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Divya Singh, Ghanshyam Upadhyay, Ananya Sengupta, Mohammed A Biplob, Shaleen Chakyayil, Tiji George, Shireen Saleque
Understanding the production and differentiation of megakaryocytes from progenitors is crucial for realizing the biology and functions of these vital cells. Previous gene ablation studies demonstrated the essential role of the transcriptional repressor Gfi1b (growth factor independence 1b) in the generation of both erythroid and megakaryocytic cells. However, our recent work has demonstrated the down-regulation of this factor during megakaryocytic differentiation. In this study we identify two new gene targets of Gfi1b, the cytoskeletal proteins Kindlin3 and Talin1, and demonstrate the inverse expression and functions of these cytoskeletal targets relative to Gfi1b, during megakaryocytic differentiation...
2016: PloS One
Kran Suknuntha, Thanyatip Thita, Padma Priya Togarrati, Piyanee Ratanachamnong, Patompon Wongtrakoongate, Sirada Srihirun, Igor Slukvin, Suradej Hongeng
Wnt signaling pathway plays a major role in leukemogenesis of myeloid leukemia. Aberrancy in its regulation results in hyperactivity of the pathway contributing to leukemia propagation and maintenance. To investigate effects of Wnt pathway inhibition in leukemia, we used human leukemia cell lines (i.e., K562, HL60, THP1, and Jurkat) and several Wnt inhibitors, including XAV939, IWP2 and FH535. Our results showed that leukemia cell lines (>95 % cells) had increased endogenous levels of β-catenin as compared to mononuclear cells from healthy donors (0 %)...
October 20, 2016: International Journal of Hematology
Carol H Miao
Current treatment of hemophilia A (HemA) patients with repeated infusions of factor VIII (FVIII; abbreviated as F8 in constructs) is costly, inconvenient, and incompletely effective. In addition, approximately 25 % of treated patients develop anti-factor VIII immune responses. Gene therapy that can achieve long-term phenotypic correction without the complication of anti-factor VIII antibody formation is highly desired. Lentiviral vector (LV)-mediated gene transfer into hematopoietic stem cells (HSCs) results in stable integration of FVIII gene into the host genome, leading to persistent therapeutic effect...
2016: Thrombosis Journal
Hui-Ju Tsai, Ching-Ping Tseng
Multiple functions of platelets in various physiological and pathological conditions have prompted considerable attention on understanding how platelets are generated and activated. Of the adaptor proteins that are expressed in megakaryocytes and platelets, Disabled-2 (Dab2) has been demonstrated in the past decades as a key regulator of platelet signaling. Dab2 has two alternative splicing isoforms p82 and p59. However, the mode of Dab2's action remains to be clearly defined. In this review, we highlight the current understanding of Dab2 expression and function in megakaryocytic differentiation, platelet activation and integrin signaling...
2016: Thrombosis Journal
Yukio Ozaki, Shogo Tamura, Katsue Suzuki-Inoue
Platelets play a key role in the pathophysiological processes of hemostasis and thrombus formation. However, platelet functions beyond thrombosis and hemostasis have been increasingly identified in recent years. A large body of evidence now exists which suggests that platelets also play a key role in inflammation, immunity, malignancy, and furthermore in organ development and regeneration, such as the liver. We have recently identified CLEC-2 on the platelet membrane, which induces intracellular activation signals upon interaction of a snake venom, rhodocytin...
2016: Thrombosis Journal
Bin Shen, Yu Zhang, Wei Dai, Yupo Ma, Yongping Jiang
BACKGROUND: Hematopoietic CD34(+) stem cells are widely used in the clinical therapy of complicated blood diseases. Stem cell factor Sall4B is a zinc finger transcription factor that plays a vital role in hematopoietic stem cell expansion. The purpose of our current study is to further evaluate how Sall4B might affect the expansion of CD34(+) cells derived from nonhuman primates. METHODS: Sall4B was overexpressed in nonhuman primate bone marrow-derived CD34(+) cells via a lentiviral transduction system...
October 20, 2016: Stem Cell Research & Therapy
Mingyi Qu, Fang Fang, Xiaojing Zou, Quan Zeng, Zeng Fan, Lin Chen, Wen Yue, Xiaoyan Xie, Xuetao Pei
A better understanding of the mechanisms involved in megakaryocyte maturation will facilitate the generation of platelets in vitro and their clinical applications. A microRNA, miR-125b, has been suggested to have important roles in the self-renewal of megakaryocyte-erythroid progenitors and in platelet generation. However, miR-125b is also critical for hematopoietic stem cell self-renewal. Thus, the function of miR-125b and the complex signaling pathways regulating megakaryopoiesis remain to be elucidated. In this study, an attentive examination of the endogenous expression of miR-125b during megakaryocyte differentiation was performed...
October 20, 2016: Cell Death & Disease
Feng Zhang, Bo Yang, Kailiang Zhang, Mei-Ling Hou, Xue-Chun Lu, Yu-Xin Li
Amifostine (AMF), 2-(3-Aminopropyl) aminoethyl phosphorothioate is a broad-spectrum cytoprotective agent used to treat nuclear radiation and chemical weapon injuries. Recently, amifostine has been shown to have a profound biological influence on tumor cells. In order to examine the effects and mechanisms underlying the effects of amifostine on human acute megakaryocytic leukemia, we evaluated the efficacy of amifostine against Dami cells and observed a cell cycle arrest in G2 /M phase. Amifostine treatment also induced cell apoptosis of Dami cells which corresponds to formal studies...
October 19, 2016: Chemical Biology & Drug Design
Raphael Leblanc, Olivier Peyruchaud
Blood platelets have been known for more than a century as important partners for successful metastatic dissemination of solid tumors. Cancer cell-induced platelet activation is a key event responsible for prometastatic activity of platelets. Blocking platelet aggregation inhibits the progression of skeletal metastases through mechanisms that are not fully understood. The establishment and progression of bone metastases are strongly influenced by the bone remodeling process. Growth factors and cytokines released upon platelet activation may contribute to both skeletal tumor growth and osteolytic lesions...
September 2016: Journal of Bone Oncology
Shilpi Yadav, Jonathan K Williamson, Maria A Aronova, Andrew A Prince, Irina D Pokrovskaya, Richard D Leapman, Brian Storrie
Platelets are small, anucleate cell fragments that are central to hemostasis, thrombosis, and inflammation. They are derived from megakaryocytes from which they inherit their organelles. As platelets can synthesize proteins and contain many of the enzymes of the secretory pathway, one might expect all mature human platelets to contain a stacked Golgi apparatus, the central organelle of the secretory pathway. By thin section electron microscopy, stacked membranes resembling the stacked Golgi compartment in megakaryocytes and other nucleated cells can be detected in both proplatelets and platelets...
October 18, 2016: Platelets
Madhumita Chatterjee, Meinrad Gawaz
Platelet membrane bedecked with a wide array of receptors offers a platform to regulate platelet responsiveness, thrombotic propensity, inflammatory disposition, and immune reactivity under diverse pathophysiological conditions. Ectopic proteolytic cleavage of such receptors irreversibly inactivates receptor-mediated intracellular signaling governing cellular functions, further releases soluble fragments into circulation which might modulate functions of target cells. Glycoprotein VI-(GPVI) is a membrane glycoprotein expressed in platelets and megakaryocytes...
October 18, 2016: Platelets
Yue Guan, Shixuan Wang, Feng Xue, Xiaofan Liu, Lei Zhang, Huiyuan Li, Renchi Yang
OBJECTIVES: We performed this study in adult patients with chronic primary immune thrombocytopenia (ITP) to explore the long-term efficacy and safety of splenectomy. METHODS: Data of 174 patients who underwent splenectomy in our hospital from 1994 to 2014 were analyzed. RESULTS: After splenectomy, 126 (72.4%) patients achieved a complete response (CR) and 28 (16.1%) achieved a response (R). Thirty-two (20.8%) responders relapsed with a median time of 24 months...
October 18, 2016: European Journal of Haematology
Steven Wang, Jie Yan, Guangde Zhou, Rebecca Heintzelman, J Steve Hou
Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies characterized by unchecked proliferation of differentiated myeloid cells. The most common BCR-ABL1-negative MPNs are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The discovery of JAK2 V617F mutation has improved our understanding of the molecular basis of MPN. The high frequency of JAK2 mutation in MPN makes JAK2 mutation testing an essential diagnostic tool and potential therapeutic target for MPN. Here, we present a rare case of a 34-year-old patient who was initially diagnosed with acute myeloid leukemia (AML) with mutated NPM1...
2016: Case Reports in Hematology
C Du, Y Xu, K Yang, S Chen, X Wang, S Wang, C Wang, M Shen, F Chen, M Chen, D Zeng, F Li, T Wang, F Wang, J Zhao, G Ai, T Cheng, Y Su, J Wang
Estrogen is reported to be involved in thrombopoiesis and the disruption of its signaling may cause myeloproliferative disease, yet the underlying mechanisms remain largely unknown. GATA-binding factor 1 (GATA1) is a key regulator of megakaryocyte differentiation and its deficiency will lead to megakaryoblastic leukemia. Here, we show that estrogen can dose-dependently promote megakaryocyte polyploidization and maturation via activation of estrogen receptor beta (ERβ), accompanied by a significant up-regulation of GATA1...
October 17, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Motasem Melhem, Mohamed Abu-Farha, Dinu Antony, Ashraf Al Madhoun, Chiara Bacchelli, Fadi Alkayal, Irina AlKhairi, Sumi John, Mohamad Alomari, Phillip L Beales, Osama Alsmadi
OBJECTIVE: To characterize the underlying genetic and molecular defects in a consanguineous family with life-long blood disorder manifested with thrombocytopenia (low platelets count) and anemia. METHODS: Genetic linkage analysis, exome sequencing and functional genomics were carried out to identify and characterize the defective gene. RESULTS: We identification of a novel truncation mutation (p.C108*) in Chromosome 6 Open Reading Frame 25 (C6orf25) gene in this family...
October 15, 2016: European Journal of Haematology
K Kollmann, W Warsch, C Gonzalez-Arias, F L Nice, E Avezov, J Milburn, J Li, D Dimitropoulou, S Biddie, M Wang, E Poynton, M Colzani, M R Tijssen, S Anand, U McDermott, B Huntly, T Green
Most MPN patients lacking JAK2 mutations harbour somatic CALR mutations that are thought to activate cytokine signalling although the mechanism is unclear. To identify kinases important for survival of CALR-mutant cells we developed a novel strategy (KISMET) which utilises the full range of kinase selectivity data available from each inhibitor and thus takes advantage of off-target noise that limits conventional siRNA or inhibitor screens. KISMET successfully identified known essential kinases in haematopoietic and non-haematopoietic cell lines and identified the MAPK pathway as required for growth of the CALR-mutated MARIMO cells...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Umberto Gianelli, Daniele Cattaneo, Anna Bossi, Ivan Cortinovis, Leonardo Boiocchi, Yen-Chun Liu, Claudia Augello, Arturo Bonometti, Stefano Fiori, Nicola Orofino, Francesca Guidotti, Attilio Orazi, Alessandra Iurlo
In this study, we investigate in detail the morphological, clinical and molecular features of 71 consecutive patients with a diagnosis of myeloproliferative neoplasms, unclassifiable. We performed a meticulous morphological analysis and found that most of the cases displayed a hypercellular bone marrow (70%) with normal erythropoiesis without left-shifting (59%), increased granulopoiesis with left-shifting (73%) and increased megakaryocytes with loose clustering (96%). Megakaryocytes displayed frequent giant forms with hyperlobulated or bulbous nuclei and/or other maturation defects...
October 14, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Anita Roy, Larissa Lordier, Stefania Mazzi, Yunhua Chang, Valérie Lapierre, Jérome Larghero, Najet Debili, Hana Raslova, William Vainchenker
Megakaryocyte polyploidy is characterized by cytokinesis failure due to defects in contractile forces at the cleavage furrow. Although immature megakaryocytes express two nonmuscle myosin II isoforms (NMIIA and NMIIB); only NMIIB localizes at the cleavage furrow and its subsequent absence contributes to polyploidy. In this study, we tried to understand why the abundant NMIIA does not localize at the furrow by focusing on RhoA/ROCK pathway that has a low activity in polyploid megakaryocytes. We observed that under low RhoA activity, NMII isoforms presented different activity that determined their localization...
October 13, 2016: Blood
Seher Erdoğan, Arzu Oto, Mehmet Boşnak
Mean platelet volume (MPV) is a simple and economical test that is easy to interpret and is routinely measured with automatic cell counters. It indicates platelet volume and platelet function and activation. Variations in platelet volume may occur more as a result of varying differentiation of megakaryocytes in association with production agents in bone marrow rather than of ageing of platelets in circulation. The purpose of this study was to evaluate the relation between mortality and changes in MPV values in patients hospitalized in the pediatric intensive care unit...
November 2015: Turkish Journal of Pediatrics
Tamara K Moyo, Michael R Savona
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematologic malignancies characterized by a hypercellular bone marrow and morphologic dysplasia in one or more lineage (i.e., myeloid, erythroid, or megakaryocytic), presenting clinically with leukopenia, anemia, and/or thrombocytopenia and with a propensity to transform to acute myelogenous leukemia. Newer technologies such as next-generation sequencing have allowed better understanding of the genetic landscape in MDS. Nearly 80 % of MDS patients have at least one mutation, and approximately 40 recurrent somatic mutations have been identified to occur in >1 % of cases...
October 12, 2016: Current Hematologic Malignancy Reports
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