bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of c-kit ligand/steel factor by antibodies reduces survival of lethally irradiated mice
Authors: Neta R , Williams D , Selzer F , Abrams J 
Published: October 2019

Abstract
Survival after irradiation with LD100/30 (radiation dose lethal to 100% of mice in 30 days) is based on recovery of impaired hematopoietic function. Our previous studies using antibodies to interleukin-1 receptor (IL–1R), tumor necrosis factor (TNF), and IL–6 demonstrated that endogenous production of these three cytokines is required for untreated mice as well as mice protected with lipopolysaccharide (LPS), IL–1, or TNF to survive lethal irradiation. In this report we show that anti-c-kit ligand/steel factor (SIF) antibody similarly abrogates LPS- and IL-1-induced radioprotection. Furthermore, administration of this antibody to unmanipulated mice increased LD50/30 radiation lethality from 50% to 100%. Such an effect was not obtained using anti-IL-3, anti- IL–4, or anti-granulocyte-macrophage colony-stimulating factor antibody. Thus, like IL–1, TNF, and IL–6, SIF is required for survival from lethal irradiation.
Alpha 4 beta 1 and alpha 5 beta 1 are differentially expressed during myelopoiesis and mediate the adherence of human CD34+ cells to fibronectin in an activation-dependent way
Authors: Kerst JM , Sanders JB , Slaper-Cortenbach IC , Doorakkers MC , Hooibrink B , van Oers RH , von dem Borne AE , van der Schoot CE 
Published: October 2019

Abstract
To study the receptors involved in the interaction between extracellular matrix proteins and hematopoietic progenitor cells, we analyzed the expression of beta 1 integrins on CD34+ bone marrow cells by means of immunoflowcytometry. Alpha 4 beta 1 and alpha 5 beta 1 were expressed, whereas alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, and alpha v beta 1 were virtually absent. Furthermore, we assessed the alpha 4 and alpha 5 expression on committed myeloid progenitor cells. These colony-forming cells were detected in the alpha 4 dull fraction and the alpha 5 dull fraction. During myeloid differentiation, both in vivo and in vitro, a differential expression of alpha 4 beta 1 and alpha 5 beta 1 was observed. alpha 5 beta 1 was found to be lost at the myelocytic-metamyelocytic stage, before the loss of alpha 4 beta 1, at the band stage. Functional studies showed no binding of erythroid progenitor-depleted, CD34+ bone marrow cells to fibronectin. However, protein kinase C activation strongly induced fibronectin binding (68% of the cells). Inhibition experiments with specific antibodies and peptides showed the binding to be mediated by both alpha 4 beta 1 and alpha 5 beta 1. Also, colony-forming cells of granulocytes and macrophages were demonstrated to adhere to fibronectin in an activation-dependent way. During granulocyte colony-stimulating factor-induced in vitro maturation, the activation-dependent fibronectin binding capacity is gradually lost. We conclude that: (1) CD34+ bone marrow cells express alpha 4 beta 1 and alpha 5 beta 1; (2) the expression of alpha 4 beta 1 and alpha 5 beta 1 is differentially expressed during myeloid differentiation; and (3) binding of CD34+ bone marrow cells to fibronectin is activation dependent.
Apoptosis and hematopoiesis in murine fetal liver
Authors: Yu H , Bauer B , Lipke GK , Phillips RL , Van Zant G 
Published: October 2019

Abstract
The fetal mouse liver (FL) is an organ of intense, but transient, hematopoietic activity during mid-gestation, with erythropoiesis being predominant during days 11 through 16. It therefore seemed reasonable to expect that hematopoietic cytokines, such as erythropoietin (epo), interleukin-3 (IL-3), and stem cell factor (SCF), may play important roles in maintaining a homeostatic balance of erythropoiesis and apoptosis in liver during ontogeny. First, we determined the effects of these growth factors on hematopoiesis by measuring colony formation and hemoglobin synthesis of cultured FLs. Secondly, we determined the protection from apoptosis afforded by these cytokines, using electrophoretic analysis of DNA and by flow cytometry of FL cells deprived in culture of epo, IL-3, and SCF. Erythropoietin was necessary and alone sufficient for hemoglobin synthesis in colony-forming units- erythroid colonies, but IL-3 was a required cofactor to obtain maximal development of burst-forming units-erythroid colonies. SCF alone caused little colony formation in methylcellulose cultures of FLs, but when combined with epo and IL-3, it had dramatic effects both on the number of colonies and their size. Secondly, indices of apoptosis were determined by measuring DNA fragmentation caused by endogenous nuclease activity in apoptotic cells. Liver cells from cultures without cytokines showed the extensive degradation of DNA to low molecular weight nucleosomal oligomers, which is characteristic of apoptosis. Protection from apoptosis afforded by epo directly corresponded to the level of erythropoiesis in FLs of different gestational age. Erythropoietin was by far the most critical cytokine in sparing FL cells from apoptosis. Analyses of agarose gels showed that SCF and IL-3 alone had no apparent effect in reducing the amount of DNA in fragments, and when combined with epo they had no more protective effect than that provided by epo alone. However, using the more sensitive flow cytometric determination of cells with subdiploid amounts of DNA, SCF, and IL-3 alone had measurable protective effects that were less than those caused by epo. Thus, we show that normal, untransformed cells of the developing hematopoietic system not only require cytokines for proliferation and differentiation, but they have an initial and absolute requirement of them for protection from apoptosis.
Protein S enhances C4b binding protein interaction with neutrophils
Authors: Furmaniak-Kazmierczak E , Hu CY , Esmon CT 
Published: October 2019

Abstract
Protein S, an inhibitor of coagulation, interacts reversibly with C4b binding protein (C4bBP). The physiologic role of this complex formation remains unknown. In this study we examined the possibility that protein S would facilitate C4bBP binding to the surface of neutrophils where, in turn, this complex could help protect the cell from complement- mediated damage at the site of inflammation. Neutrophils bind approximately 60,000 protein S molecules per cell (kd = 140 nmol/L) in a Ca(2+)-dependent fashion. C4bBP also binds to neutrophils (23,000 sites per cell at physiologic C4bBP concentration), but this binding is not Ca2+ dependent. Protein S approximately doubled C4bBP binding, but protein S only influenced C4bBP binding in the presence of Ca2+. Protein S binding to neutrophils decreased approximately twofold in the presence of saturating concentrations of C4bBP. Neutrophil activation had only minor effects on the affinity and number of sites for protein S or the protein S-C4bBP complex. These results indicate that the protein S-C4bBP complex binds to the neutrophil surface where it can presumably modulate complement assembly on the cell surface.
Epstein-Barr virus and childhood Hodgkin's disease in Honduras and the United States
Authors: Ambinder RF , Browning PJ , Lorenzana I , Leventhal BG , Cosenza H , Mann RB , MacMahon EM , Medina R , Cardona V , Grufferman S 
Published: October 2019

Abstract
In industrialized populations, Hodgkin's disease (HD) has an initial peak in young adulthood, whereas in economically developing populations the initial peak occurs in childhood. This pattern resembles that of infection with poliovirus and suggests an infectious cofactor in the etiology. Serologic studies have linked Epstein-Barr virus (EBV) to young adult and adult HD, and viral nucleic acids and antigens have been detected in a subset of Hodgkin's tumor specimens. To investigate the association of childhood HD with EBV we studied tumor specimens from 11 children treated in Honduras and 25 children treated in the United States using in situ hybridization and antigen detection techniques. Among the patients from Honduras, tumor specimens from all cases were EBV positive. Among the patients from the United States, tumor specimens from six of seven patients with mixed cellularity histology, 2 of 15 with nodular sclerosis histology, and neither of two patients with lymphocyte-predominant histologies were EBV positive. These findings support the hypothesis that EBV contributes to the pathogenesis of HD in children, particularly in mixed cellularity HD, and raises the possibility that there are important geographic, racial, or ethnic factors in the EBV association with HD.
High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of Hodgkin's disease occurring in Peru
Authors: Chang KL , Albujar PF , Chen YY , Johnson RM , Weiss LM 
Published: October 2019

Abstract
The Epstein-Barr virus (EBV) has been implicated in the pathogenesis of Hodgkin‧s disease (HD). This study was undertaken to determine whether the association of EBV with HD showed geographical variation, as in Burkitt‧s lymphoma. We studied 32 formalin-fixed, paraffin-embedded cases of HD occurring in Peru. EBV DNA-RNA in situ hybridization was performed using a 30-base biotinylated antisense oligonucleotide complementary to the EBER1 gene of EBV. EBV immunohistochemistry was also performed, using a monoclonal antibody (MoAb) to the latent membrane protein (LMP1) of EBV. Identification of the precise cellular subset staining with EBV was accomplished via double-labeling with MoAbs directed against Reed-Sternberg cells (LeuM1/CD15) and B cells (L26/CD20). EBV RNA was identified in all or virtually all of the Reed- Sternberg cells and variants in 30 of the 32 (94%) cases of HD by in situ hybridization. LMP1 expression was identified in 83% of the EBER1- positive cases. Double-labeling studies confirmed the localization of EBV RNA to CD15-expressing Hodgkin‧s cells. This study found an extremely high prevalence of EBV in Peruvian HD, in contrast to the much lower percentage of EBV-associated cases of HD occurring in “Western” patients.
Cells lacking glycan phosphatidylinositol-linked proteins have impaired ability to vesiculate
Authors: Whitlow M , Iida K , Marshall P , Silber R , Nussenzweig V 
Published: October 2019

Abstract
Erythrocytes shed membrane vesicles in response to many stimuli. It has been previously demonstrated that glycan phosphatidylinositol-linked (GPI-linked) proteins such as decay accelerating factor and acetylcholinesterase are concentrated in these vesicles relative to the erythrocyte membrane. We have examined the requirement for GPI-linked proteins for the process of vesiculation. Erythrocytes that do not express GPI-linked proteins, obtained from patients with paroxysmal nocturnal hemoglobinuria (PNH), release between 10% and 50% of the quantity of vesicles as normal cells in response to the Ca2+ ionophore A23187. Platelets from the same patients produced 10% to 20% of the amount of vesicles as normal platelets. In addition, a mutant B- lymphoblastoid cell line that lacks GPI-linked molecules produces about half of the number of vesicles as compared with the wild-type cell line in response to the Ca2+ ionophore. Prior findings indicate that vesiculation is one of the mechanisms that the cell uses to remodel the plasma membrane, as well as protect itself from membrane-damaging agents such as the terminal complement components C5b-9. On the basis of the present results, we conclude that GPI-linked proteins play an important role in membrane vesiculation.
Fetal hemoglobin induction with butyric acid: efficacy and toxicity
Authors: Blau CA , Constantoulakis P , Shaw CM , Stamatoyannopoulos G 
Published: October 2019

Abstract
Butyric acid induces fetal hemoglobin (HbF), a property of potential therapeutic advantage in patients with disorders of globin chain synthesis. We performed dose escalation studies of this compound in baboons to assess whether clinically significant increases in HbF are achievable, and to define the associated toxicities. Additionally, the effect of butyrate in combination with erythropoietin on HbF induction was assessed. HbF induction in response to butyrate was dependent on the dose and duration of treatment. Doses of butyrate less than 4 g/kg/d were associated with minimal toxicity (hypokalemia) and significant HbF induction in these nonanemic animals, with 1 g/kg/d producing an increase in HbF-containing reticulocytes (F reticulocytes) from 0.9% to 8.7% and an increase in HbF from 0.8% to 1.4%. A dose of 2 g/kg/d resulted in an increase in F reticulocytes from 2.1% to 27.8% and an increase in HbF from 0.7% to 2.2%. Doses of 4 g/kg/d in another animal produced an increase in F reticulocytes from 1% to 21.6% and in HbF from 1.9% to 5.3%. Infusions in excess of 4 g/kg/d were complicated (after a variable amount of time) by a decreased level of alertness (caused by hyperosmolality or butyrate itself) and hematologic toxicity (with declines in reticulocyte, white blood cell, and platelet counts). Prolonged infusions of high doses of butyrate (8 to 10 g/kg/d) were associated with peak F reticulocyte percentages reaching 38% to 64.5% and HbF reaching levels in excess of 20%. These high doses (8 to 10 g/kg/d) were complicated in two animals with a striking and unique neuropathologic picture and, in one animal, multiorgan system failure. Erythropoietin in combination with butyrate, induced F reticulocytosis in an additive manner. We conclude that butyric acid is a strong inducer of HbF, particularly when administered in combination with erythropoietin. As chronic toxicities remain undefined, patients in future clinical trials of this and similar compounds should be monitored closely for evidence of neurologic toxicity.
A low-affinity human granulocyte-macrophage colony-stimulating factor/murine erythropoietin hybrid receptor functions in murine cell lines
Authors: Jubinsky PT , Nathan DG , Wilson DJ , Sieff CA 
Published: October 2019

Abstract
To identify domains in hematopoietic growth factor receptors that are important for signal transduction, a hybrid receptor (GMER) was constructed by splicing the DNA of the entire extracellular and transmembrane domains of the human granulocyte-macrophage colony- stimulating factor (GM-CSF) receptor alpha 2 subunit (GMR) to the cytoplasmic domain of the murine erythropoietin receptor (mEpoR). The hybrid receptor was introduced into the interleukin-3 factor-dependent murine hematopoietic cell line Ba/F3. Cells that expressed high receptor numbers were selected by cell sorting using phycoerythrin- labeled human GM-CSF. Immunoprecipitation of GMER from Ba/F3 cells showed a band with an Mr of 105,000 daltons. Human GM-CSF binding to Ba/F3 cells that expressed GMER showed a kd of 3.0 nmol/L and 475 binding sites/cell, while the same cells that expressed GMR had 300 sites/cell and a kd of 3.5 nmol/L. The proliferative response to GM-CSF of Ba/F3 cells that expressed GMER showed 1/2 maximal cell growth (as measured by 3H-thymidine incorporation) at a GM-CSF concentration of 2.5 x 10(-8) mol/L. When cultured in human GM-CSF, Ba/F3-GMER cells expressed cell surface glycophorin. Similar results were obtained with Ba/F3 cells transfected with the mEpoR and cultured in erythropoietin. Expression of GMR plus the human GM-CSF receptor beta chain in the same cell line also resulted in human GM-CSF stimulated proliferation; however, cell surface glycophorin was not detected. These data show that a low-affinity GM-CSF/Epo hybrid receptor can promote GM-CSF- dependent proliferation and can induce the expression of glycophorin, an erythroid-specific protein.
Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells
Authors: Brunner G , Nguyen H , Gabrilove J , Rifkin DB , Wilson EL 
Published: October 2019

Abstract
We have shown previously that basic fibroblast growth factor (bFGF) is a mitogen for human bone marrow (BM) stromal cells and that bFGF stimulates myelopoiesis in primary BM cultures. In this article, we demonstrate the presence of bFGF in two cell lineages in human BM and peripheral blood as well as the deposition of bFGF into the extracellular matrix of BM stromal cell cultures. In immunofluorescence experiments on BM and peripheral blood smears, megakaryocytes and platelets stained strongly for bFGF, whereas weaker staining was observed in immature and mature cells of the granulocyte series. The presence of bFGF in platelets was confirmed by enzyme-linked immunosorbent assay as well as by immunoprecipitation followed by immunoblotting. bFGF was synthesized by BM stromal cell cultures and was found either cell associated or localized in the nucleus and the nucleoli, and its location was dependent on the fixation procedure used. Addition of exogenous bFGF to stromal cells showed the presence of extracellular binding molecules for this cytokine. bFGF could be released from these sites by soluble heparin or phosphatidylinositol- specific phospholipase C. This study supports the role of bFGF as a stromal cell mitogen and stimulator of myelopoiesis. The data indicate that the stromal cells produce bFGF and that their extracellular matrix can serve as a reservoir for this growth factor. In addition, the results suggest a possible involvement of bFGF in platelet function as well as in megakaryocytopoiesis.
A role for manganese superoxide dismutase in radioprotection of hematopoietic stem cells by interleukin-1
Authors: Eastgate J , Moreb J , Nick HS , Suzuki K , Taniguchi N , Zucali JR 
Published: October 2019

Abstract
Pretreatment with interleukin-1 (IL-1) has been shown to protect mice from the myelotoxicity associated with irradiation via a mechanism potentially mediated through the induction of the antioxidant enzyme manganese superoxide dismutase (MnSOD). In this study, we have compared the ability of IL-1 to induce MnSOD mRNA in murine bone marrow cells and human cell lines with its ability to protect these cells against the damaging effects of ionizing radiation. Bone marrow cells obtained from mice 6 hours after a single injection of IL-1 demonstrate a dose- dependent increase in the expression of MnSOD RNA. In this same study, IL-1 was also shown to be radioprotective when given to mice 20 hours before lethal irradiation. Similarly, in vitro treatment with IL-1 of bone marrow cells isolated from 5-fluorouracil-treated mice results in elevated levels of MnSOD RNA. Pretreatment with IL-1 also protected bone marrow long-term culture-initiating cells capable of reconstituting irradiated stromal cultures from an irradiation insult. Furthermore, IL-1-treated human bone marrow cells display both elevated MnSOD RNA and protein levels when compared with media controls. The human A375 melanoma, A549 adenocarcinoma, and factor-dependent TF-1 leukemic cell lines demonstrate low basal MnSOD RNA levels that increase following treatment with IL-1. For the A375 cells, this correlates with increased MnSOD protein expression and radioprotection by IL-1 using a colony assay. In contrast, the chronic myelogenous leukemic cell line, K562, displays a high basal MnSOD RNA level, and this RNA expression is not further increased by IL-1 treatment. In addition, these cells are comparatively radioresistant and are not further protected by IL-1 treatment. Finally, the Mo-7 cell line displays a low basal level of MnSOD RNA that correlates with a high sensitivity to irradiation and IL-1 pretreatment has no effect on MnSOD RNA levels. Our results indicate that increased radioprotection by IL-1 correlates with the induction of the antioxidant enzyme MnSOD and this induction may be an important factor in IL-1 radioprotection.
Expression of tal-1 and GATA-binding proteins during human hematopoiesis
Authors: Mouthon MA , Bernard O , Mitjavila MT , Romeo PH , Vainchenker W , Mathieu-Mahul D 
Published: October 2019

Abstract
Tal-1 rearrangements are associated with nearly 30% of human T acute lymphoblastic leukemia. Tal-1 gene encodes a putative transcription factor with a basic helix-loop-helix domain and is known to be predominantly expressed in hematopoietic cells. We investigated the pattern of tal-1 expression in purified human hematopoietic cells by in situ hybridization and reverse transcriptase polymerase chain reaction analysis. Both methods demonstrated that the tal-1 gene is expressed in megakaryocytes and erythroblasts as well as in basophilic granulocytes. In addition, our results indicate that the tal-1 1A promoter, which contains two consensus GATA-binding sites, is active mainly in these lineages. Because the GATA-1 gene is known to transactivate several genes specific for the erythroid, megakaryocytic, and mastocytic/basophilic lineages, we studied GATA-1 expression in these purified hematopoietic cells. We found that GATA-1 and tal-1 genes are coexpressed in these three lineages. Remarkably, the expression of both genes is downmodulated during erythroid and megakaryocytic terminal maturation. In immature hematopoietic cells, tal-1 and GATA-1 genes are coexpressed in committed progenitors cells (CD34+/CD38(2+)), whereas they are not detectable in the most primitive cells (CD34(2+)/CD38-). In contrast, GATA-2 is strongly expressed in both most primitive and committed progenitors cells, whereas GATA-3 is mostly detected in most primitive ones. Altogether our results strongly suggest that GATA-1 modulates the transcription of tal-1 during the differentiation of the erythroid, megakaryocytic, and basosophilic lineages.
Effect of uremia on the membrane transport characteristics of red blood cells
Authors: Langsdorf LJ , Zydney AL 
Published: October 2019

Abstract
Even though there is extensive evidence that uremia affects the fragility and deformability of red blood cells (RBCs), essentially all data on the RBC membrane permeability have been obtained with nonuremic blood. Permeability data were obtained for creatinine and uric acid, two metabolites of interest in hemodialysis, using a stirred ultrafiltration device with direct cell- and protein-free sampling. Experiments examined the effects of temperature and suspending phase on solute transport for both normal and uremic blood cells. Creatinine and uric acid transport from normal RBCs at 37 degrees C were characterized by saturation half-times of 40 +/- 10 minutes and 54 +/- 12 minutes, respectively. The corresponding half-times for uremic cells were significantly longer, 94 +/- 26 minutes and 180 +/- 38 minutes. Data indicated that the slower rate of creatinine transport in uremic blood was caused by an alteration in the RBC membrane, while the reduction in uric acid transport was associated with alterations in the uremic plasma. The temperature dependence of the RBC permeability was also much less pronounced for uremic cells for both solutes. These results provide important insights into the effects of uremia on the RBC membrane permeability, and have important implications for dialysis.