation, is a soluble protein composed of two sets of disulfide‐bridged Aα, Bβ, and γ‐chains. In this review, we present the clinical implications of the αC domain of the molecule in Alzheimer's disease, hereditary renal amyloidosis and a number of thrombotic and hemorrhagic disorders. In Alzheimer's disease, amyloid beta peptide (Aβ) is increased and binds to the αC domain of normal fibrinogen, triggering increased fibrin(ogen) deposition in patients’ brain parenchyma. In hereditary renal amyloidosis, fibrinogen is abnormal, with mutations located in the fibrinogen αC domain. The mutant αC domain derived from fibrinogen degradation folds incorrectly so that, in time, aggregates form, leading to amyloid deposits in the kidneys. In these patients, no thrombotic tendency has been observed. Abnormal fibrinogens with either a point mutation in the αC domain or a frameshift mutation resulting in absence of a part of the αC domain are often associated with either thrombotic events or bleeding. Mutation of an amino acid into cysteine (as in fibrinogens Dusart and Caracas V) or a frameshift mutation yielding an unpaired cysteine in the αC domain is often responsible for thrombotic events. Covalent binding of albumin to the unpaired cysteine via a disulphide bridge leads to decreased accessibility to the fibrinolytic enzymes, hence formation of poorly degradable fibrin clots, which explains the high incidence of thrombosis. In contrast, anomalies due to a frameshift mutation in the αC connector of the molecule, provoking deletion of a great part of the αC domain, are associated with bleeding.
Published: 2019
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7. Integration of Ca2+ signaling regulates the breast tumor cell response to simvastatin and doxorubicin

Author: Hong Li, Jean-Pierre Vannier, Catherine Buquet, Jean-Michel Picquenot, Souleymane Abdoul-Azize, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Groupe d'étude des proliférations lymphoïdes (GPL), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)
Subjects: 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Cancer, Cell migration, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Breast cancer, Apoptosis, Simvastatin, polycyclic compounds, Genetics, medicine, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Doxorubicin, Signal transduction, Cytotoxicity, Molecular Biology, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract: International audience; Recent studies have suggested that the lipid-lowering agent simvastatin holds great promise as a cancer therapeutic; it inhibits the growth of multiple tumors, including triple-negative breast cancer. Doxorubicin- and simvastatin-induced cytotoxicity has been associated with the modulation of Ca2+ signaling, but the underlying mechanisms remain incompletely understood. Here we identify how Ca2+ signaling regulates the breast tumor cell response to doxorubicin and simvastatin. These two drugs inhibit cell survival while increasing apoptosis in two human breast cancer cell lines and five primary breast tumor specimens through the modulation of Ca2+ signaling. Signal transduction and functional studies revealed that both simvastatin and doxorubicin trigger persistent cytosolic Ca2+ release, thereby stimulating the proapoptotic BIM pathway and mitochondrial Ca2+ overload, which are responsible for metabolic dysfunction and apoptosis induction. Simvastatin and doxorubicin suppress the prosurvival ERK1/2 pathway in a Ca2+-independent and Ca2+-dependent manner, respectively. In addition, reduction of the Ca2+ signal by chelation or pharmacological inhibition significantly prevents drug-mediated anticancer signaling. Unexpectedly, a scratch-wound assay indicated that these two drugs induce rapid cell migration, while inhibiting cell invasion and colony formation in a Ca2+-dependent manner. Further, the in vivo data for MDA-MB-231 xenografts demonstrate that upon chelation of Ca2+, the ability of both drugs to reduce the tumor burden was significantly reduced via caspase-3 deactivation. Our results establish a calcium-based mechanism as crucial for executing the cell death process triggered by simvastatin and doxorubicin, and suggest that combining simvastatin with doxorubicin may be an effective regimen for the treatment of breast cancer.
Published: 2018
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8. Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells

Author: Rémi Varin, Yessica Cristina Castellanos-Esparza, Hong Li, Anne Janin, He Lu, Berenice Sanchez-Gonzalez, Rong Shen, Limin Huang, Jean-Pierre Vannier, Olivier Boyer, Catherine Buquet, Ethel Awilda García Latorre, Shuang Wu, Jiménez-Zamudio L, Zhejiang University, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Pharmacie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hemostase, Endothelium, Angiogenese (UMR_S_553)
Subjects: 0301 basic medicine, Simvastatin, Cancer Research, [SDV]Life Sciences [q-bio], Apoptosis, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Annexin, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Autophagy, Humans, Propidium iodide, Pentoxifylline, Clonogenic assay, PI3K/AKT/mTOR pathway, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Cell growth, Drug Synergism, Cell cycle, 3. Good health, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Female
Abstract: Pentoxifylline (PTX), a xanthine family molecule and simvastatin (SIM), an anti-hypercholesterolemic agent, have recently been considered as sensitizers to chemotherapy and radiotherapy. The present in vitro study evaluated their antitumor synergistic effects on MDA‑MB‑231 breast cancer cells characterized by the triple‑negative phenotype (TNP). The anti-proliferative effects of these two agents were evaluated by MTT and clonogenic assays. Cell cycle progression was examined using propidium iodide staining. Apoptosis was investigated by Annexin V labeling, and by examining caspase 3 activity and DNA fragmentation. Autophagic vesicles and reactive oxygen species (ROS) levels were monitored by flow cytometry. Western blot analysis was performed to evaluate molecular targets. Our results revealed that when used alone, PTX and SIM exerted antitumor effects. Nevertheless, used in combination, the inhibition of cell proliferation was synergistically superior (80% vs 42%) than that observed following treatment with each agent alone after 48 h. PTX alone (0.5 mM) induced both apoptosis (25%) and autophagy (25%); however, when used in combination with SIM (0.5 µM), the balance between these processes was disrupted and the cells underwent apoptosis (>65%) as opposed to autophagy (
Published: 2018
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9. Salvage therapy with gemcitabine, vinorelbine, and pegylated liposomal doxorubicin for relapsed or refractory pediatric Hodgkin lymphoma. Results of a retrospective series of four children

Author: Nimrod Buchbinder, Marie Jaffray, Anne Lutun, Pascale Schneider, Jean-Michel Piquenot, Jean-Pierre Vannier, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), CHU Amiens-Picardie, Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Registre Multicentrique à Vocation Nationale des Mésothéliomes Pleuraux (MESONAT), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), and Micro-Environnement et Régulation Cellulaire Intégrée (MERCI)
Subjects: Male, Oncology, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Salvage therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Vinblastine, Vinorelbine, Deoxycytidine, Polyethylene Glycols, 03 medical and health sciences, 0302 clinical medicine, Nodular sclerosis, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Child, Anaplastic large-cell lymphoma, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, 030304 developmental biology, Salvage Therapy, 0303 health sciences, Chemotherapy, Cardiotoxicity, business.industry, Hematology, General Medicine, medicine.disease, Hodgkin Disease, Gemcitabine, 3. Good health, Transplantation, Treatment Outcome, Doxorubicin, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Neoplasm Recurrence, Local, business, medicine.drug
Abstract: While the vast majority of pediatric Hodgkin lymphoma (HL) is curable, the prognosis of early relapses and refractory diseases remains poor. Recently, the combination of gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) displayed encouraging results on adults with relapsed/refractory diseases. Here, we retrospectively report the results of the GVD salvage regimen on four pediatric patients of our ward with a heavily pretreated relapsed/refractory HL. Three of them had nodular sclerosis subtype. They achieved a complete remission after two, three, or four courses of GVD and received high-dose chemotherapy followed by a stem-cell transplantation (auto-auto, auto-allo, and auto). They have been in sustained remission respectively for almost 2, 4, and 5 years. The fourth patient had a lymphocyte-depleted subtype which was initially diagnosed as anaplastic large cell lymphoma. After four courses of GVD, his disease stabilized then progressed again. In total, 15 cycles of GVD were applied to the patients. The toxicity of each course of GVD was mainly hematologic. No cardiotoxicity occurred despite a prior exposure to anthracyclines and radiotherapy. Thus, the GVD combination seems to be an effective pre-transplant rescue treatment for pediatric patients.
Published: 2015
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10. Surface functionalization of cyclic olefin copolymer with aryldiazonium salts: A covalent grafting method

Author: Cécile Duclairoir-Poc, Sandrine Morin-Grognet, Franck Le Derf, Benjamin Berton, Florian Brisset, Julien Vieillard, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Sciences et Méthodes Séparatives (SMS), Normandie Université (NU)-Normandie Université (NU), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Laboratoire de Microbiologie Signaux et Microenvironnement (LMSM), and Collaboration
Subjects: Aryl radical, Surface treatment, Diazonium salt, General Physics and Astronomy, Infrared spectroscopy, COC, 02 engineering and technology, Cyclic olefin copolymer, 010402 general chemistry, 01 natural sciences, Contact angle, chemistry.chemical_compound, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Polymer chemistry, Grafting, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Aryl, Surfaces and Interfaces, General Chemistry, Interface, 021001 nanoscience & nanotechnology, Condensed Matter Physics, 0104 chemical sciences, Surfaces, Coatings and Films, chemistry, Chemical engineering, Covalent bond, Reagent, Surface modification, 0210 nano-technology
Abstract: International audience; Covalent immobilization of biomolecules on the surface of cyclic olefin copolymer (COC) is still a tough challenge. We developed a robust method for COC surface grafting through reaction with aryldiazonium. Chemical diazonium reduction generated an aryl radical and the formation of a grafted film layer on the organic surface. We also demonstrated that the chemical reduction of diazonium salt was not sufficient to form a film on the COC surface. UV illumination had to be combined with chemical reduction to graft an aryl layer onto the COC surface. We optimized organic film deposition by using different chemical reducers, different reaction times and reagent proportions. We characterized surface modifications by fluorescence microscopy and contact angle measurements, infrared spectroscopy, X-ray photoemission spectroscopy and Raman spectroscopy, and assessed the topography of the aryl film by atomic force microscopy. This original strategy allowed us to evidence various organic functions to graft biomolecules onto COC surfaces with a fast and efficient technique.
Published: 2015
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11. Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404)

Author: Sylvie Chevret, Suzanne Verlhac, Elisabeth Ducros-Miralles, Jean-Hugues Dalle, Regis Peffault de Latour, Mariane de Montalembert, Malika Benkerrou, Corinne Pondarré, Isabelle Thuret, Corinne Guitton, Emmanuelle Lesprit, Maryse Etienne-Julan, Gisèle Elana, Jean-Pierre Vannier, Patrick Lutz, Bénédicte Neven, Claire Galambrun, Catherine Paillard, Camille Runel, Charlotte Jubert, Cécile Arnaud, Annie Kamdem, Valentine Brousse, Florence Missud, Marie Petras, Lydia Doumdo-Divialle, Claire Berger, Françoise Fréard, Olivier Taieb, Elise Drain, Monique Elmaleh, Manuela Vasile, Yacine Khelif, Myriam Bernaudin, Philippe Chadebech, France Pirenne, Gérard Socié, Françoise Bernaudin, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Intercommunal de Créteil (CHIC), Hôpital Robert Debré, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Centre Léon Bérard [Lyon], Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Sud - Paris 11 (UP11), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université des Antilles (UA), CHU Pointe-à-Pitre/Abymes [Guadeloupe], CHU de la Martinique [Fort de France], Hôpital Charles Nicolle [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital de Hautepierre [Strasbourg], Université de Strasbourg (UNISTRA), CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Université de Saint-Etienne, Hôpital Avicenne [AP-HP], Université Paris 13 (UP13), Université de Caen Normandie (UNICAEN), Etablissement Français du Sang [Île-de-France Mondor], IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de Radiologie [Créteil], CHI Créteil, Hôpital Robert Debré Paris, Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Service de pédiatrie générale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Pointe à Pitre], CHU Fort de France, Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Normandie Université (NU)-Normandie Université (NU), Service d'immuno-hématologie pédiatrique [CHU Necker], Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Groupe hospitalier Pellegrin, Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Rouen, CHADEBECH, Philippe, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université Jean Monnet - Saint-Étienne (UJM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Service d'Hématologie et Oncologie pédiatriques, Hôpital Trousseau [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Male, Pediatrics, Ultrasonography, Doppler, Transcranial, medicine.medical_treatment, Hematopoietic stem cell transplantation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Cognition, 0302 clinical medicine, Genetic randomization, Medicine, Pharmacology (medical), Prospective Studies, Child, Prospective cohort study, Stroke, General Medicine, Sickle cell anemia, 3. Good health, Cerebral vasculopathy, Research Design, Child, Preschool, 030220 oncology & carcinogenesis, Female, medicine.medical_specialty, Iron Overload, Randomization, Adolescent, Anemia, Sickle Cell, Chronic transfusion, 03 medical and health sciences, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Blood Transfusion, Adverse effect, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Transfusion Reaction, Transcranial Doppler, medicine.disease, Surgery, Transplantation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Quality of Life, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030215 immunology
Abstract: Background Children with sickle cell anemia (SCA) have an 11% risk of stroke by the age of 18. Chronic transfusion applied in patients detected to be at risk by transcranial Doppler allows a significant reduction of stroke risk. However, chronic transfusion exposes to several adverse events, including alloimmunization and iron overload, and is not curative. Hematopoietic stem cell transplantation allows termination of the transfusion program, but its benefit has not been demonstrated. Design DREPAGREFFE ( NCT01340404 ) is a multicenter, prospective trial enrolling SCA children younger than 15 years receiving chronic transfusion due to a history of abnormal transcranial Doppler (velocities ≥ 200 cm/s). Only those with at least one non-SCA sibling and parents accepting HLA-typing and transplantation with a genoidentical donor were eligible. Chronic transfusion was pursued in patients with no available donor, whereas others were transplanted. Comparison between the 2 arms (transfusion vs transplantation) was analyzed using both genetic randomization and propensity-score matching as a sensitivity analysis. The primary end-point was the velocity measure at 1 year. Secondary endpoints were the incidence of stroke, silent cerebral infarcts and stenoses, cognitive performance in comparison with siblings, allo-immunization, iron-overload, phosphatidyl-serine, angiogenesis/hypoxia, brain injury-related factor expression, quality of life and cost. Objectives To show that genoidentical transplantation decreases velocities significantly more than chronic transfusion in SCA children at risk of stroke. Discussion DREPAGREFFE is the first prospective study to evaluate transplantation in SCA children. It compares the outcome of cerebral vasculopathy following genoidentical transplantation versus chronic transfusion using genetic randomization and causal inference methods.
Published: 2017
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12. A biomimetic hydrogel functionalized with adipose ECM components as a microenvironment for the 3D culture of human and murine adipocytes

Author: Louis, Fiona, Pannetier, Pauline, Souguir, Zied, Le Cerf, Didier, Valet, Philippe, Vannier, Jean-Pierre, Vidal, Guillaume, Demange, Elise, CELENYS, Environnements et Paléoenvironnements OCéaniques (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche pour la Conservation des Collections (CRCC), Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Polymères Biopolymères Surfaces (PBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Centre de recherches Paul Pascal (CRPP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2017
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13. Non syndromic childhood onset congenital sideroblastic anemia: A report of 13 patients identified with an ALAS2 or SLC25A38 mutation

Author: Thierry Leblanc, Hana Manceau, Fanny Fouyssac, J.F. Guichard, Nadja Jäkel, Patrick Lutz, Jean-Pierre Vannier, Cyrielle Fouquet, Fabienne Toutain, Mohamed Touati, Christiane Vermylen, Yves Perel, Marie-Amelyne Le Rouzic, Karim Maloum, Caroline Kannengiesser, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Université de Bordeaux (UB), Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Génétique Hématologique, Clinique Universitaire Saint-Luc, de Duve Institute, UCL, Médecine Interne-Pathologie Vasculaire - Immunologie Clinique, Hôpital Sainte Blandine, Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pontchaillou [Rennes], Hôpital Civil, Hopital Civil, Service d'hématologie pédiatrique et oncologie, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), California Institute of Technology (CALTECH)-NASA, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN)
Subjects: Pathology, medicine.medical_specialty, Pediatrics, Iron Overload, [SDV]Life Sciences [q-bio], Mitochondrial Membrane Transport Proteins, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, Humans, Chelation therapy, Child, Adverse effect, Molecular Biology, Congenital sideroblastic anemia, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, business.industry, Cell Biology, Hematology, ALAS2, Anemia, Sideroblastic, 3. Good health, Phenotype, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Molecular Medicine, business, Non syndromic, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 5-Aminolevulinate Synthetase, 030215 immunology
Abstract: The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome.
Published: 2017
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14. Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome

Author: Amandine Baptiste, Thibaud Lefebvre, Olivier Ernst, Emmanuelle Chauzit, Jean-Pierre Vannier, Agnès Guerci-Bresler, Christian Rose, Zoubida Karim, Hervé Puy, Aspasia Stamatoullas, Mariane De Montalembert, Valentine Brousse, Krimo Bouabdallah, Mohamed Touati, C. Dumesnil, Agnès Lahary, Marina Cavazzana, Caroline Elie, Jean-Antoine Ribeil, Service de pédiatrie générale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Centre de Référence de la Drépanocytose-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie générale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Hôpital Charles Nicolle [Rouen], Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Département de Biothérapie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], CHU Bordeaux [Bordeaux], Hôpital Cochin [AP-HP], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'informatique médicale et biostatistiques [CHU Necker], Radiologie interventionnelle, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie, Hôpital Saint-Vincent-de-Paul, TAN, Yossan-Var, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Référence de la Drépanocytose, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), CHU Necker - Enfants Malades [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)-Université Paris Diderot - Paris 7 (UPD7), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Blood transfusion, Physiology, Thalassemia, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lcsh:Medicine, 030204 cardiovascular system & hematology, Gastroenterology, Physical Chemistry, Biochemistry, Diagnostic Radiology, 0302 clinical medicine, hemic and lymphatic diseases, Medicine and Health Sciences, Erythropoiesis, 10. No inequality, Child, lcsh:Science, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Chelation, Radiology and Imaging, Heart, Hematology, Middle Aged, Magnetic Resonance Imaging, Sickle cell anemia, Clinical Laboratory Sciences, 3. Good health, [SDV] Life Sciences [q-bio], Chemistry, Genetic Diseases, 030220 oncology & carcinogenesis, Physical Sciences, Female, Anatomy, Research Article, Adult, medicine.medical_specialty, Iron Overload, Adolescent, Anemia, Imaging Techniques, Iron, Anemia, Sickle Cell, Research and Analysis Methods, Iron Chelating Agents, 03 medical and health sciences, Autosomal Recessive Diseases, Hepcidin, Diagnostic Medicine, Internal medicine, medicine, Humans, Blood Transfusion, Clinical Genetics, Ferritin, Sickle Cell Disease, Chemical Bonding, business.industry, Transfusion Medicine, Myelodysplastic syndromes, Myocardium, lcsh:R, Biology and Life Sciences, Proteins, Protein Complexes, medicine.disease, Hematopoiesis, Hemoglobinopathies, Myelodysplastic Syndromes, biology.protein, Cardiovascular Anatomy, lcsh:Q, business, Physiological Processes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P
Published: 2017
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15. Modulation de la sensibilité aux glucocorticoïdes dans les leucémies aiguës lymphoblastiques

Author: Abdoul-Azize, Souleymane, Dubus, Isabelle, Vannier, Jean-Pierre, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)
Subjects: [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2017
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16. Improvement of dexamethasone sensitivity by chelation of intracellular Ca2+ in pediatric acute lymphoblastic leukemia cells through the prosurvival kinase ERK1/2 deactivation

Author: Jean-Pierre Vannier, Souleymane Abdoul-Azize, Isabelle Dubus, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), and Normandie Université (NU)-Normandie Université (NU)
Subjects: 0301 basic medicine, medicine.medical_specialty, Programmed cell death, Thapsigargin, MAP Kinase Signaling System, Ca 2+ signaling, dexamethasone, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute lymphoblastic leukemia, Pharmacology, Calcium in biology, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, Internal medicine, medicine, Humans, Calcium Signaling, ERK1/2 pathway, Ca2+ signaling, Calcium Chelating Agents, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Cell Death, Kinase, business.industry, Calcium channel, apoptosis, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Mitochondria, 3. Good health, Enzyme Activation, 030104 developmental biology, Endocrinology, Oncology, chemistry, Drug Resistance, Neoplasm, Apoptosis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Calcium, Signal transduction, business, Intracellular, Research Paper
Abstract: // Souleymane Abdoul-Azize 1, 3 , Isabelle Dubus 1, 3 , Jean-Pierre Vannier 1, 2, 3 1 Micro-Environnement et Renouvellement Cellulaire Integre, MERCI UPRES EA 3829, Faculte de Medecine et Pharmacie, Universite de Rouen, 76183 Rouen Cedex, France 2 Service Immuno-Hemato-Oncologie Pediatrique, CHU Charles Nicolle, 76031 ROUEN Cedex, France 3 Current address: Unite Inserm U1234/Universite de Rouen/IRIB, Rouen, France Correspondence to: Souleymane Abdoul-Azize, email: souleymane.abdoul-azize@univ-rouen.fr , bontasso@yahoo.fr Keywords: acute lymphoblastic leukemia, dexamethasone, Ca 2+ signaling, ERK1/2 pathway, apoptosis Received: November 16, 2016 Accepted: February 15, 2017 Published: March 09, 2017 ABSTRACT Previous studies have demonstrated that glucocorticoid hormones, including dexamethasone, induced alterations in intracellular calcium homeostasis in acute lymphoblastic leukemia (ALL) cells. However, the mechanism by which intracellular calcium homeostasis participates in dexamethasone sensitivity and resistance on ALL cells remains elusive. Here, we found that treatment of cells with dexamethasone resulted in increased intracellular calcium concentrations through store-operated calcium entry stimulation, which was curtailed by store-operated calcium channel blockers. We show that BAPTA-AM, an intracellular Ca 2+ chelator, synergistically enhances dexamethasone lethality in two human ALL cell lines and in three primary specimens. This effect correlated with the inhibition of the prosurvival kinase ERK1/2 signaling pathway. Chelating intracellular calcium with Bapta-AM or inhibiting ERK1/2 with PD98059 significantly potentiated dexamethasone-induced mitochondrial membrane potential collapse, reactive oxygen species production, cytochrome c release, caspase-3 activity, and cell death. Moreover, we show that thapsigargin elevates intracellular free calcium ion level, and activates ERK1/2 signaling, resulting in the inhibition of dexamethasone-induced ALL cells apoptosis. Together, these results indicate that calcium-related ERK1/2 signaling pathway contributes to protect cells from dexamethasone sensitivity by limiting mitochondrial apoptotic pathway. This report provides a novel resistance pathway underlying the regulatory effect of dexamethasone on ALL cells.
Published: 2017
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17. Three Dimensional Tumor Engineering by Co-Culture of Breast Tumor and Endothelial Cells Using a Hyaluronic Acid Hydrogel Model

Author: Didier Le Cerf, Jean PierreVannier, Catherine Buquet, Yusra Kassim, Elias Al Tawil, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Polymères Biopolymères Surfaces (PBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cell type, Mammary tumor, Tumor microenvironment, Stromal cell, business.industry, Cell, [CHIM.MATE]Chemical Sciences/Material chemistry, Cell biology, Endothelial stem cell, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, medicine.anatomical_structure, [CHIM.POLY]Chemical Sciences/Polymers, Tissue engineering, chemistry, Immunology, Hyaluronic acid, medicine, business, ComputingMilieux_MISCELLANEOUS
Abstract: Besides tumor cells, the microenvironment harbors a variety of host-derived cells. To date, the most successful tissue engineering approaches have employed methods that recapitulate the composition, architecture and/or chemical presentation of the native microenvironment. Thus tumor engineering in biomimetic three dimensional conditions represents a dynamic cooperatively between different cell types in a spatially and functionally accurate fashion. Evidence has been provided that the cross-talk between tumor cells and stromal cells leads to enhanced tumor growth, metastasis and altered response to chemotherapeutic agents. It has been provided that endothelial cells play an important role in tumor in shaping the tumor microenvironment and controlling tumor development, in particular through neo-angiogenesis. We developed a 3D in vitro tumor model that encompasses a cross-linked hyaluronic acid hydrogel providing a physiologically relevant microenvironment for mammary tumor cell and endothelial cell co-culture. We investigated the morphological cross-talk between tumor and endothelial cells in a 3D configuration. Additionally, we observed the influence of co-culturing on the proliferation, angiogenic protein expression and secretion. We demonstrated that endothelial cells tend to acquire a spheroidal configuration with the mammary tumor cells surrounding the endothelial spheroid. We also observed that the levels of VEGF, MMP-2 and MMP-9 have tendencies to decrease within the first 6 days of co-culture, and tend to increase at day 12. This could be due to the restored polarity of the mammary tumor cells leading to a period of quiescence required to restore the malignant organization. These data confirm the importance of tissue architecture and polarity in malignant progression.
Published: 2017
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18. Collagen implants equipped with ‘fish scale’-like nanoreservoirs of growth factors for bone regeneration

Author: Sandy Eap, Guy Ladam, Jessica Schiavi, Nadia Benkirane-Jessel, Florence Fioretti, Tunay Kökten, Laetitia Keller, Alice Ferrand, D. Mainard, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Chirurgie Dentaire, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Bioingénierie Moléculaire, Cellulaire et Thérapeutique (BMCT), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Faculté de chirurgie dentaire - Strasbourg, Université de Strasbourg (UNISTRA), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Biomatériaux et ingénierie tissulaire, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), and Sciences et Méthodes Séparatives (SMS)
Subjects: Male, medicine.medical_specialty, Materials science, medicine.medical_treatment, Nanofibers, Biomedical Engineering, Mice, Nude, Medicine (miscellaneous), Bone morphogenetic protein 2, Bioengineering, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 02 engineering and technology, Development, 010402 general chemistry, 01 natural sciences, Bone morphogenetic protein 2, Bone regeneration, Collagen implant, Drug delivery, Layer-by-layer deposition, Regenerative nanomedicine, Chitosan, chemistry.chemical_compound, In vivo, medicine, Animals, Humans, General Materials Science, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Bone regeneration, Cells, Cultured, Osteoblasts, Tissue Scaffolds, Growth factor, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Regenerative nanomedicine, 021001 nanoscience & nanotechnology, Layer-by-layer deposition, Collagen implant, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 0104 chemical sciences, Surgery, Fish scale, [CHIM.POLY]Chemical Sciences/Polymers, chemistry, Nanofiber, Drug delivery, Collagen, 0210 nano-technology, Biomedical engineering
Abstract: International audience; Implants triggering rapid, robust and durable tissue regeneration are needed to shorten recovery times and decrease risks of postoperative complications for patients. Here, we describe active living collagen implants with highly promising bone regenerative properties. Bioactivity of the implants is obtained through the protective and stabilizing layer-by-layer immobilization of a protein growth factor in association with a polysaccharide (chitosan), within the form of nanocontainers decorating the collagen nanofibers. All components of the implants are US FDA approved. From both in vitro and in vivo evaluations, the sophisticated strategy described here should enhance, at a reduced cost, the safety and efficacy of the therapeutic implants in terms of large bone defects repair compared with current simplistic approaches based on the soaking of the implants with protein growth factor.
Published: 2014
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19. Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

Author: C. Heuclin, C. Petit, Isabelle Dubus, J. P. Vannier, Flore Gouel, K. Roget, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Biosims Technologies
Subjects: RPPA, 0301 basic medicine, Cancer Research, Cell Survival, Prednisolone, Cell, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Genetics, Humans, Medicine, Viability assay, Hypoxia, Cell growth, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Hypoxia (medical), medicine.disease, Cell Hypoxia, 3. Good health, Leukemia, Methotrexate, 030104 developmental biology, medicine.anatomical_structure, Oncology, Drug Resistance, Neoplasm, Cell culture, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, Signal transduction, medicine.symptom, ALL, business, Chemoresistance, Signal Transduction, Research Article
Abstract: Background Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood. Methods In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL). To look for an implication of hypoxia in chemoresistance, cell viability, total cell density and cell proliferation were analyzed. Survival and death signaling pathways were also screened by “reverse phase protein array” (RPPA) and western blotting experiments conducted on selected proteins to confirm the results. Results We found that hypoxia promotes chemoresistance in both ALL cell lines. The induction of drug-resistance by hypoxia was not associated with an increase in total cell density nor an increase in cell proliferation. Using RPPA, we show that chemoresistance induced by hypoxia was mediated through an alteration of cell death signaling pathways. This protective effect of hypoxia seems to occur via a decrease in pro-apoptotic proteins and an increase in anti-apoptotic proteins. The results were confirmed by immunoblotting. Indeed, hypoxia is able to modulate the expression of anti-apoptotic proteins independently of chemotherapy while a pro-apoptotic signal induced by a chemotherapy is not modulated by hypoxia. Conclusions Hypoxia is a factor in leukemia cell resistance and for two conventional chemotherapies modulates cell death signaling pathways without affecting total cell density or cell proliferation. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2776-1) contains supplementary material, which is available to authorized users.
Published: 2016
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20. Pyr3, a TRPC3 channel blocker, potentiates dexamethasone sensitivity and apoptosis in acute lymphoblastic leukemia cells by disturbing Ca2+ signaling, mitochondrial membrane potential changes and reactive oxygen species production

Author: Souleymane Abdoul-Azize, Isabelle Dubus, Catherine Buquet, Jean-Pierre Vannier, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Fibrose hépatique et cancer du foie, and Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, endocrine system, Programmed cell death, medicine.medical_specialty, Thapsigargin, Cell, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Acute lymphoblastic leukemia, Pyr3, Endoplasmic Reticulum, Dexamethasone, 03 medical and health sciences, chemistry.chemical_compound, TRPC3, Cell Line, Tumor, Internal medicine, medicine, polycyclic compounds, Humans, TRPC Cation Channels, Membrane Potential, Mitochondrial, Pharmacology, chemistry.chemical_classification, Reactive oxygen species, Calcium signaling, Drug Synergism, Depolarization, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, chemistry, Cell culture, Cancer research, Pyrazoles, hormones, hormone substitutes, and hormone antagonists, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Dexamethasone (Dex) is used as a chemotherapeutic drug in the treatment of acute lymphoblastic leukemia (ALL) because of its capacity to induce apoptosis. However, some ALL patients acquire resistance to glucocorticoids (GC). Thus, it is important to explore new agents to overcome GC resistance. The aim of the present work was to assess the ability of Pyr3, a selective inhibitor of transient receptor potential canonical 3 (TRPC3), to sensitize human ALL cells to Dex. We show here, for the first time, that Pyr3 enhances Dex sensitivity through the distraction of Dex-mediated Ca2+ signaling in ALL cells (in vitro) and primary blasts (ex vivo) associated with mitochondrial-mediated reactive oxygen species production in ALL cells. Pyr3 alone induced Ca2+ signaling via only endoplasmic reticulum-released Ca2+ and exerted inhibitory effect on store-operated Ca2+ entry in dose-dependent manner in ALL cell lines. Pre-incubation of cells with Pyr3 significantly curtailed the thapsigargin- and Dex-evoked Ca2+ signaling in ALL cell lines. Pyr3 synergistically potentiated Dex lethality, as shown by the induction of cell mortality, G2/M cell cycle arrest and apoptosis in ALL cell lines. Moreover, Pyr3 disrupted Dex-mediated Ca2+ signaling and increased the sensitivity of Dex-induced cell death in primary blasts from ALL patients. Additional analysis showed that co-treatment with Dex and Pyr3 results in mitochondrial membrane potential depolarization and reactive oxygen species production in ALL cells. Together, Pyr3 exhibited potential therapeutic benefit in combination with Dex to inverse glucocorticoid resistance in human ALL and probably in other lymphoid malignancies.
Published: 2016
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21. Synergistic influence of topomimetic and chondroitin sulfate-based treatments on osteogenic potential of Ti-6Al-4V

Author: Labat, Béatrice, Morin-Grognet, Sandrine, Gaudière, Fabien, Bertolini-Forno, Lucia, Thoumire, Olivier, Vannier, Jean-Pierre, Ladam, Guy, Atmani, Hassan, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Normandie Université (NU)-Normandie Université (NU), Fonctions Cellulaires et Moleculaires de l'Appareil Respiratoire et des Vaisseaux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Sciences et Méthodes Séparatives (SMS), Polymères Biopolymères Surfaces (PBS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, and Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN)
Subjects: [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, titanium alloy, [CHIM.POLY]Chemical Sciences/Polymers, topography, [CHIM.MATE]Chemical Sciences/Material chemistry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, pre-osteoblasts, genipin, chondroitin sulfate
Abstract: International audience; We combined topographical and chemical surface modifications of Ti-6Al-4V (TA6V) to improve its osteogenic potential. By acid-etching, we first generated topomimetic surface features resembling, in size and roughness, bone cavities left by osteoclasts. Next, we coated these surfaces with biomimetic Layer-by-Layer films (LbL), composed of chon-droitin sulfate A and poly-L-lysine that were mechanically tuned after a post-treatment with genipin. The structural impact of each surface processing step was thoroughly inspected. The desired nano/microrough topographies of TA6V were maintained upon LbL deposition. Whereas no significant promotion of adhesion and proliferation of MC3T3-E1 preosteoblasts were detected after independent or combined modifications of the topography and the chemical composition of the substrates, osteogenic maturation was promoted when both surface treatments were combined, as was evi-denced by significant long-term matrix mineralization. The results open promising route toward improved osseointegra-tion of titanium-based implants. V C 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00B:000-000, 2016.
Published: 2016
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22. Combining Combing and Secondary Ion Mass Spectrometry to Study DNA on Chips Using 13C and 15N Labeling

Author: Victor Norris, Tom Wirtz, Jean-Nicolas Audinot, Anne-Francoise Monnier, Yannick Coffinier, David Gibouin, Laurent Jannière, Camille Ripoll, Rabah Boukherroub, Aaron Bensimon, Henri-Noël Migeon, Armelle Cabin-Flaman, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Normandie Université (NU)-Normandie Université (NU), Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Ecole Centrale de Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Luxembourg Institute of Science and Technology (LIST), genomic vision, Institut de biologie systémique et synthétique (ISSB), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Assemblages moléculaires : modélisation et imagerie SIMS (AMMIS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Materials Research and Technology (MRT) Department, Luxembourg Institute of Science and Technology (LIST), and Laboratoire de Microbiologie du Froid – Signaux et Micro-Environnement (LMDF-SME)
Subjects: 0301 basic medicine, DNA isotope labeling, [SDV]Life Sciences [q-bio], Combing, Biology, General Biochemistry, Genetics and Molecular Biology, law.invention, silicon chip, 03 medical and health sciences, chemistry.chemical_compound, law, Molecule, General Pharmacology, Toxicology and Pharmaceutics, [PHYS.COND]Physics [physics]/Condensed Matter [cond-mat], DNA extraction, ComputingMilieux_MISCELLANEOUS, Genetics, General Immunology and Microbiology, DNA synthesis, Radiochemistry, Articles, General Medicine, Secondary ion mass spectrometry, Research Note, Surface coating, 030104 developmental biology, PCR, chemistry, surface coating, Recombinant DNA, Structure: Transcription & Translation, isotope recombination, DNA
Abstract: Dynamic secondary ion mass spectrometry (D-SIMS) imaging of combed DNA – the combing, imaging by SIMS or CIS method – has been developed previously using a standard NanoSIMS 50 to reveal, on the 50 nm scale, individual DNA fibers labeled with different, non-radioactive isotopes in vivo and to quantify these isotopes. This makes CIS especially suitable for determining the times, places and rates of DNA synthesis as well as the detection of the fine-scale re-arrangements of DNA and of molecules associated with combed DNA fibers. Here, we show how CIS may be extended to 13C-labeling via the detection and quantification of the 13C14N- recombinant ion and the use of the 13C:12C ratio, we discuss how CIS might permit three successive labels, and we suggest ideas that might be explored using CIS.
Published: 2016
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23. Importance of local hypoxia on endothelial phenotype for an in vitro approach to bone marrow angiogenesis

Author: Marc Vasse, Jean-Pierre Vannier, Isabelle Dubus, Sophie Kamanzi, Flore Gouel, Cécile Corbière, Paul Mulder, Elisabeth Legrand, Catherine Buquet, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Aliments Bioprocédés Toxicologie Environnements (ABTE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Institute for Research and Innovation in Biomedicine (IRIB), and Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Vascular Endothelial Growth Factor A, Cancer Research, Pathology, Angiogenesis, [SDV]Life Sciences [q-bio], MESH: Cell Hypoxia, Cell Culture Techniques, Endothelial Growth Factors, MESH: Endothelial Growth Factors, 0302 clinical medicine, Bone Marrow, MESH: Endothelial Cells, Angiogenic Proteins, MESH: Models, Theoretical, Receptor, Cells, Cultured, 0303 health sciences, Cell Differentiation, Hematology, Angiopoietin receptor, Cell Hypoxia, 3. Good health, Oxygen tension, Leukemia, Phenotype, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, [SDE]Environmental Sciences, MESH: Bone Marrow, MESH: Neovascularization, Physiologic, MESH: Oxygen, MESH: Cells, Cultured, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Angiogenic Proteins, Neovascularization, Physiologic, Biology, MESH: Phenotype, 03 medical and health sciences, In vivo, medicine, Humans, 030304 developmental biology, MESH: Cell Culture Techniques, MESH: Humans, MESH: Vascular Endothelial Growth Factor A, Endothelial Cells, Models, Theoretical, medicine.disease, MESH: Receptors, Vascular Endothelial Growth Factor, In vitro, Oxygen, Receptors, Vascular Endothelial Growth Factor, biology.protein, Cancer research, Bone marrow
Abstract: International audience; The vasculature of bone marrow differs from that in other organs, and its characteristics should be considered when exploring the medullar angiogenesis associated with hematological malignancies. We show here that the human bone marrow sinusoidal cell line HBME-1 has a specific expression pattern of angiogenic factors and receptors, characterized by a unique VEGFR3(+), Tie2(-) signature, that resembles the in vivo pattern. Moreover, the HBME-1 cultured for up to 3 days in hypoxic conditions, similar to those found in the bone marrow, specifically downregulated expression of VEGFR1, VEGFR2 and ETAR. Thus, a model using bone marrow sinusoidal cells cultured under reduced oxygen tension may be more relevant than classical in vitro endothelial cultures for understanding the interactions between endothelial and malignant cells in the medullar microenvironment.
Published: 2012
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24. CRMP5 Interacts with Tubulin to Inhibit Neurite Outgrowth, Thereby Modulating the Function of CRMP2

Author: Brot, Sébastien, Rogemond, Véronique, Perrot, Valérie, Chounlamountri, Naura, Auger, Carole, Honnorat, Jérôme, Moradi-Améli, Mahnaz, Moradi-Ameli, M., Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut NeuroMyoGène (INMG), 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), IFR des neurosciences de Lyon (IFNL), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier le Vinatier [Bron]-Hospices Civils de Lyon (HCL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuro-oncologie et neuro-inflammation, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: Small interfering RNA, Neurite, Hydrolases, Green Fluorescent Proteins, Nerve Tissue Proteins, Transfection, Amidohydrolases, Tubulin binding, Mice, 03 medical and health sciences, 0302 clinical medicine, Tubulin, Neurites, Animals, Immunoprecipitation, Cytoskeleton, Cells, Cultured, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, biology, General Neuroscience, Brain, Gene Expression Regulation, Developmental, Articles, Embryo, Mammalian, Protein Structure, Tertiary, Cell biology, Mice, Inbred C57BL, Animals, Newborn, Mutation, biology.protein, Intercellular Signaling Peptides and Proteins, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Axon guidance, Collapsin response mediator protein family, Microtubule-Associated Proteins, Neural development, 030217 neurology & neurosurgery, Protein Binding
Abstract: International audience; Collapsin response mediator proteins (CRMPs) are involved in signaling of axon guidance and neurite outgrowth during neural development and regeneration. Among these, CRMP2 has been identified as an important actor in neuronal polarity and axon outgrowth, these activities being correlated with the reorganization of cytoskeletal proteins. In contrast, the function of CRMP5, expressed during brain development, remains obscure. Here, we find that, in contrast to CRMP2, CRMP5 inhibits tubulin polymerization and neurite outgrowth. Knockdown of CRMP5 expression by small interfering RNA confirms its inhibitory functions. CRMP5 forms a ternary complex with MAP2 and tubulin, the latter involving residues 475-522 of CRMP5, exposed at the molecule surface. Using different truncated CRMP5 constructs, we demonstrate that inhibition of neurite outgrowth by CRMP5 is mediated by tubulin binding. When both CRMP5 and CRMP2 are overexpressed, the inhibitory effect of CRMP5 abrogates neurite outgrowth promotion induced by CRMP2, suggesting that CRMP5 acts as a dominant signal. In cultured hippocampal neurons, CRMP5 shows no effect on axon growth, whereas it inhibits dendrite outgrowth and formation, at an early developmental stage, correlated with its strong expression in neurites. At later stages, when dendrites begin to extend, CRMP5 expression is absent. However, CRMP2 is constantly expressed. Overexpression of CRMP5 with CRMP2 inhibits CRMP2-induced outgrowth both on the axonal and dendritic levels. Deficiency of CRMP5 expression enhanced the CRMP2 effect. This antagonizing effect of CRMP5 is exerted through a tubulin-based mechanism. Thus, the CRMP5 binding to tubulin modulates CRMP2 regulation of neurite outgrowth and neuronal polarity during brain development.
Published: 2010
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25. Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent

Author: Cécile Corbière, Bertrand Leblond, Catherine Buquet, Thierry Besson, Mauro Iannelli, Alicia Foucourt, Elizabeth Chosson, Carole Dubouilh-Benard, Francis Marsais, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Normandie Université (NU)-Normandie Université (NU), Institut de Chimie Organique Fine (IRCOF), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Formamide, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Organic Chemistry, Microwave technology, 010402 general chemistry, 01 natural sciences, Biochemistry, Dimroth rearrangement, Combinatorial chemistry, 0104 chemical sciences, chemistry.chemical_compound, Microtubule, Drug Discovery, Rapid access, Organic chemistry, Apoptosis inducer, ComputingMilieux_MISCELLANEOUS, Microwave
Abstract: A useful and rapid access to 4-anilino-6-nitroquinazolines was investigated in a multi-gram scale via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with imines obtained by reaction of anthranilonitriles with formamide dimethylacetal. A novel short and efficient route to Azixa™ (EPi28495, MPC-6827), a microtubule destabilizing agent and apoptosis inducer, was performed with success demonstrating that well controlled parameters offer comfortable using of microwave technology with safe and environmental benefits.
Published: 2010
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26. A New Intergenic α -Globin Deletion ( α – α Δ125 ) Found in a Kabyle Population

Author: Philippe Lacan, Philippe Joly, Patricia Bignet, Amrathlal Rabbind Singh, C. Dumesnil, Estelle Cadet, Jacques Rochette, Jean-Pierre Vannier, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), CHU Amiens-Picardie-Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Centre de Recherche et d'Innovation sur le Sport (EA647) (CRIS), and Université de Lyon-Université de Lyon
Subjects: 0301 basic medicine, Adult, Male, Adolescent, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Population, DNA Mutational Analysis, Biology, Polymerase Chain Reaction, law.invention, 03 medical and health sciences, Young Adult, Intergenic region, alpha-Globins, law, Multiplex polymerase chain reaction, Gene cluster, Humans, Allele, education, Child, Gene, Genetics (clinical), Polymerase chain reaction, ComputingMilieux_MISCELLANEOUS, Aged, Sequence Deletion, Genetics, Aged, 80 and over, education.field_of_study, Base Sequence, Biochemistry (medical), Hematology, Middle Aged, Noncoding DNA, Molecular biology, 3. Good health, 030104 developmental biology, Genetics, Population, Algeria, Child, Preschool, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: We have identified a deletion of 125 bp (α-α(Δ125)) (NG_000006.1: g.37040_37164del) in the α-globin gene cluster in a Kabyle population. A combination of singlex and multiplex polymerase chain reaction (PCR)-based assays have been used to identify the molecular defect. Sequencing of the abnormal PCR amplification product revealed a novel α1-globin promoter deletion. The endpoints of the deletion were characterized by sequencing the deletion junctions of the mutated allele. The observed deletion was located 378 bp upstream of the α1-globin gene transcription initiation site and leaves the α2 gene intact. In some patients, the α-α(Δ125) deletion was shown to segregate with Hb S (HBB: c.20A>T) and/or Hb C (HBB: c.19G>A) or a β-thalassemic allele. The α-α(Δ125) deletion has no discernible effect on red cell indices when inherited with no other abnormal globin genes. The family study demonstrated that the deletion is heritable. This is the only example of an intergenic α2-α1 non coding DNA deletion, leaving the α2-globin gene and the α1 coding part intact.
Published: 2015
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27. Les cellules leucémiques de LAL modulent-elles l'angiogenèse dans la moelle osseuse ? Rôle de l'endothéline-1 et de l'hypoxie

Author: Gouel, Flore, Corbiere, Cecile, Poullain, Amélie, Blanchard, Karine, Mulder, Paul, Dubus, Isabelle, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), and Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’adolescent (SFCE), Ligue contre le Cancer de Normandie.
Subjects: angiogenesis, bone marrow, hypoxia, [SDV]Life Sciences [q-bio], endothelin-1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Acute Lymphoblastic Leukemia, VEGF A
Abstract: Increased microvessel density has been described in the bone marrow of patients with Acute Lymphoblastic Leukemia (ALL). The bone marrow is an hypoxic microenvironment, and hypoxia is an important event in triggering angiogenesis. However, the crosstalk between ALL cells and endothelial cells has not been well explored, and usual in vitro assays use cells maintained under 21% O2, which did not mimic bone marrow environment. In this study, the angiogenic activity of factors secreted by the human B-ALL Nalm-6 cell line was tested by using conditioned serum-free medium, that was applied on the human bone marrow endothelial cells HBME-1. Under 21% O2, factors secreted by Nalm-6 cells induced an angiogenic response on HBME-1 cells in vitro. This angiogenic response was not dependent on VEGF secretion but involved, at least in part, the endothelin-endothelin receptor axis. The influence of hypoxia was then studied by culturing both cell lines under 5% O2, an oxygen tension that fits the bone marrow microenvironment. Hypoxia stimulated the secretion of VEGFA by both Nalm-6 and HBME-1 cells, but the angiogenic response to leukemic conditioned medium was altered by chronic hypoxia, which affects the ability of endothelial cells to respond to endothelin-1. Thus, we concluded that leukemic secretion products did not induce angiogenesis at oxygen conditions met in vivo. This work highlights the importance of the oxygen rate in the modulation of cell interactions within the bone marrow, not yet well explored in ALL.
Published: 2015

28. Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2

Author: Matthieu Vinchon, Jean-Pierre Vannier, Nicolas Xavier Bonne, Véronique Nève, Nicolas André, Christophe Vincent, Jean-Paul Lejeune, Marc Baroncini, Frédérique Dubrulle, Héléne Sudour Bonnange, Vianney Gaillard, Audrey Hochart, Pierre Leblond, 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, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Neurochirurgie[Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Therapies Interventionnelles Assistees Par l'Image et la Simulation - U 703 (Thiais), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), 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, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Therapies Interventionnelles Assistees Par l'Image et la Simulation, Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Cancer Research, medicine.medical_specialty, Pediatrics, Neurofibromatosis 2, Neurology, Bevacizumab, Adolescent, Hearing loss, [SDV]Life Sciences [q-bio], Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Schwannoma, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Audiometry, medicine, Humans, Neurofibromatosis type 2, 10. No inequality, Child, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Response rate (survey), business.industry, Neuroma, Acoustic, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Surgery, Tumor Burden, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Vestibular Schwannomas, Disease Progression, Female, Neurology (clinical), France, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug, Follow-Up Studies
Abstract: Vestibular schwannoma (VS) growth in neu- rofibromatosis type 2 (NF2) can be responsible for brain- stem compression and hearing loss. Surgical removal remains the standard therapy despite potential morbidity. Previous studies suggested that the inhibition of the VEGF- pathway with bevacizumab could result in hearing im- provement, reduction of the tumor volume or both in adults. We retrospectively describe the French experience of bevacizumab treatment delivered for progressive VS in pediatric NF2 patients. Patients received Bevacizumab 5 or 10 mg/kg every 2 weeks according to the physician's choice. Follow-up included clinical assessment, au- diometry and volumetric MRI every 3-6 months. Seven patients harboring 11 VS were included. The median age at inclusion was 15 years (11.4-18.8), and the median treat- ment duration was 11.3 months (3.2-55.6). At baseline, the median tumor volume was 1.2 cm 3 (0.52-13.5) and the median word recognition score was 90 % (0-100). We observed one major response, two minor responses and a decrease in the rate of tumor growth for the 4 other pa- tients. The median annual growth rate before treatment was significantly higher than after 1 year of treatment (138 vs. 36 %, n = 5, p = 0.043). We noted one hearing im- provement over the course of 1 year under treatment (hearing response rate was 14 %). Overall, the treatment was well tolerated. Our study supports that bevacizumab is an attractive therapeutic option for pediatric NF2 patients with growing VS. Thorough multidisciplinary evaluation is necessary to identify the best candidates prior to treatment. It is likely that a better functional outcome would be ex- pected if targeted therapies were discussed early in the management of the disease.
Published: 2015
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29. Ifosfamide-induced encephalopathy due to a novel formulation of ifosfamide

Author: Pascale Schneider, Jean-Pierre Vannier, Bruno Filhon, Marie Jaffray, Boris Lacarra, Charles Hervouet, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Micro-Environnement et Régulation Cellulaire Intégrée (MERCI)
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Chemistry, Pharmaceutical, Encephalopathy, MEDLINE, 03 medical and health sciences, Young Adult, 0302 clinical medicine, medicine, Humans, Ifosfamide, Child, Antineoplastic Agents, Alkylating, ComputingMilieux_MISCELLANEOUS, Brain Diseases, business.industry, Infant, Hematology, medicine.disease, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Powders, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: International audience
Published: 2015
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30. Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells

Author: Li Wang, Mélanie Di Benedetto, Anne Janin, Rémi Varin, Chaoquan Hu, Jian Jin, Hong Li, Li-Min Huang, Jielin Liu, Jean Pierre Vannier, He Lu, Laboratoire de Génie Electrique de Grenoble (G2ELab), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Guizhou Medical University (贵州医科大学), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Pharmacie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Laboratoire de génie des procédés - environnement - agroalimentaire (GEPEA), Mines Nantes (Mines Nantes)-Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des signaux et systèmes (L2S), Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Sud - Paris 11 (UP11), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Microenvironnement et régulation cellulaire intégrés (MERCI), Li, Hong, Mines Nantes (Mines Nantes)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), Hemostase, Endothelium, Angiogenese (UMR_S_553), Beijing National Laboratory for Condensed Matter Physics and Institute of Physics (IoP/CAS), Chinese Academy of Sciences [Changchun Branch] (CAS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), and Normandie Université (NU)-Normandie Université (NU)-CHU Rouen
Subjects: Cancer Research, Abcg2, sunitinib, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug resistance, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Cytotoxic T cell, Doxorubicin, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, ABC family, 0303 health sciences, drug resistance, biology, Sunitinib, business.industry, Articles, Cell cycle, endothelial cells, 3. Good health, Multiple drug resistance, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, biology.protein, cancer therapy, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, medicine.drug
Abstract: International audience; Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.
Published: 2015
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31. Intravenous Delivery of Anti-RhoA Small Interfering RNA Loaded in Nanoparticles of Chitosan in Mice: Safety and Efficacy in Xenografted Aggressive Breast Cancer

Author: Hong Li, Jeannette Soria, Jean-Rémi Bertrand, Claudine Soria, He Lu, Paule Opolon, Jean-Yves Pille, Claude Malvy, Emmanuel Blot, Linda L. Pritchard, Andrei Maksimenko, Jean-Pierre Vannier, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Epigenetique et Cancer, Centre National de la Recherche Scientifique (CNRS), Hemostase, Endothelium, Angiogenese (UMR_S_553), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Résistance et survie des cellules tumorales, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), and Harel-Bellan, Annick
Subjects: Small interfering RNA, Pathology, medicine.medical_specialty, RHOA, Genetic enhancement, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Neovascularization, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Animals, Humans, Gene silencing, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Small Interfering, Molecular Biology, Infusion Pumps, 030304 developmental biology, Chitosan, 0303 health sciences, Neovascularization, Pathologic, Cancer, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Toxicity, biology.protein, Cancer research, Nanoparticles, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, medicine.symptom, rhoA GTP-Binding Protein, Neoplasm Transplantation
Abstract: Overexpression of RhoA in cancer indicates a poor prognosis, because of increased tumor cell proliferation and invasion and tumor angiogenesis. We showed previously that anti-RhoA small interfering RNA (siRNA) inhibited aggressive breast cancer more effectively than conventional blockers of Rho-mediated signaling pathways. This study reports the efficacy and lack of toxicity of intravenously administered encapsulated anti-RhoA siRNA in chitosan-coated polyisohexylcyanoacrylate (PIHCA) nanoparticles in xenografted aggressive breast cancers (MDA-MB-231). The siRNA was administered every 3 days at a dose of 150 or 1500 microg/kg body weight in nude mice. This treatment inhibited the growth of tumors by 90% in the 150- micro g group and by even more in the 1500- micro g group. Necrotic areas were observed in tumors from animals treated with anti-RhoA siRNA at 1500 micro g/kg, resulting from angiogenesis inhibition. In addition, this therapy was found to be devoid of toxic effects, as evidenced by similarities between control and treated animals for the following parameters: body weight gain; biochemical markers of hepatic, renal, and pancreatic function; and macroscopic appearance of organs after 30 days of treatment. Because of its efficacy and the absence of toxicity, it is suggested that this strategy of anti-RhoA siRNA holds significant promise for the treatment of aggressive cancers.
Published: 2006
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32. Regulation of the cytotoxic effects of Pseudomonas fluorescens by growth temperature

Author: Lionel Cazin, Sana Mezghani-Abdelmoula, Nicole Orange, Annabelle Merieau, Olivier Lesouhaitier, Marc G. J. Feuilloley, Laurent Picot, Sylvie Chevalier, Josette Guerillon, LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Chercheur indépendant, Laboratoire de Microbiologie Signaux et Microenvironnement (LMSM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), and Micro-Environnement et Régulation Cellulaire Intégrée (MERCI)
Subjects: Lipopolysaccharides, Programmed cell death, Cell Culture Techniques, Apoptosis, Pseudomonas fluorescens, Biology, Microbiology, Bacterial Adhesion, Necrosis, 03 medical and health sciences, chemistry.chemical_compound, Lactate dehydrogenase, Animals, Secretion, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Nucleus, 0303 health sciences, Cell Death, L-Lactate Dehydrogenase, 030306 microbiology, Pseudomonas, Temperature, General Medicine, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Rats, Biochemistry, chemistry, Nitric Oxide Synthase, Neuroglia, Bacteria, Pseudomonadaceae
Abstract: We had previously shown that the psychrotrophic bacterium Pseudomonas fluorescenscan act as a pathogen, inducing apoptosis and necrosis in neurons and glial cells. In the present study, we investigated the influence of the growth temperature of P. fluorescens on its infectious potential. Adherence of P. fluorescens to glial cells was found to be maximal with bacteria grown at a low temperature (8 ◦ C). At that temperature the swimming behaviour was markedly reduced. An increase in the growth temperature to 19, 28 or 32 ◦ C strongly diminished the binding of bacteria to host cells. Thus, the adhesion phenotype of P. fluorescens appears to be independent of the motility of the bacteria. The apoptotic effect of P. fluorescens, determined by morphological (nuclear condensation) and biochemical (induction of nitric oxide synthase activity) indicators, correlated well with its binding activity on glial cells. In contrast, there was a clear dissociation between maximum binding and maximal necrotic action (measured by the release of lactate dehydrogenase) observed with bacteria grown at 19 ◦ C. As suggested by capillary electrophoresis analysis, the differences in apoptotic effects may be related to variations in the molecular structure of LPS originating from bacteria grown at low and high temperatures, whereas the necrotic effect, which was maximal at the optimum temperature for the secretion of exoenzymes, could reflect variations in the metabolic activity of bacteria.  2003 Published by Editions scientifiques et medicales Elsevier SAS.
Published: 2004
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33. Direct Effect of Bevacizumab on Glioblastoma Cell Lines In Vitro

Author: Yusra Kassim, Elise Demange, Alexandre Petit, Valérie Perrot, Didier Le Cerf, Thomas Simon, Jean-Pierre Vannier, Bérénice Coquerel, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Polymères Biopolymères Surfaces (PBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), and Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Vascular Endothelial Growth Factor A, Pathology, Indoles, genetic structures, Cell Culture Techniques, Angiogenesis Inhibitors, Pregnancy Proteins, VEGF-A, Anti-angiogenic therapies, Brain extracellular matrix, 0302 clinical medicine, Cell Movement, Sunitinib, Neoplasm, Hyaluronic Acid, 0303 health sciences, Brain Neoplasms, Hydrogels, [CHIM.MATE]Chemical Sciences/Material chemistry, Neoplasm Proteins, 3. Good health, Bevacizumab, Gene Expression Regulation, Neoplastic, Autocrine Communication, Neurology, 030220 oncology & carcinogenesis, Monoclonal, Molecular Medicine, Cell Division, Signal Transduction, medicine.drug, medicine.medical_specialty, MAP Kinase Signaling System, medicine.drug_class, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Monoclonal antibody, Autocrine loop, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cell Line, Tumor, medicine, Humans, Neoplasm Invasiveness, Pyrroles, Calcium Signaling, Autocrine signalling, Protein Kinase Inhibitors, Protein kinase B, Placenta Growth Factor, 030304 developmental biology, Vascular Endothelial Growth Factor Receptor-1, business.industry, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, eye diseases, nervous system diseases, [CHIM.POLY]Chemical Sciences/Polymers, Drug Resistance, Neoplasm, Cell culture, Cancer research, sense organs, Drug Screening Assays, Antitumor, business, Glioblastoma, Proto-Oncogene Proteins c-akt
Abstract: International audience; Bevacizumab is a humanized monoclonal antibody directed against the pro-angiogenic factor vascular and endothelial growth factor-A (VEGF-A) used in the treatment of glioblastomas. Although most patients respond initially to this treatment, studies have shown that glioblastomas eventually recur. Several non-mutually exclusive theories based on the anti-angiogenic effect of bevacizumab have been proposed to explain these mechanisms of resistance. In this report, we studied whether bevacizumab can act directly on malignant glioblastoma cells. We observe changes in the expression profiles of components of the VEGF/VEGF-R pathway and in the response to a VEGF-A stimulus following bevacizumab treatment. In addition, we show that bevacizumab itself acts on glioblastoma cells by activating the Akt and Erks survival signaling pathways. Bevacizumab also enhances proliferation and invasiveness of glioblastoma cells in hyaluronic acid hydrogel. We propose that the paradoxical effect of bevacizumab on glioblastoma cells could be due to changes in the VEGF-A-dependent autocrine loop as well as in the intracellular survival pathways, leading to the enhancement of tumor aggressiveness. Investigation of how bevacizumab interacts with glioblastoma cells and the resulting downstream signaling pathways will help targeting populations of resistant glioblastoma cells.
Published: 2014
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34. Detection of dicentric chromosome (9;20) in paediatric B-cell acute lymphoblastic leukaemia: prognostic significance

Author: Catherine Roche-Lestienne, Catherine Devoldere, Mathilde Letouzey, Brigitte Nelken, Jean-Pierre Vannier, Pascale Schneider, Dominique Penther, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie-Oncologie Pédiatrique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: Male, medicine.medical_specialty, Pediatrics, [SDV]Life Sciences [q-bio], Population, Karyotype, Chromosomes, Human, Pair 20, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, 03 medical and health sciences, Dicentric chromosome, 0302 clinical medicine, Prednisone, hemic and lymphatic diseases, Internal medicine, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, education, Child, Survival rate, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, 030304 developmental biology, Retrospective Studies, Chromosome Aberrations, 0303 health sciences, education.field_of_study, Hematology, medicine.diagnostic_test, business.industry, Infant, Retrospective cohort study, General Medicine, Prognosis, Minimal residual disease, 3. Good health, Chromosome Banding, Treatment Outcome, 030220 oncology & carcinogenesis, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, Chromosomes, Human, Pair 9, Fluorescence in situ hybridization, medicine.drug
Abstract: The dicentric chromosome (9;20) (dic(9;20)) is described in 2 % of childhood B-acute lymphoblastic leukaemia. Fluorescence in situ hybridization (FISH) is the most reliable method to identify dic(9;20) when compared with conventional cytogenetics. To define the prognostic importance of dic(9;20), we evaluated treatment response and patient survival. This was a retrospective study in three French university centres. Patients’ clinical and laboratory characteristics and treatment response are described. Nine children with dic(9;20) have been identified since 1995. All patients had at least one poor prognostic feature either among the clinical features, the initial laboratory results or in the initial treatment response: central nervous system involvement (2/9), high median leucocyte count (≥50 G/L) (8/9) and poor response to prednisone (2/9). All patients were in complete cytological remission after induction therapy but only three had a good molecular response with minimal residual disease (MRD)
Published: 2014
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35. Genipin-Cross-Linked Layer-by-Layer Assemblies: Biocompatible Microenvironments To Direct Bone Cell Fate

Author: Emmanuel Pauthe, Laurent Bidault, Hassan Atmani, Guy Ladam, Fabien Gaudière, Béatrice Labat, Sandrine Morin-Grognet, Jean-Pierre Vannier, Pierre Lembré, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche sur les relations matrice extracellulaire-cellules (ERRMECe), Fédération INSTITUT DES MATÉRIAUX DE CERGY-PONTOISE (I-MAT), Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Service d'hémato-immuno-oncologie pédiatrique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: Polymers and Plastics, Cell Survival, Bioengineering, Nanotechnology, Biocompatible Materials, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microscopy, Atomic Force, 7. Clean energy, Osseointegration, Biomaterials, chemistry.chemical_compound, Osteogenesis, Bone cell, Spectroscopy, Fourier Transform Infrared, Materials Chemistry, Native state, medicine, Cell Adhesion, Fluorescence Resonance Energy Transfer, Humans, Iridoids, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Microscale chemistry, Cells, Cultured, Cell Proliferation, Osteoblasts, Chemistry, Layer by layer, Chondroitin Sulfates, Osteoblast, Cell Differentiation, Förster resonance energy transfer, medicine.anatomical_structure, Cross-Linking Reagents, [CHIM.POLY]Chemical Sciences/Polymers, Genipin, Quartz Crystal Microbalance Techniques
Abstract: International audience; The design of biomimetic coatings capable of improving the osseointegration of bone biomaterials is a current challenge in the field of bone repair. Toward this end, layer-by-layer (LbL) films composed of natural components are suitable candidates. Chondroitin sulfate A (CSA), a natural glycosaminoglycan (GAG), was used as the polyanionic component because it promotes osteoblast maturation in vivo. In their native state, GAG-containing LbL films are generally cytophobic because of their low stiffness. To stiffen our CSA-based LbL films, genipin (GnP) was used as a natural cross-linking agent, which is much less cytotoxic than conventional chemical cross-linkers. GnP-cross-linked films display an original combination of microscale topography and tunable mechanical properties. Structural characterization was partly based on a novel donor/acceptor Forster resonance energy transfer (FRET) couple, namely, FITC/GnP, which is a promising approach for further inspection of any GnP-cross-linked system. GnP-cross-linked films significantly promote adhesion, proliferation, and early and late differentiation of preosteoblasts.
Published: 2014
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36. Biomimetic Three Dimensional Cell Culturing: Colorectal Cancer Micro-Tissue Engineering

Author: Yusra Kassim, J r me Couteau, Didier Lecerf, Elise Demange, Thomas Simon, Elias Al Tawil, Jean Pierre Vannier, Catherine Buquet, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Polymères Biopolymères Surfaces (PBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), TOXEM, and CENELYS
Subjects: Pathology, medicine.medical_specialty, Micro-tissue, Extracellular matrix, 03 medical and health sciences, 3D cell culture, chemistry.chemical_compound, 0302 clinical medicine, Tissue engineering, In vivo, Hyaluronic acid, medicine, Hyaluronan, 030304 developmental biology, 0303 health sciences, Cell growth, business.industry, [CHIM.MATE]Chemical Sciences/Material chemistry, Cell cycle, Colorectal cancer, Cell biology, Hydrogel, [CHIM.POLY]Chemical Sciences/Polymers, chemistry, Cell culture, 030220 oncology & carcinogenesis, business
Abstract: International audience; Background: Spheroid cultures are known to mimic closely the properties of tumor tissue than monolayer cultures with regard to growth kinetics and metabolic rates. The aim of this paper is to confirm that tumor micro-tissue in a 3D biocompatible microenvironment maintain the cells natural behavior when compared to 2D monolayer culturing.Method: In order to validate our 3D culture system, we compared the 3D culture within a cross-linked hydrogel of hyaluronic acid, one of the major components of the extracellular matrix and the conventional 2D culture system.Results: Interestingly within our culture system, cells could be analyzed either after retrieval from the scaffold or even without being extracted in the 3D form rendering the HA hydrogel an ideal tool for biological applications. We observed the difference in the cell cycle, cell proliferation and behavior in both culture systems. Additionally drug testing was carried out using a chemotherapeutic agent (cis-platinium) that is already in clinical use to unequivocally prove the clinical predictive significance of the test strategy as compared with less complex assay systems and more complex in vivo models. We observed the presence of cell cycle heterogeneity very similar to the situation in vivo human tumors. Moreover, we have confirmed that resistance to chemotherapeutic reagents within this 3D culture system is much higher than those used in 2D cultures, since the tight assembly of cells in 3D culture systems render them more resistant requiring chemotherapeutic doses that recapitulate the drug sensitivity of tumor cells in vivo. Additionally we have observed the difference of apoptotic protein expression between 2D and 3D cell culture.
Published: 2014
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37. Osteogenetic properties of electrospun nanofibrous PCL scaffolds equipped with chitosan-based nanoreservoirs of growth factors

Author: Ferrand, A., Eap, S., Laura Richert, Lemoine, S., Kalaskar, D., Demoustier-Champagne, S., Atmani, H., Mely, Y., Fioretti, F., Guy Schlatter, Kuhn, L., Ladam, G., Benkirane-Jessel, N., Barthel, Ingrid, Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Université Henri Poincaré - Nancy 1 (UHP), Institut de la matière condensée et des nanosciences / Institute of Condensed Matter and Nanosciences (IMCN), Université Catholique de Louvain = Catholic University of Louvain (UCL), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Biomatériaux et ingénierie tissulaire, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Ingenierie des Polymères pour les Hautes Technologies, and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], [CHIM.POLY]Chemical Sciences/Polymers, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; Bioactive implants intended for rapid, robust, and durable bone tissue regeneration are presented. The implants are based on nanofibrous 3D-scaffolds of bioresorbable poly-e-caprolactone mimicking the fibrillar architecture of bone matrix. Layer-by-layer nano-immobilization of the growth factor BMP-2 in association with chitosan (CHI) or poly-L-lysine over the nanofibers is described. The osteogenetic potential of the scaffolds coated with layers of CHI and BMP-2 is demonstrated in vitro, and in vivo in mouse calvaria, through enhanced osteopontin gene expression and calcium phosphate biomineralization. The therapeutic strategy described here contributes to the field of regenerative medicine, as it proposes a route toward efficient repair of bone defects at reduced risk and cost level.
Published: 2014
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38. Pseudomonas fluorescens as a potential pathogen: adherence to nerve cells

Author: Nicole Orange, Marc G. J. Feuilloley, Annabelle Merieau, Sana Mezghani Abdelmoula, Philippe Leroux, Lionel Cazin, Laurent Picot, LIttoral ENvironnement et Sociétés - UMRi 7266 (LIENSs), Université de La Rochelle (ULR)-Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de Microbiologie Signaux et Microenvironnement (LMSM), Normandie Université (NU)-Normandie Université (NU), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), and Laboratoire de Microbiologie du Froid – Signaux et Micro-Environnement (LMDF-SME)
Subjects: Neurite, Immunology, Cell, Apoptosis, Pseudomonas fluorescens, medicine.disease_cause, Microbiology, Bacterial Adhesion, Neuroblastoma, 03 medical and health sciences, Glial cells, medicine, Animals, Rats, Wistar, Pathogen, Cells, Cultured, 030304 developmental biology, Cerebral Cortex, Neurons, 0303 health sciences, biology, 030306 microbiology, Pseudomonas aeruginosa, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Rats, Infectious Diseases, medicine.anatomical_structure, Adherence, Neuron, Neuroglia, Pseudomonadaceae
Abstract: International audience; In order to determine the infectious potential of the psychrotrophic bacterium Pseudomonas fluorescens, a species closely related to the opportunistic pathogen P. aeruginosa, we investigated the binding activity of this bacterium on primary cultures of rat neonate cortical neurons and glial cells, adrenal paraneurons and NG108-15 neuroblastoma cells. Incubated at concentrations of 106 and 108 CFU/mL, P. fluorescens MF37 exhibited a high binding activity on neurons in the same range as that of P. aeruginosa PAO1. A significant, but lower, adherence of P. fluorescens was also detected on glial cells and adrenal paraneurons. In contrast, when P. fluorescens MF37 or P. aeruginosa PAO1 were incubated with neuroblastoma cells, no binding was observed. In neurons, the association of P. fluorescens with the plasma membrane occurred both on neurites and cell body. Leakage of the cytoplasmic content was frequently noted. Studies performed using the fluorescent probe Hoechst 33258 revealed that in 10% of neurons, P. fluorescens induced the appearance of densely stained clusters of DNA that was typical of an early step of apoptosis. In glial cells exposed to P. fluorescens, marked changes in the morphology of the nucleus, including fragmentation into lobular structures and aggregation of DNA, were also reminiscent of the existence of a possible apoptotic mechanism. Taken together, these results reveal that P. fluorescens can bind to nerve cells and affect their physiology and, in agreement with recent clinical observations, suggest that P. fluorescens could behave as a pathogen.
Published: 2001
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39. Contribution of changes in the chloride driving force to the fading ofIGABAin frog melanotrophs

Author: Lionel Cazin, Olivier Soriani, Hubert Vaudry, Frank Le Foll, Sciences Appliquées à L'Environnement (SCALE), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Stress Environnementaux et BIOsurveillance des milieux aquatiques (SEBIO), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Reims Champagne-Ardenne (URCA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 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), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), and Normandie Université (NU)-Normandie Université (NU)
Subjects: Male, medicine.medical_specialty, Patch-Clamp Techniques, Physiology, Endocrinology, Diabetes and Metabolism, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chlorides, Salientia, Physiology (medical), Internal medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Animals, Melanocyte-Stimulating Hormones, Patch clamp, Neurotransmitter, Reversal potential, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Rana ridibunda, 030304 developmental biology, 0303 health sciences, biology, Osmolar Concentration, Gramicidin, Intracellular Membranes, Receptors, GABA-A, biology.organism_classification, Resting potential, Electrophysiology, Melanotrophs, Endocrinology, nervous system, chemistry, Pituitary Gland, GRENOUILLE, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, 030217 neurology & neurosurgery
Abstract: Chloride redistribution during type A γ-aminobutyric acid (GABAA) currents ( IGABA) has been investigated in cultured frog pituitary melanotrophs with imposed intracellular chloride concentration ([Cl−]i) in the whole cell configuration or with unaltered [Cl−]iusing the gramicidin-perforated patch approach. Prolonged GABA exposures elicited reproducible decaying currents. The decay of IGABAwas associated with both a transient fall of conductance ( gGABA) and shift of current reversal potential ( EGABA). The shift of EGABAappeared to be time and driving force dependent. In the gramicidin-perforated patch configuration, repeated GABA exposures induced currents that gradually vanished. The fading of IGABAwas due to persistent shifts of EGABAas a result of gGABArecovering from one GABA application to another. In cells alternatively clamped at potentials closely flanking resting potential and submitted to a train of brief GABA pulses, a reversal of IGABAwas observed after 150 s recording. It is demonstrated that, in intact frog melanotrophs, shifts of EGABAcombine with genuine receptor desensitization to depress IGABA. These findings strongly suggest that shifts of EGABAmay act as a negative feedback, reducing the bioelectrical and secretory responses induced by an intense release of GABA in vivo.
Published: 2000
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40. Survival of cord blood haematopoietic stem cells in a hyaluronan hydrogel for ex vivo biomimicry

Author: Demange, Elise, Kassim, Yusra, Petit, Cyrille, Buquet, Catherine, Dulong, Virginie, Cerf, Didier Le, Buchonnet, Gérard, Vannier, Jean-Pierre, CENELYS, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Polymères, biopolymères, membranes (PBM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: [CHIM.POLY]Chemical Sciences/Polymers, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2013
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41. Plasmids as scribbling pads for operon formation and propagation

Author: Vic Norris, Annabelle Merieau, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), and Laboratoire de Microbiologie Signaux et Microenvironnement (LMSM)
Subjects: Genetics, 0303 health sciences, Bacteria, Models, Genetic, 030306 microbiology, Operon, Evolution, Bacterial genes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Biology, Chromosome, Microbiology, Plasmid, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Recombination, 03 medical and health sciences, bacteria, Molecular Biology, 030304 developmental biology, Plasmids
Abstract: International audience; Many bacterial genes are in operons and the process whereby operons are formed is therefore fundamental. To help elucidate this process, we propose in the Scribbling Pad hypothesis that bacteria have been constantly using plasmids for genetic experimentation and, in particular, for the construction of operons. This hypothesis simultaneously solves the problems of the creation of operons and the way operons are propagated. We cite results in the literature to support the hypothesis and make experimental predictions to test it.
Published: 2013
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42. Sensor potency of the moonlighting enzyme-decorated cytoskeleton

Author: Norris, Vic, Amar, Patrick, Legent, Guillaume, Ripoll, Camille, Thellier, Michel, Ovadi, Judit, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Complexe de recherche interprofessionnel en aérothermochimie (CORIA), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Algorithms and Models for Integrative Biology (AMIB ), Laboratoire d'informatique de l'École polytechnique [Palaiseau] (LIX), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Glycobiologie et transports chez les végétaux (GTCV), Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Hungarian Academy of Sciences (MTA), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Recherche en Informatique (LRI), and Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: macromolecular substances, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; There is extensive evidence for the interaction of metabolic enzymes with the eukaryotic cytoskeleton. The significance of these interactions is far from clear. In the cytoskeletal integrative sensor hypothesis presented here, the cytoskeleton senses and integrates the general metabolic activity of the cell. This activity depends on the binding to the cytoskeleton of enzymes and, depending on the nature of the enzyme, this binding may occur if the enzyme is either active or inactive but not both. This enzyme-binding is further proposed to stabilize microtubules and microfilaments and to alter rates of GTP and ATP hydrolysis and their levels. Evidence consistent with the cytoskeletal integrative sensor hypothesis is presented in the case of glycolysis. Several testable predictions are made. There should be a relationship between the sites on tubulin and actin that undergo post-translational modification and interaction with metabolic enzymes. Different conditions of cytoskeletal dynamics and enzyme-cytoskeleton binding should reveal significant differences in local and perhaps global levels and ratios of ATP and GTP. The different functions of moonlighting enzymes should depend on cytoskeletal binding. The physical and chemical effects arising from metabolic sensing by the cytoskeleton would have major consequences on cell shape, dynamics and cell cycle progression. The hypothesis provides a framework that helps the significance of the enzyme-decorated cytoskeleton be determined.
Published: 2013
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43. 50nm-Scale Localization of Single Unmodified, Isotopically Enriched, Proteins in Cells

Author: Delaune, Anthony, Cabin-Flaman, Armelle, Legent, Guillaume, Gibouin, David, Smet-Nocca, Caroline, Lefebvre, Fabrice, Benecke, Arndt, Vasse, Marc, Ripoll, Camille, Wrede, Paul, Expression des Gènes et comportement adaptatifs = Molecular Genetics, Neurophysiology and Behavior (NPS-15), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ``Vie & Espoir' association, ``Titoine' association, Genopole, CNRS, Université de Lille, Assemblages moléculaires : modélisation et imagerie SIMS [AMMIS], Institut des Hautes Études Scientifiques [IHES], Neuroscience Paris Seine (NPS), Groupe de physique des matériaux (GPM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université de Rouen Normandie (UNIROUEN), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Normandie Université (NU)-Normandie Université (NU), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut des Hautes Études Scientifiques, Centre National de la Recherche Scientifique (CNRS), Glycobiologie et transports chez les végétaux (GTCV), Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, Dimer, Image Processing, [SDV]Life Sciences [q-bio], lcsh:Medicine, 01 natural sciences, Biochemistry, Biophysics Simulations, chemistry.chemical_compound, Engineering, Single-cell analysis, Intracellular receptors, Chlorocebus aethiops, Image Processing, Computer-Assisted, Statistical Signal Processing, Biomacromolecule-Ligand Interactions, lcsh:Science, Mathematical Computing, ComputingMilieux_MISCELLANEOUS, Recombinant proteins, 0303 health sciences, Numerical Analysis, Multidisciplinary, Spectrometric Identification of Proteins, Chemistry, Statistics, Transport protein, Protein Transport, medicine.anatomical_structure, Data Interpretation, Statistical, COS Cells, Biophysic Al Simulations, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Single-Cell Analysis, Algorithms, Research Article, Biophysics, Biostatistics, 03 medical and health sciences, Tetramer, DNA-binding proteins, medicine, Animals, Statistical Methods, Biology, 030304 developmental biology, Cell Nucleus, Retinoid X Receptor alpha, Nitrogen Isotopes, lcsh:R, 010401 analytical chemistry, Proteins, Protein interactions, Computational Biology, Computing Methods, Thymine DNA Glycosylase, 0104 chemical sciences, Cell nucleus, Cytoplasm, Computer Science, Signal Processing, lcsh:Q, Thymine-DNA glycosylase, Nucleus, Protein Abundance, Mathematics
Abstract: International audience; Imaging single proteins within cells is challenging if the possibility of artefacts due to tagging or to recognition by antibodies is to be avoided. It is generally believed that the biological properties of proteins remain unaltered when N-14 isotopes are replaced with N-15. N-15-enriched proteins can be localised by dynamic Secondary Ion Mass Spectrometry (D-SIMS). We describe here a novel imaging analysis algorithm to detect a few N-15-enriched proteins - and even a single protein - within a cell using D-SIMS. The algorithm distinguishes statistically between a low local increase in N-15 isotopic fraction due to an enriched protein and a stochastic increase due to the background. To determine the number of enriched proteins responsible for the increase in the isotopic fraction, we use sequential D-SIMS images in which we compare the measured isotopic fractions to those expected if 1, 2 or more enriched proteins are present. The number of enriched proteins is the one that gives the best fit between the measured and the expected values. We used our method to localise N-15-enriched thymine DNA glycosylase (TDG) and retinoid X receptor alpha (RXR alpha) proteins delivered to COS-7 cells. We show that both a single TDG and a single RXR alpha can be detected. After 4 h incubation, both proteins were found mainly in the nucleus; RXR alpha as a monomer or dimer and TDG only as a monomer. After 7 h, RXR alpha was found in the nucleus as a monomer, dimer or tetramer, whilst TDG was no longer in the nucleus and instead formed clusters in the cytoplasm. After 24 h, RXR alpha formed clusters in the cytoplasm, and TDG was no longer detectable. In conclusion, single unmodified proteins in cells can be counted and localised with 50 nm resolution by combining D-SIMS with our method of analysis.
Published: 2013
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44. Efficient new synthesis of N-arylbenzo[b]furo[3,2-d]pyrimidin-4-amines and their benzo[b]thieno[3,2-d]pyrimidin-4-amine analogues via a microwave-assisted Dimroth rearrangement

Author: Loidreau, Yvonnick, Dubouilh-Benard, Carole, Marchand, Pascal, Nourrisson, Marie-Renée, Duflos, Muriel, Buquet, Catherine, Corbiere, Cecile, Besson, Thierry, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etudes et de Recherches Appliquées en Sciences Sociales (LERASS), Université Paul-Valéry - Montpellier 3 (UPVM)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), and Normandie Université (NU)-Normandie Université (NU)
Subjects: [CHIM.ORGA]Chemical Sciences/Organic chemistry, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2013
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45. Chromosome Replication in Escherichia coli: Life on the Scales

Author: Patrick Amar, Vic Norris, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Algorithms and Models for Integrative Biology (AMIB ), Laboratoire d'informatique de l'École polytechnique [Palaiseau] (LIX), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), and École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Recherche en Informatique (LRI)
Subjects: cell division, Cell division, Operations research, Chromosome replication, water, Computational biology, growth rate control, Biology, DNA replication, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Hyperstructure, evolution, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Science, Escherichia coli, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, ion condensation, 030306 microbiology, Paleontology, Cell cycle, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Replication (computing), DnaA, Space and Planetary Science, lcsh:Q, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; At all levels of Life, systems evolve on the 'scales of equilibria'. At the level of bacteria, the individual cell must favor one of two opposing strategies and either take risks to grow or avoid risks to survive. It has been proposed in the Dualism hypothesis that the growth and survival strategies depend on non-equilibrium and equilibrium hyperstructures, respectively. It has been further proposed that the cell cycle itself is the way cells manage to balance the ratios of these types of hyperstructure so as to achieve the compromise solution of living on the two scales. Here, we attempt to re-interpret a major event, the initiation of chromosome replication in Escherichia coli, in the light of scales of equilibria. This entails thinking in terms of hyperstructures as responsible for intensity sensing and quantity sensing and how this sensing might help explain the role of the DnaA protein in initiation of replication. We outline experiments and an automaton approach to the cell cycle that should test and refine the scales concept.
Published: 2012
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46. Impact of lopinavir/ritonavir use on antiretroviral resistance in recent clinical practice

Author: Sidonie, Lambert-Niclot, Bernard, Masquelier, Isabelle, Cohen Codar, Cathia, Soulie, Constance, Delaugerre, Laurence, Morand-Joubert, Charlotte, Charpentier, Virginie, Ferre, Jean-Christophe, Plantier, Brigitte, Montes, Sophie, Carret, Valerie, Perrot, Gilles, Peytavin, Dominique, Costagliola, Vincent, Calvez, Anne-Geneviève, Marcelin, A, Si-Mohamed, Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de microbiologie [Saint-Louis], 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Impacts de la puissance antivirale des antirétroviraux et de la résistance virale sur les stratégies thérapeutiques des infections par les virus de l'immunodéficience humaine, Université Paris Diderot - Paris 7 (UPD7), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Club Rhumatismes et Inflammation, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de pharmacie, Unité de Mathématiques Pures et Appliquées (UMPA-ENSL), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), Numerical Medicine (NUMED), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Paris Diderot - Paris 7 (UPD7)-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), Service de bactériologie-virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon), and Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Inria Grenoble - Rhône-Alpes
Subjects: Microbiology (medical), Adult, Male, medicine.medical_specialty, Genotype, Anti-HIV Agents, [SDV]Life Sciences [q-bio], protease inhibitors, Lopinavir/ritonavir, Fosamprenavir, HIV Infections, Microbial Sensitivity Tests, Gastroenterology, Lopinavir, 03 medical and health sciences, immune system diseases, Internal medicine, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), Protease inhibitor (pharmacology), Treatment Failure, Darunavir, 030304 developmental biology, Pharmacology, 0303 health sciences, Ritonavir, 030306 microbiology, business.industry, Proteolytic enzymes, virus diseases, Middle Aged, Viral Load, Virology, 3. Good health, Atazanavir, Infectious Diseases, Cross-Sectional Studies, resistance mutations, HIV-1, Female, France, business, medicine.drug
Abstract: International audience; Objectives This observational study was requested by French health authorities to determine the impact of lopinavir/ritonavir (Kaletra®) on antiretroviral resistance in clinical practice. Virological failures of lopinavir/ritonavir and their effects on the resistance to protease inhibitors and reverse transcriptase inhibitors were evaluated in protease inhibitor-experienced patients.Patients and methods Virological failure was defined as an HIV-1 plasma viral load >50 copies/mL after at least 3 months of lopinavir/ritonavir-containing antiretroviral therapy. For all patients, a resistance genotypic test was available at failure and before lopinavir/ritonavir treatment. Data from 72 patients with inclusion criteria were studied. Results The mean viral load at baseline was 4 log10 copies/mL (1.6–6.5). Mutations in the protease gene significantly selected between baseline and failure were L10V, K20R, L33F, M36I, I47V, I54V, A71V and I85V (P < 0.05). Patients who had more than seven protease inhibitor mutations at baseline showed a significantly increased risk of occurrence of protease inhibitor mutations. The proportion of viruses susceptible to atazanavir, fosamprenavir and darunavir decreased significantly between baseline and failure (P < 0.05). Among patients with a virus susceptible to atazanavir at day 0, 26% (n = 14) exhibited a virus resistant or possibly resistant at the time of failure. This proportion was 32% (n = 16) for fosamprenavir and 16% (n = 7) for darunavir. Conclusions A darunavir-based regimen appears to be a sequential option in the case of lopinavir/ritonavir failure. To compare and determine the best treatment sequencing, similar studies should be performed for darunavir/ritonavir and atazanavir/ritonavir.
Published: 2012
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47. Opposite regulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression, cell-associated procoagulant activity and invasiveness in MDA-MB-231 cells

Author: Anne Janin, Caroline Gest, Chaoquan Hu, Xiaodong Xi, Hong Li, He-Lin Lu, Limin Huang, Claudine Soria, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Shanghai Institute of Hematology, Shanghai Jiao Tong University School of Medicine-Shanghai Rui Jin Hospital, Service d'anatomo-pathologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Support from the institute of cancer (INCA, PL06_130), the Association pour la Recherche sur le Cancer (ARC), the Ligue Nationale contre le Cancer (Ligue) and the Fondation de France., and BMC, Ed.
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MAPK/ERK pathway, Cancer Research, Small interfering RNA, Transcription, Genetic, Wortmannin, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, Breast cancer, 0302 clinical medicine, Cell Movement, Tumor Cells, Cultured, LY294002, Tumor invasiveness, Enzyme Inhibitors, Phosphorylation, Promoter Regions, Genetic, Phosphoinositide-3 Kinase Inhibitors, Ovarian Neoplasms, Gene expression regulation, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, lcsh:Diseases of the blood and blood-forming organs, Hematology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ErbB Receptors, Gene Expression Regulation, Neoplastic, Drug Combinations, Oncology, PI3K/Akt pathway, 030220 oncology & carcinogenesis, Female, Proteoglycans, Collagen, Mitogen-Activated Protein Kinases, Signal transduction, Signal Transduction, MAP Kinase Signaling System, Blotting, Western, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, lcsh:RC254-282, Thromboplastin, Pro-coagulation activity, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Neoplasm Invasiveness, RNA, Messenger, Blood Coagulation, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, 030304 developmental biology, lcsh:RC633-647.5, Research, Tissue factor, Molecular biology, chemistry, Cancer cell, Cancer research, Laminin, Proto-Oncogene Proteins c-akt
Abstract: Background Tissue factor (TF), an initiator of blood coagulation, participates in cancer progression and metastasis. We recently found that inhibition of MAPK/ERK upregulated both full length TF (flTF) and soluble isoform TF (asTF) gene expression and cell-associated TF activity in breast cancer MDA-MB-231 cells. We explored the possible mechanisms, especially the possible interaction with EGFR and PI3K/Akt pathways. Methods A plasmid containing TF promoter −2174 ~ +128 plus luciferase reporter gene was introduced into MDA-MB-231 cells to evaluate TF promoter activity. In order to study the interaction of these pathways, ERK inhibitor (PD98059), PI3K inhibitors (LY294002, wortmannin), Akt inhibitor (A6730), and EGFR inhibitor (erlotinib) as well as the corresponding siRNAs were used to treat MDA-MB-231 cells, and ovarian cancer OVCAR-3 and SKOV-3 cells. Quantitative PCR and western blot were used to determine TF expression. One stage clotting assays were used to measure pro-coagulation activity of the MDA-MB-231 cells. Results We show that PI3K inhibitors LY294002, wortmannin and A6730 significantly inhibited TF promoter activity, and reduced TF mRNA and protein levels due to the inhibition of Akt phosphorylation. In contrast, ERK inhibitor PD98059 and ERK siRNA enhanced TF promoter activity by 2.5 fold and induced an increase in TF mRNA and protein levels in a dose dependent manner in these cells. The PI3K/Akt pathway was shown to be involved in PD98059-induced TF expression because the induction was inhibited by PI3K/Akt inhibitors. Most interestingly, the EGFR inhibitor erlotinib and EGFR siRNA also significantly suppressed PD98059- or ERK siRNA-induced TF promoter activity and TF protein expression. Similar results were found with ovarian cancer cells SKOV-3 and OVCAR-3. Furthermore, in MDA-MB-231, mRNA levels of asTF were regulated in a similar way to that of TF in response to the cell treatment. Conclusions This study showed a regulatory mechanism in which MAPK/ERK signals inhibit EGFR/PI3K/Akt-mediated TF expression in breast cancer MDA-MB-231 cells. The same regulation was observed in ovarian cancer OVCAR-3 and SKOV-3 cells. Interestingly, we observed that both flTF and asTF could be regulated in a parallel manner in MDA-MB-231. As the PI3K/Akt pathway and EGFR regulate TF expression in cancer cells, targeting these signaling components is expected to potentially inhibit TF expression-associated tumor progression.
Published: 2012
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48. Elastin-derived peptides: matrikines critical for glioblastoma cell aggressiveness in a 3-D system

Author: Virginie Dulong, Isabelle Dubus, Annie Reber, Frederic Torossian, Jean-Pierre Vannier, Bérénice Coquerel, Georges Bellon, Florent Poyer, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Interactions cellules souches-niches : physiologie, tumeurs et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Paul Brousse-Service de Santé des Armées-Université Paris-Sud - Paris 11 (UP11), Polymères, biopolymères, membranes (PBM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratory of Biochemistry and Molecular Biology (LBMB), Faculty of Medicine-UPRESA 6021, Fibrose hépatique et cancer du foie, and Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cell Culture Techniques, Receptors, Cell Surface, Statistics, Nonparametric, Extracellular matrix, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cell Movement, Tropoelastin, Cell Line, Tumor, Matrix Metalloproteinase 12, Glioma, Cell Adhesion, medicine, Extracellular, Humans, Neoplasm Invasiveness, Secretion, RNA, Messenger, 10. No inequality, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, Basement membrane, 0303 health sciences, Dose-Response Relationship, Drug, biology, Reverse Transcriptase Polymerase Chain Reaction, medicine.disease, Elastin, Extracellular Matrix, Cell biology, medicine.anatomical_structure, [CHIM.POLY]Chemical Sciences/Polymers, Neurology, Biochemistry, Cell culture, biology.protein, Matrix Metalloproteinase 2, Calcium, Glioblastoma, Oligopeptides, 030217 neurology & neurosurgery
Abstract: In the most common primary brain tumors, malignant glioma cells invade the extracellular matrix (ECM) and proliferate rapidly in the cerebral tissue, which is mainly composed of hyaluronan (HA) along with the elastin present in the basement membrane of blood vessels. To determine the role of ECM components in the invasive capacity of glioma cell lines, we developed a 3-D cell-culture system, based on a hydrogel in which HA can be coreticulated with kappa-elastin (HA-kappaE). Using this system, the invasiveness of cells from four glioma cell lines was dramatically increased by the presence of kappaE and a related, specific peptide (VGVAPG)(3). In addition, MMP-2 secretion increased and MMP-12 synthesis occurred. Extracellular injections of kappaE or (VGVAPG)(3) provoked a pronounced and dose-dependent increase in [Ca(2+)](i). kappaE significantly enhanced the expression of the genes encoding elastin-receptor and tropoelastin. We propose the existence of a positive feedback loop in which degradation of elastin generates fragments that stimulate synthesis of tropoelastin followed by further degradation as well as migration and proliferation of the very cells responsible for degradation. All steps in this ECM-based loop could be blocked by the addition of either of the EBP antagonists, lactose, and V-14 peptide, suggesting that the loop itself should be considered as a new therapeutic target.
Published: 2009
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49. Chemical Microscopy of Biological Samples by Dynamic Mode Secondary Ion Mass Spectrometry (SIMS)

Author: Marie-Claire Verdus, Cedric Dérue, Camille Ripoll, Fabrice Lefebvre, Gradimir N. Misevic, Vic Norris, Bernard Rasser, Anthony Delaune, Guillaume Legent, David Gibouin, Assemblages moléculaires : modélisation et imagerie SIMS (AMMIS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Orsay Physics (ZAC Saint Charles), Institut de biologie systémique et synthétique (ISSB), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Groupe de physique des matériaux (GPM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Polymères, biopolymères, membranes (PBM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Normandie Université (NU)-Normandie Université (NU), Glycobiologie et transports chez les végétaux (GTCV), Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), and GIBOUIN, David
Subjects: chemistry.chemical_classification, Static secondary-ion mass spectrometry, Materials science, Resolution (mass spectrometry), [SDV]Life Sciences [q-bio], 010401 analytical chemistry, Analytical chemistry, 02 engineering and technology, Biological tissue, Lateral resolution, Polymer, [SPI.MAT] Engineering Sciences [physics]/Materials, 021001 nanoscience & nanotechnology, 01 natural sciences, 0104 chemical sciences, [SPI.MAT]Engineering Sciences [physics]/Materials, [SDV] Life Sciences [q-bio], Secondary ion mass spectrometry, chemistry, Microscopy, 0210 nano-technology, ComputingMilieux_MISCELLANEOUS
Abstract: 3D chemical microscopy is one of the emerging applications of secondary ion mass spectrometry (SIMS) in biology. Tissues, cells, extracellular matrices, and polymer films can be imaged at present with a lateral resolution of 50 nm and depth resolution of 1 nm using the latest generation of CAMECA magnetic sector NanoSIMS 50 or with a lower lateral resolution (above 100 nm) using IMS 4f Cameca SIMS equipped with cold stage. Dynamic mode SIMS analysis is performed in ultrahigh vacuum and thus requires specific and careful preparation of biological samples aimed at preserving and minimizing destruction of the original structural and chemical properties of the samples. Here we describe a methodology based on the ultrafast plunge-freezing of biological tissues, preparation of the sample for SIMS analyses and transfer to the SIMS cold stage without interruption of the cold chain during the mounting procedure and subsequent SIMS analyses. Using this strategy, SIMS chemical microscopy can be performed on biological tissue in which unwanted molecular and/or structural reorganization, loss of constituents and chemical modifications are minimized and in which structures are therefore optimally preserved.
Published: 2009

50. Hyaluronan hydrogel: An appropriate three-dimensional model for evaluation of anticancer drug sensitivity

Author: M. Lamacz, Lionel Cazin, Jean-Pierre Vannier, Virginie Dulong, Didier Le Cerf, Laurent David, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Polymères, biopolymères, membranes (PBM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Polymères Biopolymères Surfaces (PBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), and Microenvironnement et régulation cellulaire intégrés (MERCI)
Subjects: Materials science, [SDV]Life Sciences [q-bio], Cytotoxicity, Cell, Biomedical Engineering, Antineoplastic Agents, Biocompatible Materials, Models, Biological, Biochemistry, Biomaterials, 03 medical and health sciences, chemistry.chemical_compound, Cell growth, 0302 clinical medicine, Cell Line, Tumor, Hyaluronic acid, medicine, Humans, Hyaluronic Acid, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Tumor Stem Cell Assay, Hyaluronan, 030304 developmental biology, 0303 health sciences, Hydrogels, Cell migration, General Medicine, [CHIM.MATE]Chemical Sciences/Material chemistry, Cell biology, Hydrogel, medicine.anatomical_structure, [CHIM.POLY]Chemical Sciences/Polymers, chemistry, Doxorubicin, Drug Resistance, Neoplasm, Cell culture, 030220 oncology & carcinogenesis, Self-healing hydrogels, Cancer cell, Immunology, Antimitotic Agent, Fluorouracil, Cell Division, Biotechnology
Abstract: International audience; The extracellular polysaccharide hyaluronan (HA) controls cell migration, differentiation and proliferation, and contributes to the invasiveness of human cancers. In order to investigate the sensitivity of cancer cells to antimitotic agents, we developed a cross-linked HA hydrogel, a three-dimensional matrix in which cells can invade and grow. We have studied three cell lines (SA87, NCI-H460 and H460M), from primary tumors and metastases, that migrated into the HA hydrogel and proliferated giving rise to clusters and colonies. Concurrently, we studied the growth of these cell lines in a usual monolayer culture system. In these two models, increasing concentrations of doxorubicin and 5-fluorouracil were evaluated for their ability to inhibit tumor cell growth and colony formation. Taken together, our data suggest that the cancer cells were more resistant in the three-dimensional model than in monolayer cell systems. The antimitotic drugs were efficient after 24 h of treatment in the monolayer cultures, whereas they were significantly efficient only after one week of incubation in the HA hydrogels. Herein, we show that this cross-linked matrix provides a three-dimensional model particularly appropriate for investigating mechanisms involved in cancer cell line sensitivity to antimitotic drugs.
Published: 2008
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