Antilymphocyte globulin for matched sibling donor transplantation in patients with myelofibrosis

The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n= 287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P= 0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versushost disease without increasing the risk of relapse.Peer reviewe

Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Erratum in : Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR. [Cell. 2019]International audienceInnate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-likereceptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatorysignals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect theimmune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DC)are exacerbated by a high fatty acid (FA) metabolic environment. FA suppress the TLR-inducedhexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changesenhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded proteinresponse (UPR) leading to a distinct transcriptomic signature, with IL-23 as hallmark. Interestingly,chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response.Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innateimmunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR

The European Hematology Association Roadmap for European Hematology Research: a consensus document

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients

The European Hematology Association Roadmap for European Hematology Research. A Consensus Document

Abstract The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at Euro 23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. Received December 15, 2015. Accepted January 27, 2016. Copyright © 2016, Ferrata Storti Foundatio

Determination of the melting temperature, heat of fusion, and purity analysis of different samples of zidovudine (AZT) using DSC

The determination of chemical purity, melting range, and variation of enthalpy in the process of characterizing medicines is one of the principal requirements evaluated in quality control of the pharmaceutical industry. In this study, the method of purity determination using DSC was outlined, as well as the application of this technique for the evaluation of commercial samples of zidovudine (AZT) (raw material) supplied by different laboratories. To this end, samples from six different laboratories (A, B, C, D, E, and F) and the standard reference (R) from the United States Pharmacopeia (USP) were analyzed. The DSC curves were obtained in the temperature range of 25 to 200 ºC under the dynamic atmosphere of N2 (50 mL min-1), heating rate of β=2 ºC min-1, using an Al capsule containing approximately 2 mg of sample material. The results demonstrated that the standard reference presented a proportion of 99.83% whereas the AZT samples presented a variation ranging from 97.59 to 99.54%. In addition, the standard reference was found to present a temperature of onset of melting point of 122.80 °C. Regarding the samples of active agents provided by the different laboratories, a variation ranging from 118.70 to 122.87 °C was measured. In terms of ΔHm, the samples presented an average value of 31.12 kJ mol-1._________________________________________________________________________________________ RESUMO: A determinação da pureza química, a faixa de fusão e a variação de entalpia envolvida no processo de caracterização de fármacos é um dos principais requisitos avaliados no controle de qualidade em indústrias farmacêuticas. Neste trabalho é feita uma breve abordagem sobre o método de determinação de pureza utilizando DSC, assim como a aplicação desta técnica para avaliação de amostras comerciais de zidovudina (AZT) (matéria-prima) fornecida por diferentes laboratórios. Para tal, foram analisadas amostras de seis diferentes laboratórios (A,B,C,D,E e F) e a substância química de referência (R) da United States Pharmacopeia (USP). As curvas DSC foram obtidas na faixa de temperatura entre 25 a 200 ºC, sob atmosfera dinâmica de N2 (50 mL min-1), β=2 ºC min-1, utilizando cápsula de Al contendo aproximadamente 2 mg de amostra. De acordo com os resultados, pode-se observar que a substância química de referência apresentou teor igual a 99,83% e que as amostras de AZT apresentaram uma faixa de variação entre 97,59 e 99,54%. Pode-se verificar, ainda, que a substância química de referência apresentou uma temperatura onset de fusão igual a 122,80 °C. Para as amostras dos princípios ativos fornecidos pelos diferentes laboratórios, pode-se verificar uma faixa de variação entre 118,70 e 122,87 °C. No que se refere ao ΔHm, as amostras apresentaram valor médio de 31,12 kJ.mol-1

RUNX1 DNA-Binding Mutants, Associated with Minimally Differentiated Acute Myelogenous Leukemia, Disrupt Myeloid Differentiation

Mutations in the RUNX1 gene are found at high frequencies in minimally differentiated acute myelogenous leukemia. In addition to null mutations, many of the mutations generate Runx1 DNA-binding (RDB) mutants. To determine if these mutants antagonize wild-type protein activity, cDNAs were transduced into murine bone marrow or human cord blood cells using retroviral vectors. Significantly, the RDB mutants did not act in a transdominant fashion in vivo to disrupt Runx1 activity in either T-cell or platelet development, which are highly sensitive to Runx1 dosage. However, RDB mutant expression impaired expansion and differentiation of the erythroid compartment in which Runx1 expression is normally down-regulated, showing that a RDB-independent function is incompatible with erythroid differentiation. Significantly, both bone marrow progenitors expressing RDB mutants or deficient for Runx1 showed increased replating efficiencies in vitro, accompanied by the accumulation of myeloblasts and dysplastic progenitors, but the effect was more pronounced in RDB cultures. Disruption of the interface that binds CBFbeta, an important cofactor of Runx1, did not impair RDB mutant replating activity, arguing against inactivation of Runx1 function by CBFbeta sequestration. We propose that RDB mutants antagonize Runx1 function in early progenitors by disrupting a critical balance between DNA-binding-independent and DNA-binding-dependent signaling. [Cancer Res 2007;67(2):537-45]