bluuebunny/crossref_metadata_2025_split huggingface dataset:
A carboxy-terminal deletion mutant of Notch1accelerates lymphoid oncogenesis in E2A-PBX1transgenic mice
Authors: Feldman Brian J. , Hampton Tracy , Cleary Michael L. 
Published: October 2019

AbstractPBX1 is a proto-oncogene that plays important roles in pattern formation during development. It was discovered as a fusion with the E2A gene after chromosomal translocations in a subset of acute leukemias. The resulting E2a-Pbx1 chimeric proteins display potent oncogenic properties that appear to require dimerization with Hox DNA binding partners. To define molecular pathways that may be impacted by E2a-Pbx1, a genetic screen consisting of neonatal retroviral infection was used to identify genes that accelerate development of T-cell tumors in E2A-PBX1 transgenic mice. Retroviral insertions in the Notch1 gene were observed in 88% of tumors arising with a shortened latency. Among these, approximately half created a NotchIC allele, encoding the intracellular, signaling portion of Notch1, suggesting a synergistic interaction between the Notch and E2a-Pbx1 pathways in oncogenesis. The remaining proviral insertions involvingNotch1 occurred in a more 3′ exon, resulting in truncating mutations that deleted the carboxy-terminal region ofNotch1 containing negative regulatory sequences (Notch1ΔC). In contrast toNotchIC, forced expression ofNotch1ΔC in transgenic mice did not perturb thymocyte growth or differentiation. However, mice transgenic for both the E2A-PBX1 and Notch1ΔC genes displayed a substantially shortened latency for tumor development compared with E2A-PBX1 single transgenic mice. These studies reveal a novel mechanism for oncogenic activation ofNotch1 and demonstrate a collaborative relationship between 2 cellular oncogenes that also contribute to cell fate determination during embryonic development.
Interleukin-15 enhances neutrophil functional activity in patients with human immunodeficiency virus infection
Authors: Mastroianni Claudio M. , d'Ettorre Gabriella , Forcina Gabriele , Lichtner Miriam , Mengoni Fabio , D'Agostino Claudia , Corpolongo Angela , Massetti Anna P. , Vullo Vincenzo 
Published: October 2019

AbstractPolymorphonuclear leukocyte (PMN) dysfunction has been reported in human immunodeficiency virus (HIV)-infected patients. Interleukin (IL)-15 is a recently discovered cytokine that potentiates antimicrobial functions of normal PMNs. We evaluated the in vitro effect of IL-15 on chemotaxis and fungicidal activity of PMNs from 9 patients with untreated advanced HIV infection, 8 patients with viral suppression after 52 to 130 weeks of highly active antiretroviral therapy (HAART), and 12 patients with treatment failure. We also studied oxidative burst and apoptosis of PMNs in 5 patients with untreated advanced HIV infection. Twelve healthy donors were included as controls. Chemotaxis and fungicidal activity of unprimed PMNs was significantly lower in patients with untreated HIV infection compared with controls. After incubation with IL-15, a significant increase in PMN chemotaxis and fungicidal activity was found; moreover, IL-15 induced a significant reduction in the number of apoptotic HIV+ PMNs. IL-15 did not modulate oxidative burst of HIV+ PMNs as measured by chemiluminescence production. The in vitro priming of PMNs with IL-15 determined a complete reversal of defective chemotaxis and killing in all HAART-treated patients with long-term HIV suppression. IL-15 significantly enhanced chemotaxis and fungicidal activity also in patients with HAART failure. In conclusion, IL-15 is an important cytokine in the activation of the functional properties of HIV+ PMNs, by delaying apoptosis and enhancing chemotaxis and fungicidal activity. The potent stimulant effect of IL-15 on PMN function was observed in antiretroviral naive patients as well as in individuals who were receiving HAART, including those with treatment failure.
Transforming growth factor-β: pleiotropic role in the regulation of hematopoiesis
Authors: Fortunel Nicolas O. , Hatzfeld Antoinette , Hatzfeld Jacques A. 
Published: October 2019

AbstractHematopoiesis is a remarkable cell-renewal process that leads to the continuous generation of large numbers of multiple mature cell types, starting from a relatively small stem cell compartment. A highly complex but efficient regulatory network is necessary to tightly control this production and to maintain the hematopoietic tissue in homeostasis. During the last 3 decades, constantly growing numbers of molecules involved in this regulation have been identified. They include soluble cytokines and growth factors, cell–cell interaction molecules, and extracellular matrix components, which provide a multifunctional scaffolding specific for each tissue. The cloning of numerous growth factors and their mass production have led to their possible use for both fundamental research and clinical application.
Solitary plasmacytoma of bone and asymptomatic multiple myeloma
Authors: Dimopoulos Meletios A. , Moulopoulos Lia A. , Maniatis Alice , Alexanian Raymond 
Published: October 2019

AbstractMost patients with multiple myeloma (MM) present with symptoms, have evidence of generalized disease, and require chemotherapy promptly to reduce the malignant clone. Some patients present with a local symptom from a single plasmacytoma but no myeloma elsewhere. Such patients usually become free of symptoms after local radiotherapy. In patients with MM without symptoms, the diagnosis is made on the basis of screening laboratory tests. In patients with either solitary plasmacytoma of bone or asymptomatic MM, systemic treatment should be deferred until there is evidence of disease progression.
Interferon-α directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1
Authors: Wang Qin , Miyakawa Yoshitaka , Fox Norma , Kaushansky Kenneth 
Published: October 2019

AbstractInterferon (IFN)-α has proven useful for treating several clinical conditions, including chronic viral hepatitis and chronic myeloproliferative and lymphoproliferative disorders. In addition to its well-known antiviral effects, the cytokine exerts antiproliferative effects on many cell types, helping to explain its therapeutic usefulness in these latter conditions. However, this same property accounts for several undesirable effects, including thrombocytopenia, which can interfere with the successful clinical application of IFN-α. Unfortunately, the mechanisms responsible for the myelosuppressive effects of the cytokine are incompletely understood. The effects of IFN-α on megakaryocyte (MK) development were studied. Using several marrow cell purification techniques and quantitative culture methods, it was found that IFN-α directly inhibits thrombopoietin (TPO)-induced MK growth. Previous studies indicated that Janus kinase (JAK) and its substrates mediate the effects of TPO on cellular proliferation and survival. It was found that IFN-α directly suppresses TPO-induced phosphorylation of the JAK2 substrates c-Mpl and STAT 5 in a TPO-dependent hematopoietic cell line and of Mpl and STAT3 in primary murine MK. Moreover, IFN-α induces SOCS-1 production in these cells, which has been shown to inhibit TPO-induced cell growth. Because SOCS protein expression is induced by many cytokines and has been reported to extinguish signaling from several hematopoietic cytokine receptors, these results identify a molecular mechanism responsible for cytokine receptor cross-talk.
Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation
Authors: Martelli Maria Paola , Lin Huamao , Zhang Weiguo , Samelson Lawrence E. , Bierer Barbara E. 
Published: October 2019

AbstractActivation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCγ-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCγ-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.
Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes
Authors: Aguayo Alvaro , Kantarjian Hagop , Manshouri Taghi , Gidel Cristi , Estey Elihu , Thomas Deborah , Koller Charles , Estrov Zeev , O'Brien Susan , Keating Michael , Freireich Emil , Albitar Maher 
Published: October 2019

AbstractAngiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-α (TNF-α), tumor growth factor-α (TGF-α), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-α, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-α levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-α in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.
Regulation of CCR6 chemokine receptor expression and responsiveness to macrophage inflammatory protein-3α/CCL20 in human B cells
Authors: Krzysiek Roman , Lefevre Eric A. , Bernard Jérôme , Foussat Arnaud , Galanaud Pierre , Louache Fawzia , Richard Yolande 
Published: October 2019

AbstractThe regulation of CCR6 (chemokine receptor 6) expression during B-cell ontogeny and antigen-driven B-cell differentiation was analyzed. None of the CD34+Lin− hematopoietic stem cell progenitors or the CD34+CD19+ (pro-B) or the CD19+CD10+ (pre-B/immature B cells) B-cell progenitors expressed CCR6. CCR6 is acquired when CD10 is lost and B-cell progeny matures, entering into the surface immunoglobulin D+ (sIgD+) mature B-cell pool. CCR6 is expressed by all bone marrow–, umbilical cord blood–, and peripheral blood–derived naive and/or memory B cells but is absent from germinal center (GC) B cells of secondary lymphoid organs. CCR6 is down-regulated after B-cell antigen receptor triggering and remains absent during differentiation into immunoglobulin-secreting plasma cells, whereas it is reacquired at the stage of post-GC memory B cells. Thus, within the B-cell compartment, CCR6 expression is restricted to functionally mature cells capable of responding to antigen challenge. In transmigration chemotactic assays, macrophage inflammatory protein (MIP)-3α/CC chemokine ligand 20 (CCL20) induced vigorous migration of B cells with differential chemotactic preference toward sIgD− memory B cells. These data suggest that restricted patterns of CCR6 expression and MIP-3α/CCL20 responsiveness are integral parts of the process of B-lineage maturation and antigen-driven B-cell differentiation.
Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study
Authors: Ruutu Tapani , Volin Liisa , Parkkali Terttu , Juvonen Eeva , Elonen Erkki 
Published: October 2019

Abstract
The role of corticosteroids in the prophylaxis of graft-versus-host disease (GVHD) is not well established. We have conducted a prospective, randomized, open-label, single-center study about the effect of adding methylprednisolone (MP) to the widely used prophylactic regimen consisting of cyclosporine A and methotrexate. A total of 108 consecutive patients treated with allogeneic bone marrow transplantation from an HLA-identical sibling donor for malignant blood disease were entered into the study; 53 patients were randomized to receive and 55 were randomized not to receive prophylactic MP. The dose of MP was 0.5 mg/kg on days 14 to 20, 1 mg/kg on days 21 to 34, 0.5 mg/kg on days 35 to 48, and thereafter the dose was slowly tapered and the administration discontinued on day 110. In the group given prophylactic MP, the incidence of acute GVHD was lower (19% vs 56%,P = .0001), there was a trend toward a lower incidence of chronic GVHD among low-risk patients (P = .06), and during the first 4 months the time spent at hospital was shorter and there were fewer infections. The total amount of MP given was similar in the study groups because of a higher incidence of acute GVHD and its treatment in the group of patients not given prophylactic MP. There were no significant differences between the study groups in relapse rate or survival. In conclusion, the addition of MP to the combination of cyclosporine and methotrexate markedly reduced the incidence of acute GVHD without causing untoward effects. The timing of corticosteroid administration is probably important for the efficacy.
Biologic significance of GATA-1 activities in Ras-mediated megakaryocytic differentiation of hematopoietic cell lines
Authors: Matsumura Itaru , Kawasaki Akira , Tanaka Hirokazu , Sonoyama Junko , Ezoe Sachiko , Minegishi Naoko , Nakajima Koichi , Yamamoto Masayuki , Kanakura Yuzuru 
Published: October 2019

AbstractLineage-specific transcription factors play crucial roles in the development of hematopoietic cells. In a previous study, it was demonstrated that Ras activation was involved in thrombopoietin-induced megakaryocytic differentiation. In this study, constitutive Ras activation by H-rasG12V evoked megakaryocytic maturation of erythroleukemia cell lines F-36P and K562, but not of myeloid cell line 32D cl3 that lacks GATA-1. However, the introduction of GATA-1 led to reprogramming of 32D cl3 toward erythrocytic/megakaryocytic lineage and enabled it to undergo megakaryocytic differentiation in response to H-rasG12V. In contrast, the overexpression of PU.1 and c-Myb changed the phenotype of K562 from erythroid to myeloid/monocytic lineage and rendered K562 to differentiate into granulocytes and macrophages in response to H-rasG12V, respectively. In GATA-1–transfected 32D cl3, the endogenous expression of PU.1 and c-Myb was easily detectable, but their activities were reduced severely. Endogenous GATA-1 activities were markedly suppressed in PU.1-transfected and c-myb–transfected K562. As for the mechanisms of these reciprocal inhibitions, GATA-1 and PU.1 were found to associate through their DNA-binding domains and to inhibit the respective DNA-binding activities of each other. In addition, c-Myb bound to GATA-1 and inhibited its DNA-binding activities. Mutant GATA-1 and PU.1 that retained their own transcriptional activities but could not inhibit the reciprocal partner were less effective in changing the lineage phenotype of 32D cl3 and K562. These results suggested that GATA-1 activities may be crucial for Ras-mediated megakaryocytic differentiation and that its activities may be regulated by the direct interaction with other lineage-specific transcription factors such as PU.1 and c-Myb.
The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity
Authors: Dörmann Dagmar , Clemetson Kenneth J. , Kehrel Beate E. 
Published: October 2019

AbstractThe role of the platelet glycoprotein (GP) Ib-V-IX receptor in thrombin activation of platelets has remained controversial although good evidence suggests that blocking this receptor affects platelet responses to this agonist. The mechanism of expression of procoagulant activity in response to platelet agonists is also still obscure. Here, the binding site for thrombin on GPIb is shown to have a key role in the exposure of negatively charged phospholipids on the platelet surface and thrombin generation, in response to thrombin, which also requires protease-activated receptor-1, GPIIb-IIIa, and platelet-platelet contact. Von Willebrand factor binding to GPIb is not essential to initiate development of platelet procoagulant activity. Inhibition of fibrinogen binding to GPIIb-IIIa also failed to block platelet procoagulant activity. Both heparin and low molecular weight heparin block thrombin-induced platelet procoagulant activity, which may account for part of their clinical efficacy. This study demonstrates a new, critical role for platelet GPIb in hemostasis, showing that platelet activation and coagulation are tightly interwoven, which may have implications for alternative therapies for thrombotic diseases.
Syndecan-1 is targeted to the uropods of polarized myeloma cells where it promotes adhesion and sequesters heparin-binding proteins
Authors: Børset Magne , Hjertner Øyvind , Yaccoby Shmuel , Epstein Joshua , Sanderson Ralph D. 
Published: October 2019

AbstractSyndecan-1 (CD138) is a heparan sulfate-bearing proteoglycan present on the surface of myeloma cells where it mediates myeloma cell-cell and cell-extracellular matrix adhesion. In this study, we examined myeloma cell lines for cell membrane localization of syndecan-1. On some cells we note a striking localization of syndecan-1 to a single small membrane protrusion, with the remainder of the cell surface being mostly negative for syndecan-1. Examination of cell morphology reveals that a proportion of cells from myeloma cell lines, as well as primary myeloma cells, are polarized, with a uropod on one end and lamellipodia on the other end. On these polarized cells, syndecan-1 is specifically targeted to the uropod, but in contrast, on nonpolarized cells syndecan-1 is evenly distributed over the entire cell surface. In addition to syndecan-1, several other cell surface molecules localize specifically to the uropod, including CD44 and CD54. Functional assays reveal that myeloma cell lines with a high proportion of polarized cells have a much higher migratory potential than cell lines with few polarized cells. Moreover, the uropod is the cell pole preferentially involved in aggregation of myeloma cells and in adhesion of myeloma cells to osteoblast-like cells. When polarized myeloma cells are incubated with heparin-binding proteins, like hepatocyte growth factor or osteoprotegerin, they concentrate in the uropod. These data indicate that syndecan-1 is targeted to the uropod of polarized myeloma cells and that this targeting plays a role in promoting cell-cell adhesion and may also regulate the biological activity of heparin-binding cytokines.
PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding
Authors: Zhang Pu , Zhang Xiaobo , Iwama Atsushi , Yu Channing , Smith Kent A. , Mueller Beatrice U. , Narravula Salaija , Torbett Bruce E. , Orkin Stuart H. , Tenen Daniel G. 
Published: October 2019

AbstractThe lineage-specific transcription factors GATA-1 and PU.1 can physically interact to inhibit each other's function, but the mechanism of repression of GATA-1 function by PU.1 has not been elucidated. Both the N terminus and the C terminus of PU.1 can physically interact with the C-terminal zinc finger of GATA-1. It is demonstrated that the PU.1 N terminus, but not the C terminus, is required for inhibiting GATA-1 function. Induced overexpression of PU.1 in K562 erythroleukemia cells blocks hemin-induced erythroid differentiation. In this system, PU.1 does not affect the expression of GATA-1 messenger RNA, protein, or nuclear localization. However, GATA-1 DNA binding decreases dramatically. By means of electrophoretic mobility shift assays with purified proteins, it is demonstrated that the N-terminal 70 amino acids of PU.1 can specifically block GATA-1 DNA binding. In addition, PU.1 had a similar effect in the G1ER cell line, in which the GATA-1 null erythroid cell line G1E has been transduced with a GATA-1–estrogen receptor fusion gene, which is directly dependent on induction of the GATA-1 fusion protein to effect erythroid maturation. Consistent with in vitro binding assays, overexpression of PU.1 blocked DNA binding of the GATA-1 fusion protein as well as GATA-1–mediated erythroid differentiation of these G1ER cells. These results demonstrate a novel mechanism by which function of a lineage-specific transcription factor is inhibited by another lineage-restricted factor through direct protein–protein interactions. These findings contribute to understanding how protein–protein interactions participate in hematopoietic differentiation and leukemogenesis.
Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia
Authors: Coustan-Smith Elaine , Sancho Jose , Hancock Michael L. , Boyett James M. , Behm Frederick G. , Raimondi Susana C. , Sandlund John T. , Rivera Gaston K. , Rubnitz Jeffrey E. , Ribeiro Raul C. , Pui Ching-Hon , Campana Dario 
Published: October 2019

AbstractBy using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, ≥0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P &lt; .001); patients with high levels of MRD at the end of the induction phase (≥1%) or at week 14 of continuation therapy (≥0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD+patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients.