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https://www.readbyqxmd.com/read/28324272/lusutrombopag-increases-hematocytes-in-a-compensated-liver-cirrhosis-patient
#1
Akira Sakamaki, Takayuki Watanabe, Satoshi Abe, Kenya Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai
A 56-year-old Japanese man with liver cirrhosis (LC) due to hepatitis C virus was admitted to our hospital for radiofrequency ablation of residual tumor following lusutrombopag administration. Laboratory tests revealed thrombocytopenia and leukopenia. The patient's LC was managed, and he was classified as Child-Pugh A. After admission, lusutrombopag was administered for 7 days. The platelet count increased to over 50,000/mm(3) after 7-14 days and returned to previous levels 50 days after administration. Leukocyte and erythrocyte counts also increased in response to the treatment and stayed elevated for over 120 days...
March 21, 2017: Clinical Journal of Gastroenterology
https://www.readbyqxmd.com/read/28301587/the-duplication-mutation-of-quebec-platelet-disorder-dysregulates-plau-but-not-c10orf55-selectively-increasing-production-of-normal-plau-transcripts-by-megakaryocytes-but-not-granulocytes
#2
Catherine P M Hayward, Minggao Liang, Subia Tasneem, Asim Soomro, John S Waye, Andrew D Paterson, Georges E Rivard, Michael D Wilson
Quebec Platelet disorder (QPD) is a unique bleeding disorder that markedly increases urokinase plasminogen activator (uPA) in megakaryocytes and platelets but not in plasma or urine. The cause is tandem duplication of a 78 kb region of chromosome 10 containing PLAU (the uPA gene) and C10orf55, a gene of unknown function. QPD increases uPA in platelets and megakaryocytes >100 fold, far more than expected for a gene duplication. To investigate the tissue-specific effect that PLAU duplication has on gene expression and transcript structure in QPD, we tested if QPD leads to: 1) overexpression of normal or unique PLAU transcripts; 2) increased uPA in leukocytes; 3) altered levels of C10orf55 mRNA and/or protein in megakaryocytes and leukocytes; and 4) global changes in megakaryocyte gene expression...
2017: PloS One
https://www.readbyqxmd.com/read/28297583/assessment-of-drug-sensitivity-in-hematopoietic-stem-and-progenitor-cells-from-acute-myelogenous-leukemia-and-myelodysplastic-syndrome-ex-vivo
#3
Katherine L B Knorr, Laura E Finn, B Douglas Smith, Allan D Hess, James M Foran, Judith E Karp, Scott H Kaufmann
Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28297572/safety-and-efficacy-of-megakaryocytes-induced-from-hematopoietic-stem-cells-in-murine-and-nonhuman-primate-models
#4
Xin Guan, Meng Qin, Yu Zhang, Yanan Wang, Bin Shen, Zhihua Ren, Xinxin Ding, Wei Dai, Yongping Jiang
Because of a lack of platelet supply and a U.S. Food and Drug Administration-approved platelet growth factor, megakaryocytes have emerged as an effective substitute for alleviating thrombocytopenia. Here, we report the development of an efficient two-stage culture system that is free of stroma, animal components, and genetic manipulations for the production of functional megakaryocytes from hematopoietic stem cells. Safety and functional studies were performed in murine and nonhuman primate models. One human cryopreserved cord blood CD34(+) cell could be induced ex vivo to produce up to 1...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28294327/fibroblast-dynamics-as-an-in-vitro-screening-platform-for-anti-fibrotic-drugs-in-primary-myelofibrosis
#5
Ciprian Tomuleasa, Sonia Selicean, Grigore Gafencu, Bobe Petrushev, Laura Pop, Cristian Berce, Anca Jurj, Adrian Trifa, Ana-Maria Rosu, Sergiu Pasca, Lorand Magdo, Mihnea Zdrenghea, Delia Dima, Alina Tanase, Ioana Frinc, Anca Bojan, Ioana Berindan- Neagoe, Gabriel Ghiaur, Stefan O Ciurea
Although the cause for bone marrow fibrosis in patients with myelofibrosis remains controversial, it has been hypothesized that it is caused by extensive fibroblast proliferation under the influence of cytokines generated by the malignant megakaryocytes. Moreover, there is no known drug therapy which could reverse the process. We studied the fibroblasts in a novel system using the hanging drop method, evaluated whether the fibroblasts obtain from patients are part of the malignant clone of not and, using this system, we screen a large library of FDA-approved drugs to identify potential drugs candidates that might be useful in the treatment of this disease, specifically which would inhibit fibroblast proliferation and the development of bone marrow fibrosis...
March 11, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28293407/thrombocytopenia-in-patients-with-chronic-hepatitis-c-virus-infection
#6
REVIEW
Sumit Dahal, Smrity Upadhyay, Rashmi Banjade, Prajwal Dhakal, Nabin Khanal, Vijaya Raj Bhatt
Thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection is a major problem. The pathophysiology is multifactorial, with auto-immunogenicity, direct bone marrow suppression, hypersplenism, decreased production of thrombopoietin and therapeutic adverse effect all contributing to thrombocytopenia in different measures. The greatest challenge in the care of chronic HCV patients with thrombocytopenia is the difficulty in initiating or maintaining IFN containing anti-viral therapy. Although at present, it is possible to avoid this challenge with the use of the sole Direct Antiviral Agents (DAAs) as the primary treatment modality, thrombocytopenia remains of particular interest, especially in cases of advanced liver disease...
2017: Mediterranean Journal of Hematology and Infectious Diseases
https://www.readbyqxmd.com/read/28292442/eto2-glis2-hijacks-transcriptional-complexes-to-drive-cellular-identity-and-self-renewal-in-pediatric-acute-megakaryoblastic-leukemia
#7
Cécile Thirant, Cathy Ignacimouttou, Cécile K Lopez, M'Boyba Diop, Lou Le Mouël, Clarisse Thiollier, Aurélie Siret, Phillipe Dessen, Zakia Aid, Julie Rivière, Philippe Rameau, Céline Lefebvre, Mehdi Khaled, Guy Leverger, Paola Ballerini, Arnaud Petit, Hana Raslova, Catherine L Carmichael, Benjamin T Kile, Eric Soler, John D Crispino, Christian Wichmann, Françoise Pflumio, Jürg Schwaller, William Vainchenker, Camille Lobry, Nathalie Droin, Olivier A Bernard, Sébastien Malinge, Thomas Mercher
Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28277061/%C3%AE-granule-biogenesis-from-disease-to-discovery
#8
Chang Hua Chen, Richard W Lo, Denisa Urban, Fred G Pluthero, Walter H A Kahr
Platelets are critical to hemostasis and thrombosis. Upon detecting injury, platelets show a range of responses including the release of protein cargo from α-granules. This cargo is synthesized by platelet precursor megakaryocytes or endocytosed by megakaryocytes and/or platelets. Insights into α-granule biogenesis have come from studies of hereditary conditions where these granules are immature, deficient or absent. Studies of Arthrogryposis, Renal dysfunction, and Cholestasis (ARC) syndrome identified the first proteins essential to α-granule biogenesis: VPS33B and VPS16B...
March 2017: Platelets
https://www.readbyqxmd.com/read/28273187/-the-role-of-driver-and-subclonal-mutations-in-pathogenesis-of-primary-myelofibrosis
#9
Réka Mózes, Ambrus Gángó, Zsófia Boha, Judit Csomor, Csaba Bödör
Primary myelofibrosis (PMF) is a Philadelphia chromosome negative, clonal myeloproliferative neoplasm characterised by a progressive nature. Morphologically, the bone marrow biopsy shows features of abnormal proliferation of terminally differentiated megakaryocytes and subsequent bone marrow fibrosis. The molecular landscape of PMF includes phenotypic driver mutations (JAK2 V617F, CALR and MPL) which represent major diagnostic criteria, and subclonal mutations that also occur in several other myeloid diseases, but have a prognostic value in disease progression of MF...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28270692/imetelstat-a-telomerase-inhibitor-differentially-affects-normal-and-malignant-megakaryopoiesis
#10
G Mosoyan, T Kraus, F Ye, K Eng, J D Crispino, R Hoffman, C Iancu-Rubin
Imetelstat (GRN163L) is a specific telomerase inhibitor which has demonstrated clinical activity in patients with myeloproliferative neoplasms (MPN) and in patients with solid tumors. The antitumor effects were associated with the development of thrombocytopenia, one of the common side effects observed in patients treated with imetelstat. The events underlying these adverse effects are not apparent. In this report we investigated the potential mechanisms that account for imetelstat's beneficial effects in MPN patients and the manner by which imetelstat treatment leads to a reduction in platelet numbers...
March 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28264687/hyperglycemia-enhances-arsenic-induced-platelet-and-megakaryocyte-activation
#11
Jonathan D Newman, Christina T Echagarruga, Yoscar M Ogando, Emilie Montenont, Yu Chen, Edward A Fisher, Jeffrey S Berger
OBJECTIVE: Low to moderate inorganic arsenic (iAs) exposure is independently associated with cardiovascular disease (CVD), particularly for patients with diabetes mellitus (DM). The mechanism of increased CVD risk from iAs exposure in DM has not been adequately characterized. We evaluated whether increasing concentrations of glucose enhance the effects of iAs on platelet and megakaryocyte activity, key steps in atherothrombosis. METHODS: Healthy donor whole blood was prepared in a standard fashion and incubated with sodium arsenite in a range from 0 to 10 µM...
March 6, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28260027/pstat5-and-erk-exhibit-different-expression-in-myeloproliferative-neoplasms
#12
Ewa Wiśniewska-Chudy, Łukasz Szylberg, Grzegorz Dworacki, Ewa Mizera-Nyczak, Andrzej Marszałek
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic progenitor cell disorders characterized by the proliferation of one or more hematopoietic lineages. The classical MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) entities. These disorders are characterized by bone marrow morphology typical for each disease, and by the presence of JAK2V617F mutation in the marrow and blood. However, JAK2V617F cannot account for the phenotypic heterogeneity of MPNs because approximately half of all cases of ET and PMF show no evidence of this molecular marker...
February 24, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28256646/magnetic-nanoparticles-for-drug-targeting-from-design-to-insights-into-systemic-toxicity-preclinical-evaluation-of-hematological-vascular-and-neurobehavioral-toxicology
#13
Mariela A Agotegaray, Adrián E Campelo, Roberto D Zysler, Fernanda Gumilar, Cristina Bras, Ariel Gandini, Alejandra Minetti, Virginia L Massheimer, Verónica L Lassalle
A simple two-step drug encapsulation method was developed to obtain biocompatible magnetic nanocarriers for the potential targeted treatment of diverse diseases. The nanodevice consists of a magnetite core coated with chitosan (Chit@MNPs) as a platform for diclofenac (Dic) loading as a model drug (Dic-Chit@MNPs). Mechanistic and experimental conditions related to drug incorporation and quantification are further addressed. This multi-disciplinary study aims to elucidate the toxicological impact of the MNPs at hematological, vascular, neurological and behavioral levels...
March 3, 2017: Biomaterials Science
https://www.readbyqxmd.com/read/28255014/macrothrombocytopenia-and-dense-granule-deficiency-associated-with-fli1-variants-ultrastructural-and-pathogenic-features
#14
Paul Saultier, Léa Vidal, Matthias Canault, Denis Bernot, Céline Falaise, Catherine Pouymayou, Jean-Claude Bordet, Noémie Saut, Agathe Rostan, Véronique Baccini, Franck Peiretti, Marie Favier, Pauline Lucca, Jean-François Deleuze, Robert Olaso, Anne Boland, Pierre Emmanuel Morange, Christian Gachet, Fabrice Malergue, Sixtine Fauré, Anita Eckly, David-Alexandre Trégouët, Marjorie Poggi, Marie-Christine Alessi
Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel FLI1 variants (c.1010G>A and c.1033A>G) responsible for macrothrombocytopenia. The FLI1 variant carriers platelets exhibited a defect in aggregation induced by low dose ADP, collagen and TRAP, a defect in ATP secretion, a reduced mepacrine uptake and release and a reduced CD63 expression upon TRAP stimulation...
March 2, 2017: Haematologica
https://www.readbyqxmd.com/read/28254560/homeopathic-medicines-cause-th1-predominance-and-induce-spleen-and-megakaryocytes-changes-in-balb-c-mice-infected-with-leishmania-infantum
#15
Ana Paula Bacellar Cajueiro, Ester Puna Goma, Hilton Antônio Mata Dos Santos, Igor Almeida Rodrigues, Helena Keiko Toma, Silvana Marques Araújo, Leoni Villano Bonamin, Nelson Brêtas de Noronha Gomes, Morgana Teixeira Lima Castelo-Branco, Edilma Paraguai de Souza Dias, Alexandre Dos Santos Pyrrho, Carla Holandino
The prevalence of Th1/Th2 response, spleen changes and megakaryocytes were investigated in BALB/c mice (n=138) infected with Leishmania infantum, and treated with Leishmania infantum 30× (10(-30)) biotherapy - BioLi30×. We performed controlled experiments using 8-to-12-week-old mice, infected with 5×10(7)L. infantum promastigotes, divided into eight groups: G1 (healthy), G2 (infected with L. infantum), G3 (BioLi30× pre-treated), G4 (BioLi30× pre/post-treated), G5 (BioLi30× post-treated), G6 (Water 30× post-treated), G7 (Antimonium crudum 30× post-treated) and G8 (Glucantime® post-treated)...
February 27, 2017: Cytokine
https://www.readbyqxmd.com/read/28252626/-numbers-of-early-cd34-progenitors-of-bone-marrow-hematopoiesis-in-patients-with-diffuse-large-b-cell-lymphoma
#16
E I Dorokhina, A U Magomedova, I V Galtseva, V N Dvirnyk, S A Glinkina, S M Kulikov, S K Kravchenko
AIM: To estimate the number of early progenitors of bone marrow (BM) hematopoiesis in patients with diffuse large B-cell lymphoma (DLBCL) in the late period after high-dose chemotherapy (HDCT) according to the mNHL-BFM-90 program. SUBJECTS AND METHODS: The investigators analyzed the results of BM immunophenotypic and histological studies in 40 patients (median age, 57 years) with DLBCL who received HDCT according to the mNHL-BFM-90 program at the Hematology Research Center (HRC), Ministry of Health of the Russian Federation (MHRF), in the period 2002 to 2009...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/28251237/identification-of-a-functional-genetic-variant-driving-racially-dimorphic-platelet-gene-expression-of-the-thrombin-receptor-regulator-pctp
#17
Xianguo Kong, Lukas M Simon, Michael Holinstat, Chad A Shaw, Paul F Bray, Leonard C Edelstein
Platelet activation in response to stimulation of the Protease Activated Receptor 4 (PAR4) receptor differs by race. One factor that contributes to this difference is the expression level of Phosphatidylcholine Transfer Protein (PCTP), a regulator of platelet PAR4 function. We have conducted an expression Quantitative Trait Locus (eQTL) analysis that identifies single nucleotide polymorphisms (SNPs) linked to the expression level of platelet genes. This analysis revealed 26 SNPs associated with the expression level of PCTP at genome-wide significance (p < 5×10(-8))...
March 2, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28243916/myeloid-precursors-in-the-bone-marrow-of-mice-after-a-30-day-space-mission-on-a-bion-m1-biosatellite
#18
E V Sotnezova, E A Markina, E R Andreeva, L B Buravkova
The content of myeloid stem CFU in bone marrow karyocytes from the tibial bone of C57Bl/6 mice was evaluated after a 30-day Bion-M1 pace flight/ground control experiment and subsequent 7-day recovery period. After the space flight, we observed a significant decrease in the number of erythroid progenitors in the bone marrow, including common myeloid precursor - granulocyte, erythrocyte, monocyte/macrophage, megakaryocyte CFU. After 7-day readaptation, CFU level in flight animals did not recover completely. In the ground control, the count of erythroid burst-forming units was higher than in vivarium animals...
February 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28240607/downregulation-of-gata1-drives-impaired-hematopoiesis-in-primary-myelofibrosis
#19
Laure Gilles, Ahmet Dirim Arslan, Christian Marinaccio, Qiang Jeremy Wen, Priyanka Arya, Maureen McNulty, Qiong Yang, Jonathan C Zhao, Katerina Konstantinoff, Terra Lasho, Animesh Pardanani, Brady Stein, Isabelle Plo, Sriram Sundaravel, Amittha Wickrema, Annarita Migliaccio, Sandeep Gurbuxani, William Vainchenker, Leonidas C Platanias, Ayalew Tefferi, John D Crispino
Primary myelofibrosis (PMF) is a clonal hematologic malignancy characterized by BM fibrosis, extramedullary hematopoiesis, circulating CD34+ cells, splenomegaly, and a propensity to evolve to acute myeloid leukemia. Moreover, the spleen and BM of patients harbor atypical, clustered megakaryocytes, which contribute to the disease by secreting profibrotic cytokines. Here, we have revealed that megakaryocytes in PMF show impaired maturation that is associated with reduced GATA1 protein. In investigating the cause of GATA1 downregulation, our gene-expression study revealed the presence of the RPS14-deficient gene signature, which is associated with defective ribosomal protein function and linked to the erythroid lineage in 5q deletion myelodysplastic syndrome...
February 27, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28239144/increased-megakaryocytic-proliferation-pro-platelet-deposition-and-expression-of-fibrosis-associated-factors-in-children-with-chronic-myeloid-leukemia-with-bone-marrow-fibrosis
#20
K Hussein, A Stucki-Koch, G Göhring, H Kreipe, M Suttorp
Pediatric chronic myeloid leukemia (ped-CML) is rare and ped-CML with fibre accumulation in the bone marrow (MF) is thought to be even rarer. In adults (ad-CML), fibrosis represents an adverse prognostic factor. So far, the pro-fibrotic changes in the bone marrow microenvironment have not been investigated in detail in ped-CML. From a total of 66 ped-CML in chronic phase, biopsies were analysable and 10 had MF1/2 (MF1, n=8/10; MF2, n=2/10). We randomly selected 16 ped-CML and 16 ad-CML cases with and without fibrosis (each n=8) as well as 18 non-neoplastic controls...
February 27, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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