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57 results on '"Chancellerie des Universités de Paris"'

1. Changes in Liver Lipidomic Profile in G2019S- LRRK2 Mouse Model of Parkinson's Disease

Author: Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Cultura y Deporte (España), Universidad de Extremadura, Junta de Extremadura, Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Fondation ARC pour la Recherche sur le Cancer, Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], Corral Nieto, Yaiza, Yakhine-Diop, Sokhna M. S., Moreno-Cruz, Paula, Manrique García, Laura, Gabrielly Pereira, Amanda, Morales-García, José A., Niso-Santano, Mireia, González-Polo, Rosa A., Uribe-Carretero, Elisabet, Durand, Sylvère, Maiuri, Maria Chiara, Paredes-Barquero, Marta, Alegre-Cortés, Eva, Canales-Cortés, Saray, López de Munain, Adolfo, Pérez-Tur, Jordi, Pérez-Castillo, Ana, Kroemer, Guido, Fuentes, José M., Bravo-San-Pedro, José Manuel, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Cultura y Deporte (España), Universidad de Extremadura, Junta de Extremadura, Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Fondation ARC pour la Recherche sur le Cancer, Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], Corral Nieto, Yaiza, Yakhine-Diop, Sokhna M. S., Moreno-Cruz, Paula, Manrique García, Laura, Gabrielly Pereira, Amanda, Morales-García, José A., Niso-Santano, Mireia, González-Polo, Rosa A., Uribe-Carretero, Elisabet, Durand, Sylvère, Maiuri, Maria Chiara, Paredes-Barquero, Marta, Alegre-Cortés, Eva, Canales-Cortés, Saray, López de Munain, Adolfo, Pérez-Tur, Jordi, Pérez-Castillo, Ana, Kroemer, Guido, Fuentes, José M., and Bravo-San-Pedro, José Manuel
Abstract: The identification of Parkinson's disease (PD) biomarkers has become a main goal for the diagnosis of this neurodegenerative disorder. PD has not only been intrinsically related to neurological problems, but also to a series of alterations in peripheral metabolism. The purpose of this study was to identify metabolic changes in the liver in mouse models of PD with the scope of finding new peripheral biomarkers for PD diagnosis. To achieve this goal, we used mass spectrometry technology to determine the complete metabolomic profile of liver and striatal tissue samples from WT mice, 6-hydroxydopamine-treated mice (idiopathic model) and mice affected by the G2019S-LRRK2 mutation in LRRK2/PARK8 gene (genetic model). This analysis revealed that the metabolism of carbohydrates, nucleotides and nucleosides was similarly altered in the liver from the two PD mouse models. However, long-chain fatty acids, phosphatidylcholine and other related lipid metabolites were only altered in hepatocytes from G2019S-LRRK2 mice. In summary, these results reveal specific differences, mainly in lipid metabolism, between idiopathic and genetic PD models in peripheral tissues and open up new possibilities to better understand the etiology of this neurological disorder.
Published: 2023

2. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

Author: Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Agence Nationale de la Recherche (France), Ligue Nationale contre le Cancer (France), Association de la Recherche Contre le Cancer (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, Institut National du Cancer (France), Fondation Leducq, Université de Paris, Biotechnology and Biological Sciences Research Council (UK), European Research Council, Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Chondronasiou, Dafni, Gill, Diljeet, Mosteiro, Lluc, Urdinguio, Rocío G., Berenguer-Llergo, Antonio, Aguilera,Mònica, Durand, Sylvère, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Abad, Maria, Martin-Herranz, Daniel E., Stephan-Otto Attolini, Camille, Prats, Neus, Kroemer, Guido, Fraga, Mario F., Reik, Wolf, Serrano, Manuel, Fundación la Caixa, Fundación Científica Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Agence Nationale de la Recherche (France), Ligue Nationale contre le Cancer (France), Association de la Recherche Contre le Cancer (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, Institut National du Cancer (France), Fondation Leducq, Université de Paris, Biotechnology and Biological Sciences Research Council (UK), European Research Council, Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Chondronasiou, Dafni, Gill, Diljeet, Mosteiro, Lluc, Urdinguio, Rocío G., Berenguer-Llergo, Antonio, Aguilera,Mònica, Durand, Sylvère, Aprahamian, Fanny, Nirmalathasan, Nitharsshini, Abad, Maria, Martin-Herranz, Daniel E., Stephan-Otto Attolini, Camille, Prats, Neus, Kroemer, Guido, Fraga, Mario F., Reik, Wolf, and Serrano, Manuel
Abstract: The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.
Published: 2022

3. Variation(s) sur la norme

Author: Association des lauréats de la Chancellerie des Universités de Paris
Published: 2013

4. Acyl-CoA-binding protein is a lipogenic factor that triggers food intake and obesity

Author: Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, European Research Council, Institut National du Cancer (France), Institut Universitaire de France, Fondation Leducq, Swedish Research Council, Austrian Science Fund, Federal Ministry of Science, Research and Economy (Austria), Bravo-San-Pedro, José Manuel [0000-0002-5781-1133], Sica, Valentina [0000-0003-2770-5847], Martins, Isabelle [0000-0003-0885-613X], Pol, Jonathan G. [0000-0002-8355-7562], Loos, Friedemann [0000-0002-5976-5978], Maiuri, Maria Chiara [0000-0001-9760-7674], Niso-Santano, Mireia [0000-0002-6506-422X], Aranda, Fernando [0000-0002-9364-474X], Gorwood, Philip [0000-0003-1845-3676], Ramoz, Nicolas [0000-0002-8070-9938], Cleḿent, Karine [0000-0002-2489-3355], Pelloux, Véronique [0000-0003-3630-4746], Raverdy, Violeta [0000-0001-5754-2028], Denis, Raphaël G.P. [0000-0002-7677-7460], Boya, Patricia [0000-0003-3045-951X], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Madeo, Frank [0000-0002-5070-1329], Cruciani-Guglielmacci, Céline [0000-0002-2562-5360], Tavernarakis, Nektarios [0000-0002-5253-1466 ], López-Otín, Carlos [0000-0001-6964-1904], Magnan, Christophe [0000-0002-7044-2571], Kroemer, Guido [0000-0002-9334-4405], Bravo-San-Pedro, José Manuel, Sica, Valentina, Martins, Isabelle, Pol, Jonathan G., Loos, Friedemann, Maiuri, Maria Chiara, Durand, Sylvère, Bossut, Noélie, Aprahamian, Fanny, Anagnostopoulos, Gerasimos, Niso-Santano, Mireia, Aranda, Fernando, Ramírez-Pardo, Ignacio, Lallement, Justine, Denom, Jessica, Boedec, Erwan, Gorwood, Philip, Ramoz, Nicolas, Cleḿent, Karine, Pelloux, Véronique, Rohia, Alili, Pattou, François, Raverdy, Violeta, Caïazzo, Robert, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Migrenne-Li, Stephanie, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, Kroemer, Guido, Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, European Research Council, Institut National du Cancer (France), Institut Universitaire de France, Fondation Leducq, Swedish Research Council, Austrian Science Fund, Federal Ministry of Science, Research and Economy (Austria), Bravo-San-Pedro, José Manuel [0000-0002-5781-1133], Sica, Valentina [0000-0003-2770-5847], Martins, Isabelle [0000-0003-0885-613X], Pol, Jonathan G. [0000-0002-8355-7562], Loos, Friedemann [0000-0002-5976-5978], Maiuri, Maria Chiara [0000-0001-9760-7674], Niso-Santano, Mireia [0000-0002-6506-422X], Aranda, Fernando [0000-0002-9364-474X], Gorwood, Philip [0000-0003-1845-3676], Ramoz, Nicolas [0000-0002-8070-9938], Cleḿent, Karine [0000-0002-2489-3355], Pelloux, Véronique [0000-0003-3630-4746], Raverdy, Violeta [0000-0001-5754-2028], Denis, Raphaël G.P. [0000-0002-7677-7460], Boya, Patricia [0000-0003-3045-951X], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Madeo, Frank [0000-0002-5070-1329], Cruciani-Guglielmacci, Céline [0000-0002-2562-5360], Tavernarakis, Nektarios [0000-0002-5253-1466 ], López-Otín, Carlos [0000-0001-6964-1904], Magnan, Christophe [0000-0002-7044-2571], Kroemer, Guido [0000-0002-9334-4405], Bravo-San-Pedro, José Manuel, Sica, Valentina, Martins, Isabelle, Pol, Jonathan G., Loos, Friedemann, Maiuri, Maria Chiara, Durand, Sylvère, Bossut, Noélie, Aprahamian, Fanny, Anagnostopoulos, Gerasimos, Niso-Santano, Mireia, Aranda, Fernando, Ramírez-Pardo, Ignacio, Lallement, Justine, Denom, Jessica, Boedec, Erwan, Gorwood, Philip, Ramoz, Nicolas, Cleḿent, Karine, Pelloux, Véronique, Rohia, Alili, Pattou, François, Raverdy, Violeta, Caïazzo, Robert, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Migrenne-Li, Stephanie, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, and Kroemer, Guido
Abstract: Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities.
Published: 2019

5. Diaphragmatic Activity and Respiratory Function Following C3 or C6 Unilateral Spinal Cord Contusion in Mice

Author: Afaf Bajjig, Pauline Michel-Flutot, Tiffany Migevent, Florence Cayetanot, Laurence Bodineau, Stéphane Vinit, Isabelle Vivodtzev, HAL UVSQ, Équipe, Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation du Souffle, FdS, Institut National de la Santé et de la Recherche Médicale, Inserm, Fondation de France, Chancellerie des Universités de Paris, Sorbonne Université, This research was funded by ' La Fondation du Souffle' (I.V.), Inserm (I.V., F.C. and L.B.), Sorbonne university (I.V., F.C. and L.B.), Chancellerie des Universités de Paris (Legs Poix) (S.V.), the Fondation de France (S.V.), the Fondation Médisite (S.V.) and Université de Versailles Saint Quentin en Yvelines (S.V.)., and Institutional Review Board Statement: Ethics Committee Charles Darwin CEEACD/N◦5 (Project authorization APAFIS No. 2020070317412138 v3).
Subjects: [SDV] Life Sciences [q-bio], diaphragmatic activity, General Immunology and Microbiology, spinal cord injury, contusion model, respiratory function, phrenic motoneurons, [SDV]Life Sciences [q-bio], General Agricultural and Biological Sciences, musculoskeletal system, General Biochemistry, Genetics and Molecular Biology
Abstract: The majority of spinal cord injuries (SCIs) are cervical (cSCI), leading to a marked reduction in respiratory capacity. We aimed to investigate the effect of hemicontusion models of cSCI on both diaphragm activity and respiratory function to serve as preclinical models of cervical SCI. Since phrenic motoneuron pools are located at the C3–C5 spinal level, we investigated two models of preclinical cSCI mimicking human forms of injury, namely, one above (C3 hemicontusion—C3HC) and one below phrenic motoneuron pools (C6HC) in wild-type swiss OF-1 mice, and we compared their effects on respiratory function using whole-body plethysmography and on diaphragm activity using electromyography (EMG). At 7 days post-surgery, both C3HC and C6HC damaged spinal cord integrity above the lesion level, suggesting that C6HC potentially alters C5 motoneurons. Although both models led to decreased diaphragmatic EMG activity in the injured hemidiaphragm compared to the intact one (−46% and −26% in C3HC and C6HC, respectively, both p = 0.02), only C3HC led to a significant reduction in tidal volume and minute ventilation compared to sham surgery (−25% and −20% vs. baseline). Moreover, changes in EMG amplitude between respiratory bursts were observed post-C3HC, reflecting a change in phrenic motoneuronal excitability. Hence, C3HC and C6HC models induced alteration in respiratory function proportionally to injury level, and the C3HC model is a more appropriate model for interventional studies aiming to restore respiratory function in cSCI.
Published: 2022
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6. Effects of aerobic exercise training on muscle plasticity in a mouse model of cervical spinal cord injury

Author: Alexia Paucard, Therese B. Deramaudt, Stéphane Vinit, Pauline Michel-Flutot, Marcel Bonay, Isley Jesus, Valentin Vanhee, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale, Inserm, Chancellerie des Universités de Paris, This work was supported by funding from the Chancellerie des Universités de Paris (Legs Poix) (SV, MB), INSERM (MB), Université de Versailles Saint-Quentin-en-Yvelines (MB, SV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Hôpital Ambroise Paré [AP-HP], and HAL UVSQ, Équipe
Subjects: Male, 0301 basic medicine, Cell biology, Physiology, Science, [SDV]Life Sciences [q-bio], Diaphragmatic breathing, Diseases, Electromyography, Article, Incremental exercise, 03 medical and health sciences, 0302 clinical medicine, medicine, Respiratory muscle, Animals, Humans, Myocyte, Aerobic exercise, Respiratory system, Exercise, Spinal Cord Injuries, Multidisciplinary, medicine.diagnostic_test, business.industry, Muscles, Cervical Cord, Recovery of Function, 3. Good health, Diaphragm (structural system), [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Anesthesia, Medicine, Female, business, 030217 neurology & neurosurgery
Abstract: Cervical spinal cord injury (SCI) results in permanent life-altering motor and respiratory deficits. Other than mechanical ventilation for respiratory insufficiency secondary to cervical SCI, effective treatments are lacking and the development of animal models to explore new therapeutic strategies are needed. The aim of this work was to demonstrate the feasibility of using a mouse model of partial cervical spinal hemisection at the second cervical metameric segment (C2) to investigate the impact of 6 weeks training on forced exercise wheel system on locomotor/respiratory plasticity muscles. To measure run capacity locomotor and respiratory functions, incremental exercise tests and diaphragmatic electromyography were done. In addition, muscle fiber type composition and capillary distribution were assessed at 51 days following chronic C2 injury in diaphragm, extensor digitorum communis (EDC), tibialis anterior (TA) and soleus (SOL) muscles. Six-week exercise training increased the running capacity of trained SCI mice. Fiber type composition in EDC, TA and SOL muscles was not modified by our protocol of exercise. The vascularization was increased in all muscle limbs in SCI trained group. No increase in diaphragmatic electromyography amplitude of the diaphragm muscle on the side of SCI was observed, while the contraction duration was significantly decreased in sedentary group compared to trained group. Cross-sectional area of type IIa myofiber in the contralateral diaphragm side of SCI was smaller in trained group. Fiber type distribution between contralateral and ipsilateral diaphragm in SCI sedentary group was affected, while no difference was observed in trained group. In addition, the vascularization of the diaphragm side contralateral to SCI was increased in trained group. All these results suggest an increase in fatigue resistance and a contribution to the running capacity in SCI trained group. Our exercise protocol could be a promising non-invasive strategy to sustain locomotor and respiratory muscle plasticity following SCI.
Published: 2021
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7. Immunodynamics of explanted human tumors for immuno‐oncology

Author: Dubuisson, Agathe, Fahrner, Jean Eudes, Goubet, Anne Gaëlle, Terrisse, Safae A., Voisin, Nicolas, Bayard, Charles, Lofek, Sébastien, Drubay, Damien, Bredel, Delphine, Mouraud, Séverine, Susini, Sandrine, Cogdill, Alexandria P., Rebuffet, Lucas, Ballot, Elise, Jacquelot, Nicolas, Thomas de Montpreville, Vincent, Casiraghi, Odile, Radulescu, Camélia, Ferlicot, Sophie, Figueroa, David J., Yadavilli, Sapna, Waight, Jeremy D., Ballas, Marc S., Hoos, Axel X., Condamine, Thomas, Parier, Bastien, Gaudillat, Christophe, Routy, Bertrand, Ghiringhelli, François, Derosa, Lisa, Breuskin, Ingrid, Rouanne, Mathieu, André, Fabrice, Lebacle, Cédric, Baumert, Hervé, Wislez, Marie, Fadel, Élie, Cremer, Isabelle, Albiges, Laurence, Geoerger, Birgit, Scoazec, Jean Yves, Loriot, Yohann, Kroemer, Guido, Marabelle, Aurélien, Bonvalet, Mélodie, Zitvogel, Laurence, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), The University of Texas M.D. Anderson Cancer Center [Houston], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, The Walter and Eliza Hall Institute of Medical Research (WEHI), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Département de médecine oncologique [Gustave Roussy], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Foch [Suresnes], Direction de la recherche [Gustave Roussy], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Chancellerie des Universités de Paris Agence Nationale de la Recherche, ANR Seerave Foundation Association pour la Recherche sur le Cancer, ARC ANR‐16‐RHUS‐0008 Ligue Contre le Cancer European Commission, EC Fondation pour la Recherche Médicale, FRM Institut National Du Cancer, INCa Institut Universitaire de France, IUF European Research Council, ERC Fondation Leducq RP170067 Association pour la Recherche sur le Cancer, ARC, LZ and GK were supported by the Ligue contre le Cancer (équipe labelisée), Agence Nationale de la Recherche (ANR) francogermanique ANR‐19‐CE15‐0029, ANR Projects blancs, ANR under the frame of E‐Rare‐2, the ERA‐Net for Research on Rare Diseases, Association pour la recherche sur le cancer (ARC), Bristol‐Myers Squibb Company (International Immuno‐Oncology Network), Cancéropôle Ile‐de‐France, Chancellerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM), a donation by Elior, the European Commission (ArtForce), the European Research Council (ERC), Fondation Carrefour, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, LeDucq Foundation, the LabEx Immuno‐Oncology, the RHU Torino Lumière (ANR‐16‐RHUS‐0008), H2020 ONCOBIOME, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), FHU CARE, Dassault, and Badinter Philantropia, and the Paris Alliance of Cancer Research Institutes (PACRI). AC is supported by the CPRIT Research Training Program (RP170067). JEF was supported by Transgene and AGG was supported by FRM. AM has been or is currently an investigator in clinical trials sponsored by BMS, MSD, GSK/Tesaro, Janssen, Roche/Genentech, Pfizer, Astra Zeneca (AZ), Amgen. AM has been or is currently a member of Clinical Trial Scientific Steering Committee for AZ and GSK. AM has been or is currently a member of the scientific advisory board of the following companies: Merck Serono, Novartis, BMS, Symphogen, Amgen, Tesaro/GSK, Pfizer, Astra Zeneca/Medimmune, Servier, Sanofi. AM has provided Scientific & Medical Consulting to the following companies: Roche, Sanofi. AM is a member of the Data Safety and Monitoring Board for the following trial NCT02423863 (TLR3 agonist, Oncovir). AM has received research funding and or drug supply for pre‐Clinical and clinical research projects from: BMS, Boehringer Ingelheim, Idera, MSD, Fondation MSD Avenir, SIRIC (INCa‐DGOS‐Inserm_12551)., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC)
Subjects: Medicine (General), [SDV]Life Sciences [q-bio], Immunology, QH426-470, Medical Oncology, immune checkpoint inhibitors, R5-920, immunomonitoring, Report, precision oncology, Neoplasms, Genetics, “in sitro” assay, Tumor Microenvironment, cancer, Humans, Immunotherapy, Prospective Studies, Reports
Abstract: Decision making in immuno‐oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno‐assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti‐PD‐1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay., To predict cancer resistance to PD‐1 blockade and design suitable combinations of immunomodulators, a 60‐h functional in sitro assay was set up in 43 tumors that allowed calculation of the “Immune Reactivity Score (IRS)” based on 17 TCR‐dependent‐ cytokines/chemokines.
Published: 2020
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8. Effects of Chronic High-Frequency rTMS Protocol on Respiratory Neuroplasticity Following C2 Spinal Cord Hemisection in Rats

Author: Pauline Michel-Flutot, Isley Jesus, Valentin Vanhee, Camille H. Bourcier, Laila Emam, Abderrahim Ouguerroudj, Kun-Ze Lee, Lyandysha V. Zholudeva, Michael A. Lane, Arnaud Mansart, Marcel Bonay, Stéphane Vinit, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infection et inflammation (2I), National Sun Yat-Sen University (NSYSU), Gladstone Institutes [San Francisco], Drexel University, National Institutes of Health, NIH, National Institute of Neurological Disorders and Stroke, NINDS: F32 NS119348, R01 NS104291, Lisa Dean Moseley Foundation, Institut National de la Santé et de la Recherche Médicale, Inserm, Fondation de France, Ministry of Science and Technology, Taiwan, MOST: 109-2636-B-110-001, Chancellerie des Universités de Paris, Funding: This research was funded by the Chancellerie des Universités de Paris (Legs Poix) (SV, MB), the Fondation de France (SV), the Fondation Médisite (SV), INSERM (MB, SV, AM), Université de Versailles Saint-Quentin-en-Yvelines (SV, AM), the National Institutes of Health, NINDS, R01 NS104291 (MAL) and F32 NS119348 (LVZ), the Lisa Dean Moseley Foundation (MAL), and Ministry of Science and Technology 109-2636-B-110-001 (KZL). The supporters had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript., This research was funded by the Chancellerie des Universit?s de Paris (Legs Poix) (SV, MB), the Fondation de France (SV), the Fondation M?disite (SV), INSERM (MB, SV, AM), Universit? de Versailles Saint-Quentin-en-Yvelines (SV, AM), the National Institutes of Health, NINDS, R01 NS104291 (MAL) and F32 NS119348 (LVZ), the Lisa Dean Moseley Foundation (MAL), and Ministry of Science and Technology 109-2636-B-110-001 (KZL). The supporters had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript., This study has benefited from the facilities of CYMAGES and histology (UFR SVS, UVSQ, Université Paris-Saclay, 78180 Montigny-le-Bretonneux, France)., and HAL UVSQ, Équipe
Subjects: [SDV.IB] Life Sciences [q-bio]/Bioengineering, General Immunology and Microbiology, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], neuroplasticity, diaphragm muscle, repetitive transcranial magnetic stimulation, spinal cord injury, General Biochemistry, Genetics and Molecular Biology, nervous system, motoneuron excitability, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], phrenic motor network, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], General Agricultural and Biological Sciences
Abstract: International audience; High spinal cord injuries (SCIs) lead to permanent diaphragmatic paralysis. The search for therapeutics to induce functional motor recovery is essential. One promising noninvasive therapeutic tool that could harness plasticity in a spared descending respiratory circuit is repetitive transcranial magnetic stimulation (rTMS). Here, we tested the effect of chronic high-frequency (10 Hz) rTMS above the cortical areas in C2 hemisected rats when applied for 7 days, 1 month, or 2 months. An increase in intact hemidiaphragm electromyogram (EMG) activity and excitability (diaphragm motor evoked potentials) was observed after 1 month of rTMS application. Interestingly, despite no real functional effects of rTMS treatment on the injured hemidiaphragm activity during eupnea, 2 months of rTMS treatment strengthened the existing crossed phrenic pathways, allowing the injured hemidiaphragm to increase its activity during the respiratory challenge (i.e., asphyxia). This effect could be explained by a strengthening of respiratory descending fibers in the ventrolateral funiculi (an increase in GAP-43 positive fibers), sustained by a reduction in inflammation in the C1–C3 spinal cord (reduction in CD68 and Iba1 labeling), and acceleration of intracellular plasticity processes in phrenic motoneurons after chronic rTMS treatment. These results suggest that chronic high-frequency rTMS can ameliorate respiratory dysfunction and elicit neuronal plasticity with a reduction in deleterious post-traumatic inflammatory processes in the cervical spinal cord post-SCI. Thus, this therapeutic tool could be adopted and/or combined with other therapeutic interventions in order to further enhance beneficial outcomes.
Published: 2022
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9. Analysis of inspiratory and expiratory muscles using ultrasound in rats: A reproducible and non-invasive tool to study respiratory function

Author: Stéphane Vinit, Arnaud Mansart, Mostafa El Hajjam, Pauline Michel-Flutot, Frédéric Lofaso, Robert Carlier, Abdallah Fayssoil, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Raymond Poincaré [AP-HP], Hôpital Ambroise Paré [AP-HP], Infection et inflammation (2I), Chancellerie des Universités de Paris Institut National de la Santé et de la Recherche Médicale, Inserm Fondation de France, Funding: This work was supported by funding from the Chancellerie des Universités de Paris (Legs Poix) (SV) , the Fondation de France (SV) , the Fondation Médisite (SV) , INSERM (SV, AM) and Université de Versailles Saint-Quentin-en-Yvelines (SV, AM) . The supporters had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., CCSD, Accord Elsevier, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Supine position, Physiology, Diaphragm, Rats, Sprague-Dawley, Rectus abdominis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Ultrasound, Tidal Volume, medicine, Animals, Plethysmograph, Respiratory function, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Respiratory system, Tidal volume, Ultrasonography, business.industry, General Neuroscience, Histological Techniques, Reproducibility of Results, Respiratory Muscles, Rats, Diaphragm (structural system), Plethysmography, 030228 respiratory system, Rapid shallow breathing index, Cardiology, Rat, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, 030217 neurology & neurosurgery
Abstract: International audience; Ultrasound imaging is a non-invasive technique to assess organ function. Its potential application in rodents to evaluate respiratory function remains poorly investigated. We aimed to assess and validate ultrasound technique in rats to analyze inspiratory and expiratory muscles. We measured respiratory parameters to provide normal eupneic values. Histological studies and plethysmography were used to validate the technique and assess the physiological implications. A linear relationship was observed between ultrasound and histological data for diaphragm and rectus abdominis (RA) measurement. The tidal volume was significantly correlated with the right + left RA area (r = 0.76, p < 0.001), and the rapid shallow breathing index was significantly and inversely correlated with the right + left RA area (r=-0.53, p < 0.05). In the supine position, the right and left diaphragm expiratory thickness were not associated with tidal volume obtained in the physiological position. Ultrasound imaging is highly accurate and reproducible to assess and follow up diaphragm and RA structure and function in rats.
Published: 2021
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10. Permanent diaphragmatic deficits and spontaneous respiratory plasticity in a mouse model of incomplete cervical spinal cord injury

Author: Therese B. Deramaudt, Isley Jesus, Stéphane Vinit, Arnaud Mansart, Marcel Bonay, Kun-Ze Lee, Pauline Michel-Flutot, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infection et inflammation (2I), National Sun Yat-Sen University (NSYSU), Chancellerie des Universités de Paris Institut National de la Santé et de la Recherche Médicale, Inserm Ministerio de Ciencia y Tecnología, MICYT: 109-2636-B-110-001 Fondation de France, This work was supported by funding from the Chancellerie des Universités de Paris (Legs Poix) (SV, MB), the Fondation de France (SV), the Fondation Médisite (SV), INSERM (MB, SV, AM), Université de Versailles Saint-Quentin-en-Yvelines (MB, SV, AM) and Ministry of Science and Technology 109-2636-B-110-001 (KZL). The supporters had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., CCSD, Accord Elsevier, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: Male, Pulmonary and Respiratory Medicine, Micee, Physiology, Diaphragm, Spontaneous recovery, Diaphragmatic breathing, Phrenic motoneuron, Plasticity, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Respiratory system, Spinal Cord Injuries, Motor Neurons, Asphyxia, Electromyography, business.industry, General Neuroscience, Cervical Cord, Diaphragm EMG, Spinal cord, Pathophysiology, Diaphragm (structural system), Mice, Inbred C57BL, Phrenic Nerve, Disease Models, Animal, C2 spinal cord injury, medicine.anatomical_structure, 030228 respiratory system, Anesthesia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; High spinal cord injuries (SCI) lead to permanent respiratory insufficiency, and the search for new therapeutics to restore this function is essential. To date, the most documented preclinical model for high SCI is the rat cervical C2 hemisection. However, molecular studies with this SCI model are limited due to the poor availability of genetically modified specimens. The aim of this work was to evaluate the pathophysiology of respiratory activity following a cervical C2 injury at different times post-injury in a C57BL/6 mouse model. No significant spontaneous recovery of diaphragmatic activity was observed up to 30 days post-injury in eupneic condition. However, during a respiratory challenge, i.e. mild asphyxia, a partial restoration of the injured diaphragm was observed at 7 days post-injury, corresponding to the crossed phrenic phenomenon. Interestingly, the diaphragmatic recording between 2 respiratory bursts on the injured side showed an amplitude increase between 1–7 days post-injury, reflecting a change in phrenic motoneuronal excitability. This increase in inter-burst excitability returned to pre-injured values when the crossed phrenic phenomenon started to be effective at 7 days post-injury. Taken together, these results demonstrate the ability of the mouse respiratory system to express long-lasting plasticity following a C2 cervical hemisection and genetically modified animals can be used to study the pathophysiological effects on these plasticity phenomena.
Published: 2021
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11. Changes in Liver Lipidomic Profile in G2019S-LRRK2 Mouse Model of Parkinson’s Disease

Author: Yaiza Corral Nieto, Sokhna M. S. Yakhine-Diop, Paula Moreno-Cruz, Laura Manrique García, Amanda Gabrielly Pereira, José A. Morales-García, Mireia Niso-Santano, Rosa A. González-Polo, Elisabet Uribe-Carretero, Sylvère Durand, Maria Chiara Maiuri, Marta Paredes-Barquero, Eva Alegre-Cortés, Saray Canales-Cortés, Adolfo López de Munain, Jordi Pérez-Tur, Ana Pérez-Castillo, Guido Kroemer, José M. Fuentes, José M. Bravo-San Pedro, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Cultura y Deporte (España), Universidad de Extremadura, Junta de Extremadura, Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Fondation ARC pour la Recherche sur le Cancer, Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, European Research Council, and Pérez-Tur, Jordi
Subjects: Liver, Metabolome, LRRK2, Parkinson, General Medicine, lipids, liver, metabolome, neurodegeneration, Veterinaria, Neurodegeneration, Lipids, Psicología
Abstract: 15 páginas, 4 figuras, The identification of Parkinson's disease (PD) biomarkers has become a main goal for the diagnosis of this neurodegenerative disorder. PD has not only been intrinsically related to neurological problems, but also to a series of alterations in peripheral metabolism. The purpose of this study was to identify metabolic changes in the liver in mouse models of PD with the scope of finding new peripheral biomarkers for PD diagnosis. To achieve this goal, we used mass spectrometry technology to determine the complete metabolomic profile of liver and striatal tissue samples from WT mice, 6-hydroxydopamine-treated mice (idiopathic model) and mice affected by the G2019S-LRRK2 mutation in LRRK2/PARK8 gene (genetic model). This analysis revealed that the metabolism of carbohydrates, nucleotides and nucleosides was similarly altered in the liver from the two PD mouse models. However, long-chain fatty acids, phosphatidylcholine and other related lipid metabolites were only altered in hepatocytes from G2019S-LRRK2 mice. In summary, these results reveal specific differences, mainly in lipid metabolism, between idiopathic and genetic PD models in peripheral tissues and open up new possibilities to better understand the etiology of this neurological disorder., This research was supported by “Instituto de Salud Carlos III”, “Fondo de Investigaciones Sanitarias” (PI15/0034), “CIBERNED-ISCIII” (CB06/05/0041 and 2015/03), and partially supported by “European Regional Development Fund (ERDF)” from the European Union. J.M.B.-S.P. is funded by “Ramon y Cajal Program” (RYC-2018-025099-I) and supported by Spain’s Ministerio de Ciencia e Innovación (PID2019-108827RA-I00). Y.C.N. and L.M.G. are funded by Community of Madrid (CT5/21/PEJ-2020-TL/BMD-17685 and CT36/22-41-UCM-INV respectively). S.M.S.Y.-D. was supported by CIBERNED-ISCIII. P.M.-C. is funded by the MINECO Spanish Ministry (FPI grant, PRE2020-092668). M.N.-S. was funded by “Ramon y Cajal Program” (RYC-2016-20883). E.U.-C. and S.C.-C. were supported by an FPU predoctoral fellowship (FPU16/00684) and FPU19/04435), respectively, from “Ministerio de Educación, Cultura y Deporte”. M.P-B was funded by a University of Extremadura fellowship. E.A-C was supported by a Grant (IB18048) from Junta de Extremadura, Spain. J.M.F. received research support from the “Instituto de Salud Carlos III”; “Fondo de Investigaciones Sanitarias” (PI15/0034) and CIBERNED-ISCIII (CB06/05/0041 and 2015/03). A.P.-C. was supported by MINECO (SAF2014-52940-R and SAF2017-85199-P). J.P.-T. received funding from CIBERNED-ISCIII (CB06/05/1123 and 2015/03). G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR)—Projets blancs; ANR under the frame of E-Rare-2, the ERANet for Research on Rare Diseases; AMMICa US/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Le Cancer du Sein, Parlons-en!”; Cancéropôle Ile de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).
Published: 2023
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12. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

Author: Dafni Chondronasiou, Diljeet Gill, Lluc Mosteiro, Rocio G. Urdinguio, Antonio Berenguer‐Llergo, Mònica Aguilera, Sylvere Durand, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Abad, Daniel E. Martin‐Herranz, Camille Stephan‐Otto Attolini, Neus Prats, Guido Kroemer, Mario F. Fraga, Wolf Reik, Manuel Serrano, Gill, Diljeet [0000-0002-5725-2466], Mosteiro, Lluc [0000-0003-4041-9706], Urdinguio, Rocio G [0000-0003-2736-5758], Berenguer-Llergo, Antonio [0000-0002-3742-8161], Aguilera, Mònica [0000-0003-0763-7947], Abad, Maria [0000-0002-1462-2498], Martin-Herranz, Daniel E [0000-0002-2285-3317], Stephan-Otto Attolini, Camille [0000-0001-8045-320X], Prats, Neus [0000-0001-5653-7390], Fraga, Mario F [0000-0001-8450-2603], Reik, Wolf [0000-0003-0216-9881], Serrano, Manuel [0000-0001-7177-9312], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Chondronasiou D, Berenguer-Llergo A, Aguilera M] Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [Gill D] Epigenetics Programme, Babraham Institute, Cambridge, UK. [Mosteiro L] Genentech, San Francisco, USA. [Urdinguio RG] Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN CSIC), Oviedo, Spain. Health Research Institute of Asturias (ISPA), Oviedo, Spain. Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo, Spain. Department of Organisms and Systems Biology (BOS), University of Oviedo, Oviedo, Spain. CIBER of Rare Diseases (CIBERER), Oviedo, Spain. [Abad M] Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Fundación 'la Caixa', Fundación Científica Asociación Española Contra el Cáncer, Principado de Asturias, European Commission, Instituto de Salud Carlos III, Agence Nationale de la Recherche (France), Ligue Nationale contre le Cancer (France), Association de la Recherche Contre le Cancer (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, European Research Area Network on Cardiovascular Diseases, Institut National du Cancer (France), Fondation Leducq, Université de Paris, Biotechnology and Biological Sciences Research Council (UK), European Research Council, Ministerio de Economía y Competitividad (España), and Generalitat de Catalunya
Subjects: Aging, transcriptomic clocks, Induced Pluripotent Stem Cells, epigenetic clocks, Yamanaka, RESEARCH ARTICLES, RESEARCH ARTICLE, Epigenome, Mice, Envelliment, Genetic Phenomena [PHENOMENA AND PROCESSES], Animals, Rejuvenation, Ratolins, aging, reprogramming, Cell Differentiation, Cell Biology, DNA Methylation, pluripotency, Cellular Reprogramming, Epigenètica, fenómenos genéticos [FENÓMENOS Y PROCESOS], OSKM, Epigenetics, sense organs, Cèl·lules - Envelliment, Cèl·lules mare
Abstract: The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum., D.C. was recipient of a fellowship from “laCaixa” Foundation. Work in the laboratory of M.F.F. was funded by Fundación Científica Asociación Española Contra el Cáncer (AECC) (PROYE18061FER), the Asturias Government (PCTI) co-funding 2018- 2022/FEDER (IDI/2018/146), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527). Work in the laboratory of G.K. was supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR)—Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Ruban Rose”; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. Work in the laboratory of W.R. was funded by the Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0425). Work in the laboratory of M.S. was funded by the IRB, and by grants from Spanish Ministry of Economy co-funded by European Regional Development Fund (ERDF) (SAF2013-48256-R), European Research Council (ERC-2014-AdG/669622), Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282) and “laCaixa” Foundation.
Published: 2022

13. Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition

Author: Sabine Paternot, Eric Raspé, Clément Meiller, Maxime Tarabichi, Jean‐Baptiste Assié, Frederick Libert, Myriam Remmelink, Xavier Bisteau, Patrick Pauwels, Yuna Blum, Nolwenn Le Stang, Séverine Tabone‐Eglinger, Françoise Galateau‐Sallé, Christophe Blanquart, Jan P. Van Meerbeeck, Thierry Berghmans, Didier Jean, Pierre P. Roger, Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire = Insitute of Interdisciplinary Research [Bruxelles, Belgique] (IRIBHM), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Erasme [Bruxelles] (ULB), Antwerp University Hospital [Edegem] (UZA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut Jules Bordet [Bruxelles], Chancellerie des Universités de Paris, Fondation pour la Recherche Médicale, Innoviris, Institut National de la Santé et de la Recherche Médicale, Institut National Du Cancer, Koning Boudewijnstichting, Ligue Contre le Cancer, 2014‐130, Stichting Tegen Kanker, and Centre National de la Recherche Scientifique
Subjects: Mesothelioma, Cancer Research, palbociclib, Oncology, [SDV]Life Sciences [q-bio], CDK4 Thr172-phosphorylation, senescence-associated secretory phenotype, Genetics, biomarker, Molecular Medicine, cell cycle, General Medicine, Human medicine
Abstract: International audience; Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with high p16(INK4A) (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild-type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumors from short survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.
Published: 2022
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14. Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma

Author: Franck Letourneur, Jérémy Augustin, Mark J. Kurth, Julie Le Naour, Sylvie Lachkar, Pamela Caudana, Eliane Piaggio, Youra Kim, Sarah Levesque, Jie S. Zhu, Guido Kroemer, Jonathan Pol, Bouchra Lekbaby, Andrea Checcoli, Patrick S.C. Leung, Allan Sauvat, Shashi Gujar, Agathe Delaune, Chantal Housset, Pierre de la Grange, Paule Opolon, Laura Fouassier, Noémie Robil, Laurence Zitvogel, Patrick Soussan, Juliette Paillet, Céleste Plantureux, Jimena Tosello Boari, M. Eric Gershwin, Isabelle Martins, Maria Chiara Maiuri, Cédric Coulouarn, Gautier Stoll, Norma Bloy, Gwennhael Autret, Juliette Hamroune, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Gustave Roussy (IGR), Institut Curie [Paris], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), GenoSplice [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of California [Los Angeles] (UCLA), University of California, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dalhousie University [Halifax], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska University Hospital [Stockholm], Association pour la lutte contre les maladies inflammatoires du foie et des voies biliaires, Dalhousie Medical Research Foundation, Agence National de la Recherche, ERA-Net for Research on Rare Diseases, Association pour la recherche sur le cancer, Cancéropôle Ile-de-France, Chancellerie des universités de Paris, Fondation pour la Recherche Médicale, Elior, European Research Area Network on Cardiovascular Diseases, Gustave Roussy Odyssea, European Union Horizon 2020, Canadian Cancer Society, Project Oncobiome, Fondation Carrefour, GDW20171100085, High-end Foreign Expert Program in China, Institut National du Cancer, Inserm, Institut Universitaire de France, LeDucq Foundation, LabEx, Recherche Hospitalo-Universitaire Torino Lumière, Seerave Foundation, Canadian Institutes of Health Research, Site de Recherche intégrée sur le Cancer Stratified Oncology Cell DNA Repair and Tumor Immune Elimination, Cancer Research and Personalized Medicine, Multi-Organism Institute (ITMO) Aviesan Cancer, Association Française d'Hépatologie, Site de Recherche intégrée sur le Cancer Cancer Research and Personalized Medicine, Ligue contre le Cancer, École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: CD4-Positive T-Lymphocytes, Cholangitis, Autoimmunity, CD8-Positive T-Lymphocytes, Inbred C57BL, medicine.disease_cause, Medical and Health Sciences, Malignant transformation, Cholangiocarcinoma, Mice, 0302 clinical medicine, Immunologic, Neoplasms, 2.1 Biological and endogenous factors, Immunology and Allergy, Medicine, Aetiology, Cancer, 0303 health sciences, Tumor, Liver Disease, Forkhead Transcription Factors, 3. Good health, Immunosurveillance, medicine.anatomical_structure, Liver, Biliary tract, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, cardiovascular system, Cytokines, Female, Biotechnology, Liver Cancer, Monitoring, T cell, Chronic Liver Disease and Cirrhosis, Immunology, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Autoimmune Disease, digestive system, Cell Line, Primary sclerosing cholangitis, Experimental, 03 medical and health sciences, Rare Diseases, Monitoring, Immunologic, Cell Line, Tumor, parasitic diseases, Animals, cardiovascular diseases, Digestive Diseases - (Gallbladder), 030304 developmental biology, business.industry, Neoplasms, Experimental, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Bile Duct Neoplasms, Cancer research, Digestive Diseases, business
Abstract: International audience; Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
Published: 2021
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15. Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

Author: Meiller, Clément, Montagne, François, Hirsch, Theo Z., Caruso, Stefano, de Wolf, Julien, Bayard, Quentin, Assié, Jean-Baptiste, Meunier, Léa, Blum, Yuna, Quetel, Lisa, Gibault, Laure, Pintilie, Ecaterina, Badoual, Cécile, Humez, Sarah, Galateau-Sallé, Françoise, Copin, Marie-Christine, Letouzé, Eric, Scherpereel, Arnaud, Zucman-Rossi, Jessica, Le Pimpec-Barthes, Françoise, Jaurand, Marie-Claude, Jean, Didier, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHI Créteil, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Cité (UPCité), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Réseau National Expert pour le Mésothéliome Pleural Malin [Lille] (MESOCLIN), This work was supported by Inserm, the Ligue Contre le Cancer (Ile de France committee and national program Cartes d’Identité des Tumeurs (CIT)), Hadassah France, the Chancellerie des Universités de Paris (Legs POIX) and Cancéropôle Île-de-France (Emergence). JBA, FM, LQ and JdW were supported by grants from Fondation pour la Recherche Médicale (FRM), from the Institut thématique multi-organismes (ITMO) Cancer (Plan Cancer 2014–2019), from Cancéropôle Île-de-France and from the Fondation ARC, respectively. JdW and FM were also supported by grant of the Société Française de Chirurgie Thoracique et Cardio-Vasculaire (SFCTCV). The Inserm research unit is supported by the Labex OncoImmunology (investissement d’avenir), Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, the Institut thématique multi-organismes (ITMO) Cancer (Plan Cancer 2014-2019) and Cancéropôle Île-de-France., Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)], Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique [CEpiA], Centre Hospitalier Intercommunal de Créteil [CHIC], (le programme) Cartes d'identité des tumeurs [CIT], Hôpital Européen Georges Pompidou [APHP] [HEGP], Université Paris Cité [UPCité], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Centre Hospitalier Intercommunal de Créteil (CHIC), Université Paris Cité (UPC), CHU Lille, Université de Lille, MESOPATH Referent National Center, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université de Paris (UP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Jean, Didier
Subjects: Biopsy, Pleural Neoplasms, DNA Mutational Analysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, QH426-470, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, NF2 subclonal mutation, Genetic Heterogeneity, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Exome Sequencing, Genetics, Biomarkers, Tumor, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Precision Medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Thoracic tumor, Research, Gene Expression Profiling, Mesothelioma, Malignant, Computational Biology, Disease Management, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Spatial molecular intra-tumor heterogeneity, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Clonality, Tumor microenvironment, Prognosis, Molecular Diagnostic Techniques, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicine, Disease Susceptibility
Abstract: Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-021-00931-w.
Published: 2021
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16. Multifaceted modes of action of the anticancer probiotic Enterococcus hirae

Author: Marion Leduc, Didier Raoult, Laura Mondragón, Kristina Iribarren, Anne-Gaëlle Goubet, Diane Derrien, Satoru Yonekura, Noélie Bossut, Valerio Iebba, Nicola Segata, Guo Chen, Ivo G. Boneca, Lisa Derosa, Adrien Joseph, Fabrice Andre, Sylvère Durand, Aurélie Fluckiger, Maryam Tidjani Alou, Fanny Aprahamian, Richard J. Wheeler, Maryse Moya-Nilges, Eugenie Pizzato, Bo Qu, Guido Kroemer, Oliver Kepp, Nicolas Pons, Romain Daillère, Fabien Lemaitre, Laurence Zitvogel, Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France, Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Shanghai Jiao Tong University [Shanghai], Institut Gustave Roussy (IGR), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, UMR 1015 Immunologie des tumeurs et immunothérapie contre le cancer (ITIC), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris], MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Trento [Trento], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Fondation pour la Recherche Médicale, Ligue contre le Cancer (équipes labellisées), Leducq Foundation, Seerave Foundation, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), Fondation ARC pour la Recherche sur le Cancer, Région Ile-de-France, Chancellerie des universités de Paris (Legs Poix), FRM, European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), Gustave Roussy Odyssea, Fondation Carrefour, High-end Foreign Expert Program in China: GDW20171100085 and GDW20181100051, Institut National du Cancer (INCA) France, Inserm (HTE), Institut Universitaire de France, ANR-10-COHO-0004,CANTO,Etude des toxicités chroniques des traitements anticancéreux chez les patientes porteuses cancer(2010), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 680969,H2020,H2020-HCO-2015,ERA-CVD(2015), European Project: 825410, H2020-EU.3.1., H2020-EU.3.1.2.,ONCOBIOME (2019), Institut Pasteur [Paris] (IP)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Ligue Nationale Contre le Cancer (LNCC), Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Goubet, A. -G., Wheeler, R., Fluckiger, A., Qu, B., Lemaitre, F., Iribarren, K., Mondragon, L., Tidjani Alou, M., Pizzato, E., Durand, S., Derosa, L., Aprahamian, F., Bossut, N., Moya-Nilges, M., Derrien, D., Chen, G., Leduc, M., Joseph, A., Pons, N., Le Chatelier, E., Segata, N., Yonekura, S., Iebba, V., Kepp, O., Raoult, D., Andre, F., Kroemer, G., Boneca, I. G., Zitvogel, L., Daillere, R., Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Université Paris Cité (UPC), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), and European Project: 825410,ONCOBIOME
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], microbiome, law.invention, Probiotic, Mice, 0302 clinical medicine, Cancer immunotherapy, Enterococcus hirae, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Neoplasms, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, CD137, 3. Good health, Bifidobacterium animalis, Anti-Bacterial Agents, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, immunotherapy, Immunotherapy, microbiota, cancer, tumor, probiotic, intratumoral IFNγ, Biology, Article, Microbiology, 03 medical and health sciences, Memory T Cells, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiome, Molecular Biology, Probiotics, Autophagy, Cell Biology, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Dysbiosis
Abstract: International audience; A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFN gamma-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
Published: 2021
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17. Metabolic reprograming of LPS-stimulated human lung macrophages involves tryptophan metabolism and the aspartate-arginosuccinate shunt

Author: Etienne A. Thévenot, Elodie Lamy, Marion Brollo, Fanta Fall, Philippe Devillier, Stanislas Grassin-Delyle, Emmanuel Naline, Natacha Lenuzza, Infection et inflammation (2I), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire de recherche sur les mécanismes moléculaires et pharmacologiques de l’obstruction bronchique (LOBIP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département des maladies des voies respiratoires [Suresnes], Hôpital Foch [Suresnes], Laboratoire Sciences des Données et de la Décision (LS2D), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, This work was supported by the French Ministry of Higher Education and Research (PhD grant, Fanta Fall) and by the Chancellerie des Universités de Paris (Legs Gaston Poix)., Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), and Bodescot, Myriam
Subjects: Lipopolysaccharides, Male, 0301 basic medicine, Ionization, Lipopolysaccharide, Pathway analysis, Biochemistry, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Macrophage M1 polarization, White Blood Cells, chemistry.chemical_compound, Aromatic Amino Acids, 0302 clinical medicine, lung inflammatory disesase, Drug Metabolism, Animal Cells, Medicine and Health Sciences, Macrophage, Alveolar Macrophages, Amino Acids, Receptor, Cells, Cultured, pathophysiology, mass spectrometry, Gas chromatography, Multidisciplinary, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Organic Compounds, Chemistry, Tryptophan, Chemical Reactions, bioinformatics, Middle Aged, inflammation regulation, metabolomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Targeted metabolic profiling, Lung macrophage, classification, Physical Sciences, Medicine, metabolic alteration, Female, Cellular Types, medicine.symptom, Intracellular, data processing, Research Article, Signal Transduction, clustering, Cell Physiology, Immune Cells, Science, Immunology, macrophage immunometabolome, Liquid chromatography, Inflammation, spectrum analysis, Argininosuccinic Acid, Proinflammatory cytokine, lung, 03 medical and health sciences, statistical analysis, Macrophages, Alveolar, Extracellular, Metabolome, medicine, Humans, Pharmacokinetics, Aged, Pharmacology, Aspartic Acid, polarization, Blood Cells, antimicrobial activity, Macrophages, Organic Chemistry, Chemical Compounds, Biology and Life Sciences, Proteins, Cell Biology, Macrophage Activation, Cell Metabolism, Amino Acid Metabolism, Metabolism, 030104 developmental biology, 030228 respiratory system, Multivariate analysis, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Abstract: International audience; Lung macrophages (LM) are in the first line of defense against inhaled pathogens and can undergo phenotypic polarization to the proinflammatory M1 after stimulation with Toll-like receptor agonists. The objective of the present work was to characterize the metabolic alterations occurring during the experimental M1 LM polarization. Human LM were obtained from resected lungs and cultured for 24 hrs in medium alone or with 10 ng.mL-1 lipopolysaccharide. Cells and culture supernatants were subjected to extraction for metabolomic analysis with high-resolution LC-MS (HILIC and reverse phase -RP- chromatography in both negative and positive ionization modes) and GC-MS. The data were analyzed with R and the Worklow4Metabolomics and MetaboAnalyst online infrastructures. A total of 8,741 and 4,356 features were detected in the intracellular and extracellular content, respectively, after the filtering steps. Pathway analysis showed involvement of arachidonic acid metabolism, tryptophan metabolism and Krebs cycle in the response of LM to LPS, which was confirmed by the specific quantitation of selected compounds. This refined analysis highlighted a regulation of the kynurenin pathway as well as the serotonin biosynthesis pathway, and an involvement of aspartate-arginosuccinate shunt in the malate production. Macrophages M1 polarization is accompanied by changes in the cell metabolome, with the differential expression of metabolites involved in the promotion and regulation of inflammation and antimicrobial activity. The analysis of this macrophage immunometabolome may be of interest for the understanding of the pathophysiology of lung inflammatory disesases.
Published: 2020
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18. The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

Author: Christophe Blanquart, Marie-Claude Jaurand, Didier Jean, Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEX IGO Immunothérapie Grand Ouest, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), This work was supported by Inserm, CNRS, Hadassah France, the National Research Agency under the Programme d’Investissements d’Avenir (ANR-16-IDEX-0007), the Pays de la Loire Region research program by a financial support from the Institut de Recherche en Santé Respiratoire des Pays de la Loire, the Chancellerie des Universités de Paris (Legs POIX), the Ligue Contre le Cancer (Ile de France committee), and ARSMeso44. The authors thank the cluster LUNG innOvatiOn (LUNG O2) for logistic support., Jean, Didier, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Cancer Research, Stromal cell, medicine.medical_treatment, In silico, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Review, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, thoracic cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], tumor heterogeneity, medicine, Mesothelioma, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Tumor microenvironment, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Immunotherapy, medicine.disease, Precision medicine, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, preclinical models, animal models, cell models, 3. Good health, molecular characteristics, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Oncology, 030220 oncology & carcinogenesis, mesothelioma, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Carcinogenesis
Abstract: International audience; Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra- and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.
Published: 2020
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19. Genetic alterations of malignant pleural mesothelioma: association to tumor heterogeneity and overall survival Author names

Author: Quetel, Lisa, Meiller, Clément, Assié, Jean-Baptiste, Blum, Yuna, Imbeaud, Sandrine, Montagne, François, Tranchant, Robin, de Wolf, Julien, Caruso, Stefano, Copin, Marie-Christine, Hofman, Véronique, Gibault, Laure, Badoual, Cecile, Pintilie, Ecaterina, Hofman, Paul, Monnet, Isabelle, Scherpereel, Arnaud, Le Pimpec-Barthes, Françoise, Zucman-Rossi, Jessica, Jaurand, Marie-Claude, Jean, Didier, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Genexpress, Génomique Fonctionnelle et Biologie Systémique pour la Santé, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC), Service d'Anatomo-cytopathologie [Hôpital Européen Georges Pompidou - APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Chirurgie Thoracique [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Pneumologie et de Pathologie Professionnelle [CHI Créteil], CHI Créteil, Réseau National Expert pour le Mésothéliome Pleural Malin [Lille] (MESOCLIN), Pneumologie et Oncologie Thoracique [CHRU de Lille], PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Albert Calmette-Faculté de Médecine Henri Warembourg, Service de Chirurgie Thoracique (Hôpital Européen Georges Pompidou [APHP] HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by Inserm, the Ligue Contre le Cancer (Ile de France committee and national program Cartes d’Identité des Tumeurs (CIT)), the Fondation ARC pour la recherche sur le cancer, Hadassah France, and the Chancellerie des Universités de Paris (Legs POIX). LQ, JBA, FM and JdW were supported by grants from Cancéropôle Région Île-de France, from Fondation pour la Recherche Médicale (FRM), from the Institut thématique multi-organismes (ITMO) Cancer (Plan Cancer 2014-2019) and from the Fondation ARC, respectively. JdW and FM were also supported by grant of the Société Française de Chirurgie Thoracique et Cardio-Vasculaire (SFCTCV). The Inserm research unit is supported by the Labex OncoImmunology (investissement d’avenir), Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, the Institut thématique multi-organismes (ITMO) Cancer (Plan Cancer 2014-2019) and Cancéropôle Île-de-France., École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille-Hôpital Albert Calmette, and Jean, Didier
Subjects: tumor molecular classification, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Thoracic cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], tumor heterogeneity, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], prognosis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, gene mutations
Abstract: International audience; Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well-annotated with histologic, molecular and clinical data of patients. Targeted next generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioïd-like and sarcomatoïd-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2 and LATS2 were more frequent in non-epithelioid MPM and positively associated to the S.score. BAP1, NF2, TERT promoter, TP53 and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2 and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.
Published: 2020
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20. Cervical Spine Hyperextension and Altered Posturo-Respiratory Coupling in Patients With Obstructive Sleep Apnea Syndrome

Author: Clavel, Louis, Remy-Neris, Ségolène, Skalli, Wafa, Rouch, Philippe, Lespert, Yoann, Similowski, Thomas, Sandoz, Baptiste, Attali, Valérie, Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported in part by the Legs Poix (LEG1604) of the Chancellerie des Universités de Paris. LC wassupported by a Ph.D. fellowship from ENS Cachan. VA wasthe recipient of a grant poste d’accueil APHP/Arts et Métiersdélégation à la Recherche Clinique et à l’Innovation (DRCI),Assistance Publique Hôpitaux de Paris (APHP). SR-N wasthe recipient of a grant of ResMed (France). The authorsacknowledge the support of the Paristech BiomeCAM chair onsubject specific modeling, with the support of Société Généraleand COVEA., HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Service de Pathologies du sommeil [CHU Pitié-Salpêtrière], and Administrateur Ensam, Compte De Service
Subjects: [SDV] Life Sciences [q-bio], cervical spine hyperextension, personalized 3D models of the spine, [SDV]Life Sciences [q-bio], posturo- respiratory coupling, Sciences du vivant, biplanar X-ray, obstructive sleep apnea syndrome, respiratory emergence, hyperkyphosis, General Medicine, head forward
Abstract: Obstructive sleep apnea syndrome (OSAS) is associated with postural dysfunction characterized by abnormal spinal curvature and disturbance of balance and walking, whose pathophysiology is poorly understood. We hypothesized that it may be the result of a pathological interaction between postural and ventilatory functions. Twelve patients with OSAS (4 women, age 53 years [51-63] (median [quartiles]), apnea hypopnea index 31/h [24-41]) were compared with 12 healthy matched controls. Low dose biplanar X-rays (EOS® system) were acquired and personalized three-dimensional models of the spine and pelvis were reconstructed. We also estimated posturo-respiratory coupling by measurement of respiratory emergence, obtaining synchronized center of pressure data from a stabilometric platform and ventilation data recorded by an optico-electronic system of movement analysis. Compared with controls, OSAS patients, had cervical hyperextension with anterior projection of the head (angle OD-C7 12° [8; 14] vs. 5° [4; 8]; p = 0.002), and thoracic hyperkyphosis (angle T1-T12 65° [51; 71] vs. 49° [42; 59]; p = 0.039). Along the mediolateral axis: (1) center of pressure displacement was greater in OSAS patients, whose balance was poorer (19.2 mm [14.2; 31.5] vs. 8.5 [1.4; 17.8]; p = 0.008); (2) respiratory emergence was greater in OSAS patients, who showed increased postural disturbance of respiratory origin (19.2% [9.9; 24.0] vs. 8.1% [6.4; 10.4]; p = 0.028). These results are evidence for the centrally-mediated and primarily respiratory origin of the postural dysfunction in OSAS. It is characterized by an hyperextension of the cervical spine with a compensatory hyperkyphosis, and an alteration in posturo-respiratory coupling, apparently secondary to upper airway instability. This work was supported in part by the Legs Poix (LEG 1604) of the Chancellerie des Universités de Paris. LC was supported by a Ph.D. fellowship from ENS Cachan. VA was the recipient of a grant poste d’accueil APHP/Arts et Métiers délégation à la Recherche Clinique et à l’Innovation (DRCI), Assistance Publique Hôpitaux de Paris (APHP). SR-N was the recipient of a grant of ResMed (France). The authors acknowledge the support of the Paristech BiomeCAM chair on subject specific modeling, with the support of Société Générale and COVEA.
Published: 2020
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21. Two-hybrid screening of FAM13A protein partners in lung epithelial cells

Author: Ruffin, Manon, Thompson, Kristin E., Corvol, Harriet, Guillot, Loic, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], To perform this study, LG received a research grant from the French cystic fibrosis non-profit organization Vaincre la mucoviscidose (RF20150501336) and a Legs Poix grant from the publicly funded source Chancellerie des Universités de Paris. KT and MR received a post-doctoral fellowship from the French cystic fibrosis non-profit organization Vaincre la mucoviscidose., Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Pneumologie Pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Bodescot, Myriam, Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Lung Neoplasms, lcsh:Medicine, Two-hybrid screening, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cell Line, Tumor, Two-Hybrid System Techniques, Humans, lcsh:Science (General), lcsh:QH301-705.5, Lung, Gene Library, Lung epithelium, lcsh:R, GTPase-Activating Proteins, Epithelial Cells, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Research Note, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], lcsh:Biology (General), A549 Cells, FAM13A, Chronic lung diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Carrier Proteins, lcsh:Q1-390, Protein Binding
Abstract: International audience; OBJECTIVES:Family with sequence similarity 13 member A (FAM13A) genetic variants have been associated with several chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF) and lung cancer. The FAM13A protein includes a RhoGTPase activating protein (RhoGAP) domain known to participate in various cellular mechanisms including cell proliferation. While intensive genomic studies have been performed to reveal its involvement in lung diseases, the biological role of FAM13A protein is still not completely elucidated.RESULTS:We therefore performed a two-hybrid screening to identify protein partners of FAM13A using a human lung cancer cDNA library. We identified several protein partners with a high confidence score. Researchers in the field of chronic lung diseases may benefit from this two-hybrid screening data which may reveal new research pathways to decipher.
Published: 2020
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22. Decreased respiratory-related postural perturbations at the cervical level under cognitive load

Author: Louis Clavel, Isabelle Rivals, Marie-Cécile Niérat, Valérie Attali, Philippe Rouch, Baptiste Sandoz, Pierantonio Laveneziana, Thomas Similowski, Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), INSERM, U708, Neuroepidemiology, F-75005, Paris, France, This work was funded by the Chancellerie des Universités de Paris (Grant number: Legs Poix (LEG 1604)), ENS Cachan (Grant number: Ph.D. fellowship), Assistance Publique - Hôpitaux de Paris (Grant number: Grant 'poste d’accueil APHP/Arts et Métiers' délé-gation à la Recherche Clinique et à l’Innovation (DRCI)), and Paristech (Grant number: BiomeCAM chair).
Subjects: Posturo-ventilatory interaction, medicine.medical_specialty, Respiratory rate, Physiology, [SDV]Life Sciences [q-bio], Kinematics, Centre of pressure, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Cog, Postural control, Physiology (medical), Cervical spine, Medicine, Orthopedics and Sports Medicine, Respiratory system, Balance (ability), business.industry, Public Health, Environmental and Occupational Health, Joint kinematics, 030229 sport sciences, General Medicine, Optoelectronic plethysmography, Cognitive dual task, Breathing, Sciences du vivant, business, 030217 neurology & neurosurgery, Cognitive load
Abstract: PURPOSE: In healthy humans, postural and respiratory dynamics are intimately linked and a breathing-related postural perturbation is evident in joint kinematics. A cognitive dual-task paradigm that is known to induce both postural and ventilatory disturbances can be used to modulate this multijoint posturo-ventilatory (PV) interaction, particularly in the cervical spine, which supports the head. The objective of this study was to assess this modulation. METHODS: With the use of optoelectronic sensors, the breathing profile, articular joint motions of the cervical spine, hip, knees and ankles, and centre of pressure (CoP) displacement were measured in 20 healthy subjects (37 years old [29; 49], 10 females) during natural breathing (NB), a cognitive dual task (COG), and eyes-closed and increased-tidal-volume conditions. The PV interaction in the CoP and joint motions were evaluated by calculating the respiratory emergence (REm). RESULTS: Only the COG condition induced a decrease in the cervical REm (NB: 17.2% [7.8; 37.2]; COG: 4.2% [1.8; 10.0] p = 0.0020) concurrent with no changes in the cervical motion. The CoP REm (NB: 6.2% [3.8; 10.3]; COG: 12.9% [5.8; 20.7] p = 0.0696) and breathing frequency (NB: 16.6 min-1 [13.3; 18.7]; COG: 18.6 min-1 [16.3; 19.4] p = 0.0731) tended to increase, while the CoP (p = 0.0072) and lower joint motion displacements (p
Published: 2020
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23. Livre / Typographie

Author: Campaignolle-Catel, Hélène, Sophie, Lesiewicz, Theval, Gaëlle, THALIM - Théorie et histoire des arts et des littératures de la modernité - UMR 7172 (THALIM), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Sorbonne Nouvelle - Paris 3, Bibliothéque littéraire Jacques Doucet (BLJD), Chancellerie des Universités de Paris, LIVRESC, Université Sorbonne Nouvelle - Paris 3-Centre National de la Recherche Scientifique (CNRS)-Département Arts - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Subjects: poésie, [SHS.INFO]Humanities and Social Sciences/Library and information sciences, arts, [INFO.INFO-GL]Computer Science [cs]/General Literature [cs.GL], histoire du livre, typographie, [SHS.ART]Humanities and Social Sciences/Art and art history, [SHS.MUSEO]Humanities and Social Sciences/Cultural heritage and museology, livres d'artiste
Abstract: Un ouvrage imprimé par la Maison Bortolazzi à Vérone de format 170 x 240 comptant 256 pagesImpression couleur (60 ill. in texte) sur munken lynxCouverture à larges rabatsimpression quadri et gaufrage sur Old Mill puredes papeteries Fedrigoni; International audience; Issu du séminaire de recherche 2012-2013 co-organisé par l'université Paris 3 Sorbonne nouvelle et la Bibliothèque littéraire Jacques Doucet, e, 2012-2013, l'ouvrage Livre / typographie fait suite à Livre / poésie, issu de la même série. Construit chronologiquement autour d’œuvres formant autant d’étapes marquantes de l’histoire du livre de création, le volume analyse les rééditions et réinterprétations d’Un coup de dés jamais n’abolira le hasard, rassemblant Massin, Tibor Papp, Albert DuPont et Isabella Checcaglini ; le livre symboliste à la fin du xixe siècle (Alfred Jarry, Marcel Schwob, Georges de Feure) ; les années dix-vingt pour sonder « l’esprit nouveau » des œuvres des poètes Apollinaire et Cendrars ; les années cinquante avec l’étude de trois œuvres post-dada et/ou surréalistes (Georges Hugnet, Tristan Tzara, Joan Miró) ; la notion de livre-objet développée dans l’espace culturel mexicain et brésilien (Vicente Rojo et Octavio Paz, Waltercio Caldas et Mira Schendel) ; l’imaginaire francophone du livre sonore des années 70 (Bernard Heidsieck, Michèle Métail) en écho aux expérimentations antérieures de la revue poétique Sic. Le volume se clôt sur des études d’œuvres d’André Frénaud et du Bouchet et un entretien avec Julius Baltazar, offrant un regard rétrospectif sur trente années de création fertile dans le champ du livre d’artiste.
Published: 2020

24. Basophil activation through TLR2 and TLR4 signaling pathways

Author: Abdulraouf Ramadan, Elke Schneider, Nathalie Thieblemont, François Machavoine, Manal Alkan, Michel Dy, Fadel Sayes, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytokines, hématopoïèse et réponse immune (CHRI), LabEx Inflamex, This work was supported by individual funding, as follows: CNRS (PEPS, N Thieblemont), Labex Inflamex, the Chancellerie des Universités de Paris (Legs Poix, N. Thieblemont). Manal Alkan was supported by the Syrian government (PhD fellowship) and by the Fondation pour la Recherche Médicale (FRM)., The authors acknowledge Muriel Andrieu and Karine Labroquère of the Cochin Cytometry and Immunobiology Facility, Agnès Lebon and the staff of the Animal Care Facilities at the Cochin Institute, Martine Caroff (Orsay, France), Armelle Blondel (Institut Cochin, Paris, France), and Jean-Marc Cavaillon (Institut Pasteur, Paris, France) providing reagents and for their assistance in experimental studies, Shizuo Akira (Japan) for providing mice, the assistance of Jean Fioramonti providing crude extract of parasite (INRA, Toulouse, France), and the excellent technical assistance of Céline Dietrich for some in vitro experiments., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), XLIM (XLIM), and Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, Ocean Engineering, Basophil, Allergic inflammation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, TLR, parasitic diseases, medicine, Safety, Risk, Reliability and Quality, Histamine Production, Interleukin 4, basophils| PAMP| IL-4| histamine| TLR, IL-4, Degranulation, hemic and immune systems, PAMP, histamine, Basophil activation, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Immunology, TLR4, lcsh:RC581-607, basophils, Histamine
Abstract: Basophils are effector cells that respond to protease allergens and parasites, thus contributing to allergic inflammation and Th2 differentiation. However, the molecular interactions through which pathogens promote activation as well as recruitment of these cells to sites of inflammation remain poorly understood. We found that administration of extracts from Nippostrongylus brasiliensis induced both basophil recruitment into blood and liver in vivo and IL-4 and histamine production by purified bone marrow-derived basophils in vitro. Starting from this finding, we set out to identify putative pathogen-derived molecules for their capacity to activate murine basophils, using a basophil population differentiated and expanded from bone marrow cells cultured with IL-3 and sorted as a CD49b+ c-kit– subset. Among a number of Toll-like receptor (TLR) agonists tested, we found that the lipopeptide Pam2CSK4 and lipopolysaccharide (LPS) activate basophils in terms of IL-4, IL-6 and histamine production through TLR2 and TLR4, respectively. By contrast, TLR3 or TLR7 agonists had no such effect. We further identified nitric oxide (NO) as key mediator for LPS stimulation and established that in vivo administration of LPS led to basophil recruitment into the liver. Our results reveal the important contribution of MyD88 and NO signaling to antigen recognition through TLR2 and TLR4 pathways leading to activation, degranulation and release of immunoregulatory mediators.
Published: 2018
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25. Valorisation des données pour l'amélioration des plateformes d'hébergement de MOOC

Author: Bigrat, Frédérick, LAURENT, Mélody, Méadel, Cécile, Université Panthéon-Assas (UP2), Chancellerie des Universités de Paris, Centre de Sociologie de l'Innovation i3 (CSI i3), MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Data, Technology, Platforms, Données, [SHS.INFO]Humanities and Social Sciences/Library and information sciences, MOOC, Agent conversationnel, Plateformes, Technologies, Chatbot
Abstract: International audience; Throughout the duration of a Massive Open Online Courses (MOOC), Professors, instructional-designers and learners either directly or indirectly generate very large amounts of data. Some are used by platform hosts to feed their statistics or to facilitate the learner experience and others are still undervalued. How can we build efficient indicators based on a modeled track management system relying on the forums of a MOOC Hosting platform ?; Durant toute la durée d'un MOOC (Massive Open Online Courses), les professeurs, les ingénieurs pédagogiques et les apprenants génèrent soit de manière directe soit de manière indirecte des données en quantité très importante. Certaines sont utilisées par les hébergeurs de plateformes pour alimenter leurs statistiques ou pour faciliter l'expérience de l'apprenant et d'autres sont encore peu valorisées. Comment peut-on construire des indicateurs efficients sur la base d'un système de gestion de traces modélisées s'appuyant sur les forums d'une plateforme d'hébergement de MOOC ?
Published: 2019

26. Compensation of Respiratory-Related Postural Perturbation Is Achieved by Maintenance of Head-to-Pelvis Alignment in Healthy Humans

Author: Attali, Valérie, Clavel, Louis, Rouch, Philippe, Rivals, Isabelle, Rémy-Néris, Ségolène, Skalli, Wafa, Sandoz, Baptiste, Similowski, Thomas, Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service des Pathologies du sommeil [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Biomecanique Humaine Georges Charpak, Université Paris 13 (UP13)-Arts et Métiers ParisTech, Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (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), Fédération des Pathologies du Sommeil, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de biomécanique (LBM), Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Mécanique et Technologie (LMT), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Institut de Mécanique et d'Ingénierie de Bordeaux (I2M), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Arts et Métiers ParisTech, HESAM Université (HESAM), Service de Pneumologie - R3S [CHU Pitié-Salpêtrière] (SPMIR-R3S), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), 'Legs Poix' (LEG 1604) of the Chancellerie des Universités de Paris. VA is the recipient of a grant 'poste d’accueil APHP/Artset Métiers ParisTech,' délégation à la Recherche Clinique et à l’Innovation (DRCI), Assistance Publique Hôpitaux de Paris(APHP). LC was supported by a Ph.D. fellowship from ENS Cachan. The authors acknowledge the support of the ParistechBiomeCAM chair on subject specific modeling, with the support of Société Générale and COVEA., Service des Explorations des Pathologies du Sommeil [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Equipe de Statistique Appliquée (ESA), ESPCI ParisTech, École Nationale Supérieure d'Arts et Métiers (ENSAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Service de Pneumologie et de Soins Intensifs [CHU Pitié-Salpêtrière], Administrateur Ensam, Compte De Service, Service de Pneumologie, Médecine Intensive et Réanimation - R3S [CHU Pitié-Salpêtrière] (SPMIR-R3S), Université Paris sciences et lettres (PSL), Service de Pneumologie et Réanimation Médicale [CHU Pitié-Salpêtrière] (Département ' R3S '), Service de Pathologies du sommeil [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Service de Médecine Intensive et Réanimation - R3S [CHU Pitié-Salpêtrière], and Gestionnaire, Hal Sorbonne Université
Subjects: [SDV.IB] Life Sciences [q-bio]/Bioengineering, postural alignment, Physiology, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], ingénierie bio-médicale [Sciences du vivant], [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], personalized 3D models of the spine, [SPI.MECA.BIOM] Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], biplanar X-ray, [SDV.IB]Life Sciences [q-bio]/Bioengineering, lung volume, cervical and pelvic compensatory mechanisms, Mécanique: Biomécanique [Sciences de l'ingénieur], Original Research
Abstract: The maintenance of upright balance in healthy humans requires the preservation of a horizontal gaze, best achieved through dynamical adjustments of spinal curvatures and a pelvic tilt that keeps the head-to-pelvis alignment close to vertical. It is currently unknown whether the spinal and pelvic compensations of respiratory-related postural perturbations are associated with preservation of the head-to-pelvis vertical alignment. We tested this hypothesis by comparing postural alignment variables at extreme lung volume (total lung capacity, TLC; residual volume, RV) with their reference value at functional residual capacity (FRC). Forty-eight healthy subjects [22 women; median age of 34 (26; 48) years] were studied using low dose biplanar X-rays (BPXR; EOS system). Personalized three-dimensional models of the spine and pelvis were reconstructed at the three lung volumes. Extreme lung volumes were associated with changes of thoracic curvature bringing it outside the normal range. Maximal inspiration reduced thoracic kyphosis [T1–T12 angle = 47◦ (37; 56), −4◦ variation (−9; 1), p = 0.0007] while maximal expiration induced hyperkyphosis [T1–T12 angle = 63◦ (55; 68); C10◦ variation (5; 12), p = 9 × 10−12]. Statistically significant (all p < 0.01) cervical and pelvic compensatory changes occurred [C3–C7 angle: C4◦ (−2; 11) and pelvic tilt C1◦ (0; 3) during maximal inspiration; C3–C7 angle: −7◦ (−18; −1) and pelvic tilt C5◦ (1; 8) during maximal expiration], resulting in preserved head-to-pelvis alignment (no change in the angle between the vertical plane and the line connecting the odontoid process and the midpoint of the line connecting the center of the two femoral heads ODHA). Lung volume related postural perturbations were more marked as a function of age, but age did not affect the head-to-pelvis alignment. These findings should help understand balance alterations in patients with chronic respiratory diseases that modify lung volume and rib cage geometry. “Legs Poix” (LEG 1604) of the Chancellerie des Universités de Paris. VA is the recipient of a grant “poste d’accueil APHP/Arts et Métiers ParisTech,” délégation à la Recherche Clinique et à l’Innovation (DRCI), Assistance Publique Hôpitaux de Paris (APHP). LC was supported by a Ph.D. fellowship from ENS Cachan. The authors acknowledge the support of the Paristech BiomeCAM chair on subject specific modeling, with the support of Société Générale and COVEA.
Published: 2019
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27. Liberté d'action d'un apprenant dans un environnement virtuel : Modélisation numérique du monde contemporain

Author: Laurent, Mélody, LAURENT, Mélody, and Chancellerie des Universités de Paris
Subjects: Freedom, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Contemporary, [SHS.INFO]Humanities and Social Sciences/Library and information sciences, [SHS.EDU]Humanities and Social Sciences/Education, Simulacrum, Intelligence, [SHS.EDU] Humanities and Social Sciences/Education, Digital, [SHS.INFO] Humanities and Social Sciences/Library and information sciences, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Contemporain, Mathématiques, Numérique, EVAH, Artificielle, Liberté, Artificial, Simulacre, Virtual Training, Mathematics, Rhizome
Abstract: This article aims to provide an answer to the issue of the freedom of action of a learner in a virtual environment. It proposes the definition of Intelligence, Artificial and Liberty from a mathematical, political and contemporary point of view. A theoretical positioning has been proposed based on the introduction of a political and philosophical book, Rhizome., Cet article s'intéresse à la problématique de la liberté d'action d'un apprenant en environnement virtuel. Pour cela, on y propose la définition d'Intelligence, d'Artificielle et de Liberté d'un point de vue mathématique, politique et contemporain. Puis, d'après un positionnement théorique s'appuyant sur l'introduction d'un ouvrage politique et philosophique, nous proposons deux systèmes comme solutions : le rhizome comme processus à la liberté d'action et le simulacre comme modèle d'environnement virtuel.
Published: 2019

28. The BET Bromodomain Inhibitor I-BET-151 Induces Structural and Functional Alterations of the Heart Mitochondria in Healthy Male Mice and Rats

Author: Christine Péchoux, Natalia Gambaryan, Marc Humbert, Fabrice Antigny, Sharon Mumby, Angèle Boet, Ian M. Adcock, Benoit Ranchoux, Mélanie Gressette, Catherine Rucker-Martin, Mélanie Lambert, Valérie Domergue, David Montani, Anne Garnier, Jérôme Piquereau, Frédéric Perros, Perros, Frédéric, Jeunes Chercheuses et Jeunes Chercheurs - Mécanismes épigénétiques dans l'inflammation et le remodelage vasculaire de l'hypertension pulmonaire - - EMIR2013 - ANR-13-JSV1-0011 - JC - VALID, Idex Paris-Saclay - - IPS2011 - ANR-11-IDEX-0003 - IDEX - VALID, Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Réanimation des cardiopathies congénitales [Le Plessis-Robinson] (Centre chirurgical Marie Lannelongue), Centre Chirurgical Marie Lannelongue (CCML), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Institut Paris Saclay d’Innovation Thérapeutique (IPSIT), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This work was supported by research grants from INSERM, National Funding Agency for Research (ANR) (Grant ANR-13-JSV1-0011-01), Laboratoire d’Excellence (LabEx) en Recherche sur le Médicament et l’Innovation Thérapeutique (LERMIT), Assistance Publique Hôpitaux de Paris (Département Hospitalo-Universitaire Thorax Innovation), Legs Poix (Chancellerie des Universités de Paris). F.A. was supported by a post-doctoral grant from Aviesan and by Lefoulon Delalande Institute. INSERM UMR_S 999 research unit, ANR-13-JSV1-0011,EMIR,Mécanismes épigénétiques dans l'inflammation et le remodelage vasculaire de l'hypertension pulmonaire(2013), ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre chirurgical Marie Lannelongue, and AgroParisTech-Institut National de la Recherche Agronomique (INRA)
Subjects: Male, 0301 basic medicine, Chemistry, Multidisciplinary, Cardiomyopathy, MELANOMA, Mitochondrion, Mitochondria, Heart, lcsh:Chemistry, Electrocardiography, 0302 clinical medicine, Medicine, Citrate synthase, lcsh:QH301-705.5, Spectroscopy, biology, COMBINING BET, General Medicine, 3. Good health, Computer Science Applications, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, mitochondria, Chemistry, medicine.anatomical_structure, Organ Specificity, 030220 oncology & carcinogenesis, Physical Sciences, HDAC INHIBITORS, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, medicine.medical_specialty, PROTEINS, 0699 Other Biological Sciences, bromodomain and extra-terminal domain, cardiotoxicity, heart, Heterocyclic Compounds, 4 or More Rings, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, bromodomain and extra-terminal domain inhibitor, medicine.artery, Internal medicine, 0399 Other Chemical Sciences, C-MYC, Animals, STRATEGY, Rats, Wistar, Physical and Theoretical Chemistry, Molecular Biology, 0604 Genetics, Cardiotoxicity, Aorta, Science & Technology, Chemical Physics, business.industry, Organic Chemistry, Skeletal muscle, medicine.disease, Bromodomain, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, lcsh:Biology (General), lcsh:QD1-999, Pulmonary artery, biology.protein, business
Abstract: The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications.
Published: 2019
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29. L'innovation technologique au service de la transmission du patrimoine de l'humanité : Projets numériques sur les lieux de patrimoine en France

Author: LAURENT, Mélody, Bigrat, Frédérick, LAURENT, Mélody, and Chancellerie des Universités de Paris
Subjects: Numérique, Patrimoine, [SHS.MUSEO] Humanities and Social Sciences/Cultural heritage and museology, Communication, [SHS.INFO]Humanities and Social Sciences/Library and information sciences, Heritage, Technologies, Innovation, [SHS.MUSEO]Humanities and Social Sciences/Cultural heritage and museology, [SHS.INFO] Humanities and Social Sciences/Library and information sciences
Abstract: The digital evolution opens new perspectives and new challenges. In this article we will focus on its contribution in the field of culture. We will more particularly that of the heritage related to its issues of conservation, restoration and especially transmission to future generations. Our hypothesis is to mobilize Information and Communication Technologies as well as a network of experts from the fields of heritage, communication and digital to propose the establishment of digital services in heritage places by fitting into the era of decentralization. Our work is based on a concrete application case developed in the Sorbonne, whose perspective is a scalability linked to the components of reproducibility, accessibility and international visibility., L'évolution numérique en cours ouvre de nouvelles perspectives et de nouveaux défis. Dans cet article nous nous intéresserons à son apport dans le domaine de la culture et plus particulièrement celui du patrimoine liée à ses problématiques de conservation, restauration et surtout de transmission aux générations à venir. Notre hypothèse est de mobiliser les Technologies de l'Information et de la Communication ainsi qu'un réseau d'experts issus des domaines du patrimoine, de la communication et du numérique pour proposer la mise en place de services numériques dans des lieux de patrimoine en s'insérant dans l'ère de la décentralisation. Nos travaux s'appuient sur un cas d'application concret développé en Sorbonne, et dont la perspective est un passage à l'échelle lié aux composantes de reproductibilité, accessibilité et visibilité à l'internationale.
Published: 2019

30. Cholinergic modulation of hierarchical inhibitory control over cortical resting state dynamics: Local circuit modeling of schizophrenia-related hypofrontality

Author: Fani Koukouli, Uwe Maskos, Marie Rooy, Ivan Lazarevich, Boris Gutkin, Moheb, Tara, Frontières en cognition - - FrontCog2017 - ANR-17-EURE-0017 - EURE - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Human Brain Project Specific Grant Agreement 2 - HBP SGA2 - - H20202018-04-01 - 2020-03-31 - 785907 - VALID, Laboratoire de Neurosciences Cognitives & Computationnelles (LNC2), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vysšaja škola èkonomiki = National Research University Higher School of Economics [Moscow] (HSE), Lobachevsky State University [Nizhni Novgorod], Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), FK would like to thank the L’Oréal UNESCO for Women in Science Programme, the UNAFAM association (Union nationale de families et amis de personnes maladies et/ou handicapées psychiques), the Chancellerie des universités de Paris (Sorbonne Universities), the Pasteur Paris University Programme (PPU) and the European Union's Horizon 2020 Human Brain Project SGA2. BSG, MR and IL aknowledge support from CNRS, INSERM, ANR-17-EURE-0017 and ANR-10-IDEX-0001-02. IL's work was supported by the Russian Science Foundation, grant nr. 18-11-00294. BSG aknowledges support for his work from Basic Research Program at the National Research University Higher School of Economics (HSE University)., ANR-17-EURE-0017,FrontCog,Frontières en cognition(2017), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), European Project: 785907,H2020,HBP SGA2(2018), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), National Research University Higher School of Economics [Moscow] (HSE), and Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Interneuron, Vasoactive intestinal peptide, Population, Neurosciences. Biological psychiatry. Neuropsychiatry, Hypofrontality, Inhibitory postsynaptic potential, Article, [SCCO]Cognitive science, 03 medical and health sciences, 0302 clinical medicine, medicine, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, biology, Chemistry, General Engineering, [SCCO] Cognitive science, Local cortical circuit mechanisms, medicine.anatomical_structure, Nicotinic agonist, Computational modelling, nervous system, Nicotinic receptors, Schizophrenia, biology.protein, Cholinergic, Neuroscience, Hierarchical inhibitory circuitry, 030217 neurology & neurosurgery, Parvalbumin, RC321-571
Abstract: Nicotinic acetylcholine receptors (nAChRs) modulate the cholinergic drive to a hierarchy of inhibitory neurons in the superficial layers of the PFC, critical to cognitive processes. It has been shown that genetic deletions of the various types of nAChRs impact the properties of ultra-slow transitions between high and low PFC activity states in mice during quiet wakefulness. The impact characteristics depend on specific interneuron populations expressing the manipulated receptor subtype. In addition, recent data indicate that a genetic mutation of the α5 nAChR subunit, located on vasoactive intestinal polypeptide (VIP) inhibitory neurons, the rs16969968 single nucleotide polymorphism (α5 SNP), plays a key role in the hypofrontality observed in schizophrenia patients carrying the SNP. Data also indicate that chronic nicotine application to α5 SNP mice relieves the hypofrontality. We developed a computational model to show that the activity patterns recorded in the genetically modified mice can be explained by changes in the dynamics of the local PFC circuit. Notably, our model shows that these altered PFC circuit dynamics are due to changes in the stability structure of the activity states. We identify how this stability structure is differentially modulated by cholinergic inputs to the parvalbumin (PV), somatostatin (SOM) or the VIP inhibitory populations. Our model uncovers that a change in amplitude, but not duration of the high activity states can account for the lowered pyramidal (PYR) population firing rates recorded in α5 SNP mice. We demonstrate how nicotine-induced desensitization and upregulation of the β2 nAChRs located on SOM interneurons, as opposed to the activation of α5 nAChRs located on VIP interneurons, is sufficient to explain the nicotine-induced activity normalization in α5 SNP mice. The model further implies that subsequent nicotine withdrawal may exacerbate the hypofrontality over and beyond one caused by the SNP mutation., Graphical abstract Image 1, Highlights • Prefrontal cortex shows ultra-slow alterations between low and high activity states at rest. This activity is characteristically decreased in schizophrenia patients. • Model identifies local circuit origin of hypofrontality associated with schizophrenia and a5 nicotinic receptor malfunction. • Decrease in PFC VIP-interneuron excitability drives decrease in high-activity-state stability and overall hypofrontality. • Model shows desensitization/upregulation of SOM-expressed β2-NAChRs drive nicotine-induced renormalization of PFC activity.
Published: 2021
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31. Hétérogénéité moléculaire des mésothéliomes pleuraux malins

Author: Robin Tranchant, Didier Jean, Marie-Claude Jaurand, François Montagne, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology [Paris] ( Université Paris Descartes - Paris 5 - PRES Sorbonne Paris Cité), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire de Technologie - Saint-Denis (IUT Saint-Denis), Université Sorbonne Paris Nord, Service de Chirurgie Thoracique [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, Les travaux de recherche de notre laboratoire mentionnés dans cet article de synthèse ont été soutenus par le programme « Cartes d’identité des tumeurs » de la Ligue contre le Cancer, les comités de l’Oise et d’Ile de France de la Ligue contre le Cancer, la Fondation ARC, la Chancellerie des Universités de Paris (Legs Poix) et le Groupement des entreprises françaises dans la lutte contre le cancer (Gefluc)., and Jean, Didier
Subjects: 0301 basic medicine, Molecular alteration, Cancer Research, medicine.medical_specialty, Tumor heterogeneity, Malignant pleural mesothelioma, Cancer thoracique, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Thoracic cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Carcinogens, MESH: Pleural Neoplasms, MESH: Prognosis, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, MESH: Chromosome Aberrations, Radiology, Nuclear Medicine and imaging, MESH: Epigenesis, Genetic, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Hétérogénéité tumorale, Gynecology, MESH: Humans, MESH: Mesothelioma, MESH: Transcription, Genetic, Precision medicine, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hematology, General Medicine, Altération moléculaire, 3. Good health, MESH: Lung Neoplasms, Génomique, 030104 developmental biology, Oncology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Genomic, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Asbestos, Mésothéliome pleural malin, Médecine de précision
Abstract: Malignant pleural mesothelioma (MPM) is predominantly an occupational cancer, most often linked to asbestos exposure. Malignant pleural mesothelioma prognosis is poor with a short survival median, due to the aggressiveness of tumor cells and the weak efficiency of conventional anti-cancer therapies. Clinical, histological, and molecular data suggest tumor heterogeneity between patients as it was also shown for other cancer types. Consequently, there is an urgent need to develop new therapies that take into account this heterogeneity and the molecular characteristics of malignant pleural mesothelioma, in particular by identifying new anti-cancer drugs targeting the molecular specificities of each malignant pleural mesothelioma. Malignant pleural mesothelioma is characterized by numerous molecular alterations at the chromosomal, genetic and epigenetic levels. Molecular classification based on gene expression profile has firstly defined two tumor groups, C1 and C2, and more recently, four groups. By integrating genetic and transcriptomic analysis, a C2LN tumor subgroup of the C2 group has been identified and characterized. In addition to tumor heterogeneity between patients, intra-tumor heterogeneity is supported by several evidences. Most therapeutic strategies that take into account the tumor molecular characteristics have focused on targeted therapies based on mutated genes. A more appropriate strategy would be to consider better-defined tumor groups on the basis of several molecular alterations types as it has been proposed for the C2LN subgroup. A robust definition of homogeneous tumor groups sharing common molecular characteristics is necessary for the development of effective precision medicine for malignant pleural mesothelioma., Le mésothéliome pleural malin (MPM) est un cancer majoritairement d'origine professionnelle, lié le plus souvent à une exposition à l’amiante. Le pronostic du MPM est sombre avec une médiane de survie courte, car ce cancer est très agressif et les thérapies conventionnelles anti-cancéreuses sont peu efficaces. Comme pour d’autres types de cancer, les données cliniques, histologiques et moléculaires suggèrent l’existence d’une hétérogénéité tumorale entre les patients. Il est donc urgent de développer de nouvelles thérapies qui prennent en compte cette hétérogénéité et les caractéristiques moléculaires des MPM, notamment en identifiant de nouveaux agents anti-cancéreux ciblant les spécificités moléculaires de chaque MPM.Le MPM est caractérisé par de nombreuses altérations moléculaires au niveau chromosomique, génétique et épigénétique. Une classification moléculaire sur la base du profil d’expression génique a défini deux groupes tumoraux C1 et C2 et, plus récemment, quatre groupes. En couplant analyse génétique et transcriptomique, un sous-groupe tumoral C2LN du groupe C2 a été identifié et caractérisé. Outre l'hétérogénéité entre les tumeurs des patients, de nombreuses évidences supportent également l’existence d’une hétérogénéité intra-tumorale. La plupart des stratégies thérapeutiques prenant en compte les caractéristiques moléculaires de la tumeur ont proposé des thérapies ciblées visant les gènes présentant des mutations. Il pourrait être plus judicieux de cibler des groupes tumoraux mieux définis, en intégrant plusieurs types d’altérations moléculaires, comme cela a été proposé pour le sousgroupe C2LN. Une définition robuste de groupes homogènes de tumeurs partageant descaractéristiques moléculaires communes est nécessaire au développement d’une médecine de précision efficace pour le MPM.
Published: 2018
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32. Absence of Fungal Spore Internalization by Bronchial Epithelium in Mouse Models Evidenced by a New Bioimaging Approach and Transmission Electronic Microscopy

Author: Jean-Christophe Olivo-Marin, Dea Garcia-Hermoso, Fabrice de Chaumont, Charlotte Renaudat, Stéphane Bretagne, Grégory Jouvion, Fabrice Chrétien, Blandine Rammaert, Claire Szczepaniak, Françoise Dromer, CHU Necker - Enfants Malades [AP-HP], Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Mycologie moléculaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Analyse d'Images biologiques, Centre Imagerie Cellulaire Santé (CICS), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Centre Hospitalier Sainte Anne [Paris], Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Supported by the Prix de la Chancellerie des Universités de Paris, LegsPoix and the Institut Pasteur (Program de Recherche transversal, PTR 409).B.R. is recipient of Institut Pasteur, Ecole Polytechnique, Arts et MetiersParisTech, École supérieure de physique et de chimie industrielles de laville de Paris (ESPCI Paris Tech), Université de technologie de Compiégne(UTC), Commissariat á l’énergie atomique et aux énergies alternatives(CEA), CNRS, Labex BioPsy, and AP-HP fellowships., We thank Huot Khun for technical assistance with histology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: MESH: Sordariales, Male, MESH: Sequence Analysis, DNA, Pathology, Cell Membrane Permeability, Lichtheimia corymbifera, MESH: Molecular Diagnostic Techniques, Aspergillosis, Epithelium, Aspergillus fumigatus, Mice, MESH: Animals, MESH: Cell Membrane Permeability, MESH: Phagocytosis, Internalization, Lung, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Treatment Outcome, media_common, MESH: Middle Aged, biology, Spores, Fungal, respiratory system, medicine.anatomical_structure, MESH: Young Adult, MESH: Epithelial Cells, MESH: Survival Analysis, MESH: Microscopy, Electron, Transmission, MESH: Aspergillus fumigatus, medicine.medical_specialty, media_common.quotation_subject, Phagocytosis, Pathology and Forensic Medicine, MESH: Mycoses, Microscopy, Electron, Transmission, MESH: Spores, Fungal, medicine, Animals, Humans, MESH: Lung, MESH: Aspergillosis, MESH: Mice, MESH: Humans, fungi, Epithelial Cells, medicine.disease, biology.organism_classification, MESH: Male, respiratory tract diseases, Spore, MESH: Epithelium, Disease Models, Animal, MESH: Disease Models, Animal
Abstract: International audience; Clinical data and experimental studies suggest that bronchial epithelium could serve as a portal of entry for invasive fungal infections. We therefore analyzed the interactions between molds and the bronchial/bronchiolar epithelium at the early steps after inhalation. We developed invasive aspergillosis (Aspergillus fumigatus) and mucormycosis (Lichtheimia corymbifera) murine models that mimic the main clinical risk factors for these infections. Histopathology studies were completed with a specific computer-assisted morphometric method to quantify bronchial and alveolar spores and with transmission electron microscopy. Morphometric analysis revealed a higher number of bronchial/bronchiolar spores for A. fumigatus than L. corymbifera. The bronchial/bronchiolar spores decreased between 1 and 18 hours after inoculation for both fungi, except in corticosteroid-treated mice infected with A. fumigatus, suggesting an effect of cortisone on bronchial spore clearance. No increase in the number of spores of any species was observed over time at the basal pole of the epithelium, suggesting the lack of transepithelial crossing. Transmission electron microscopy did not show spore internalization by bronchial epithelial cells. Instead, spores were phagocytized by mononuclear cells on the apical pole of epithelial cells. Early epithelial internalization of fungal spores in vivo cannot explain the bronchial/bronchiolar epithelium invasion observed in some invasive mold infections. The bioimaging approach provides a useful means to accurately enumerate and localize the fungal spores in the pulmonary tissues.
Published: 2015
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33. Co-occurring Mutations of Tumor Suppressor Genes, LATS2 and NF2 , in Malignant Pleural Mesothelioma

Author: Françoise Le Pimpec-Barthes, Marie-Claude Jaurand, Jessica Zucman-Rossi, Leanne De Koning, Anne Tallet, Lisa Quetel, Clément Meiller, Aurélien de Reyniès, Annie Renier, Robin Tranchant, Didier Jean, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris 13 (UP13), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Laboratoire des biomarqueurs tumoraux circulants [Institut Curie, Paris] (SiRIC - Département de recherche translationnelle), Institut Curie [Paris]-Université Paris sciences et lettres (PSL), Programme CIT, Ligue Nationale Contre le Cancer (LNCC), Service de Chirurgie Thoracique (Hôpital Européen Georges Pompidou [APHP] HEGP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by INSERM, the Fondation ARC pour la recherche sur le cancer, the Ligue Contre le Cancer (Ile de France and Oise committees), the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), and the Chancellerie des Universités de Paris (Legs POIX)., Jean, Didier, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Ligue Nationale Contre le Cancer
Subjects: 0301 basic medicine, Cancer Research, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Exon, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Neurofibromatosis 2, MESH: Aged, Mutation, MESH: Middle Aged, Reverse phase protein lysate microarray, MESH: Gene Expression Regulation, Neoplastic, 3. Good health, Oncology, MESH: Cell Survival, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Mutation, Tumor suppressor gene, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Protein-Serine-Threonine Kinases, MESH: Pleural Neoplasms, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Pyridones, MESH: Cell Proliferation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, MESH: Tumor Suppressor Proteins, Protein kinase B, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, PI3K/AKT/mTOR pathway, MESH: TOR Serine-Threonine Kinases, Hippo signaling pathway, MESH: Humans, MESH: Mesothelioma, Point mutation, MESH: Apoptosis, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Neoplasm Invasiveness, MESH: Genes, Tumor Suppressor, MESH: Male, MESH: Lung Neoplasms, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Pyrimidines, Cancer research, MESH: Female
Abstract: Purpose: To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor gene LATS2, a member of the Hippo signaling pathway, which plays a key role in mesothelial carcinogenesis. Experimental Design: Sixty-one MPM primary cultures established in our laboratory were screened for mutations in LATS2. Gene inactivation was modeled using siRNAs. Gene and protein expressions were analyzed by quantitative RT-PCR, Western blot analysis, and reverse phase protein array. Cell proliferation, viability, apoptosis, mobility, and invasion were determined after siRNA knockdown or YAP (verteporfin), mTOR (rapamycin), and mTOR/PI3K/AKT (PF-04691502) inhibitor treatment. Results: The LATS2 gene was altered in 11% of MPM by point mutations and large exon deletions. Genetic data coupled with transcriptomic data allowed the identification of a new MPM molecular subgroup, C2LN, characterized by a co-occurring mutation in the LATS2 and NF2 genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation of LATS2 and NF2 leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2LN MPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. The MOK gene was identified as a potential biomarker of the C2LN MPM subgroup and PF-04691502 sensitivity. Conclusions: We identified a new MPM molecular subgroup that shares common genetic and transcriptomic characteristics. Our results made it possible to highlight a greater sensitivity to an anticancer compound for this MPM subgroup and to identify a specific potential biomarker. Clin Cancer Res; 23(12); 3191–202. ©2016 AACR.
Published: 2017
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34. Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity

Author: Nektarios Tavernarakis, Mireia Niso-Santano, Lorenzo Galluzzi, Violeta Raverdy, Friedemann Loos, Guido Kroemer, François Pattou, Céline Cruciani-Guglielmacci, Patricia Boya, Justine Lallement, Frank Madeo, Jessica Denom, Ignacio Ramírez-Pardo, Karine Clément, Christophe Magnan, Isabelle Martins, Sylvère Durand, Raphaël G. P. Denis, Noélie Bossut, Maria Chiara Maiuri, Véronique Pelloux, Robert Caiazzo, Valentina Sica, Erwan Boedec, Alili Rohia, Stéphanie Migrenne-Li, José Manuel Bravo-San Pedro, Jonathan Pol, Nicolas Ramoz, Fernando Aranda, Philip Gorwood, Gerasimos Anagnostopoulos, Fanny Aprahamian, Carlos López-Otín, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Université Paris-Saclay, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biológicas (CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Clinique des maladies mentales et de l'encéphale (CMME - Service de psychiatrie), Hôpital Sainte-Anne-Université Paris Descartes - Paris 5 (UPD5), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Yale University School of Medicine, BioTechMed-Graz, Graz University of Technology [Graz] (TU Graz)-Medical University Graz-Karl-Franzens-Universität [Graz, Autriche], Institute of Molecular Biosciences, Karl-Franzens-Universität [Graz, Autriche], University of Crete [Heraklion] (UOC), Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Foundation for Research and Technology - Hellas (FORTH), Universidad de Oviedo [Oviedo], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Science & Technology of China [Suzhou], Karolinska Institutet [Stockholm], The authors thank CRC Core Facilities (CGB, CHIC, and CEF). G.K. is supported by the Ligue Contre le Cancer (équipe labelisée), Agence National de la Recherche (ANR) – projets blancs, Cancéropôle Île-de-France, Chancelerie Des universités de Paris (Legs Poix), the European Research Council (ERC), Inserm Transfert, Fondation Carrefour, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, Leducq Foundation, the Labex immuno-Oncology, the RHU Torino Lumière, the Seattle Foundation, and the SIRICs SOCRATE and CARPEM. C.M. and C.C.-G. are supported by Agence National de la Recherche (ANR-16-CE14-0026, fat4brain proposal), C.L.-O. is supported by 'Juan de Madariaga fellowship', S.B. is supported by the Swedish Research Council Vetenskapsrådet (2015-05468) and the Austrian Science Fund FWF (P27183-B24), and F.M. is supported by the Austrian Science Fund FWF (grants P23490-B20, P29262, P24381, P29203, and P27893), DKplus Metabolic and Cardiovascular Diseases (W1226), Austrian Science Ministry, Karl Franzens University ('Unkonventionelle Forschung' and 'flysleep'), NAWI Graz, and BioTechMed-Graz flagship project 'EPIAge.' K.C. is supported by ANR MICRO-Obes and AP/HP (PHRC Microbaria). L.G. is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, US) and by Sotio a.c. (Prague, Czech Republic)., The authors thank PreclinICAN (Institute of Cardiometabolism and Nutrition, IHU-ICAN, Paris, France) and 'Plateforme Imageries du Vivant' INSERM UMR 970 (PARCC-HEGP) for analyses of mouse whole-body composition and Functional & Physiological Exploration Platform (FPE) of the Unit 'Biologie Fonctionnelle et Adaptative' (University Paris Diderot, Sorbonne Paris Cité, BFA, UMR 8251 CNRS, Paris, France) for metabolic analyses., Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Chancellerie des Universités de Paris, European Research Council, Institut National du Cancer (France), Fondation Leducq, Swedish Research Council, Austrian Science Fund, Federal Ministry of Science, Research and Economy (Austria), Bravo-San-Pedro, José Manuel [0000-0002-5781-1133], Sica, Valentina [0000-0003-2770-5847], Martins, Isabelle [0000-0003-0885-613X], Pol, Jonathan G. [0000-0002-8355-7562], Loos, Friedemann [0000-0002-5976-5978], Maiuri, Maria Chiara [0000-0001-9760-7674], Niso-Santano, Mireia [0000-0002-6506-422X], Aranda, Fernando [0000-0002-9364-474X], Gorwood, Philip [0000-0003-1845-3676], Ramoz, Nicolas [0000-0002-8070-9938], Cleḿent, Karine [0000-0002-2489-3355], Pelloux, Véronique [0000-0003-3630-4746], Raverdy, Violeta [0000-0001-5754-2028], Denis, Raphaël G.P. [0000-0002-7677-7460], Boya, Patricia [0000-0003-3045-951X], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Madeo, Frank [0000-0002-5070-1329], Cruciani-Guglielmacci, Céline [0000-0002-2562-5360], Tavernarakis, Nektarios [0000-0002-5253-1466 ], López-Otín, Carlos [0000-0001-6964-1904], Magnan, Christophe [0000-0002-7044-2571], Kroemer, Guido [0000-0002-9334-4405], CCSD, Accord Elsevier, Université Paris Descartes - Paris 5 (UPD5)-Hôpital Sainte-Anne, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Yale School of Medicine [New Haven, Connecticut] (YSM), Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität Graz-Medical University Graz, Karl-Franzens-Universität Graz, École Pratique des Hautes Études (EPHE), Centre de Psychiatrie et Neurosciences (U894), ANR-16-CE14-0026,Fat4Brain,Le métabolisme des lipides dans le cerveau est un regulateur essentiel de l'homéostasie énergétique(2016), Bravo-San Pedro, J. M., Sica, V., Martins, I., Pol, J., Loos, F., Maiuri, M. C., Durand, S., Bossut, N., Aprahamian, F., Anagnostopoulos, G., Niso-Santano, M., Aranda, F., Ramirez-Pardo, I., Lallement, J., Denom, J., Boedec, E., Gorwood, P., Ramoz, N., Clement, K., Pelloux, V., Rohia, A., Pattou, F., Raverdy, V., Caiazzo, R., Denis, R. G. P., Boya, P., Galluzzi, L., Madeo, F., Migrenne-Li, S., Cruciani-Guglielmacci, C., Tavernarakis, N., Lopez-Otin, C., Magnan, C., Kroemer, G., Bravo-San-Pedro, José Manuel, Sica, Valentina, Martins, Isabelle, Pol, Jonathan G., Loos, Friedemann, Maiuri, Maria Chiara, Niso-Santano, Mireia, Aranda, Fernando, Gorwood, Philip, Ramoz, Nicolas, Cleḿent, Karine, Pelloux, Véronique, Raverdy, Violeta, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, and Kroemer, Guido
Subjects: Male, 0301 basic medicine, obesity, Anorexia Nervosa, Physiology, Mice, Obese, Weight Gain, Eating, Mice, 0302 clinical medicine, lipid metabolism, Acyl-CoA-binding protein, Beta oxidation, media_common, Diazepam Binding Inhibitor, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, 0303 health sciences, Leptin Deficiency, Chemistry, Fatty Acids, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Anorexia, 3. Good health, anorexia, Lipogenesis, Female, medicine.symptom, Human, autophagy, medicine.medical_specialty, media_common.quotation_subject, Context (language use), Cell Line, 03 medical and health sciences, Internal medicine, Macroautophagy, Weight Loss, Autophagy, medicine, Animals, Humans, Obesity, Molecular Biology, 030304 developmental biology, Animal, Lipogenesi, Appetite, Cell Biology, Weight Lo, Mice, Inbred C57BL, Lipid metabolism, 030104 developmental biology, Endocrinology, Fatty Acid, 030217 neurology & neurosurgery
Abstract: 24 p.-6 fig.-1 tab.-1 graph. abst., Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities., G.K. is supported by the Ligue Contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – projets blancs; Cancéropôle Île-de-France; Chancelerie Des universités de Paris (Legs Poix); the European Research Council (ERC); Inserm Transfert, Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; Leducq Foundation; the Labex immuno-Oncology; the RHU Torino Lumière; the Seattle Foundation; and the SIRICs SOCRATE and CARPEM. C.M. and C.C.-G. are supported by Agence National de la Recherche (ANR-16-CE14-0026, fat4brain proposal); C.L.-O. is supported by “Juan de Madariaga fellowship”; S.B. is supported by the Swedish Research Council Vetenskapsrådet (2015-05468) and the Austrian Science Fund FWF (P27183-B24); and F.M. is supported by the Austrian Science Fund FWF (grants P23490-B20, P29262, P24381, P29203, and P27893), DKplus Metabolic and Cardiovascular Diseases (W1226), Austrian Science Ministry, Karl Franzens University (“Unkonventionelle Forschung” and “flysleep”), NAWI Graz, and BioTechMed-Graz flagship project “EPIAge.” K.C. is supported by ANR MICRO-Obes and AP/HP (PHRC Microbaria). L.G. is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, US) and by Sotio a.c. (Prague, Czech Republic).
Published: 2019
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35. Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis

Author: Raphaël Thuillet, Timothée Quatremarre, Marc Humbert, Laurent Savale, Sven Günther, Carole Nicco, Thong Hua-Huy, Christophe Guignabert, Frédéric Batteux, Gaël Jalce, Anh Tuan Dinh-Xuan, Jennifer Bordenave, Amélie Cumont, Thomas Guilbert, Ly Tu, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Sorbonne Paris Cité (USPC), Service de physiologie et explorations fonctionelles [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud [Le Kremlin-Bicêtre] (Faculté de Médecine), Université Paris-Saclay, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), APAXEN [Gosselies, Belgique], Service d'Anesthésie et de Soins Intensifs [Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This research was supported by grants from the French National Institute for Health and Medical Research (INSERM), the University of Paris-Sud and the University Paris-Saclay, the Marie Lannelongue Hospital, the French National Agency for Research (ANR) grant No. ANR-16-CE17-0014 (TAMIRAH), the Fondation de la Recherche Médicale (FRM) grant No. DEQ20150331712 (Equipe FRM 2015), the Legs Poix (Chancellerie des Universités de Paris), and in part by the Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), the Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire Sévère, the LabEx LERMIT (grant No ANR-10-LABX-0033), and the French PAH patient association (HTAP France). S.G. is supported by the French Fonds de Dotation 'Recherche en Santé Respiratoire' (FRSR), Fondation du Souffle (FdS). J.B. is supported by the FRM., ANR-16-CE17-0014,TAMIRAH,Cibler l'activation anormale du récepteur des minéralocorticoïdes dans l'Hypertension Artérielle Pulmonaire : Une étude translationnelle vers un traitement(2016), ANR-10-LABX-0033,LERMIT,Research Laboratory on Drugs and Therapeutic Innovation(2010), Guignabert, Christophe, Cibler l'activation anormale du récepteur des minéralocorticoïdes dans l'Hypertension Artérielle Pulmonaire : Une étude translationnelle vers un traitement - - TAMIRAH2016 - ANR-16-CE17-0014 - AAPG2016 - VALID, Research Laboratory on Drugs and Therapeutic Innovation - - LERMIT2010 - ANR-10-LABX-0033 - LABX - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Pharmacology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, CXCR4, molecular target, lcsh:Chemistry, Mice, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, Fibrosis, Pulmonary fibrosis, Medicine, Lung, lcsh:QH301-705.5, Spectroscopy, General Medicine, respiratory system, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Computer Science Applications, Intramolecular Oxidoreductases, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Female, Receptors, CXCR4, Hypertension, Pulmonary, idiopathic pulmonary fibrosis associated with pulmonary hypertension (IPF-PH), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Vascular Remodeling, Bleomycin, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Animals, Humans, Physical and Theoretical Chemistry, Macrophage Migration-Inhibitory Factors, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Inflammation, business.industry, Organic Chemistry, Histocompatibility Antigens Class II, Isoxazoles, medicine.disease, Pulmonary hypertension, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Antigens, Differentiation, B-Lymphocyte, Disease Models, Animal, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, chemistry, macrophage migration inhibitory factor, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Macrophage migration inhibitory factor, business, pulmonary vascular remodeling
Abstract: Background: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation. Objectives: We tested the effects of two small molecules targeting MIF on bleomycin (BLM)-induced collagen deposition, PH, and vascular remodeling in mouse lungs. Methods: We examined the distribution pattern of MIF, CD74, and CXCR4 in the lungs of patients with IPF-PH and the lungs of BLM-injected mice. Then, treatments were realized with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N-(3-hydroxy-4-fluorobenzyl)-5 trifluoromethylbenzoxazol-2-thione 31 (20 mg/kg/day per os for 3 weeks) started 24 h after an intratracheal BLM administration. Results: More intense immunoreactivity was noted for MIF, CD74, and CXCR4 in lungs from IPF-PH patients and BLM-injected mice. Furthermore, we found that treatments of BLM-injected mice with ISO-1 or compound 31 attenuated lung collagen deposition and right ventricular systolic pressure increase. Additionally, reduced pulmonary inflammatory infiltration and pulmonary arterial muscularization were observed in the lungs of BLM-injected mice treated with ISO-1 or compound 31. Conclusions: Treatments with ISO-1 or compound 31 attenuates BLM-induced inflammation and fibrosis in lung, and prevents PH development in mice, suggesting that MIF is an important factor for IPF-PH development.
Published: 2018
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36. Livre / Poésie

Author: Campaignolle-Catel, Hélène, Sophie, Lesiewicz, Theval, Gaëlle, THALIM - Théorie et histoire des arts et des littératures de la modernité - UMR 7172 (THALIM), Université Sorbonne Nouvelle - Paris 3-Centre National de la Recherche Scientifique (CNRS)-Département Arts - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Bibliothéque littéraire Jacques Doucet (BLJD), Chancellerie des Universités de Paris, LIVRESC, Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Sorbonne Nouvelle - Paris 3
Subjects: poésie, [INFO.INFO-GL]Computer Science [cs]/General Literature [cs.GL], littérature, typographie, histoire du livre, [SHS.ART]Humanities and Social Sciences/Art and art history, [SHS.MUSEO]Humanities and Social Sciences/Cultural heritage and museology, livres d'artiste
Abstract: 170 x 240 - broché à rabats - tirage limité - nombreuses illustrations couleurs.; International audience; Issu du séminaire de recherche co-organisé par l'université Paris 3 Sorbonne nouvelle et la Bibliothèque littéraire Jacques Doucet de 2011 à 2012, l’ouvrage Livre / Poésie : une histoire en pratique(s) décrit un parcours séculaire, allant de l’extrême contemporain jusqu’à l’ouvrage de Mallarmé, pierre fondatrice de la création poétique et de la réflexion esthétique sur le livre du XXe siècle : Un coup de dés… Chaque texte caractérise un moment, un courant ou un lieu culturel spécifique de l’histoire du livre de création : poésie expérimentale, poésie de la performance (Serge Pey et Julien Blaine) ; concrète et spatialiste (Pierre et Ilse Garnier) ; graphique et combinatoire (Queneau et ses ré-interprétations) ; idéographique, calligrammatique ou « à voir » (Pierre Albert-Birot, Tardieu) ; « sortie de ses gonds » dans le contexte dadaïste et futuriste (Marinetti, Duchamp, Picabia) ; influencée ou inspirée par l’Extrême-Orient (Mallarmé, Claudel, Segalen, Sharoff). Les contributions présentées sont différentes tant par leurs postures que par leurs auteurs, chercheurs, témoins de la création, artistes : Julien Blaine, Jean-Pierre Bobillot, Claire Bustarret, John Crombie, Marc Décimo, Claude Debon, Muriel Detrie, Yoon-Jung Do, Pierre Duplan, Gabby Gappmayr, Ilse et Pierre Garnier, Martial Lengellé, Frédérique Martin-Scherrer, Massin, Isabelle Maunet, Barbara Meazzi, Serge Pey, Shirley Sharoff, Marianne Simon-Oikawa, Gaëlle Théval. L’ouvrage est complété par une présentation de l’œuvre de l’éditeur KICKSHAWS suivi d’une bibliographie de son travail.La publication a accompagné le vernissage de l’exposition Kickshaws, le 1er mars 2017. Ouvrage publié sous la direction de Hélène Campaignolle-Catel, Sophie Lesiewicz et Gaëlle Théval224 pages - 170 x 240 - broché à rabats - tirage limité - nombreuses illustrations couleurs - 35 euros - isbn 978-2-86742-262-1
Published: 2016

37. Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma

Author: M.C. Copin, Françoise Galateau-Sallé, Jessica Zucman-Rossi, J-C Nault, Ilir Hysi, Paul Hofman, Anne Tallet, Pascal Andujar, Didier Jean, A Renier, F. Le Pimpec-Barthes, M-C Jaurand, Aurélie Cazes, Génomique fonctionnelle des tumeurs solides (U674), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Service de chirurgie cardiaque [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nice (CHU Nice), CHI Créteil, 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), Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Chirurgie Thoracique, Paris, This work was supported by funds and grants from INSERM, the University of Paris-Descartes, the French League against Cancer (Ligue Nationale Contre le Cancer, 'Carte d’Identité des Tumeurs' CIT1 and CIT2 programs and the Comité de l’Oise), and the Chancellerie des Universités de Paris (Legs POIX)., Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jean, Didier
Subjects: telomerase reverse transcriptase (TERT), Cancer Research, Telomerase, Lung Neoplasms, Thoracic neoplasm, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Bioinformatics, 0302 clinical medicine, Gene expression, CDKN2A Gene Inactivation, Promoter Regions, Genetic, Regulation of gene expression, 0303 health sciences, telomere, MESH: Telomerase, MESH: Gene Expression Regulation, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, mesothelioma, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Mutation, MESH: Neoplastic, Pleural Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Pleural Neoplasms, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Promoter Regions, Genetic, Genetics, medicine, Humans, Telomerase reverse transcriptase, RNA, Messenger, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, MESH: Mesothelioma, Mesothelioma, Malignant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, asbestos, Telomere, MESH: Lung Neoplasms, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cancer cell, Cancer research, mutation, Carcinogenesis
Abstract: International audience; Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT-PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 'hot spot' of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P
Published: 2014
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38. Azithromycin analogue CSY0073 attenuates lung inflammation induced by LPS challenge

Author: V, Balloy, A, Deveaux, D, Lebeaux, O, Tabary, P, le Rouzic, J M, Ghigo, P F, Busson, P Y, Boëlle, J Guez, Guez, U, Hahn, A, Clement, M, Chignard, H, Corvol, M, Burnet, L, Guillot, Défense innée et inflammation, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Biofilms, Institut Pasteur [Paris], ESIM - Déterminants Sociaux de la Santé et du Recours aux Soins (DS3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], LG received a grant from the French cystic‐fibrosis non‐profit organization Vaincre la mucoviscidose, a Legs Poix grant from the publicly funded source Chancellerie des Universités de Paris and a grant from Aviesan ITMO (Institut Multi‐Organismes) Immunologie Hématologie Pneumologie (IHP). DL received a grant from the AXA Research Fund., We thank Amruta Joshi‐Datar, Isabelle Ventre, Alain Filloux and Lhousseine Touqui who generously provided the bacterial strains used in this study, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Synovo [Tübingen], Mucoviscidose: physiopathologie et phénogénomique [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), and SITBON, Pascale
Subjects: Lipopolysaccharides, Time Factors, Dose-Response Relationship, Drug, macrolides, [SDV]Life Sciences [q-bio], lung inflammation, Anti-Inflammatory Agents, Pneumonia, Azithromycin, respiratory system, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], cystic fibrosis, Disease Models, Animal, Mice, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Biofilms, Pseudomonas aeruginosa, Animals, COPD, Inflammation Mediators, Bronchoalveolar Lavage Fluid, Lung, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Research Paper
Abstract: International audience; BACKGROUND AND PURPOSE:Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulating effects. Long-term azithromycin therapy in patients with chronic lung diseases such as cystic fibrosis has been associated with increased antimicrobial resistance, emergence of hypermutable strains, ototoxicity and cardiac toxicity. The aim of this study was to assess the anti-inflammatory effects of the non-antibiotic azithromycin derivative CSY0073.EXPERIMENTAL APPROACH:We compared the effects of CSY0073 with those of azithromycin in experiments on bacterial cultures, Pseudomonas aeruginosa biofilm, lung cells and mice challenged intranasally with P. aeruginosa LPS.KEY RESULTS:In contrast to azithromycin, CSY0073 did not inhibit the growth of P. aeruginosa, Staphylococcus aureus or Haemophilus influenzae and had no effect on an established P. aeruginosa biofilm. Bronchoalveolar lavage (BAL) fluids and lung homogenates collected after the LPS challenge in mice showed that CSY0073 and azithromycin (200 mg·kg(-1), i.p.) decreased neutrophil counts at 24 h and TNF-α, CXCL1 and CXCL2 levels in the BAL fluid after 3 h and IL-6, CXCL2 and IL-1β levels in the lung after 3 h compared with the vehicle. However, only azithromycin reduced IL-1β levels in the lung 24 h post LPS challenge. CSY0073 and azithromycin similarly diminished the production of pro-inflammatory cytokines by macrophages, but not lung epithelial cells, exposed to P. aeruginosa LPS.CONCLUSIONS AND IMPLICATIONS:Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases.
Published: 2014
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39. CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium

Author: Nathalie Coolen, Virginie Prulière-Escabasse, Pierre-Régis Burgel, Daniel Dusser, Estelle Escudier, André Coste, Yongzheng Wu, Isabelle Fajac, Lhousseine Touqui, Guiti Thévenot, Clémence Martin, Jean-François Papon, Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Défense innée et inflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Service d'ORL [Créteil], Centre Hospitalier Intercommunal de Créteil (CHIC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Physiologie et Explorations Fonctionnelles [Cochin APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was funded by grants from Chancellerie des Universités de Paris (Legs Poix), Association Vaincre la Mucoviscidose and Association Cardif., The authors thank Sophie Danel-Beaucaire (Cochin Hospital, Paris, France) for help with immunohistochemical staining and Claire Danel (Bichat Hospital, Paris, France) for providing human CF tissues., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Wu, Yongzheng
Subjects: Vascular Endothelial Growth Factor A, Pathology, Cystic Fibrosis, Angiogenesis, medicine.medical_treatment, Cystic Fibrosis Transmembrane Conductance Regulator, MESH: Trachea / metabolism, Cystic fibrosis, Tyrosine-kinase inhibitor, Epithelium, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Cystic Fibrosis Transmembrane Conductance Regulator / physiology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Lung / blood supply, MESH: Animals, MESH: Cystic Fibrosis / physiopathology, Epidermal growth factor receptor, MESH: Cystic Fibrosis / genetics, Phosphorylation, RNA, Small Interfering, Lung, Aorta, Cells, Cultured, 0303 health sciences, biology, MESH: Gene Expression Regulation, MESH: Bronchi / metabolism, respiratory system, 3. Good health, Vascular endothelial growth factor, ErbB Receptors, Trachea, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Mice, Inbred CFTR, MESH: Cells, Cultured, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, MESH: Mice, Transgenic, medicine.drug_class, MESH: Aorta / pathology, MESH: ErbB Receptors / metabolism, Bronchi, Mice, Transgenic, Cell Line, 03 medical and health sciences, medicine, Animals, Humans, Mice, Inbred CFTR, MESH: Mice, 030304 developmental biology, MESH: RNA, Small Interfering / metabolism, MESH: Humans, MESH: Phosphorylation, business.industry, Growth factor, MESH: Vascular Endothelial Growth Factor A / metabolism, medicine.disease, MESH: Cystic Fibrosis Transmembrane Conductance Regulator / genetics, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Epithelium / metabolism, MESH: Cell Line, respiratory tract diseases, Transplantation, 030228 respiratory system, chemistry, Gene Expression Regulation, Cancer research, biology.protein, Respiratory epithelium, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business
Abstract: International audience; Peribronchial angiogenesis may occur in cystic fibrosis and vascular endothelial growth factor (VEGF)-A regulates angiogenesis in airways. Peribronchial vascularity and VEGF-A expression were examined using immunocytochemistry and morphometric analysis in lung sections obtained in 10 cystic fibrosis patients at transplantation versus 10 control nonsmokers, and in two strains of Cftr-deficient mice versus wild-type littermates. Airway epithelial NCI-H292 cells and primary cultures of noncystic fibrosis human airway epithelial cells were treated with cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors (CFTR-inh(172) or PPQ-102) or transfected with a CFTR small interfering (si)RNA with or without a selective epidermal growth factor receptor tyrosine kinase inhibitor. Concentrations of VEGF-A and phosphorylated epidermal growth factor receptor were measured by ELISA. Peribronchial vascularity was increased in cystic fibrosis patients, but not in Cftr-deficient mice. VEGF-A immunostaining was localised to airway epithelium and was increased in cystic fibrosis patients and in Cftr-deficient mice. In cultured airway epithelial cells, treatment with CFTR inhibitors or transfection with CFTR siRNA induced a twofold increase in VEGF-A production. CFTR inhibitors triggered epidermal growth factor receptor phosphorylation that was required for VEGF-A synthesis. Cystic fibrosis airways at transplantation showed increased peribronchial vascularity and epithelial VEGF-A expression. CFTR dysfunction triggered epithelial synthesis of VEGF-A, which may contribute to vascular remodelling.
Published: 2013
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40. Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma

Author: Jessica Zucman-Rossi, Pierre Laurent-Puig, Issam Abd-Alsamad, Jean-Claude Pairon, M. A. Billon-Galland, Ilir Hysi, Bénédicte Clin, Didier Jean, Pascal Andujar, Jean-François Regnard, Denis Debrosse, Françoise Le Pimpec-Barthes, Françoise Galateau-Sallé, Marc Letourneux, Bruno Housset, Marie-Claude Jaurand, Hélène Blons, Annie Renier, Alexis Descatha, Isabelle Monnet, Claire Danel, Pierre Validire, Jean, Didier, 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), Service de Pneumologie et de Pathologie Professionnelle [CHI Créteil], CHI Créteil, Oncogenèse des tumeurs respiratoires et urogénitales, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10, Génomique fonctionnelle des tumeurs solides (U674), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Anatomo-Pathologie, Laboratoire d'Etude des Particules Inhalées (LEPI), Ville de Paris, Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), 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 Santé au Travail et Pathologie Professionnellel [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Anatomie et cytologie pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut Mutualiste de Montsouris (IMM), Laboratoire d'Anatomie Pathologique [CHU Caen], Toxicologie Moleculaire (U490), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancers et Populations : Facteurs de Risque, Depistage, Pratiques Diagnostiques et Therapeutiques, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), 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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), Dpt of thoracic surgery, Paris Centre University Hospitals, This work was supported by funds for the conduct of the research from INSERM, Chancellerie des Universités de Paris (Legs POIX) and University of Paris-Est Créteil Val de Marne, grants from Ministère de l’Emploi et de la Solidarité (n° 1DC004C), Agence Nationale de la Recherche (n° 05 9 31/ANR), Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (ANSES) (n° RD-2004-015) and Comité de l’Oise de la Ligue contre le Cancer., Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Mesothelioma, Lung Neoplasms, Health, Toxicology and Mutagenesis, Toxicology, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Tobacco smoke, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Medicine, Genetics (clinical), 0303 health sciences, Neurofibromin 2, Smoking, Middle Aged, 3. Good health, ErbB Receptors, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, KRAS, Pleural Neoplasms, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Asbestos, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Proto-Oncogene Proteins, Genetics, Humans, Lung cancer, neoplasms, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Aged, Polymorphism, Genetic, business.industry, Histology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Cancer research, Etiology, ras Proteins, Tumor Suppressor Protein p53, business, Carcinogenesis
Abstract: International audience; Given the interest in defining biomarkers of asbestos exposure and to provide insights into asbestos-related and cell-specific mechanisms of neoplasia, the identification of gene alterations in asbestos-related cancers can help to a better understanding of exposure risk. To understand the aetiology of asbestos-induced malignancies and to increase our knowledge of mesothelial carcinogenesis, we compared genetic alterations in relevant cancer genes between lung cancer, induced by asbestos and tobacco smoke, and malignant pleural mesothelioma (MPM), a cancer related to asbestos, but not to tobacco smoke. TP53, KRAS, EGFR and NF2 gene alteration analyses were performed in 100 non-small cell lung cancer (NSCLC) patients, 50 asbestos-exposed and 50 unexposed patients, matched for age, gender, histology and smoking habits. Detailed assessment of asbestos exposure was based on both specific questionnaires and asbestos body quantification in lung tissue. Genetic analyses were also performed in 34 MPM patients. TP53, EGFR and KRAS mutations were found in NSCLC with no link with asbestos exposure. NF2 was only altered in MPM. Significant enhancement of TP53 G:C to T:A transversions was found in NSCLC from asbestos-exposed patients when compared with unexposed patients (P = 0.037). Interestingly, TP53 polymorphisms in intron 7 (rs12947788 and rs12951053) were more frequently identified in asbestos-exposed NSCLC (P = 0.046) and MPM patients than in unexposed patients (P < 0.001 and P = 0.012, respectively). These results emphasise distinct genetic alterations between asbestos-related thoracic tumours, but identify common potential susceptibility factors, i.e. single nucleotide polymorphisms in intron 7 of TP53. While genetic changes in NSCLC are dominated by the effects of tobacco smoke, the increase of transversions in TP53 gene is consistent with a synergistic effect of asbestos. These results may help to define cell-dependent mechanisms of action of asbestos and identify susceptibility factors to asbestos.
Published: 2013
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41. Le clonage chez l’animal : état de lieux, enjeux et perspectives

Author: Chavatte-Palmer, Pascale, Biologie du développement et reproduction (BDR), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), and Association des Lauréats de la Chancellerie des Universités de Paris (ALCUP). FRA.
Subjects: perspective, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, état des lieux, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2012

42. Bibliothèque littéraire Jacques Doucet : première campagne de désacidification

Author: Nobécourt-Mutarelli, Marie-Dominique, Jacquot, Olivier, Bibliothéque littéraire Jacques Doucet (BLJD), and Chancellerie des Universités de Paris
Subjects: [SHS.INFO]Humanities and Social Sciences/Library and information sciences, [SHS.INFO] Humanities and Social Sciences/Library and information sciences
Abstract: National audience; La spécificité des collections de la BLJD, particulièrement précieuses, induisait un choix de traitement des documents feuille à feuille et en interne. La société PTLP a réalisé la désacidification des documents du 19 au 22 avril 2010, dans les locaux de la Réserve de la Bibliothèque Sainte-Geneviève.
Published: 2012

43. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension

Author: Tu, Ly, Dewachter, Laurence, Gore, Benoit, Fadel, Elie, Dartevelle, Philippe, Simonneau, Gérald, Humbert, Marc, Eddahibi, Saadia, Guignabert, Christophe, Guignabert, Christophe, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université libre de Bruxelles (ULB), Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This research was supported by grants from the French National Institute for Health and Medical Research (INSERM), the Legs Poix (Chancellerie des Universités de Paris), and the French National Agency for Research ('Agence Nationale de la Recherche' - ANR), Paris, France, and grant no. P007948 GENOPATH-ATOL.
Subjects: endothelium, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], proliferation, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Phenotype, survival, MESH: bcl-X Protein, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Cell Proliferation, growth factors, MESH: RNA, Small Interfering, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH: Blotting, Western, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: RNA, Messenger, MESH: Adolescent, MESH: Humans, MESH: Middle Aged, MESH: Fibroblast Growth Factor 2, MESH: Hypertension, Pulmonary, MESH: Phosphorylation, MESH: Apoptosis, MESH: Adult, MESH: Case-Control Studies, MESH: Male, MESH: Proto-Oncogene Proteins c-bcl-2, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Young Adult, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, FGF-receptors, MESH: Endothelium, Vascular, MESH: Autocrine Communication, MESH: Female, MESH: Cells, Cultured
Abstract: International audience; Pulmonary vascular remodeling is key to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We recently reported that fibroblast growth factor (FGF)2 is markedly overproduced by pulmonary endothelial cells (P-ECs) in IPAH and contributes significantly to smooth muscle hyperplasia and disease progression. Excessive FGF2 expression in malignancy exerts pathologic effects on tumor cells by paracrine and autocrine mechanisms.We hypothesized that FGF2 overproduction contributes in an autocrine manner to the abnormal phenotype of P-ECs, characteristic of IPAH. In distal pulmonary arteries (PAs) of patients with IPAH, we found increased numbers of proliferating ECs and decreased numbers of apoptotic ECs, accompanied with stronger immunoreactivity for the antiapoptotic molecules, B-cell lymphoma (BCL)2, and BCL extra long (BCL-xL) compared with PAs from control patients. These in situ observations were replicated in vitro, with cultured P-ECs from patients IPAH exhibiting increased proliferation and diminished sensitivity to apoptotic induction with marked increases in the antiapoptotic factors BCL2 and BCL-xL and levels of phosphorylated extracellular signal-regulated (ERK)1/2 compared with control P-ECs. IPAH P-ECs also exhibited increased FGF2 expression and an accentuated proliferative and survival response to conditioned P-EC media or exogenous FGF2 treatment. Decreasing FGF2 signaling by RNA interference normalized sensitivity to apoptosis and proliferative potential in the IPAH P-ECs. Our findings suggest that excessive autocrine release of endothelial-derived FGF2 in IPAH contributes to the acquisition and maintenance of an abnormal EC phenotype, enhancing proliferation through constitutive activation of ERK1/2 and decreasing apoptosis by increasing BCL2 and BCL-xL.
Published: 2011
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44. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension.: Autocrine Loop of EC-Derived FGF2 in IPAH

Author: Philippe Dartevelle, Saadia Eddahibi, Ly Tu, Laurence Dewachter, Gérald Simonneau, Elie Fadel, Marc Humbert, Benoit Gore, Christophe Guignabert, Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Université libre de Bruxelles (ULB), Hôpital Antoine Béclère, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This research was supported by grants from the French National Institute for Health and Medical Research (INSERM), the Legs Poix (Chancellerie des Universités de Paris), and the French National Agency for Research ('Agence Nationale de la Recherche' - ANR), Paris, France, and grant no. P007948 GENOPATH-ATOL.
Subjects: MAPK/ERK pathway, Male, Clinical Biochemistry, Apoptosis, 030204 cardiovascular system & hematology, Fibroblast growth factor, Pathogenesis, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: RNA, Small Interfering, Familial Primary Pulmonary Hypertension, Phosphorylation, RNA, Small Interfering, Cells, Cultured, 0303 health sciences, MESH: Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Middle Aged, MESH: Case-Control Studies, 3. Good health, Autocrine Communication, medicine.anatomical_structure, Phenotype, Proto-Oncogene Proteins c-bcl-2, MESH: Young Adult, Female, Fibroblast Growth Factor 2, FGF-receptors, MESH: Endothelium, Vascular, MESH: Cells, Cultured, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, endothelium, Endothelium, Adolescent, proliferation, Hypertension, Pulmonary, Blotting, Western, bcl-X Protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Phenotype, survival, Article, MESH: bcl-X Protein, 03 medical and health sciences, Paracrine signalling, Young Adult, MESH: Cell Proliferation, Internal medicine, growth factors, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, MESH: Blotting, Western, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Autocrine signalling, Molecular Biology, MESH: RNA, Messenger, 030304 developmental biology, Cell Proliferation, MESH: Adolescent, MESH: Humans, MESH: Fibroblast Growth Factor 2, MESH: Hypertension, Pulmonary, MESH: Phosphorylation, MESH: Apoptosis, MESH: Adult, Cell Biology, Smooth muscle hyperplasia, medicine.disease, Pulmonary hypertension, MESH: Male, Endocrinology, MESH: Proto-Oncogene Proteins c-bcl-2, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Endothelium, Vascular, MESH: Autocrine Communication, MESH: Female
Abstract: International audience; Pulmonary vascular remodeling is key to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We recently reported that fibroblast growth factor (FGF)2 is markedly overproduced by pulmonary endothelial cells (P-ECs) in IPAH and contributes significantly to smooth muscle hyperplasia and disease progression. Excessive FGF2 expression in malignancy exerts pathologic effects on tumor cells by paracrine and autocrine mechanisms.We hypothesized that FGF2 overproduction contributes in an autocrine manner to the abnormal phenotype of P-ECs, characteristic of IPAH. In distal pulmonary arteries (PAs) of patients with IPAH, we found increased numbers of proliferating ECs and decreased numbers of apoptotic ECs, accompanied with stronger immunoreactivity for the antiapoptotic molecules, B-cell lymphoma (BCL)2, and BCL extra long (BCL-xL) compared with PAs from control patients. These in situ observations were replicated in vitro, with cultured P-ECs from patients IPAH exhibiting increased proliferation and diminished sensitivity to apoptotic induction with marked increases in the antiapoptotic factors BCL2 and BCL-xL and levels of phosphorylated extracellular signal-regulated (ERK)1/2 compared with control P-ECs. IPAH P-ECs also exhibited increased FGF2 expression and an accentuated proliferative and survival response to conditioned P-EC media or exogenous FGF2 treatment. Decreasing FGF2 signaling by RNA interference normalized sensitivity to apoptosis and proliferative potential in the IPAH P-ECs. Our findings suggest that excessive autocrine release of endothelial-derived FGF2 in IPAH contributes to the acquisition and maintenance of an abnormal EC phenotype, enhancing proliferation through constitutive activation of ERK1/2 and decreasing apoptosis by increasing BCL2 and BCL-xL.
Published: 2010
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45. Differential expression of cyclic nucleotide phosphodiesterases 4 in developing rat lung

Author: Lopez, Emmanuel, Jarreau, Pierre-Henri, Zana, Elodie, Franco-Montoya, Marie-Laure, Schmitz, Thomas, Evain-Brion, Danièle, Bourbon, Jacques, Delacourt, Christophe, Méhats, Céline, La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus (UMR_S 767), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Service de réanimation néonatale Port-Royal, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants from la Chancellerie des Universités de Paris (Legs Poix 2006) and from Air Liquide Foundation., Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus ( UMR_S 767 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -CHI Créteil-Université Paris Descartes - Paris 5 ( UPD5 ) -Sorbonne Universités-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Cochin [AP-HP], 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 ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]
Subjects: [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract: International audience; During the perinatal period, lungs undergo changes to adapt to air breathing. The genes involved in these changes are developmentally regulated by various signaling pathways, including the cyclic nucleotide cAMP. As PDE4s are critical enzymes for regulation of cAMP levels, the objective of this study was to investigate PDE4's ontogeny in developing rat lung during the perinatal period. Pulmonary PDE4 activity, PDE4A-D, PDE4B, and PDE4D variant expression levels, PDE4B and PDE4D protein levels, and PDE4D localization in distal lung were determined. PDE4 activity increased towards term, dropped at birth, and increased thereafter to reach a plateau at the end of the second week of life. PDE4B2 and PDE4D long forms demonstrated a pattern of expression that increased markedly at birth. After birth, PDE4D was expressed in alveolar epithelial and mesenchymal cells. The study, therefore, evidenced striking variations in expression patterns among the PDE4 family that differed from changes in global PDE4 activity.
Published: 2010
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46. PDE4 in developing rat lung

Author: Lopez, Emmanuel, Jarreau, Pierre-Henri, Zana, Elodie, Franco-Montoya, Marie-Laure, Schmitz, Thomas, Evain-Brion, Danièle, Bourbon, Jacques, Delacourt, Christophe, Méhats, Céline, La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus (UMR_S 767), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de réanimation néonatale Port-Royal, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants from la Chancellerie des Universités de Paris (Legs Poix 2006) and from Air Liquide Foundation., and Méhats, Céline
Subjects: [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract: International audience; During the perinatal period, lungs undergo changes to adapt to air breathing. The genes involved in these changes are developmentally regulated by various signaling pathways, including the cyclic nucleotide cAMP. As PDE4s are critical enzymes for regulation of cAMP levels, the objective of this study was to investigate PDE4's ontogeny in developing rat lung during the perinatal period. Pulmonary PDE4 activity, PDE4A-D, PDE4B, and PDE4D variant expression levels, PDE4B and PDE4D protein levels, and PDE4D localization in distal lung were determined. PDE4 activity increased towards term, dropped at birth, and increased thereafter to reach a plateau at the end of the second week of life. PDE4B2 and PDE4D long forms demonstrated a pattern of expression that increased markedly at birth. After birth, PDE4D was expressed in alveolar epithelial and mesenchymal cells. The study, therefore, evidenced striking variations in expression patterns among the PDE4 family that differed from changes in global PDE4 activity.
Published: 2010
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47. NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts

Author: Amara, Nadia, Goven, Delphine, Prost, Fabienne, Muloway, Rachel, Crestani, Bruno, Boczkowski, Jorge, Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie A, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), 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), Service de physiologie, explorations fonctionnelles [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de pneumologie et pathologie professionnelle, CHI Créteil, Nadia Amara was supported by Chancellerie des Universités de Paris (legs Poix), and Jorge Boczkowski by INSERM and Assistance Publique-Hôpitaux de Paris (Contrat d'Interface). This work was supported by the European Commission (FP 7, European IPF Network) and by the Agence Nationale de la Recherche (ANR Physio 2006, FIBROPNEUMO)., ANR-06-PHYS-0011,FIBROPNEUMO,Fibroblastes et Fibrogénèse pulmonaire(2006), and European Project: 202224,EC:FP7:HEALTH,FP7-HEALTH-2007-A,EURIPFNET(2008)
Subjects: MESH: Aged, MESH: Cell Differentiation, MESH: Middle Aged, MESH: Humans, MESH: Gene Expression Regulation, Enzymologic, MESH: Idiopathic Pulmonary Fibrosis, MESH: Platelet-Derived Growth Factor, MESH: Reactive Oxygen Species, MESH: Adult, MESH: Male, MESH: Transforming Growth Factor beta1, MESH: Fibroblasts, MESH: Reverse Transcriptase Polymerase Chain Reaction, cardiovascular system, MESH: Up-Regulation, MESH: Smad3 Protein, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: NADPH Oxidase, MESH: Smad2 Protein, MESH: Female, MESH: RNA, Messenger, MESH: Cells, Cultured
Abstract: International audience; BACKGROUND: Persistence of myofibroblasts is believed to contribute to the development of fibrosis in idiopathic pulmonary fibrosis (IPF). Transforming growth factor beta1 (TGFbeta1) irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin (alpha-SMA) and produce extracellular matrix proteins, such as procollagen I (alpha1). Reactive oxygen species produced by NADPH oxidases (NOXs) have been shown to regulate cell differentiation. It was hypothesised that NOX could be expressed in parenchymal pulmonary fibroblasts and could mediate TGFbeta1-stimulated conversion of fibroblasts into myofibroblasts. METHODS: Fibroblasts were cultured from the lung of nine controls and eight patients with IPF. NOX4, alpha-SMA and procollagen I (alpha1) mRNA and protein expression, reactive oxygen species production and Smad2/3 phosphorylation were quantified, in the absence and in the presence of incubation with TGFbeta1. Migration of platelet-derived growth factor (PDGF)-induced fibroblasts was also assessed. RESULTS: It was found that (1) NOX4 mRNA and protein expression was upregulated in pulmonary fibroblasts from patients with IPF and correlated with mRNA expression of alpha-SMA and procollagen I (alpha1) mRNA; (2) TGFbeta1 upregulated NOX4, alpha-SMA and procollagen I (alpha1) expression in control and IPF fibroblasts; (3) the change in alpha-SMA and procollagen I (alpha1) expression in response to TGFbeta1 was inhibited by antioxidants and by a NOX4 small interfering RNA (siRNA); (4) NOX4 modulated alpha-SMA and procollagen I (alpha1) expression by controlling activation of Smad2/3; and (5) NOX4 modulated PDGF-induced fibroblast migration. CONCLUSION: NOX4 is critical for modulation of the pulmonary myofibroblast phenotype in IPF, probably by modulating the response to TGFbeta1 and PDGF.
Published: 2010
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48. Le Ladakh (Jammu & Cachemire, Inde) de l'âge du Bronze à l'introduction du Bouddhisme: une étude de l'art rupestre

Author: Bruneau, Laurianne, Archéologie de L'Asie centrale, Archéologies et Sciences de l'Antiquité (ArScAn), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Institut national de recherches archéologiques préventives (Inrap)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Institut national de recherches archéologiques préventives (Inrap)-Centre National de la Recherche Scientifique (CNRS), Je remercie les instituts suivants pour leur participation financière à mes recherches : l’INHA, les Ministères des Affaires Etrangères français et italien, la Fondation Maison des sciences de l’homme (Paris) et la Higher Education Commission (Islamabad) gérant le Programme de Collaboration en Sciences Sociales entre la France et le Pakistan, la Chancellerie des Universités de Paris, le DAAD, la Fondation Pierre Ledoux-Jeunesse Internationale, l’EFEO, la Fondation Carlo Leone et Mariena Montandon (Suisse), la Fondation des Treilles (France)., Université Paris 1 Panthéon-Sorbonne, and Henri-Paul Francfort
Subjects: Bronze Age, Âge du Fer, [SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory, Iron Age, Asie centrale, Himalaya, Pétroglyphe, India, Tibet, Chorten, Central Asia, Archéologie, Architecture, Art animalier des steppes, Buddhism, Carving, Art of the steppes, Himalayas, Histoire de l’art, Rock art studies, Stūpa, Protohistoire, Engraving, Art rupestre, History of art, Âge du Bronze, Archaeology, Bouddhisme, Ladakh, Animal style, Inde, Petroglyph, Gravure, Protohistory
Abstract: Ladakh is the largest, highest and westernmost region of the Himalayas. Although it belongs to India’s state of Jammu and Kashmir, it is located at the crossroads of Central Asia, China, Tibet and India. We may assume that this unique location resulted into a major historical importance. However Ladakh’s history prior the 15th century is rather fragmentary and legendary. Very limited archaeological researches have been conducted in this Himalayan region. In the light of successful rock art projects lead in Central Asia and in the northern areas of Pakistan, petroglyphs appeared as the most promising and easily available material to carry out the first systematic archaeological study of Ladakh. In the course of my PhD I gathered about 15, 000 petroglyphs scattered over 100 rock sites. A comparative analysis of zoomorphic and anthropomorphic representations shows that during the Bronze and Iron Ages (2500-300 BC) Ladakh shared thematic and stylistic traits with the Central Asian steppes. Later on, at the beginning of the 1st millennium AD, several rock inscriptions in kharosthi and brahmi are firm testimonies that Ladakh was under the influence of the Indian cultural expansion. Then, Tibetan rock inscriptions in Ladakh datable to the second half of the first millennium provide evidence for the expansion of the Tibetan empire (7th-11th centuries) into the western regions. These inscriptions are frequently accompanied by engraved representations of Buddhist stūpa. The typological and comparative study of these enables us to better apprehend the introduction and diffusion of Buddhism into Ladakh. In summary my researches on the rock art of Ladakh allows for the first time to propose a secure cultural sequence of the region from Protohistory to the Medieval Period. It also demonstrates that the Himalayas have never been a barrier between Central Asia, the Indian subcontinent and the Tibetan plateau and that Ladakh always has been a cultural crossroad.; Le Ladakh constitue la plus vaste, la plus élevée et la plus occidentale des régions naturelles de l’Himalaya. Bien que politiquement rattachée à l’état indien du Jammu et Cachemire, elle est géographiquement située aux confins de l’Asie Centrale, de la Chine, du Tibet et de l’Inde. Par conséquent nous pouvons présumer que cette situation privilégiée lui a conféré une importance historique majeure. Cependant, le Ladakh a fait l’objet de peu de recherches archéologiques : on compte seulement trois sondages. Le manque de données est aujourd’hui comblé par un matériel abondant, varié et fiable : l’art rupestre. Véritables créations picturales ou simples graffiti, les pétroglyphes sont des marqueurs spatio-temporels immuables, qui ne peuvent mentir ni sur leur provenance ni celle de leurs auteurs. De part leur quantité (on en connaît plusieurs milliers) et leur variété (ils illustrent des êtres anthropomorphes, zoomorphes, des monuments et des signes), ils recèlent des informations essentielles pour l’histoire du peuplement. Puisque les représentations rupestres couvrent une période s’étendant de la Préhistoire à l’époque moderne nous avons opéré un choix pour notre étude. Par une analyse comparative thématique et stylistique des images gravées nous sommes en mesure d’inscrire le Ladakh au sein du groupe des cultures des steppes à l’Âge du Bronze et à l’Âge du Fer ainsi que de l’identifier comme carrefour culturel pour la diffusion du Bouddhisme au Ier millénaire de notre ère. Les axes de recherches retenus s’inscrivent dans la thématique des recherches archéologiques menées actuellement en Asie centrale.
Published: 2010

49. Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in france

Author: Gil Bellis, Véronique Vincent, Nathalie Soismier, Martin Rottman, Lydie Lemonnier, Sophie Ravilly, Brigitte Fauroux, Jean-Louis Gaillard, Cristina Gutierrez, Emilie Catherinot, Marie-Anne Vibet, Evelyne Le Roux, Anne-Laure Roux, Fabienne Ripoll, Edouard Macheras, Didier Guillemot, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Raymond Poincaré [AP-HP], Hôpital Foch [Suresnes], Hôpital Ambroise Paré [AP-HP], Association Vaincre La Mucoviscidose, Institut national d'études démographiques (INED), Pharmacoepidemiologie et évaluation de l'impact des produits de santé sur les populations, Université Bordeaux Segalen - Bordeaux 2-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes moléculaires de la pathogenèse bactérienne, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM), World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pharmacoépidémiologie et maladies infectieuses (PhEMI), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), This work received financial support from Legs Poix (Chancellerie des Universités de Paris) and from the Vaincre La Mucoviscidose association., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Lung Diseases, Male, Cystic Fibrosis, Prevalence, Cystic fibrosis, MESH: Lung Diseases, 0302 clinical medicine, MESH: Child, Epidemiology, EPIDEMIOLOGY, Child, 0303 health sciences, biology, Nontuberculous Mycobacteria, MESH: Mycobacterium Infections, Nontuberculous, Mycobacterium avium Complex, 3. Good health, MESH: Nontuberculous Mycobacteria, MESH: Young Adult, Female, France, Microbiology (medical), Adult, medicine.medical_specialty, MESH: Cystic Fibrosis, Adolescent, Mycobacterium avium-intracellulare infection, Mycobacterium Infections, Nontuberculous, MESH: Mycobacterium avium Complex, 03 medical and health sciences, Young Adult, CYSTIC_FIBROSIS, Mycobacterium bolletii, Internal medicine, medicine, Humans, MESH: Prevalence, Mycobacterium avium-intracellulare Infection, MESH: Adolescent, MESH: Humans, Mycobacterium massiliense, 030306 microbiology, business.industry, MESH: Adult, Mycobacteriology and Aerobic Actinomycetes, MESH: Mycobacterium avium-intracellulare Infection, medicine.disease, biology.organism_classification, bacterial infections and mycoses, MESH: Male, MESH: France, 030228 respiratory system, Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Nontuberculous mycobacteria, business, MESH: Female, Mycobacterium
Abstract: We performed a multicenter prevalence study of nontuberculous mycobacteria (NTM) involving 1,582 patients (mean age, 18.9 years; male/female ratio, 1.06) with cystic fibrosis in France. The overall NTM prevalence (percentage of patients with at least one positive culture) was 6.6% (104/1,582 patients), with prevalences ranging from 3.7% (in the east of France) to 9.6% (in the greater Paris area). Mycobacterium abscessus complex (MABSC; 50 patients) and Mycobacterium avium complex (MAC; 23 patients) species were the most common NTM, and the only ones associated with fulfillment of the American Thoracic Society bacteriological criteria for NTM lung disease. The "new" species, Mycobacterium bolletii and Mycobacterium massiliense, accounted for 40% of MABSC isolates. MABSC species were isolated at all ages, with a prevalence peak between 11 and 15 years of age (5.8%), while MAC species reached their highest prevalence value among patients over 25 years of age (2.2%). Nontuberculous mycobacteria (NTM) have emerged as "new" pathogens in cystic fibrosis (CF) patients over the last 2 decades (10). CF centers worldwide have reported isolation of NTM from the respiratory tracts of CF patients, with prevalence values ranging from 5% to 20% (5, 6, 8, 9, 13, 14, 16, 19, 22, 25). Mycobacterium avium complex (MAC) and Mycobac-terium abscessus complex (MABSC) species are the most frequently isolated NTM and together account for 95% of NTM lung diseases affecting CF patients. The MAC, a member of the subgroup comprising slowly growing mycobacteria, ranks first in North America (22), whereas the MABSC, a member of the subgroup comprising rapidly growing mycobacteria, seems to predominate in Western Europe (15, 23, 25) and is also more prevalent than the MAC in Israel (19). Previous studies have reported isolation of NTM from 6.6 to 9.8% of French CF cohorts (9, 23, 25). These studies also reported a much higher isolation rate for MABSC than for MAC or other NTM species (23, 25). However, these studies were done exclusively in pediatric CF centers in Paris. This may have distorted the results since MABSC species are more prevalent than MAC species in children (23). Moreover, the epidemiology of NTM in Paris does not necessarily reflect the situation in other regions of France. For example, studies involving non-CF patients have reported higher rates of NTM disease in urban areas (20). Moreover, previous French studies were performed before M. abscessus (now M. abscessus sensu lato, or the MABSC) was shown to include at least three distinct species, M. abscessus (sensu stricto) (hereafter referred to as M. abscessus), Mycobacterium massiliense, and Mycobac-terium bolletii (1, 3). The prevalences of these three species in CF patients in France were therefore unknown. We thus conducted a large, prospective, nationwide study addressing NTM prevalence in CF patients in France. This study shows relatively low prevalence figures for French CF centers. It also provides evidence that MABSC species are currently the most prevalent NTM in the French CF population , far more frequent than MAC species, and that MABSC species mainly infect children and young adults. The 49 French CF centers were asked to participate in the study. Each patient included was asked to provide at least three sputum samples (or other respiratory specimens) for NTM analysis between 1 January 2004 and 31 December 2004. Prior NTM isolation did not exclude subjects. Patients with a positive NTM sample had to submit three more sputum samples at monthly intervals and then every 3 months for a total of 18 months. All the patients, or their parents if they were chil-* Corresponding author. Mailing address: Laboratoire de Microbi-ologie, Hôpital Ambroise Paré
Published: 2009
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50. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production

Author: Michel Samson, Elvire Bourgeois, Pierre Gourdy, Séverine Diem, Stéphane Roga, Elke Schneider, Michel Dy, Linh Pham Van, Jean-Philippe Girard, Anne Barra, André Herbelin, Jean-Marc Gombert, 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), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Laboratoire d'immunologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, 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), Université Paris Descartes - Paris 5 (UPD5), CNRS, Université de Paris Descartes, Ligue Nationale contre le Cancer, la Chancellerie des Universités de Paris, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Slama, Catherine, Université de Rennes (UR), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Interleukin-12, MESH: Spleen, medicine.medical_treatment, MESH: Mice, Knockout, Interleukin 21, Mice, 0302 clinical medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: Animals, IL-2 receptor, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, Mice, Inbred BALB C, ZAP70, Natural killer T cell, Interleukin-12, Killer Cells, Natural, Cytokine, Liver, Interleukin 12, Cytokines, Natural killer cells, Natural killer T cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Killer Cells, Natural, MESH : Spleen, MESH: Killer Cells, Natural, MESH: Interleukins, MESH: Interferon-gamma, Immunology, MESH: Mice, Inbred BALB C, MESH : Mice, Inbred C57BL, Biology, MESH : Interleukin-4, 03 medical and health sciences, Interferon-gamma, Th2 Cells, MESH: Mice, Inbred C57BL, MESH: Th2 Cells, MESH : Mice, medicine, MESH : Interleukin-12, Animals, Humans, MESH: Mice, MESH : Mice, Inbred BALB C, MESH : Interferon-gamma, 030304 developmental biology, Inflammation, Lymphokine-activated killer cell, MESH: Humans, Interleukins, MESH : Humans, MESH : Liver, MESH: Interleukin-4, Interleukin-33, MESH : Natural Killer T-Cells, MESH : Th2 Cells, Interleukin 33, Mice, Inbred C57BL, MESH: Natural Killer T-Cells, Natural Killer T-Cells, MESH : Mice, Knockout, Th1/Th2 cells, Interleukin-4, MESH : Animals, MESH : Interleukins, MESH: Female, Spleen, 030215 immunology, MESH: Liver
Abstract: International audience; IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-gamma rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-gamma production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.
Published: 2009
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