Papers by Olivier Hermine
Biomedicines
Erythropoietin (Epo) is widely used for the treatment of anemia; however, non-hematopoietic effec... more Erythropoietin (Epo) is widely used for the treatment of anemia; however, non-hematopoietic effects and cancer risk limit its clinical applications. Therefore, alternative molecules to improve erythropoiesis in anemia patients are urgently needed. Here, we investigated the potential effects of a phytoestrogen diarylheptanoid (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol, (ASPP 049) isolated from Curcuma comosa on promoting erythropoiesis. Treatment with C. comosa extract improved anemia symptoms demonstrated by increasing red blood cell numbers, hematocrit, and hemoglobin content in anemic mice. In addition, ASPP 049, the major compound isolated from C. comosa, enhanced the suboptimal Epo dosages to improve erythroid cell differentiation from hematopoietic stem cells, which was inhibited by the estrogen receptor (ER) antagonist, ICI 182,780. Moreover, the ASPP 049-activated Epo-Epo receptor (EpoR) complex subsequently induced phosphorylation of EpoR-mediated erythropoiesis pathways: ...
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The New England journal of medicine, Jan 30, 2016
Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a po... more Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response. The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure ...
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Biology of Blood and Marrow Transplantation, 2006
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Alzheimer's Research & Therapy
Background Masitinib is an orally administered tyrosine kinase inhibitor that targets activated c... more Background Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer’s disease (AD). Methods Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12–25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of...
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<p><b>a)</b> S1P<sub>1</sub> expression ascertained by flow cytomet... more <p><b>a)</b> S1P<sub>1</sub> expression ascertained by flow cytometry in total human thymocytes and CD4/CD8-defined subsets as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103405#pone-0103405-g001" target="_blank">Figure 1c</a>. DN-1: CD4<sup>−</sup>CD8<sup>−</sup> cells; DN-2: CD4<sup>low</sup>CD8<sup>low</sup>; DP: CD4<sup>+</sup>CD8<sup>+</sup>; CD4-1: CD4<sup>low</sup>CD8<sup>−</sup>; CD4-2: CD4<sup>high</sup>CD8<sup>−</sup>; CD8-1: CD4<sup>−</sup>CD8<sup>low</sup>; CD8-2: CD4<sup>−</sup>CD8<sup>high</sup>. n = 4. <b>b)</b> Bars represent migration of thymocytes in a transwell system. Results are represented by migration ratio, and controls without stimuli were normalized to 1.0. n = 4. Cells migrate towards S1P and when SEMA3F was combined with S1P, it inhibited S1P-induced thymocyte migration. <b>c)</b> Migration response of thymocytes from a representative experiment. Bottom panel show the migration of thymocyte subpopulations based on CD4/CD8 expression, showing that SEMA3F had effect and impaired S1P-induced migration in all thymocyte subpopulations. DP = double-positive, CD4 = CD4 single positive, CD8 = CD8 single-positive. <b>d)</b> Bars show the numbers of migrating thymocytes. The black bar represent thymocyte migration of cells pre-treated with anti-NRP2 blocking antibody which partially abrogated SEMA3F action, as the difference observed between S1P and S1P+SEMA3F+anti-NRP2 is no longer significant (n = 3). <b>e)</b> F-actin modulation of human thymocytes (n = 4) was analyzed by flow cytometry and represented as [(MFI after addition of ligand)/(MFI before addition of ligand)]×100. MFI values obtained before addition of ligand were arbitrarily set at 100% that corresponded to time zero. Data are represented as means ± SEM.Results were analyzed by the unpaired Student's <i>t</i> test, comparing each time point with time zero. Differences were considered statistically significant when p<0.05 (*).</p
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Cell Death & Differentiation
Red blood cell production is negatively controlled by the rate of apoptosis at the stage of CFU-E... more Red blood cell production is negatively controlled by the rate of apoptosis at the stage of CFU-E/pro-erythroblast differentiation, depending on the balance between erythropoietin (EPO) levels and activation of the Fas/FasL pathway. At this stage, activation of transient caspases through depolarization via mitochondrial outer membrane permeabilization (MOMP) is also required for terminal erythroid differentiation. Molecular mechanisms regulating the differential levels of MOMP during differentiation and apoptosis, however, remain poorly understood. Here we show a novel and essential role for the caspase-10-P13-tBID axis in erythroid terminal differentiation. Caspase-10 (but not caspase-8, which is activated during apoptosis) is activated at the early stages of erythroid terminal differentiation leading to the cleavage of P22-BID into P18-tBID, and later into P13-tBID. Erythropoietin (EPO) by inducing casein kinase I alpha (CKIα) expression, which in turn phosphorylates P18-tBID, pre...
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<p>(A-C) Nrp1<sup>-</sup> Tfh, Nrp1<sup>+</sup> Tfh and non-Tfh cel... more <p>(A-C) Nrp1<sup>-</sup> Tfh, Nrp1<sup>+</sup> Tfh and non-Tfh cells were sorted as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085589#pone-0085589-g001" target="_blank">Figure 1</a> and cultured with autologous B cells in the absence of exogenous stimuli. (A) Representative expression of CD25 and Nrp1 on T cells (top) and B cells (bottom) after 5 days of culture. (B) Percentage of Nrp1<sup>+</sup> cells among T or B cells after 5 days of culture. (C) Percentage of Nrp1<sup>+</sup> cells among T cells after 24, 48 and 72 hours of culture. In B and C, representative data from one out of three distinct experiments are shown. (D) Nrp1 expression on sorted Nrp1<sup>+</sup> Tfh cells after 5 days of culture alone (dark line) or with autologous B cells (shaded histogram). (E-F) Nrp1<sup>-</sup> Tfh cells were cultured with autologous B cells in the absence or presence of a transwell membrane separating the two cell types. (E) Representative Nrp1 expression on T cells after 5 days of culture. (F) Number of live B cells per well after 5 days of culture. (G-J) Autologous or allogeneic cocultures were performed using Nrp1<sup>-</sup> Tfh and B cells sorted from two distinct tonsils (a) and (b). (G) Nrp1 expression on T cells after 5 days of culture. Data represent one experiment with triplicate wells and are representative of three distinct experiments. (I-J) IgG production in culture supernatant after 10 days of culture. (K-L) Sorted naive, GC or memory B cells were cultured in the absence or presence of autologous CXCR5<sup>-</sup> Nrp1<sup>-</sup> non-Tfh cells or CXCR5<sup>+</sup> Nrp1<sup>-</sup> Tfh cells. (K) Nrp1 expression on non-Tfh cells and Nrp1<sup>-</sup> Tfh cells after 4 days of culture. (L) IgG production in culture supernatants after 14 days of culture. Data were compared using Student’s impaired t-test (*: p≤0.05, **: p≤0.01).</p
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Therapeutic Advances in Neurological Disorders, 2021
Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated th... more Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to init...
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Introduction Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by the t(11;14) transl... more Introduction Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by the t(11;14) translocation and cyclin D1 overexpression. MCLs compose 3% to 6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries. MCL has been identified as aggressive, with median survival reaching only 3 to 4 years. However, while most MCL cases fit a pattern of continuous relapses, the results of several studies indicate that new therapeutic strategies appear to improve outcomes. It is not yet entirely clear how these results will translate into the general population. In addition, MCL is a heterogeneous entity; a significant number of indolent patients with MCL do not require any treatment for months or even years. On the other hand, a minority of patients with MCL, whose disease becomes resistant to standard therapies, has a particularly unfavorable outcome.
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Mucosal Immunology, 2021
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F1000Research, 2019
Mastocytosis is a rare disease due to the abnormal accumulation of mast cells in various tissues.... more Mastocytosis is a rare disease due to the abnormal accumulation of mast cells in various tissues. Its clinical presentation is heterogeneous depending on mast cell infiltration and mediators release. In some cases, it is associated with hematological malignancies. Prognosis varies from very good with a life expectancy similar to the general population in indolent forms of the disease to a survival time of just a few months in mast cell leukemia. Although in most cases a somatic KIT D816V mutation is found in tumor mast cells, the physiopathology of the disease is not yet fully understood. Additional germline and somatic mutations may explain this heterogeneity. Treatments aim at blocking effect of mast cell mediators, reducing mast cell activation and tumor burden. New drugs mainly directed against the tyrosine kinase activity of KIT have dramatically changed the quality of life and prognosis of mast cell diseases. Present and future therapeutic strategies are discussed in this review.
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Frontiers in Microbiology, 2020
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Annals of Lymphoma, 2020
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Retrovirology, 2020
Background Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature lymphoid proliferation as... more Background Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature lymphoid proliferation associated with poor prognosis. Standard of care includes chemotherapy and/or the combination of zidovudine and interferon-alpha. However, most patients experience relapse less than 6 months after diagnosis. Allogeneic stem cell transplantation is the only curative treatment, but is only feasible in a minority of cases. We previously showed in a mouse model that Arsenic trioxide (As2O3) targets ATL leukemia initiating cells. Results As2O3 consolidation was given in 9 patients with ATL (lymphoma n = 4; acute n = 2; and indolent n = 3), who were in complete (n = 4) and partial (n = 3) remission, in stable (n = 1) and in progressive (n = 1) disease. Patients received up to 8 weeks of As2O3 at the dose of 0.15 mg/kg/day intravenously in combination with zidovudine and interferon-alpha. One patient in progression died rapidly. Of the remaining eight patients, three with indolent ATL subtype sho...
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Blood, 2004
Red blood cell production depends on apoptosis rate of erythroid progenitors and precursors. This... more Red blood cell production depends on apoptosis rate of erythroid progenitors and precursors. This process is mainly regulated by the glycoprotein Erythropoietin (Epo), which positively regulates through the JAK/STAT5 pathway, in synergy with the transcription factor GATA-1, the expression of the antiapoptotic protein Bcl-XL. Thus, Epo starvation results in caspase-3 activation through the intrinsic mitochondrial pathway, and as a consequence GATA-1 is cleaved and apoptosis occurs. Recently we have shown that caspase-3 activation is also absolutely required for the morphological changes that occur during normal human terminal erythroid differentiation, including chromatin condensation as well as nucleus and cell size reduction. In this context, although activated caspase-3 colocalizes in the nucleus with GATA-1, apoptosis and GATA-1 cleavage do not occur (Zermati et al J exp med, 2001, 193; 247–254). Heat Shock Proteins (Hsp) are chaperons that play a major role as a modulator of apo...
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Advances in therapy, 2018
Adult T-cell leukemia-lymphoma (ATL), a rare and aggressive T-cell malignancy caused by human T-c... more Adult T-cell leukemia-lymphoma (ATL), a rare and aggressive T-cell malignancy caused by human T-cell lymphotropic virus type 1 (HTLV-1), is associated with a poor prognosis. Evidence-based standard treatment options are lacking and outcomes are generally unsatisfactory, particularly for patients with relapsed or refractory disease. Continued research is contributing to changing treatment landscape as a number of existing and investigational agents are evaluated. We describe the epidemiology of HTLV-1 and ATL, discuss the biology behind the disease, review current treatment practices and guidelines, and provide an overview of emerging therapies in ATL, with a focus on those for relapsed or refractory disease.
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Blood and Lymphatic Cancer: Targets and Therapy, 2017
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Neurobiology of Aging, 2016
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Leukemia, 2016
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Current Opinion in Hematology, 2016
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Papers by Olivier Hermine