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Experimental Hematology

Anne-Marie Lyne, David G Kent, Elisa Laurenti, Kerstin Cornils, Ingmar Glauche, Leila Perié
International experts from multiple disciplines gathered at Homerton College in Cambridge, UK from September 12-14, 2018 to consider recent advances and emerging opportunities in the clonal tracking of hematopoiesis in one of a series of StemCellMathLab workshops. The group included thirty-five participants with experience in the fields of theoretical and experimental aspects of clonal tracking, and ranged from PhD students to senior professors. Data from a variety of model systems as well as from clinical gene therapy trials were discussed alongside strategies for data analysis and sharing, as well as challenges arising due to underlying assumptions in data interpretation and communication...
November 15, 2018: Experimental Hematology
Connie Eaves
No abstract text is available yet for this article.
November 12, 2018: Experimental Hematology
Stephen Couban, Peggy C Wong, Kirk R Schultz
G-CSF stimulated peripheral blood progenitor cells (G-PB) from either a related or unrelated donor continue to be the preferred donor source for most allogeneic hematopoietic cell transplantation (HCT). Recently, the ASBMT has recommended that marrow instead of G-PB as an unrelated graft source due to its lower rate of chronic graft-versus-host disease (cGVHD). The use of marrow is limited by both clinical considerations (slower rate of engraftment and increased donor morbidity) and logistic considerations (use of operating room resources and increased physician utilization), hence this recommendation has not been widely adopted...
November 11, 2018: Experimental Hematology
Saar Shapira, Pia Raanani, Aladin Samara, Arnon Nagler, Ido Lubin, Nadir Arber, Galit Granot
Despite high remission rate after therapy, only 40-50% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. The main cause of treatment failure is thought to be insufficient eradication of CD34+ CD38- AML cells. In order to induce preferential cell death in CD34+ CD38- AML cells two separate events may be necessary: (1) inhibition of survival signals such as NF-κB and (2) induction of stress responses such as oxidative stress response. Thus, regimens that mediate both effects may be favorable...
November 8, 2018: Experimental Hematology
Biaoru Li, Xingguo Zhu, Christina M Ward, Athena Starlard-Davenport, Mayuko Takezaki, Amber Berry, Alexander Ward, Caroline Wilder, Cindy Neunert, Abdullah Kutlar, Betty S Pace
Inherited genetic modifiers and pharmacologic agents that enhance fetal hemoglobin (HbF) expression reverse the clinical severity of sickle cell disease (SCD). Recent efforts to develop novel strategies of HbF induction include discovery of molecular targets that regulate γ-globin gene transcription and translation. The purpose of this study was to perform genome-wide microRNA (miRNA) analysis identify genes associated with HbF expression in patients with SCD. We isolated RNA from purified reticulocytes for microarray-based miRNA expression profiling...
November 6, 2018: Experimental Hematology
Jane Jialu Xu, Monique F Smeets, Shuh Ying Tan, Meaghan Wall, Louise E Purton, Carl R Walkley
Myelodysplastic syndromes (MDS) and related myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal stem cell disorders, primarily affecting patients over 65 years of age. Mapping of the MDS and MDS/MPN genome identified recurrent heterozygous mutations in the RNA splicing machinery, with SF3B1, SRSF2 and U2AF1 frequently mutated. To better understand how spliceosomal mutations contribute to MDS pathogenesis in vivo, numerous groups have sought to establish conditional murine models of SF3B1, SRSF2 and U2AF1 mutations...
November 5, 2018: Experimental Hematology
Massimo Bonora, Kyoko Ito, Claudia Morganti, Paolo Pinton, Keisuke Ito
Proper control of mitochondrial function is a key factor in the maintenance of hematopoietic stem cells (HSCs). Mitochondrial content is commonly measured by staining with fluorescent cationic dyes. However, dye staining can be affected, not only by xenobiotic efflux pumps, but also by dye intake, which is dependent on the negative charge of mitochondria. Therefore, mitochondrial membrane potential (ΔΨmt ) must be considered in these measurements because a high ΔΨmt due to respiratory chain activity can enhance dye intake, leading to the overestimation of mitochondrial volume...
November 3, 2018: Experimental Hematology
Jin Shang, Wei-Min Chen, Zhi-Hong Wang, Tian-Nan Wei, Zhi-Zhong Chen, Wen-Bing Wu
The contribution and role of circular RNAs (circRNAs) in mediating chemoresistance in acute myeloid leukemia (AML) are still poorly understood and need further investigation. In this study, we established a doxorubicin (ADM)-resistant THP-1 AML cell line (THP-1/ADM). A high-throughput microarray was used to identify circRNA expression profiles of THP-1/ADM cells and naive THP-1 cells. The identified potential functional circRNA molecule was further validated in THP-1/ADM cells and bone marrow (BM) specimens from 42 AML patients...
November 3, 2018: Experimental Hematology
Long Gao, Joanna Tober, Peng Gao, Changya Chen, Qin Zhu, Kai Tan, Nancy A Speck
The transcription factor RUNX1 is required in the embryo for formation of the adult hematopoietic system. Here, we describe the seminal findings that led to the discovery of RUNX1 and of its critical role in blood cell formation in the embryo from hemogenic endothelium (HE). We also present RNA-sequencing data demonstrating that HE cells in different anatomic sites, which produce hematopoietic progenitors with dissimilar differentiation potentials, are molecularly distinct. Hemogenic and non-HE cells in the yolk sac are more closely related to each other than either is to hemogenic or non-HE cells in the major arteries...
October 31, 2018: Experimental Hematology
João Tadeu Damian Souto Filho, Rodrigo Doyle Portugal, Marcio Nucci
Benign constitutional neutropenia (BCN) is an asymptomatic condition characterized by mild chronic neutropenia in patients with no history of recurrent infections. Most patients are referred for further testing, increasing health care costs. We present an alternative form of assessment of individuals with BCN based on neutrophil circadian variation. The objective of this study was to evaluate whether circadian variations of neutrophil counts would result in neutrophil values higher than neutropenia threshold in individuals with BCN...
October 25, 2018: Experimental Hematology
Genna M Luciani, Lihua Xie, David Dilworth, Anne Tierens, Yoni Moskovitz, Alex Murison, Magdalena M Szewczyk, Amanda Mitchell, Mathieu Lupien, Liran Shlush, John E Dick, Cheryl H Arrowsmith, Dalia Barsyte-Lovejoy, Mark D Minden
Acute myeloid leukemia (AML) is a complex, heterogeneous disease with variable outcomes following curative intent chemotherapy. AML with inv(3) is a genetic subgroup characterized by a very low response rate to current induction type chemotherapy and thus has among the worst long-term survivorship of the AMLs. Here, we describe OCI-AML-20, a new AML cell line with inv(3) and deletion of chromosome 7; the latter is a common co-occurrence in inv(3) AML. In OCI-AML-20, CD34 expression is maintained and required for repopulation in vitro and in vivo...
October 22, 2018: Experimental Hematology
Ryo Kurita, Koji Funato, Takaaki Abe, Yoshihisa Watanabe, Masayuki Shiba, Kenji Tadokoro, Yukio Nakamura, Tadashi Nagai, Masahiro Satake
Immortalized erythroid progenitor cell lines, which exhibit potential for enucleated red blood cell (RBC) production, are expected to serve as an in vitro source of RBCs. These erythroid progenitor cell lines have previously been established from a variety of sources; however, large numbers of cell lines have not been established, characterized, and compared from a common cell source. In the present study, 37 cell lines were established from human bone marrow cells from a single donor. The time required for the establishment of each cell line varied greatly from 46 to 246 days...
October 13, 2018: Experimental Hematology
Agnieszka Arthur, Thao M Nguyen, Sharon Paton, Andrew C W Zannettino, Stan Gronthos
The bone marrow stromal microenvironment contributes to the maintenance and function of hematopoietic stem/progenitor cells (HSPCs). The Eph receptor tyrosine kinase family members have been implicated in bone homeostasis and stromal support of HSPCs. The present study examined the influence of EfnB1-expressing osteogenic lineage on HSPC function. Mice with conditional deletion of EfnB1 in the osteogenic lineage (EfnB1OB -/- ), driven by the Osterix promoter, exhibited a reduced prevalence of osteogenic progenitors and osteoblasts, correlating to lower numbers of HSPCs compared with Osx:Cre mice...
October 13, 2018: Experimental Hematology
Zhijie Wu, Valentina Giudice, Jichun Chen, Wanling Sun, Zenghua Lin, Keyvan Keyvanfar, Nidhi Talasani, Sachiko Kajigaya, Xingmin Feng, Neal S Young
Interleukin (IL)-18, also known as interferon-gamma (INF-γ)-inducing factor, is involved in Th1 responses and regulation of immunity. Accumulating evidence implicates IL-18 in autoimmune diseases, but little is known of its role in acquired aplastic anemia (AA), immune-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). IL-18 protein levels were significantly elevated in sera of severe AA patients, including both responders and non-responders assayed before treatment, and decreased after treatment...
October 12, 2018: Experimental Hematology
Florentien E M In 't Hout, Jolanda van Duren, Davide Monteferrario, Emma Brinkhuis, Niccolo Mariani, Theresia M Westers, Dana Chitu, Gorica Nikoloski, Arjan A van de Loosdrecht, Bert A van der Reijden, Joop H Jansen, Gerwin Huls
Transcription factor 4 (TCF4) is implicated in lymphoid cell differentiation and its expression predicts outcome in acute myeloid leukemia. Here, we investigated the role of TCF4 in myelopoiesis. Overexpression of TCF4 (TCF4OE ) in umbilical cord blood (UCB) cells resulted in a twofold increase in erythroid colony forming units (CFU-Es), whereas knock-down (KD) of TCF4 (TCF4KD ) caused a dramatic decrease in the number of erythroid colonies. In megakaryocyte CFUs (CFU-MKs), both TCF4KD and TCF4OE inhibited MK colony formation...
October 10, 2018: Experimental Hematology
Yufei Chen, Kenneth L Jones, Konstantinos Anastassiadis, Andrea Kranz, A Francis Stewart, Jolanta Grembecka, Matthew Meyerson, Patricia Ernst
Disrupting protein-protein interaction for molecularly targeted cancer therapeutics can be a challenging but promising strategy. Compounds that disrupt the interaction between Menin, a chromatin-binding protein, and oncogenic MLL fusion proteins (FPs) have shown significant promise in pre-clinical models of leukemia and show a high degree of selectivity for leukemia versus normal hematopoietic cells. Biochemical and structural studies demonstrate that, in addition to disrupting Menin-MLL-FP interaction, such compounds also inhibit Menin-MLL1, Menin-MLL2, and other Menin interacting proteins...
October 10, 2018: Experimental Hematology
Valentina Giudice, Angélique Biancotto, Zhijie Wu, Foo Cheung, Julián Candia, Giovanna Fantoni, Sachiko Kajigaya, Olga Rios, Danielle Townsley, Xingmin Feng, Neal S Young
Single-stranded oligonucleotides containing deoxyuridine are aptamers (SOMAmers) that can bind proteins with high specificity and affinity and slow dissociation rates. SOMAscan, an aptamer-based proteomic technology, allows measurement of more than 1,300 proteins simultaneously for the identification of new disease biomarkers. The aim of the present study was to identify new serum and plasma protein markers for diagnosis of acquired aplastic anemia (AA) and response to immunosuppressive therapies (IST). SOMAscan was used to screen 1,141 serum proteins in 28 AA patients before and after therapy and 1,317 plasma proteins in seven SAA patients treated with standard IST and a thrombopoietin receptor agonist...
October 9, 2018: Experimental Hematology
Laura M Haunstrup, Lene H Ebbesen, Maria Hansen, Marianne T Severinsen, Anni Aggerholm
Detection of somatic mutations in cardinal driver genes is a strong argument for diagnosis in classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Driver mutations in Janus kinase 2 (JAK2), calreticulin (CALR), and XXXX (MPL), are generally considered mutually exclusive, but several reports have suggested that they coexist in a small subgroup of patients. In this study, we retrospectively searched for CALR mutations in 136 suspected MPN patients with low allelic burden (≤5%) JAK2 V617F. Fifteen patients with concomitant JAK2 V617F and CALR mutations were identified, of whom 10 were diagnosed with essential thrombocytosis (ET)...
October 4, 2018: Experimental Hematology
Daniela Senft, Irmela Jeremias
After initially successful chemotherapy, relapse frequently jeopardizes the outcome of patients with acute leukemia. Because of their adverse characteristics of self-renewal and dormancy, leukemia stem cells have been hypothesized to play a critical role in resistance to antiproliferative chemotherapy and the development of relapse. The high abundance of stem-like cells in acute lymphoblastic leukemia (ALL), however, suggests that not all leukemia-initiating cells carry these adverse characteristics, complicating the biological characterization of relapse-inducing cells in this malignancy...
September 24, 2018: Experimental Hematology
Stuart B Hay, Kyle Ferchen, Kashish Chetal, H Leighton Grimes, Nathan Salomonis
The Human Cell Atlas (HCA) is expected to facilitate the creation of reference cell profiles, marker genes, and gene regulatory networks that will provide a deeper understanding of healthy and disease cell types from clinical biospecimens. The hematopoietic system includes dozens of distinct, transcriptionally coherent cell types, including intermediate transitional populations that have not been previously described at a molecular level. Using the first data release from the HCA bone marrow tissue project, we resolved common, rare, and potentially transitional cell populations from over 100,000 hematopoietic cells spanning 35 transcriptionally coherent groups across eight healthy donors using emerging new computational approaches...
September 21, 2018: Experimental Hematology
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