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Experimental Hematology

Connie J Eaves
No abstract text is available yet for this article.
September 12, 2018: Experimental Hematology
Xin Li, Lan Xu, Xianfu Shen, Jiayi Cai, Jia Liu, Tingyu Yin, Fei Xiao, Fangyuan Chen, Hua Zhong
The selection of chemotherapy regimen for elderly patients with acute myeloid leukemia (AML) remains challenging. Here, we report that granulocyte colony-stimulating factor (G-CSF) upregulates the expression of microRNA (miR)-146a in a nuclear factor (NF)-κB-dependent manner, leading to direct decreases in the expression of the target proteins CXCR4 and Smad4 in AML cells in vitro. The reduction in CXCR4 expression suppressed the migration abilities of leukemia cells. Downregulation of Smad4 promoted cell cycle entry in leukemia cells...
September 9, 2018: Experimental Hematology
Andrea Doescher, Jochen Casper, Doris Kraemer, Hans-Hermann Kapels, Eduard K Petershofen, Thomas H Müller
Platelet engraftment after allogeneic hematopoietic stem cell transplantation is conventionally monitored by daily platelet counts. Platelet transfusions are frequently required and obscure the detection of platelet engraftment. Digital PCR of mitochondrial DNA isolated from platelets reliably quantifies circulating platelets derived from the stem cell graft and allows to distinguish them from transfused single-donor apheresis platelets. In a feasibility study, consecutive daily peripheral blood samples from day 7 to day 20 post-transplantation were analyzed by digital PCR in 22 patients after allogeneic transplantation...
September 6, 2018: Experimental Hematology
Bin Pan, Jing Yang, Xiangmin Wang, Kailin Xu, Takayuki Ikezoe
BCR-ABL1-independent mechanisms had been indicated to mediate drug resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). The pro-oncogenic anterior gradient 2 (AGR2) mediates drug resistance of cancer cells. In this study, we observed increased level of AGR2 in TKIs-resistant CML cells. Silence of AGR2 in dasatinib-resistant K562 (K562DR) cells led to restored sensitivity to dasatinib both in vitro and in vivo. Exposure to dasatinib induced up-regulation of AGR2 in K562 cells, which indicated a probable treatment related drug resistance...
September 5, 2018: Experimental Hematology
Maël Heiblig, Delphine Rea, Marie-Lorraine Chrétien, Aude Charbonnier, Philippe Rousselot, Valérie Coiteux, Martine Escoffre-Barbe, Viviane Dubruille, Françoise Huguet, Emilie Cayssials, Eric Hermet, Agnès Guerci-Bresler, Shanti Amé, Lucila Sackmann-Sala, Lydia Roy, Mohamad Sobh, Stéphane Morisset, Gabriel Etienne, Franck E Nicolini
BACKGROUND: Ponatinib represents a remarkable progress in the treatment of heavily pretreated CML and de novo Ph+ ALL patients despite significant toxicity in clinical trials. To date, "real-life" data remain few and the use of Ponatinib in this setting and its consequences remain mostly unknown. METHODS: We report, within a national observational study, the use of ponatinib in unselected CML patients who had previously failed ≥2 lines of TKI therapy (or 1 line if an ABLT315I mutation was identified), in real-life conditions (2013-2014) in a compassionate program...
September 5, 2018: Experimental Hematology
Shenmeng Gao, Bin Zhou, Haiying Li, Xingzhou Huang, Yanfei Wu, Chongyun Xing, Xiaozhuo Yu, Yanhong Ji
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder initiated from a small subset of leukemia stem cell (LSC), which presents unrestricted self-renewal and proliferation. Long non-coding RNA HOTAIR is abundantly expressed and plays oncogenic roles in solid cancer and AML. However, whether HOTAIR regulates the self-renewal of LSC is largely unknown. Here, we reported that the expression of HOTAIR was increased in LSC than in normal hematological stem and progenitor cells (HSPCs). HOTAIR inhibition by short hairpin RNAs (shRNAs) decreased colony formation in leukemia cell lines and primary AML blasts...
August 30, 2018: Experimental Hematology
Angela Rivers, Kestis Vaitkus, Ramasamy Jagadeeswaran, Maria Armila Ruiz, Vinzon Ibanez, Filippo Ciceri, Fernando Cavalcanti, Robert E Molokie, Yogen Saunthararajah, James Douglas Engel, Joseph DeSimone, Donald Lavelle
Increased levels of fetal hemoglobin (HbF) lessen the severity of symptoms and increase the life span of patients with sickle cell disease (SCD). More effective strategies to increase HbF are needed because the current standard of care, hydroxyurea, is not effective in a significant proportion of patients. Treatment of the millions of patients projected worldwide would best be accomplished with an orally administered drug therapy that increased HbF. LSD1 is a component of corepressor complexes that repress γ-globin gene expression and are a therapeutic target for HbF reactivation...
August 17, 2018: Experimental Hematology
Aditya Barve, Lavona Casson, Maxwell Krem, Mark Wunderlich, James C Mulloy, Levi J Beverly
Cell-line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) in immune-deficient mice have revolutionized our understanding of normal and malignant human hematopoiesis. Transgenic approaches further improved in vivo hematological research, allowing the development of human-cytokine-producing mice, which show superior human cell engraftment. The most popular mouse strains used in research, the NOG (NOD.Cg-Prkdcscid  Il2rγtm1Sug /Jic) and the NSG (NOD/SCID-IL2Rγ-/- , NOD.Cg-Prkdcscid Il2rγtm1Wjl /SzJ) mouse, and their human-cytokine-producing (interleukin-3, granulocyte-macrophage colony-stimulating factor, and stem cell factor) counterparts (huNOG and NSGS), rely partly on a mutation in the DNA repair protein PRKDC, causing a severe combined immune deficiency (SCID) phenotype and rendering the mice less tolerant to DNA-damaging therapeutics, thereby limiting their usefulness in the investigation of novel acute myeloid leukemia (AML) therapeutics...
August 17, 2018: Experimental Hematology
Benigno C Valdez, Xiaowen Tang, Yang Li, David Murray, Yan Liu, Uday Popat, Richard E Champlin, Borje S Andersson
The combination of the DNA-alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pretransplantation conditioning therapy for myeloid leukemias. However, it is associated with significant nonrelapse mortality, which prohibits dose escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase antileukemic efficacy without jeopardizing patient safety. A preclinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC), and the hypomethylating agent decitabine (DAC) in human acute myeloid leukemia (AML) cell lines...
August 10, 2018: Experimental Hematology
Tobias Maetzig, Michael Morgan, Axel Schambach
Hematopoiesis depends on the controlled differentiation of hematopoietic stem cells to mature cells with defined functions. Although each cell population within the hematopoietic hierarchy can be described by phenotypic markers, isolation of marker pure populations does not necessarily result in cells with homogeneous functionality. However, techniques that enable the efficient characterization of cell behavior with high resolution are limited. Although single-cell transplantation assays demand high mouse numbers and workload, sequencing-based fate tracking techniques require the destruction of the host cell, substantial financial resources, and bioinformatics expertise and suffer from a delay between sample acquisition and data interpretation...
August 8, 2018: Experimental Hematology
Lane H Miller, Cheng-Kui Qu, Melinda Pauly
The relationship between the hematopoietic stem cell (HSC) population and its surrounding bone marrow microenvironment is a rapidly evolving area of research. Normal HSC processes rely heavily on a complex communication network involving various marrow niches. Although leukemogenesis largely results from abnormal genetic activity within the leukemia stem cell itself, mounting evidence indicates a significant contributory role played by marrow niche dysregulation. Furthermore, numerous instances of activating or inactivating germline mutations within marrow microenvironment cells have been shown to be sufficient for development of myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia, even in the context of wild-type HSCs...
August 1, 2018: Experimental Hematology
Camilla de S Borges, Aline F Ferreira, Vitor H Almeida, Fausto G Gomes, Maria Gabriela Berzoti-Coelho, Maira da Costa Cacemiro, Natalia S Nunes, Lorena L Figueiredo-Pontes, Belinda P Simões, Fabíola A Castro, Robson Q Monteiro
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which generates the oncogene BCR-ABL1. Protease-activated receptor 1 (PAR1) is involved in tumor progression and angiogenesis. We have previously reported that PAR1 expression is elevated in human leukemias that display a more aggressive clinical behavior, including the blast crisis of CML. In this study, we analyzed the crosstalk between the oncoprotein BCR-ABL and PAR1 in CML. Leukemic cell lines transfected with the BCR-ABL1 oncogene showed significantly higher expression levels of PAR1 compared with that of wild-type counterparts...
August 1, 2018: Experimental Hematology
Ahmed Kotb, Riad El Fakih, Amr Hanbali, Yousef Hawsawi, Feras Alfraih, Shahrukh Hashmi, Mahmoud Aljurf
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by suboptimal outcomes in the adult age group. Recently, a new subtype called Philadelphia (Ph)-like ALL has been described. This subgroup is characterized by high cytokine receptor and tyrosine kinase signaling expression, resulting in kinase activation through stimulation of two main pathways, the ABL and JAK/STAT pathways. The diagnostic method or approach for Ph-like ALL is still not standardized and efforts are ongoing to identify an easy and applicable diagnostic method...
July 31, 2018: Experimental Hematology
Sara Ghorashian, Persis Amrolia, Paul Veys
T cells that are genetically modified to express chimeric antigen receptors (CARs) specific for CD19 show great promise for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). The first U.S. Food and Drug Administration approval of a cellular cancer therapy in 2017, Novartis's CD19-targeting CAR T-cell product Kymriah™ within the context of relapsed/refractory pediatric ALL, followed rapidly by approval of Kite's Yescarta™ and, more recently, Kymriah™ for diffuse large B-cell indications in adults, highlights the pace of progress made in this field...
July 20, 2018: Experimental Hematology
Mara Salomé, Lisa Hopcroft, Karen Keeshan
TRIBBLES pseudokinases (TRIB1, TRIB2, and TRIB3) are important regulators of normal and malignant hemopoiesis. The relative abundance of each TRIBBLES family member may be important for distinct oncogenic or tumor suppressor functions. We map the expression profiles of TRIB1, TRIB2, and TRIB3 in human and murine hemopoietic stem, progenitor and mature cells, and in human leukemia datasets. Our data show that TRIB1-TRIB2 have an inverse expression relationship in normal hemopoiesis, whereas TRIB1-TRIB3 have a positive correlation...
July 20, 2018: Experimental Hematology
Nilanjana Sadhu, Ellie H Jhun, Yingwei Yao, Ying He, Robert E Molokie, Diana J Wilkie, Zaijie Jim Wang
The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B = -3.76, p = 0.037; dominant model: B = -5.61, p = 0.021) and rs3783641 (additive model: incident rate ratio [IRR] = 1...
July 19, 2018: Experimental Hematology
Niu Li, Lixia Ding, Benshang Li, Jian Wang, Alan D D'Andrea, Jing Chen
Fanconi anemia (FA) is a rare recessive disease characterized by progressive bone marrow failure, congenital abnormalities, and increased incidence of cancers. To date, mutations in 22 genes can cause FA or an FA-like phenotype. In China, in addition to clinical information, FA diagnosis primarily relies on genetic sequencing because the chromosome breakage test is rarely performed. Here, we employed multiple genetic diagnostic tools (DNA sequencing, multiplex ligation-dependent probe amplification, and chromosome microarray) and a variant-based functional assay platform to investigate the genetic cause in 25 Chinese suspected FA patients...
July 19, 2018: Experimental Hematology
Stina Wichert, Åsa Pettersson, Thomas Hellmark, Åsa Johansson, Markus Hansson
In experimental studies, eosinophils have been shown to promote the survival, proliferation, and retention of plasma cells in the bone marrow (BM). The clinical significance of eosinophils in plasma cell disorders (PCDs) in humans is largely unknown. This study focuses on the frequency and phenotype of eosinophils in the BM and peripheral blood (PB) in patients with untreated PCD compared with healthy controls. The number of eosinophils per se did not correlate with the number of BM plasma cells or disease stage...
July 5, 2018: Experimental Hematology
Clea S Grace, Hanna K A Mikkola, Diana R Dou, Vincenzo Calvanese, Roger E Ronn, Louise E Purton
Hematopoietic stem cells (HSCs) are multipotent cells responsible for the maintenance of the hematopoietic system throughout life. Dysregulation of the balance in HSC self-renewal, death, and differentiation can have serious consequences such as myelodysplastic syndromes or leukemia. All-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A/RA, has been shown to have pleiotropic effects on hematopoietic cells, enhancing HSC self-renewal while also increasing differentiation of more mature progenitors...
September 2018: Experimental Hematology
Soghra Fatima, Sheng Zhou, Brian P Sorrentino
Abcg2, a member of the ATP-binding cassette transporter family, is expressed in adult hematopoietic stem cells (HSCs) and is required for the side population phenotype of adult bone marrow HSCs and other adult tissue-specific stem cells. Lineage tracing in adult mice using the Abcg2-Cre mouse model showed that Abcg2 marks HSCs, intestinal stem cells, and spermatogonial stem cells. It is unclear whether definitive HSCs or their precursors in early embryonic development can be marked by Abcg2 expression. Here, we treated pregnant Abcg2 Cre/Cre RosaLSL-YFP mice with a single injection of 4-hydroxytamoxifen at embryonic day 7...
September 2018: Experimental Hematology
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