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Experimental Hematology

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https://www.readbyqxmd.com/read/29108926/a-thalidomide-hydroxyurea-hybrid-increases-hbf-production-in-sickle-cell-mice-and-reduces-the-release-of-proinflammatory-cytokines-in-cultured-monocytes
#1
Carolina Lanaro, Carla Franco-Penteado, Fabio H Silva, Kleber Y Fertrin, Jean Leandro Dos Santos, Marlene Wade, Shobha Yerigenahally, Thais R de Melo, Chung Man Chin, Abdullah Kutlar, Steffen E Meiler, Fernando Ferreira Costa
Fetal hemoglobin induction by hydroxyurea therapy is associated with decreased morbidity and mortality in SCA patients, but not all respond to or tolerate hydroxyurea, which provides a rationale for the development of novel HbF inducers as treatment options for SCA. Thalidomide analogs have a combined ability to induce HbF production and to inhibit the release of tumor necrosis factor α. Molecular hybridization of hydroxyurea and thalidomide was used to synthesize 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate (compound 4C)...
November 3, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29111429/megakaryocyte-and-polyploidization
#2
REVIEW
Stefania Mazzi, Larissa Lordier, Najet Debili, Hana Raslova, William Vainchenker
In mammals, platelets are produced in the blood by cytoplasmic fragmentation of megakaryocytes (MKs). Platelet production is thus dependent on both the MK number and size. During differentiation, MKs switch from a division by mitosis to polyploidization by endomitosis to increase their size. The endomitotic process includes several successive rounds of DNA replication with an entry in mitosis with a failure in late cytokinesis and a defect in karyokinesis. This leads to a giant cell with a modal ploidy at 16N and one multilobulated nucleus...
October 27, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29111428/kdm6-and-kdm4-histone-lysine-demethylases-emerge-as-molecular-therapeutic-targets-in-human-acute-myeloid-leukemia
#3
Liberalis Debraj Boila, Shankha Subhra Chatterjee, Debasis Banerjee, Amitava Sengupta
Acute myeloid leukemia (AML) remains an aggressive hematopoietic malignancy caused by proliferation of immature myeloid cells, which is frequently characterized by perturbations in chromatin modifying enzymes. Emerging evidences indicate that histone demethylases play instructive role in tumorigenesis. However, due to the complexity of this enormous family of histone-modifying enzymes, substrate redundancy and context-specific roles, the contribution of each member remains ambiguous and targeting them remains challenging...
October 27, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29031704/evaluation-of-cooperative-antileukemic-effects-of-nilotinib-and-vildagliptin-in-ph-chronic-myeloid-leukemia
#4
Michael Willmann, Irina Sadovnik, Gregor Eisenwort, Martin Entner, Tina Bernthaler, Gabriele Stefanzl, Emir Hadzijusufovic, Daniela Berger, Harald Herrmann, Gregor Hoermann, Peter Valent, Thomas Rülicke
Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although the disease can be kept under control using BCR/ABL1 tyrosine kinase inhibitors (TKIs) in most cases, some patients relapse or have resistant disease, so there is a need to identify new therapeutic targets in this malignancy. Recent data suggest that leukemic SCs (LSCs) in CML display the stem-cell (SC)-mobilizing cell surface enzyme dipeptidyl-peptidase IV (DPPIV = CD26) in an aberrant manner. In the present study, we analyzed the effects of the DPPIV blocker vildagliptin as single agent or in combination with the BCR/ABL1 TKI imatinib or nilotinib on growth and survival of CML LSCs in vitro and on LSC engraftment in an in vivo xenotransplantation nonobese diabetic SCID-IL-2Rγ(-/-) (NSG) mouse model...
October 12, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29030084/characterization-and-use-of-the-novel-human-multiple-myeloma-cell-line-mc-b11-14-to-study-biological-consequences-of-crispr-mediated-loss-of-immunoglobulin-a-heavy-chain
#5
Denise K Walters, Bonnie K Arendt, Renee C Tschumper, Xiaosheng Wu, Diane F Jelinek
The genetic abnormalities underlying multiple myeloma (MM) are notoriously complex and intraclonal heterogeneity is a common disease feature. In the current study, we describe the establishment of a monoclonal IgA kappa (κ) MM cell line, designated MC-B11/14. Cytogenetic and FISH analyses of the original and relapse patient samples revealed the MM clone was non-hyperdiploid and possessed an 11;14 chromosomal translocation. The MC-B11/14 cell line, established from the relapse sample, is tetraploid and houses the t(11;14) abnormality...
October 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29030083/human-bone-marrow-mesenchymal-stem-cells-secrete-endocannabinoids-that-stimulate-in-vitro-hematopoietic-stem-cell-migration-effectively-comparable-to-beta-adrenergic-stimulation
#6
Sevil Köse, Fatima Aerts-Kaya, Ağla Zübeyde Köprü, Emirhan Nemutlu, Barış Kuşkonmaz, Beren Karaosmanoğlu, Zihni Ekim Taşkıran, Belgin Altun, Duygu Uçkan Çetinkaya, Petek Korkusuz
Granulocyte Colony-Stimulating Factor (G-CSF) is a well-known hematopoietic stem cell (HSC) mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize sufficient number of cells. New mobilization agents are therefore needed. Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors (CB1, CB2). We suggest that eCBs may act as mobilizers of hematopoietic stem cells (HSC) from the BM under stress conditions as beta adrenergic receptors (Adrβ)...
October 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29024710/determination-of-complex-subclonal-structures-of-haematological-malignancies-by-multiplexed-genotyping-of-blood-progenitor-colonies
#7
Francesca L Nice, Charlie E Massie, Thorsten Klampfl, Anthony R Green
Current next generation sequencing (NGS) technologies allow unprecedented insights into the mutational profiles of tumours. Recent studies in myeloproliferative neoplasms have further demonstrated that not only the mutational profile, but also the order in which these mutations are acquired is relevant for our understanding of the disease. Our ability to assign mutation order from NGS data alone, is however limited. Here we present a strategy of highly multiplexed genotyping of burst forming unit-erythroid (BFU-E) colonies based on NGS results to assess subclonal tumour structure...
October 9, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28947392/glutaminase-inhibition-improves-flt3-inhibitor-therapy-for-acute-myeloid-leukemia
#8
Mark A Gregory, Travis Nemkov, Julie A Reisz, Vadym Zaberezhnyy, Kirk C Hansen, Angelo D'Alessandro, James DeGregori
Acute myeloid leukemia (AML) is a blood cancer that is poorly responsive to conventional cytotoxic chemotherapy and a diagnosis of AML is usually fatal. More effective and better-tolerated therapies for AML are desperately needed. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are one of the most frequently observed genetic defects in AML. FLT3 inhibitors have shown impressive anti-leukemic activity in clinical trials; however, sustained remissions using these inhibitors as monotherapy have not been achieved...
September 22, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28943295/the-slippery-slope-of-hematopoietic-stem-cell-aging
#9
Martin Wahlestedt, David Bryder
The late stages of life, in most species including humans, are associated with a decline in the overall maintenance and health of the organism. This applies also to the hematopoietic system, where aging is not only associated with an increased predisposition for hematological malignancies, but also identified as a strong comorbidity factor for other diseases. Research during the last two decades has proposed that alterations at the level of hematopoietic stem cells (HSCs) might be a root cause for the hematological changes observed with age...
September 21, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28941711/persistent-elevation-of-plasma-thrombopoietin-levels-after-treatment-in-severe-aplastic-anemia
#10
Xin Zhao, Xingmin Feng, Zhijie Wu, Thomas Winkler, Ronan Desmond, Matthew Olnes, Bogdan Dumitriu, Danielle M Townsley, Cynthia E Dunbar, Neal S Young
Although hematopoietic growth factors are found at high levels in aplastic anemia (AA) patients, little is known about their dynamic change over time after treatment. We examined plasma concentrations of hematopoietic growth factors sequentially in 55 severe AA patients, including 45 treatment-naive patients who had received immunosuppressive therapy (IST) or IST and eltrombopag, and 10 IST-refractory patients who had received eltrombopag only, focusing on thrombopoietin (TPO). TPO concentrations were much higher than normal in patients before treatment and then decreased in responders but not in nonresponders...
September 20, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28939416/the-gnas-r201c-mutation-associated-with-clonal-hematopoiesis-supports-transplantable-hematopoietic-stem-cell-activity
#11
Elizabeth L Ostrander, Won Kyun Koh, Cates Mallaney, Ashley C Kramer, W Casey Wilson, Bo Zhang, Grant A Challen
Genome sequencing efforts have identified virtually all of the important mutations in adult myeloid malignancies. More recently, population studies have identified cancer-associated variants in the blood of otherwise healthy individuals as they age, a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). This suggests that these mutations may occur in hematopoietic stem cells (HSCs) long before any clinical presentation but are not necessarily harbingers of transformation because only a fraction of individuals with CHIP develop hematopoietic pathologies...
September 20, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28911908/enhancement-of-mouse-hematopoietic-stem-progenitor-cell-function-via-transient-gene-delivery-using-integration-deficient-lentiviral-vectors
#12
Maria E Alonso-Ferrero, Niek P van Til, Kerol Bartolovic, Márcia F Mata, Gerard Wagemaker, Dale Moulding, David A Williams, Christine Kinnon, Simon N Waddington, Michael D Milsom, Steven J Howe
Integration-deficient lentiviruses (IdLVs) deliver genes effectively to tissues but are lost rapidly from dividing cells. This property can be harnessed to express transgenes transiently to manipulate cell biology. Here, we demonstrate the utility of short-term gene expression to improve functional potency of hematopoietic stem and progenitor cells (HSPCs) during transplantation by delivering HOXB4 and Angptl3 using IdLVs to enhance the engraftment of HSPCs. Constitutive overexpression of either of these genes is likely to be undesirable, but the transient nature of IdLVs reduces this risk and those associated with unsolicited gene expression in daughter cells...
September 11, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28911907/microrna-22-controls-interferon-alpha-production-and-erythroid-maturation-in-response-to-infectious-stress-in-mice
#13
Claudine S Kadmon, Cameron T Landers, Haiyan S Li, Stephanie S Watowich, Antony Rodriguez, Katherine Y King
MicroRNA-22 (miR-22) is a highly conserved microRNA that can regulate cell proliferation, oncogenesis, and cell maturation, especially during stress. In hematopoietic stem cells (HSCs), miR-22 has been reported to be involved in the regulation of key self-renewal factors, including Tet2. Recent work demonstrates that miR-22 also participates in regulation of the interferon (IFN) response, and expression profiling studies suggest that it is variably expressed at different stages in erythroid differentiation...
September 11, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28911906/identification-of-novel-biomarkers-for-mll-translocated-acute-myeloid-leukemia
#14
Karine Lagacé, Fréderic Barabé, Josée Hébert, Sonia Cellot, Brian T Wilhelm
Acute myeloid leukemias (AMLs) with translocations of the mixed lineage leukemia (MLL/KMT2A) gene are common in young patients and are generally associated with poor clinical outcomes. The molecular biology of MLL fusion genes remains incompletely characterized and is complicated by the fact that more than 100 different partner genes have been identified in fusions with MLL. The continuously growing list of MLL fusions also represents a clinical challenge with respect to identification of novel fusions and tracking of the fusions to monitor progression of the disease after treatment...
September 11, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28893618/lenalidomide-modulates-gene-expression-in-human-abc-dlbcl-cells-by-regulating-ikaros-interaction-with-an-intronic-control-region-of-spib
#15
Lauren A Solomon, Carolina R Batista, Rodney P DeKoter
Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is associated with a poor prognosis compared with other DLBCL types and therefore represents a top priority for developing novel therapies. Lenalidomide, an immunomodulatory drug in trials for treatment of ABC-DLBCL, targets the transcription factor IKAROS for degradation by the cereblon E3 ubiquitin ligase complex. In this study, we investigated whether the gene encoding the transcription factor SPI-B is a target of IKAROS. Using cultured ABC-DLBCL cell lines, we found that high levels of SPI-B expression conferred resistance to lenalidomide...
September 8, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28867537/thermal-injury-of-the-skin-induces-g-csf-dependent-attenuation-of-epo-mediated-stat-signaling-and-erythroid-differentiation-arrest-in-mice
#16
John G Noel, Benjamin J Ramser, Jose A Cancelas, Francis X McCormack, Jason C Gardner
Inflammation-mediated impairment of erythropoiesis plays a central role in the development of the anemia of critical illness (ACI). ACI develops despite elevation of endogenous erythropoietin (EPO), does not respond to exogenous erythropoietin (EPO) supplementation, and contributes significantly to transfusion requirements in burned patients. We have reported previously that the reduction of red blood cell mass in the bone marrow of a burn-injured ACI mouse model is granulocyte colony-stimulating factor (G-CSF) dependent...
September 1, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28866324/effects-of-in-vivo-deletion-of-gata2-in-bone-marrow-stromal-cells
#17
Shin Hasegawa, Tohru Fujiwara, Yoko Okitsu, Hiroki Kato, Yuki Sato, Noriko Fukuhara, Yasushi Onishi, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae
The bone marrow (BM) microenvironment comprises multiple stem cell niches derived from BM mesenchymal stem cells (MSCs). Previous in vitro analyses have suggested that transcription factor GATA2 plays an important role in adipocyte differentiation of BM-MSCs and in hematopoietic support, but the role of GATA2 in vivo remains unknown. We evaluated GATA2 effects in BM-MSCs in vivo. Expression profiling analysis of Gata2-knockout Ter119(-)CD45(-) mesenchymal stromal cells obtained from compact bone from tamoxifen-treated Gata2 conditional knockout mice (Gata2(f/f)/ER-Cre mice) revealed upregulation of 110 genes and downregulation of 141 genes by a factor of 2...
September 1, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28826860/the-microenvironment-in-myelodysplastic-syndromes-niche-mediated-disease-initiation-and-progression
#18
REVIEW
Allison J Li, Laura M Calvi
Myelodysplastic syndromes (MDSs) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression...
November 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28826859/tet2-restrains-inflammatory-gene-expression-in-macrophages
#19
Alyssa H Cull, Brooke Snetsinger, Rena Buckstein, Richard A Wells, Michael J Rauh
Tet methylcytosine dioxygenase 2 (TET2) is one of the earliest and most frequently mutated genes in clonal hematopoiesis of indeterminate potential (CHIP) and myeloid cancers, including myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). TET2 catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, leading to DNA demethylation, and also affects transcription by recruiting histone modifiers. Inactivating TET2 mutations cause epigenetic dysregulation, clonal hematopoietic stem cell (HSC) dominance, and monocytic lineage skewing...
November 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28760689/comprehensive-discovery-of-noncoding-rnas-in-acute-myeloid-leukemia-cell-transcriptomes
#20
Jin Zhang, Malachi Griffith, Christopher A Miller, Obi L Griffith, David H Spencer, Jason R Walker, Vincent Magrini, Sean D McGrath, Amy Ly, Nichole M Helton, Maria Trissal, Daniel C Link, Ha X Dang, David E Larson, Shashikant Kulkarni, Matthew G Cordes, Catrina C Fronick, Robert S Fulton, Jeffery M Klco, Elaine R Mardis, Timothy J Ley, Richard K Wilson, Christopher A Maher
To detect diverse and novel RNA species comprehensively, we compared deep small RNA and RNA sequencing (RNA-seq) methods applied to a primary acute myeloid leukemia (AML) sample. We were able to discover previously unannotated small RNAs using deep sequencing of a library method using broader insert size selection. We analyzed the long noncoding RNA (lncRNA) landscape in AML by comparing deep sequencing from multiple RNA-seq library construction methods for the sample that we studied and then integrating RNA-seq data from 179 AML cases...
November 2017: Experimental Hematology
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