Mutational analysis of BCORL1 in the leukemic transformation of chronic myeloproliferative neoplasms.

BCORL1 mutations do not seem to be commonly associated with leukemic transformation of MPN, further substantiating the different molecular profile compared with denovo leukemias. Although the small number of cases does not allow us to exclude that BCORL1 mutations can be found also in post-MPN AML, their occurrence is, at least, very infrequent and their detection does not appear to deserve clinical relevance

Shared and Distinctive Ultrastructural Abnormalities Expressed by Megakaryocytes in Bone Marrow and Spleen From Patients With Myelofibrosis

Numerous studies have documented ultrastructural abnormalities in malignant megakaryocytes from bone marrow (BM) of myelofibrosis patients but the morphology of these cells in spleen, an important extramedullary site in this disease, was not investigated as yet. By transmission-electron microscopy, we compared the ultrastructural features of megakaryocytes from BM and spleen of myelofibrosis patients and healthy controls. The number of megakaryocytes was markedly increased in both BM and spleen. However, while most of BM megakaryocytes are immature, those from spleen appear mature with well-developed demarcation membrane systems (DMS) and platelet territories and are surrounded by platelets. In BM megakaryocytes, paucity of DMS is associated with plasma (thick with protrusions) and nuclear (dilated with large pores) membrane abnormalities and presence of numerous glycosomes, suggesting a skewed metabolism toward insoluble polyglucosan accumulation. By contrast, the membranes of the megakaryocytes from the spleen were normal but these cells show mitochondria with reduced crests, suggesting deficient aerobic energy-metabolism. These distinctive morphological features suggest that malignant megakaryocytes from BM and spleen express distinctive metabolic impairments that may play different roles in the pathogenesis of myelofibrosis

STAT1 activation in association with JAK2 exon 12 mutations

La inclusión de la perspectiva de género en la actividad jurisdiccional es una demanda sostenida de los colectivos feministas y de mujeres, dado que las sentencias tienen un poder performativo y envían un mensaje a la sociedad: “[…] tienen un poder individual y colectivo que impactan en la vida de las personas y conforman la identidad del poder judicial como un actor imprescindible en la construcción de un Estado democrático de derecho” (Suprema Corte de Justicia de la Nación, 2013:7). La incorporación de la perspectiva de género viene a garantizar la igualdad de posiciones (Kessler, 2014) entre mujeres y varones como una meta, trascendiendo la mera igualdad de oportunidades que hasta el presente se ha demostrado insuficiente para que las mujeres consigamos una ciudadanía plena. Al momento de incorporar la perspectiva de género en las sentencias, quienes juzgan deben tener presente en primer lugar, el impacto diferenciado de las normas en base al sexo de las personas. En segundo lugar, la interpretación y aplicación de las leyes en relación con (y en base a) estereotipos de género. Si, por ejemplo, quienes imparten justicia no tienen presentes los estereotipos de género vigentes detrás de las violaciones a los derechos humanos de las mujeres, si no los detectan ni cuestionan, entonces los reproducen. Tal como sostiene Scott (1996) el género es una categoría imprescindible para el análisis social. En tercer lugar, al momento del juzgamiento, se deben tener en cuenta las exclusiones legitimadas por la ley por pensar el mundo en términos binarios y androcéntricos; en cuarto lugar, la distribución no equitativa de recursos y poder que opera entre varones y mujeres en el marco de una organización social patriarcal, y, por último, el trato diferenciado por género legitimado por las propias leyes.Eje 3: Tramas violentas y espacios de exclusión.Instituto de Cultura Jurídic

Comparing the safety and efficacy of ruxolitinib in patients with Dynamic International Prognostic Scoring System low-, intermediate-1-, intermediate-2-, and high-risk myelofibrosis in JUMP, a Phase 3b, expanded-access study

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, has demonstrated durable improvements in patients with myelofibrosis. In this analysis of the Phase 3b JUMP study, which included patients aged =18 years with a diagnosis of primary or secondary myelofibrosis, we assessed the safety and efficacy of ruxolitinib in patients stratified by Dynamic International Prognostic Scoring System (DIPSS) risk categories. Baseline characteristic data were available to assess DIPSS status for 1844 of the 2233 enrolled patients; 60, 835, 755, and 194 in the low-, intermediate (Int)-1-, Int-2-, and high-risk groups, respectively. Ruxolitinib was generally well tolerated across all risk groups, with an adverse-event (AE) profile consistent with previous reports. The most common hematologic AEs were thrombocytopenia and anemia, with highest rates of Grade =3 events in high-risk patients. Approximately, 73% of patients experienced =50% reductions in palpable spleen length at any point in the =24-month treatment period, with highest rates in lower-risk categories (low, 82.1%; Int-1, 79.3%; Int-2, 67.1%; high risk, 61.6%). Median time to spleen length reduction was 5.1 weeks and was shortest in lower-risk patients. Across measures, 40%–57% of patients showed clinically meaningful symptom improvements, which were observed from 4 weeks after treatment initiation and maintained throughout the study. Overall survival (OS) was 92% at Week 72 and 75% at Week 240 (4.6 years). Median OS was longer for Int-2-risk than high-risk patients (253.6 vs. 147.3 weeks), but not evaluable in low-/Int-1-risk patients. By Week 240, progression-free survival (PFS) and leukemia-free survival (LFS) rates were higher in lower-risk patients (PFS: low, 90%; Int-1, 82%; Int-2, 46%; high risk, 15%; LFS: low, 92%; Int-1, 86%; Int-2, 58%; high risk, 19%). Clinical benefit was seen across risk groups, with more rapid improvements in lower risk patients. Overall, this analysis indicates that ruxolitinib benefits lower-risk DIPSS patients in addition to higher risk

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

Background: The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods: We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. Results: PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. Conclusions: These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed

Role of nutrients on lipid peroxidation and antioxidant defense system

Espécies reativas de oxigênio são formadas durante o metabolismo aeróbico e podem danificar lipídios, proteínas, carboidratos e o DNA. Essas reações, potencialmente deletérias, são controladas por um sistema de antioxidantes enzimáticos e não enzimáticos, que eliminam os próoxidantes e “varrem” os radicais livres. Esta revisão mostra o papel de alguns nutrientes na peroxidação lipídica e no sistema de defesa antioxidante. Enfatizam-se os mecanismos que levam ao dano oxidativo e sua proteção, assim como as implicações na saúde humana.Reactive oxygen species are generated in aerobic metabolism and can damage lipids, proteins, carbohydrates and DNA. These potentially deleterious reactions are controlled by a system of enzymatic and non-enzymatic antioxidants which eliminates prooxidants and scavenge free radicals. This revision focuses the role of particular nutrients in lipid peroxidation and antioxidant defense system. Emphasis was placed on mechanisms for damage and protection, as well implications in human healthy issues

Results of Phase II Clinical Trial MPD-RC 101: Allogeneic Hematopoietic Stem Cell Transplantation Conditioned with Fludarabine/Melphalan in Patients with Myelofibrosis

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Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea

Prior studies have reported high response rates with recombinant interferon-a (rIFN-a) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-a,we investigated the outcomes of pegylated-rIFN-a2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PVwho were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 monthswere 69.2%(43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P 5 .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was 26% (range, 284%to 47%) in patients achieving a CR vs 14%(range, 218% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU