Time filter

Source Type

Marseille, France

Latour C.,University Paul Sabatier | Besson-Fournier C.,University Paul Sabatier | Meynard D.,University Paul Sabatier | Silvestri L.,San Raffaele Scientific Institute | And 7 more authors.
Hepatology | Year: 2016

Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. Conclusion: These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice. © 2016 by the American Association for the Study of Liver Diseases. Source

Aissi D.,Paris-Sorbonne University | Aissi D.,French Institute of Health and Medical Research | Aissi D.,ICAN Institute for Cardiometabolism and Nutrition | Dennis J.,University of Toronto | And 17 more authors.
PLoS ONE | Year: 2014

In order to investigate whether DNA methylation marks could contribute to the incomplete penetrance of the FV Leiden mutation, a major genetic risk factor for venous thrombosis (VT), we measured genome-wide DNA methylation levels in peripheral blood samples of 98 VT patients carrying the mutation and 251 VT patients without the mutation using the dedicated Illumina HumanMethylation450 array. The genome-wide analysis of 388,120 CpG probes identified three sites mapping to the SLC19A2 locus whose DNA methylation levels differed significantly (p<3 10-8) between carriers and noncarriers. The three sites replicated (p<2 10-7) in an independent sample of 214 individuals from five large families ascertained on VT and FV Leiden mutation among which 53 were carriers and 161 were non-carriers of the mutation. In both studies, these three CpG sites were also associated (2.33 10-11,p<3.02 10-4) with biomarkers of the Protein C pathway known to be influenced by the FV Leiden mutation. A comprehensive linkage disequilibrium (LD) analysis of the whole locus revealed that the original associations were due to LD between the FV Leiden mutation and a block of single nucleotide polymorphisms (SNP) located in SLC19A2. After adjusting for this block of SNPs, the FV Leiden mutation was no longer associated with any CpG site (p<0.05). In conclusion, our work clearly illustrates some promises and pitfalls of DNA methylation investigations on peripheral blood DNA in large epidemiological cohorts. DNA methylation levels at SLC19A2 are influenced by SNPs in LD with FV Leiden, but these DNA methylation marks do not explain the incomplete penetrance of the FV Leiden mutation. © 2014 Aïssi et al. Source

Nicolini F.E.,Center Hospitalier Lyon Sud | Nicolini F.E.,French Institute of Health and Medical Research | Nicolini F.E.,French group of CML Fi LMC group | Etienne G.,Institute Bergonie | And 35 more authors.
The Lancet Haematology | Year: 2015

Background: Nilotinib is now recommended for patients with newly diagnosed chronic myeloid leukaemia in chronic phase and leads to important rates of molecular response 4.5 log (MR4.5), allowing the prospect of therapy cessation. However, most patients do not reach this criterion and nilotinib is taken for lengthy periods, resulting in chronic or late-onset adverse events. Nilotinib combined with interferon might further increase rates of MR4.5, avoid late sideeffects, and allow therapy cessation. In a phase 2 trial we aimed to assess the feasibility, safety, and deep molecular response of the combination of nilotinib (600 mg daily) and peginterferon alfa-2a in newly diagnosed patients with chronic-phase chronic myeloid leukaemia (CML). Methods: In a non-randomised, open-label, phase 2 trial, we enrolled adult patients (age ≥18 years) without any organ failure who had BCR-ABL-positive, chronic-phase CML, at diagnosis. After a priming procedure with 90 μg per week of peginterferon alfa-2a alone for a month, we gave patients peginterferon alfa-2a 45 μg per week combined with nilotinib 600 mg daily until 24 months after interferon initiation. The primary endpoint was the cumulative incidence of MR4.5 at 12 months after initiation of peginterferon alfa-2a. Data were analysed by a modifi ed intention-to-treat principle. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-019786-28. Findings: Between March 24, 2011, and Sept 27, 2011, we enrolled 42 patients. One patient withdrew consent before receiving any study treatment so was excluded from analysis; 41 patients received treatment with peginterferon alfa-2a and nilotinib. At 12 months, seven (17%) patients had achieved MR4.5. Haematological and hepatic adverse events were frequent-with grade 3-4 neutropenias occurring in ten (24%) patients, grade 3-4 thrombocytopenias occurring in ten (24%) patients, grade 3-4 cholestatic events occurring in seven (17%) patients, and grade 3-4 elevations in aspartate aminotransferase or alanine aminotransferase occurring in three (7% patients-particularly during the fi rst 3 months. However, 30 (73%) patients remained on interferon therapy at 1 year. Three grade 3-4 cardiac events (7% of patients, all coronary stenoses) occurred at later timepoints. Interpretation: The combination of peginterferon alfa-2a resulted in good molecular responses in patients. Despite substantial toxic eff ects, most patients remained on the study drugs for more than a year. This combination should now be tested in a randomised controlled trial. Source

Khoo A.-L.,Radboud University Nijmegen | Joosten I.,Nijmegen Institute for Infection Inflammation and Immunity N4i | Michels M.,Radboud University Nijmegen | Woestenenk R.,Laboratory of Haematology | And 5 more authors.
Immunology | Year: 2011

Vitamin D 3 is known to induce regulatory T (Treg) cells by rendering antigen-presenting cells tolerogenic, its direct effect on human naturally occurring Treg cells is unclear. Here, we investigated if and how 1,25-dihydroxyvitamin D 3 [1,25(OH) 2D 3] can directly affect the proliferation and function of human naturally occurring Treg cells in vitro. First, we demonstrated that these Treg cells express vitamin D receptors that were up-regulated following anti-CD3/CD28-bead stimulation. 1,25(OH) 2D 3 inhibited proliferation of Treg cells even when exogenous interleukin-2 was provided. Treg cells were more susceptible to the inhibitory effect of 1,25(OH) 2D 3 than conventional T cells . 1,25(OH) 2D 3 neither affected the anergic state nor the suppressive function of Treg cells but induced a subtle increase in interleukin-10-secreting cells. The cell-division-inhibiting effect of 1,25(OH) 2D 3 on Treg cells was also demonstrated in vivo by supplementing vitamin D-deficient HIV-1-infected patients with 2000IU cholecalciferol (vitamin D 3). Increased serum 1,25(OH) 2D 3 levels were associated with a drop in the number and percentage of Treg cells, which may be attributed to a decrease in the proliferating Foxp3 + Treg cell population. In conclusion, 1,25(OH) 2D 3 directly affects Treg cell growth and promotes interleukin-10 production without apparent effects on activation status and suppressive phenotype whereas in vivo, high serum 1,25(OH) 2D 3 levels are associated with reduced Treg cell proliferation and a reduced number of Treg cells. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd. Source

Faivre M.,CEA Grenoble | Peltie P.,CEA Grenoble | Planat-Chretien A.,CEA Grenoble | Cosnier M.-L.,CEA Grenoble | And 4 more authors.
Journal of Biomedical Optics | Year: 2011

We report a new technique to measure coagulation dynamics on whole-blood samples. The method relies on the analysis of the speckle figure resulting from a whole-blood sample mixed with coagulation reagent and introduced in a thin chamber illuminated with a coherent light. A dynamic study of the speckle reveals a typical behavior due to coagulation.We compare our measured coagulation times to a reference method obtained in a medical laboratory. © 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). Source

Discover hidden collaborations