Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. The cell functions of cyclin D1 depend on its partners and/or subcellular distribution, resulting in different oncogenic properties. We observed the accumulation of cyclin D1 in the cytoplasm of a subset of MCL cell lines and primary cells. In primary cells, this cytoplasmic distribution was correlated with a more frequent blastoid phenotype. We performed immunoprecipitation assays and mass spectrometry on enriched cytosolic fractions from two cell lines. The cyclin D1 interactome was found to include several factors involved in adhesion, migration and invasion. We found that the accumulation of cyclin D1 in the cytoplasm was associated with higher levels of migration and invasiveness. We also showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Our data reveal a role of cytoplasmic cyclin D1 in the control of MCL cell migration and invasion, and as a true operator of MCL pathogenesis.
ISSN: 2045-2322

hal-01635754
https://hal.archives-ouvertes.fr/hal-01635754
DOI : 10.1038/s41598-017-14222-1
PUBMED : 29066743

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans.
ISSN: 0041-008X

inserm-00872871
http://www.hal.inserm.fr/inserm-00872871
DOI : 10.1016/j.taap.2012.05.004
PUBMED : 22617429

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
ISSN: 0309-0167

hal-01118504
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118504
PUBMED : 20716175
DOI : 10.1111/j.1365-2559.2010.03605.x

Éditeur(s) : HAL CCSD American Society for Biochemistry and Molecular Biology
Résumé : International audience
Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (B(a)P) are widely distributed environmental contaminants, known as potent ligands of the aryl hydrocarbon receptor (AhR). These chemicals trigger an early and transient increase of intracellular calcium concentration ([Ca(2+)](i)), required for AhR-related effects of PAHs. The mechanisms involved in this calcium mobilization were investigated in the present study. We demonstrated that B(a)P-mediated [Ca(2+)](i) induction was prevented in endothelial HMEC-1 cells by counteracting β2-adrenoreceptor (β2ADR) activity using pharmacological antagonists, anti-β2ADR antibodies, or siRNA-mediated knockdown of β2ADR expression; by contrast, it was strongly potentiated by β2ADR overexpression in human kidney HEK293 cells. B(a)P was shown, moreover, to directly bind to β2ADR, as assessed by in vitro binding assays and molecular modeling. Pharmacological inhibition and/or siRNA-mediated silencing of various signaling actors acting downstream of β2ADR in a sequential manner, such as G protein, adenylyl cyclase, Epac-1 protein, and inositol 1,4,5-trisphosphate (IP(3))/IP(3) receptor, were next demonstrated to prevent B(a)P-induced calcium signal. Inhibition or knockdown of these signaling elements, as well as the use of chemical β-blockers, were finally shown to counteract B(a)P-mediated induction of cytochrome P-450 1B1, a prototypical AhR target gene. Taken together, our results show that B(a)P binds directly to β2ADR and consequently utilizes β2ADR machinery to mobilize [Ca(2+)](i), through activation of a G protein/adenylyl cyclase/cAMP/Epac-1/IP(3) pathway. This β2ADR-dependent signaling pathway activated by PAHs may likely be crucial for PAH-mediated up-regulation of AhR target genes, thus suggesting a contribution of β2ADR to the health-threatening effects of these environmental pollutants.
ISSN: 0021-9258

hal-00682497
https://hal.archives-ouvertes.fr/hal-00682497
DOI : 10.1074/jbc.M111.319970
PUBMED : 22167199

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
Background. An association with cancer is described in 17–32% of cases of dermatomyositis (DM) and in 5–16% of cases of anti-synthetase syndrome (ASS). The literature contains very few studies involving Afro-Caribbean patients with DM or ASS. The aim of our retrospective study was to determine the prevalence of cancer in a series of patients with DM or ASS at the University Hospital of Pointe-à-Pitre between 1st January 2000 and 31st December 2012. The secondary objective was to review the clinical and laboratory features as well as the course of DM/ASS in these patients.Patients and methods. The inclusion criteria were as follows: Afro-Caribbean origin; age >15 years; patient living in Guadeloupe; screening for malignancy.Results. Twenty-two patients were included (15 DM, 7 ASS). Only one case of cancer was diagnosed in the entire study population at a mean follow-up of 6±4 years (prevalence: 6.7%, CI95% [1.7–31.9]). Of the 15 patients presenting DM (sex ratio F/M: 4, mean age: 45±14 years), 6 (40%) had associated connective tissue disease.Conclusion. Our study suggests a weak association between DM and cancer in Afro-Caribbean patients. These results may be explained by the features of the disease seen in these patients (female gender, young age at onset, associated connective tissue disease) and the low prevalence in the Caribbean region of cancers typically associated with DM.
Introduction. Dix-sept à 32 % des cas de dermatomyosite (DM) et 5 à 16 % des cas de syndrome des anti-synthétases (SAS) sont associés à un cancer. Les séries de patients afro-caribéens atteints de DM ou de SAS sont exceptionnellement rapportées dans la littérature. Le but de notre étude rétrospective était d’estimer la prévalence des cancers dans une série de patients guadeloupéens atteints de DM ou de SAS. L’objectif secondaire était de préciser les caractéristiques cliniques, biologiques et évolutives de la maladie chez ces patients.Patients et méthode. Les critères d’inclusion étaient les suivants : patient afro-caribéen ; âge >15ans ; patient vivant en Guadeloupe ; réalisation d’un bilan d’extension à la recherche d’une néoplasie.Résultats. Vingt-deux patients ont été inclus (15 atteints de DM, 7 de SAS). Un seul cancer a été diagnostiqué, avec une durée moyenne de suivi de 6±4ans sur l’ensemble de la série (prévalence de 6,7 % ; IC 95 % [1,7 ; 31,9]). Parmi les 15 patients atteints de DM (sex-ratio H/F=1/4 ; âge moyen : 45±14ans), 6 (40 %) avaient une connectivite associée.Conclusion. Notre étude suggère une faible association entre DM et cancer chez les patients afro-caribéens. Ces résultats s’expliquent principalement par les caractéristiques de la maladie chez ces patients (sexe féminin, jeune âge, connectivite associée) et la faible prévalence, aux Antilles, des cancers classiquement associés aux DM.
ISSN: 0151-9638

inserm-01110999
http://www.hal.inserm.fr/inserm-01110999
http://www.hal.inserm.fr/inserm-01110999/document
http://www.hal.inserm.fr/inserm-01110999/file/2014%2C%20Tersiguel%20-%20Epid%C3%A9miologie%20de%20la%20dermatomyosite%20et%20du%20syndrome%20des%20anti-synth%C3%A9tases%20en%20population%20afro-carib%C3%A9enne.pdf
PUBMED : 25288059

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Painful vaso-occlusive crisis, a hallmark of sickle cell anaemia, results from complex, incompletely understood mechanisms. Red blood cell (RBC) damage caused by continuous endogenous and exogenous oxidative stress may precipitate the occurrence of vaso-occlusive crises. In order to gain insight into the relevance of oxidative stress in vaso-occlusive crisis occurrence, we prospectively compared the expression levels of various oxidative markers in 32 adults with sickle cell anaemia during vaso-occlusive crisis and steady-state conditions. Compared to steady-state condition, plasma levels of free haem, advanced oxidation protein products and myeloperoxidase, RBC caspase-3 activity, as well as the concentrations of total, neutrophil- and RBC-derived microparticles were increased during vaso-occlusive crises, whereas the reduced glutathione content was decreased in RBCs. In addition, natural anti-band 3 autoantibodies levels decreased during crisis and were negatively correlated with the rise in plasma advanced oxidation protein products and RBC caspase-3 activity. These data showed an exacerbation of the oxidative stress during vaso-occlusive crises in sickle cell anaemia patients and strongly suggest that the higher concentration of harmful circulating RBC-derived microparticles and the reduced anti-band 3 autoantibodies levels may be both related to the recruitment of oxidized band 3 into membrane aggregates.
ISSN: 0007-1048

hal-01668325
https://hal.univ-antilles.fr/hal-01668325
DOI : 10.1111/bjh.14476

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
Introduction: Hydroxyurea is an antimetabolite widely used in the treatment of myeloproliferative diseases. Usual side effects are mainly hematological, gastrointestinal, neurological disorders and induced-fevers. More rarely, hydroxyurea-induced pneumonitis are reported. Case report: We report a case of a patient treated for polycythemia vera. She was admitted 20 days after introduction of hydroxyurea for a high fever, productive cough and clear sputum associated with nausea. Chest CT-scan found diffuse bilateral ground-glass opacities. The microbiological investigations were negative. Symptoms disappeared few days after discontinuation of treatment. Its reintroduction led to recurrence of symptoms. Conclusion: This additional case completes the 15 cases of hydroxyurea-induced pneumonitis described in the literature. Two forms of this disease seem to exist: an acute form with fever occurring in the month following introduction of hydroxyurea; and a chronic form without fever. Even if it is uncommon, pulmonologists should be aware of this complication.
ISSN: 0761-8425

hal-00916333
https://hal.archives-ouvertes.fr/hal-00916333
https://hal.archives-ouvertes.fr/hal-00916333/document
https://hal.archives-ouvertes.fr/hal-00916333/file/hydroxyurA_e_version_rA_visA_e.pdf
DOI : 10.1016/j.rmr.2013.09.001

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
All-trans retinoic acid (atRA) is the active form of vitamin A, known to activate retinoid receptors, especially the heterodimer retinoid X receptor (RXR):retinoic acid receptor (RAR) that otherwise may play a role in regulation of some drug transporters. The present study was designed to characterize the nature of human hepatic transporters that may be targeted by atRA and the heterodimer RXR:RAR. Exposure of human hepatoma HepaRG cells and primary human hepatocytes to 5μM atRA down-regulated mRNA levels of various sinusoidal solute carrier (SLC) influx transporters, including organic anion transporting polypeptide (OATP) 2B1, OATP1B1, organic cation transporter (OCT) 1 and organic anion transporter (OAT) 2, and induced those of the canalicular breast cancer resistance protein (BCRP). The retinoid concomitantly reduced protein expression of OATP2B1 and OATP1B1 and activity of OATPs and OCT1 and induced BCRP protein expression in HepaRG cells. Some transporters such as OATP1B3 and the bile salt export pump (BSEP) were however down-regulated by atRA in primary human hepatocytes, but induced in HepaRG cells, thus pointing out discrepancies between these two liver cell models in terms of detoxifying protein regulation. atRA-mediated repressions of OATP2B1, OATP1B1, OAT2 and OCT1 mRNA expression were finally shown to be counteracted by knocking-down expression of RARα and RXRα through siRNA transfection in HepaRG cells. atRA thus differentially regulated human hepatic drug transporters, mainly in a RXR:RAR-dependent manner, therefore establishing retinoids and retinoid receptors as modulators of liver drug transporter expression.
ISSN: 0928-0987

inserm-00804935
http://www.hal.inserm.fr/inserm-00804935
DOI : 10.1016/j.ejps.2013.01.005
PUBMED : 23352986

Éditeur(s) : HAL CCSD IOS Press
Résumé : International audience
Strenuous exercise is associated with an inflammatory response involving the activation of several types of blood cells. In order to document the specific activation of these cell types, we studied the effect of three maximal exercise tests conducted to exhaustion on the quantitative and qualitative pattern of circulating cell-derived microparticles and inflammatory molecules in healthy subjects. This study mainly indicated that the plasma concentration of microparticles from platelets and polymorphonuclear neutrophils (PMN) was increased immediately after the strenuous exercise. In addition, the increase in plasma concentration of microparticles from PMN and platelets was still observed after 2 hours of recovery. A similar pattern was observed for the IL-6 plasma level. In contrast, no change was observed for either soluble selectins or plasma concentration of microparticles from red blood cells, monocytes and endothelial cells. In agreement, sVCAM-1 and sICAM-1 levels were not changed by the exercise. We conclude that a strenuous exercise is accompanied by platelet-and PMN-derived microparticle production that probably reflects the activation of these two cell types.
ISSN: 1386-0291

hal-01163965
https://hal.univ-antilles.fr/hal-01163965
DOI : 10.3233/CH-2010-1361

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
The levels and duration of physical activity that can be considered as completely safe in patients with sickle cell anemia (SCA) is unknown. The present study compared the hemorheological and hematological profile, cell density distribution and basic biochemistry between a group of 17 patients with SCA and 21 healthy subjects before and after a 20 min duration submaximal cycling exercise at the same absolute workload. Blood was sampled at rest and 3 min after the end of exercise for measurement of biological parameters. Exercise did not affect the hematocrit and blood viscosity in the two groups. Plasma viscosity was not different between the two groups at rest and similarly increased with exercise. The proportion of intermediary dense cells (with density between 1.11 and 1.12 g/ml) decreased with exercise in the SCA group resulting in an increase in the proportion of red blood cells with a density > 1.12 g/ml. No change was observed in the control group. The present study suggests that mild-moderate exercise is not very harmful for SCA patients. The hemorheological and hematological changes very mild, except for the formation of dense cells but no clinically significant signs of medical complication were present in any of the patients.
ISSN: 0007-1048

hal-00640629
https://hal.archives-ouvertes.fr/hal-00640629
https://hal.archives-ouvertes.fr/hal-00640629/document
https://hal.archives-ouvertes.fr/hal-00640629/file/PEER_stage2_10.1111%252Fj.1365-2141.2011.08728.x.pdf
DOI : 10.1111/j.1365-2141.2011.08728.x