Éditeur(s) : HAL CCSD American Society of Hematology
Résumé : International audience
Polycythemia vera (PV) is characterized by an increased RBC mass, spontaneous erythroid colony formation, and the JAK2V617F mutation. PV is associated with a high risk of mesenteric and cerebral thrombosis. PV RBC adhesion to endothelial laminin is increased and mediated by phosphorylated erythroid Lu/BCAM. In the present work, we investigated the mechanism responsible for Lu/BCAM phosphorylation in the presence of JAK2V617F using HEL and BaF3 cell lines as well as RBCs from patients with PV. High levels of Rap1-GTP were found in HEL and BaF3 cells expressing JAK2V617F compared with BaF3 cells with wild-type JAK2. This finding was associated with increased Akt activity, Lu/BCAM phosphorylation, and cell adhesion to laminin that were inhibited by the dominant-negative Rap1S17N or by the specific Rap1 inhibitor GGTI-298. Surprisingly, knocking-down EpoR in HEL cells did not alter Akt activity or cell adhesion to laminin. Our findings reveal a novel EpoR-independent Rap1/Akt signaling pathway that is activated by JAK2V617F in circulating PV RBCs and responsible for Lu/BCAM activation. This new characteristic of JAK2V617F could play a critical role in initiating abnormal interactions among circulating and endothelial cells in patients with PV.
ISSN: 0006-4971

inserm-00821109
http://www.hal.inserm.fr/inserm-00821109
http://www.hal.inserm.fr/inserm-00821109/document
http://www.hal.inserm.fr/inserm-00821109/file/De_Grandis_Blood_2013.pdf
DOI : 10.1182/blood-2012-07-440487

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Primary hepatocyte cultures are now considered as convenient models for in vitro analyzing liver drug transport. However, if primary human and rat hepatocytes have been well-characterized with respect to drug transporter expression and regulation, much less is known for primary mouse hepatocytes. The present study was therefore designed to gain insights about this point. The profile of sinusoidal and canalicular drug transporter mRNA expression in short time (4h)-cultured mouse hepatocytes was found to be highly correlated with that of freshly isolated hepatocytes; by contrast, those of counterparts cultured for a longer time (until 4days) either in monolayer configurations on plastic or collagen or in sandwich configuration with matrigel were profoundly altered: uptake drug transporters such as Oct1, Oatps and Oat2 were thus down-regulated, whereas most of efflux transporters such as Mdr1a/b, Mrp3, Mrp4 and Bcrp were induced. Moreover, short time-cultured hepatocytes exhibited the highest levels of sinusoidal influx transporter activities. Transporter-mediated drug secretion into canalicular networks was however only observed in sandwich-cultured hepatocytes. Mouse hepatocytes cultured either in monolayer or sandwich configurations were finally shown to exhibit up-regulation of referent transporters in response to exposure to prototypical activators of the drug sensing receptors pregnane X receptor, aryl hydrocarbon receptor or constitutive androstane receptor. Taken together, these data demonstrate the feasibility of using primary mouse hepatocytes for investigating potential interactions of xenobiotics with hepatic transporter activity or regulation, provided that adequate culture conditions are retained.
ISSN: 0928-0987

inserm-00823243
http://www.hal.inserm.fr/inserm-00823243
DOI : 10.1016/j.ejps.2013.01.013
PUBMED : 23396053

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Implication of immune processes in bipolar disorder (BD) has recently gained increasing attention. Tolerogenic molecules, among which HLA-G plays a prominent role, mediate the modulation of such processes. The HLA-G locus is characterized by a high number of polymorphisms including a functionally relevant 14 base pair (bp) insertion/deletion (Ins/Del) allele affecting the HLA-G expression. Here, we analyzed the distribution of this polymorphism in 561 BD patients and 161 healthy and found that the HLA-G 14bp Ins/Ins genotype was significantly more prevalent in healthy controls than in patients (corrected p; pc=0.032) and that the prevalence of such protective genotype is lower among patients born during the winter season as compared to those born in other periods (pc=0.006). Possible mechanisms between low HLA G expression and resistance to infections as well as potential relationships between infections in early life and susceptibility to BD are discussed.
ISSN: 0198-8859

inserm-00864639
http://www.hal.inserm.fr/inserm-00864639
http://www.hal.inserm.fr/inserm-00864639/document
http://www.hal.inserm.fr/inserm-00864639/file/HLA-G_and_BD_manuscript_-1.pdf
DOI : 10.1016/j.humimm.2012.11.032

Éditeur(s) : HAL CCSD IOS Press
Résumé : International audience
Because of the metabolic changes induced by a physical activity, the hemorheological properties of patients with sickle cell anemia could be further impaired and increase the risks for vaso-occlusive complications. However, few studies suggest that moderate physical activity could be beneficial rather than harmful in patients with sickle cell anemia (SCA). However, the definition of what can be considered as a moderate physical activity in SCA patients is imprecise. The present study tested the effects of a short incremental cycling exercise test conducted until the first ventilatory threshold on different biomarkers. Hematological and hemorheological parameters were compared between 8 patients with SCA and 13 healthy subjects (CONT) before, immediately after the end of the exercise and at 12, 36 and 60 hours after the exercise. We observed no significant hematological or hemorheological alteration induced by the exercise in the two groups. However, the exercise resulted in a delayed improvement of the red blood cell disaggregation threshold at 36 and 60 hrs after exercise in the SCA group which was paralleled to the decrease in the platelet count in this group. The present study suggests that such an exercise might be beneficial for microcirculatory blood flow.
ISSN: 1386-0291

hal-01137567
https://hal.univ-antilles.fr/hal-01137567

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 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
Résumé : International audience
Leishmania parasites induce an immunomodulation by subverting the host immune response towards a CD4(+) Th2 lymphocytic cell response that favors parasite persistence. Here, we report that after successful treatment of visceral leishmaniasis due to Leishmania infantum, an immune reconstitution syndrome revealing hip septic arthritis was associated with a switch from Th2 towards a Th1 cytokine profile, and a decrease in the level of immunomodulating factors, such as soluble HLA-G and indoleamine 2,3-dioxygenase (IDO) activity. We then measured IDO activity in a cohort of 39 patients and uninfected control subjects. Results showed significantly enhanced IDO activity in patients with visceral Leishmania infection, compared with uninfected control subjects (P < 0.001), but also compared with treated patients (P < 0.05). A decrease in IDO activity could constitute a relevant biomarker for the restoration of the immune response during visceral leishmaniasis.
Innate Immunity

inserm-00818884
http://www.hal.inserm.fr/inserm-00818884
DOI : 10.1177/1753425912473170
PUBMED : 23413147

Éditeur(s) : HAL CCSD
Résumé : International audience
European journal of cancer (Oxford, England : 1990)

hal-01567818
https://hal.archives-ouvertes.fr/hal-01567818
PUBMED : 28527392