bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin-Like Growth Factor II Is an Autocrine Growth Factor To Prevent Apoptosis as Well as To Enhance Proliferation and Maturation of Erythroid Progenitor Cells.
Authors: Nagatomo Taro , Muta Koichiro , Ohga Shouichi , Ochiai Masayuki , Hikino Shunji , Hara Toshiro 
Published: April 2020

Abstract
To reveal the novel function of erythroid progenitor cells in fetal erythropoiesis, the gene expression pattern in umbilical cord blood (CB)-derived CD36+ erythroid progenitor cells (EPCs) was analyzed using cDNA microarray containing 240 cytokine and growth factor related genes. Among the genes analyzed, insulin-like growth factor II (IGF-II) gene showed a 124-fold higher level of expression in CB-EPCs, compared with that seen in phytohemagglutinin (PHA)-stimulated adult peripheral blood mononuclear cells (PBMCs) (table1). Real-time PCR revealed that the IGF-II mRNA levels in CB-EPCs were higher than those seen in lymphocytes or monocytes separated from CB or PBMCs. When CB-EPCs were cultured with erythropoietin (EPO) in serum-free medium, the number of erythroid colonies was decreased in the presence of IGF-II-neutralizing antibody. To further assess the role of IGF-II in erythropoiesis, we purified erythroid colony-forming cells (ECFCs) from human umbilical cord blood by magnetic selection and liquid culture with IL-3, stem cell factor and EPO. The expression levels of IGF-II, type 1 or 2 IGF receptor in the mature ECFCs were higher than those in the immature ECFCs. Addition of IGF-II-neutralizing antibody decreased the number of ECFCs in liquid culture with EPO. The anti-proliferative effect of IGF-II-neutralizing antibody was evident in both dimethylthiazole tetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) incorporation assays. When apoptosis of cells was examined using Annexin V, the addition of IGF-II-neutralizing antibody increased apoptosis, thereby indicating the anti-apoptotic effects of IGF-II secreted from erythroid cells. Furthermore, ECFCs failed to undergo normal erythroid maturation in the presence of IGF-II-neutralizing antibody, as assessed by flow cytometric and morphologic analyses. These findings indicate that IGF-II, which is produced by erythroid progenitor cells themselves, has crucial roles in controlling erythropoiesis by modulating apoptosis, proliferation and maturation via an autocrine mechanism.
Cytokine and growth factor genes highly expressed in CB-EPCs selected by cDNA microarray analyses ratio gene 124.0 insulin-like growth factor II 7.9 vascular endothelial growth factor 3.9 interleukin 8 3.4 GRO2 oncogene 3.0 GRO1 oncogene 1.6 transforming growth factor, beta 1 1.4 vascular endothelial growth factor B
Delta-1 Promotes Soluble IL-6R-Mediated Action of IL-6 on Human Erythropoiesis While Counteracting the Effect of IL-6 on the Generation of Myeloid-Lineage Cells.
Authors: Yamamura Kentaro , Ohishi Kohshi , Katayama Naoyuki , Shiku Hiroshi , Nishikawa Mitsuo , Nakahata Tatsutoshi 
Published: April 2020

Abstract
Notch ligand Delta-1 is shown to influence proliferation and differentiation of hematopoietic progenitors by interacting with various cytokines. IL-6 exerts various effects on human hematopoiesis by activating gp130 via soluble IL-6 receptor (R) as well as membrane-bound IL-6R. However, little is known about the interaction between Delta-1 and gp130 activation in human hematopoiesis. We previously reported that Delta-1 in combination with IL-6R/IL-6 fusion protein FP6, which directly and agonistically activates gp130, enhances the production of mixed and pure erythroid progenitors from cord blood CD34+CD38− cells, while not significantly affecting the generation of myeloid progenitors (ASH 2004). Here, we examined the interaction between Delta-1 and gp130 activation in the generation of erythroid cells and myeloid-lineage cells from cord blood CD34+CD38− cells in serum-free suspension cultures. In the presence of SCF, Flt3L, TPO, and IL-3 (4GF), Delta-1 acted synergistically with FP6 to promote the production of CD36+glycophorin A (GPA)high erythroid cells from CD34+CD38− cells, whereas few CD36+GPAhigh erythroid cells were generated by Delta-1, IL-6, and Delta-1 plus IL-6. When we assessed the stage of erythroid cells affected by Delta-1 and FP6, Delta-1, in conjunction with FP6, augmented the generation of CD36+GPAhigh erythroid cells from CD34+CD38− cell-derived CD36+GPA− erythroid progenitors equivalent to BFU-E stage but not from CD34+CD38−cell-derived CD36+GPAlow erythroid progenitors equivalent to CFU-E stage. On the other hand, IL-6 and FP6 increased the production of CD14+ monocytic cells and CD15+ granulocytic cells from CD34+CD38− cells. Delta-1 had opposite effect and antagonized the stimulatory effect of IL-6 and FP6 on the generation of monocytic and granulocytic cells. Although the development of CD1a+CD14− dendritic cells from CD34+CD38− cells was suppressed by IL-6 and FP6 but instead potentiated by Delta-1, Delta-1 competed with the inhibitory effect of IL-6 and FP6 on the generation of dendritic cells. These data indicate that Delta-1 modulates the effect of IL-6 on human hematopoiesis by enhancing its soluble IL-6R-mediated action on early erythropoiesis while antagonizing its effect on the generation of myeloid-lineage cells.
Gfi-1 Represses C/EBPe and Is Required for the Survival and Proliferation of Myeloid Cells Stimulated by G-CSF.
Authors: Dong Fan , Zhuang Dazhong , Qiu Yaling 
Published: April 2020

Abstract
Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that plays a major role in granulopoiesis. G-CSF supports the proliferation, differentiation and survival of myeloid progenitor cells. Treatment of cells with G-CSF activates multiple intracellular signal transduction pathways leading to alterations in the activities of transcription factors involved in myeloid development. Gfi-1 is a zinc-finger transcriptional repressor that is required for granulopoiesis. Mutations in Gfi-1 have been associated with severe congenital neutropenia (SCN). How Gfi-1 acts in myeloid cells is still poorly understood. Expression of Gfi-1 was upregulated during granulocytic differentiation induced by G-CSF in myeloid 32D cells. Truncation of the carboxy terminus of the G-CSF receptor, as seen in patients with acute myeloid leukemia (AML) evolving from SCN, disrupted the ability of the G-CSF receptor to upregulate Gfi-1. Ectopic expression of a naturally occurring dominant negative Gfi-1 mutant, N382S, identified in patients with SCN, resulted in premature apoptosis and reduced proliferation of cells induced to differentiate with G-CSF. The expression of neutrophil elastase (NE) and C/EBPe was significantly increased in 32D cells expressing N382S. In contrast, overexpression of wild type Gfi-1 abolished G-CSF-induced upregulation of C/EBPe, but had no apparent effect on NE upregulation by G-CSF. Notably, G-CSF-dependent proliferation and survival were inhibited upon overexpression of C/EBPe, but not NE. These data suggest that a key role of Gfi-1 in granulopoiesis is to repress C/EBPe and that overt C/EBPe overexpression may be deleterious to the proliferation and survival of myeloid cells. Our data may explain why loss of Gfi-1 function, either as a result of gene knockout in mice or gene mutations in human, results in a block of granulocytic differentiation and severe neutropenia.
The IL-7 Receptor alpha Promoter Is Activated at Distinct Stages during B Cell Development by the Ets Transcription Factors PU.1 and GABP.
Authors: DeKoter Rodney P. , Schweitzer Brock L. , Jones Darrel , Hildeman David A. , Huang Kelly J. 
Published: April 2020

Abstract
The cytokine interleukin-7 (IL-7) is required for B and T lymphocyte development, and for the survival and maintenance of both naive and memory T lymphocytes. The receptor for IL-7 (IL-7R) is heterodimeric, consisting of a common gamma chain (γc) and an alpha subunit (IL-7Rα). The γc is expressed in most hematopoietic cell types, but the IL-7Rα gene is regulated in a cell type and developmental stage-specific manner. We have previously shown that the Ets-family transcription factor PU.1 is required to activate transcription of the IL-7Rα gene during fetal lymphocyte development. However, several questions remain unanswered. First, the IL-7Rα promoter is poorly characterized. Second, the IL-7Rα is expressed at high levels in the T cell lineage where PU.1 is not expressed. Third, the transcription factor early B cell factor (EBF) can activate IL-7Rα transcription in developing B cells in the absence of PU.1. To address these questions, we have characterized the IL-7Rα promoter region in detail. First, we determined that the major transcription start sites in the IL-7Rα gene are downstream of an Ets/PU.1 binding site. We found that the intact Ets site is required for IL-7Rα promoter activity, as well as to mediate enhancer action from a distance. IL-7Rα promoter activity depends on the proper orientation of the Ets site relative to functional initiator sequences. We found, using gel shift analysis, that both PU.1 and the Ets transcription factor GA binding protein (GABP) are expressed in developing B cells, and can interact with the Ets binding site in the IL-7Rα promoter. However, the function of PU.1 is distinct from GABP during B cell development. Retroviral transduction of PU.1 mutant progenitor cells with a PU.1 retrovirus robustly rescues IL-7Rα transcription and IL-7-dependent B cell development. In contrast, transduction with GABPα and GABPβ1 subunits fails to activate IL-7Rα transcription in PU.1 mutant progenitor cells. We conclude that activation of the IL-7Rα gene requires PU.1 during the earliest stages of lymphocyte development, but is alternatively utilized by PU.1 and GABP after commitment to the B cell lineage.
Asthma Is Associated with Mortality in Children with Sickle Cell Anemia.
Authors: Boyd Jessica H. , Macklin Eric , Strunk Robert C. , DeBaun Michael R. 
Published: April 2020

Abstract
Background: Acute chest syndrome (ACS) is one of the leading causes of premature death among people with sickle cell anemia (SCA). Children with SCA and asthma have an increased risk of ACS (Boyd et al, Pediatric Pulmonology, 2004). The Cooperative Study of Sickle Cell Disease (CSSCD) has previously reported the median age at death to be approximately 45 years, 42 years for males and 48 years for females (Platt et al, New England Journal of Medicine, 1994). The objective of this study is to determine if asthma in patients with SCA is associated with mortality.
Methods: The cohort was comprised of African American participants with SCA anemia enrolled in the CSSCD from birth to 66 years of age who were followed beyond five years and were evaluated for asthma. Patients who died before age 5 years were not included in the cohort. Asthma was classified by physician diagnosis, documentation of an acute asthma event, and/or record of use of prescribed asthma medication. Mortality was determined for patients with and without asthma. Cox regression analysis included the following established risk factors for death (Platt et al, 1994): covariates age, white blood cell count level, renal failure, hemoglobin F level, seizure, and acute chest syndrome.
Results: A total of 1963 African American individuals with SCA were classifiable for asthma, enrolled in the study and followed for a total of 18,496 patient-years. The average age at study entry was 13.9 years, and the mean length of follow-up was 9.4 years. A total of 138 individuals (7.0%) had asthma; 70% were classified by a physician diagnosis, 10% by documentation of an acute asthma event, and 20% by record of using a prescribed asthma medication. Individuals with asthma had a median lifespan of 52.5 years in comparison to 64.3 years and over a two-fold higher risk of mortality after controlling for age, white blood cell count, renal failure, hemoglobin F level, seizure, and acute chest syndrome rate (hazard ratio 2.36 by Cox regression, 95% CI 1.21 to 4.62, p=0.01).
Conclusion: Asthma was associated with a significant increase in the risk of all-cause mortality among patients with SCA who lived to 5 years of age. In addition to previously identified risk factors, asthma is an independent predictor of mortality.
Fetal Hemoglobin Protects Against Activation of Hemostasis Endothelial and Circulating Blood Cells in Sickle Cell Anemia.
Authors: Setty Yamaja , Vaidyula Vijender R. , Dampier Carlton D. , Rao A. Koneti , Stuart Marie J. 
Published: April 2020

Abstract
To determine whether fetal hemoglobin (HbF) protects against activation of hemostasis, endotheliium, and circulating blood elements, infants, children and young adults with homozygous SS disease (n=35) were studied. F-cell numbers, biomarkers of endothelial activation (including sVCAM-1, sE- and sP-selectin), white cell and platelet activation (sL-selectin and sP-selectin respectively) and markers of hemostatic activation, including D-Dimer and prothrombin fragment F1.2 were analyzed. Subjects with HbSS demonstrated significant increases (P&lt;0.001) in all cell activation and hemostatic biomarkers. Analyses revealed a dominant, statistically significant correlation between F-cell and biomarkers of endothelial, white cell and hemostatic activation. F-cells correlated inversely with sVCAM-1 (R = −0.64, P&lt;0.00005), sE-selectin (R = −0.51, P = 0.03) and sP-selectin (R = −0.41, P&lt;0.02). Since HbF protects against HbS polymerization, our data suggests a role for the sickle erythrocyte in endothelial activation and is consistent with reported decreases in sVCAM-1 following hydroxyurea therapy or a chronic transfusion regimen. sP- and sE-selectin levels correlated with neutrophil counts (R = 0.63 and R = 0.42, P&lt;0.00006 and P&lt;0.02 respectively) while no relationship between platelets and sP-selectin was noted. An additional correlation between sP- and sE-selectin (R = 0.50, P&lt;0.003) was also observed, reflecting enhanced neutrophil-endothelial interaction as part of an inflammatory and prothrombotic HbSS phenotype. Surprisingly, a positive correlation between sL-selectin and F-cells occurred (R = 0.4, P&lt;0.02) with the young infant with HbSS demonstrating higher levels of this leucocyte activation marker than the older subject. A dysregulation of L-selectin shedding following neutrophil activation has been proposed to occur in sickle cell anemia. Our results suggest that HbF protects against this dysregulation. D-Dimer levels correlated negatively with F-cells (R = −0.76, P&lt;0.000001), with a striking relationship between D-Dimer and markers of endothelial activation, including sVCAM-1 (R = 0.53, P&lt;0.001), sE-selectin (R = 0.39, P&lt;0.03) and sP-selectin (R = 0.41, P&lt;0.02). Such findings are in keeping with D-Dimer’s well-documented role as a biomarker in other inflammatory and ischemia-related disorders including coronary, cerebrovascular and peripheral arterial ischemic states. This report expands our knowledge regarding the protective effects of HbF against endothelial and hemostatic activation, and suggests a role for D-Dimer as a prothrombotic and proinflammatory marker in sickle cell anemia.
Do Pediatric Sickle Cell Disease Patients Develop Diastolic Dysfunction?.
Authors: Zilberman Mark V. , Du Wei , Whitten-Surney Wanda J. , Sarnaik Sharada A. 
Published: April 2020

Abstract
Sickle cell disease (SCD) is a known cause of chronic volume overload. Although systolic dysfunction is rare, as many as 80% of adult patients with SCD have an echocardiographic mitral valve inflow pattern suggestive of abnormal left ventricular (LV) diastolic function (DF). DF has not been studied in pediatric SCD patients. Therefore, the objective of this study was to evaluate DF in pediatric SCD patients using echocardiographic velocities of mitral inflow and tissue Doppler (TDI) indices. Echocardiograms were performed in 79 SCD patients (ages 2 – 18 years), and 84 controls matched for age and race. LV and left atrial (LA) volumes, LV mass, early (E) and late (A) mitral inflow velocities, and TDI velocities at the septal and lateral aspects of the mitral valve were obtained. LV dilatation was defined as LV end-diastolic dimension more then 2 standard deviations above the median (z-value &gt;2). LV hypertrophy was defined as LV mass/volume index&gt;1.15 g/ml. For SCD patients, average hemoglobin (Hb) levels for the year prior to the study were recorded. Data were analyzed using t-test and Spearman correlation analysis.
Of 79 SCD subjects, 32 (43%) had LV dilatation, 11(14.9%) had LV hypertrophy and 3 had both. LV z-scores were inversely related to Hb (r −0.62, p&lt;0.0001) but unrelated to age. The early mitral inflow velocities E were negatively correlated with Hb levels(r − 0.34, p&lt;0.04) and were positively correlated with LV z-scores (r 0.41, p&lt;0.04) reflecting pre-load dependency of mitral inflow indices. DTI diastolic velocities were unrelated to Hg or LV size reflecting pre-load independent nature of these indices. DTI systolic velocities S’ correlated positively with LV mass/volume index (r 0.28, p&lt;0.02).
SCD patients had significantly larger LV and LA volumes than controls (p&lt;0.01). The early E and late A mitral inflow velocities were higher in the SCD group than the control, although the differences were not statistically significant. DTI indices did not differ between SCD patients and the control.
Conclusion: Despite high incidence of left ventricular dilatation, pediatric SCD patients don’t demonstrate diastolic dysfunction when evaluated using pre-load independent echocardiographic tissue Doppler indices.
The Determination of the Inhibitory Activity of Some Factor VIII Type II Inhibitor Antibodies Is Biased by the Type of Factor VIII Assay.
Authors: Jacquemin Marc G. , Lamprecht Seb , Lavend’homme Renaud , Roodt Jan , Chatelain Bernard , Deneys Veronique , Dewaele Jeroen , Stassen Jean-Marie , Meiring Muriel , Saint-Remy Jean Marie , Pieters Henry , Badenhorst Philip 
Published: April 2020

Abstract
Although type II Factor VIII (FVIII) inhibitor antibodies inhibit only partially FVIII activity, even when such antibodies are in very large excess over FVIII, they frequently cause severe bleedings in patients with acquired or congenital hemophilia A. During the preclinical evaluation of anti-FVIII antibodies as potential antithrombotic agents in baboons, we observed severe bleedings in animals treated with an antibody (mAb-LE2E9) inhibiting in vitro about 70% baboon FVIII. The administration of another antibody (mAb-LE2E9Q), inhibiting less than 20% baboon FVIII in vitro did not induce any significant hemoglobin drop by comparison to control animals. Surprisingly, mAb-LE2E9Q significantly reduced thrombus development in extracorporeal circulation models of venous and arterial thrombosis. The discrepancy between the levels of FVIII inhibition observed with these two antibodies and their in vivo activity prompted us to use modified types of FVIII assays to further evaluate in human plasma the inhibitory activity of these antibodies. When a FVIII chromogenic assay was performed with a low phospholipid concentration rather than with the standard concentration, the inhibitory activity of mAb-LE2E9 increased from 83 to 93% and that of mAb-LE2E9Q from 36 to 49%. Similarly, when activated platelets were used as a source of phospholipid, the maximal inhibitory activity of both antibodies increased to the same levels. Likewise, the use of different one stage and two stages commercial FVIII assays allowed to record maximal inhibitory activities ranging from 20 to 59% in a reference human plasma spiked with mAb-LE2E9Q. Thus, type II anti-FVIII antibodies induce qualitative FVIII alterations that are poorly detected by some FVIII assays. Variability inherent to the FVIII assays may therefore contribute to the large interlaboratory variability encountered even with a standardized method such as the Nijmegen modification of the Bethesda assay. This phenomenon may also account for the discrepancies frequently observed between severity of bleedings and residual FVIII activity in patients with type II inhibitor antibodies.
Evidence for an Inhibitor-Blocking Antibody in an "Acquired Hemophiliac".
Authors: Litwiller Robert , Pruthi Rajiv , Fass David 
Published: April 2020

Abstract
Factor VIII (FVIII) inhibitors have been classified as Type I, linear inactivation kinetics and complete inhibition of FVIII at saturation, or Type II, non-linear kinetics and residual FVIII activity. To investigate the hypothesis that "inhibitor-blocking antibodies" contribute to the characteristics of Type II inhibitors, mixing studies were performed between fractionated Type II antiserum and various Type I inhibitor preparations. Type II IgG fractions were tested for inhibitory capacity and ability to prevent inhibition mediated by inhibitors from other hemophiliacs. The IgG from Type II plasma (II) (29 BU, 8% FVIII) and several Type I plasmas ((I) plasmas) were fractionated with DEAE resin. Late-eluting Type II fractions (II):6 and (II):7, showed slight protection of FVIII from the inhibiting activity of several Type I plasmas and additive inhibition with others. When tested against Type I IgG fractions instead of type I plasmas, (II):6 and (II):7 provided significant protection of FVIII from the inhibitory action of some immunoglobulins and additive inhibition with others. When (II):6, which contained slightly less than 1 BU of inhibitory activity, was preincubated with normal plasma, it blocked about 3 BU of inhibitory activity in an equal volume of fraction (I):1; residual FVIII increased from 11.4% to 27.2%. IgG fraction (II):6 provided protection from DEAE fraction 2, (I):2, from another type I patient (residual FVIII went from 15.1% to 31.7%) but was additive with (I):4 from the same patient (residual FVIII went from 8.0% to 3.2%). Preincubation with (II):7 increased residual FVIII activity in normal plasma incubated with (I):1 from 10.1% to 20.7%. Fraction (II):7 was processed further by hydrophobic interaction chromatography on phenyl sepharose and two fractions, Phen(II):5 and Phen(II):6 provided significant protection of FVIII from inhibition by (I):1; residual FVIII activity increased from 11.5% to 34.1% and from 7.9% to 28.2%, respectively. DEAE fractions (II):6 and (II):7 were shown to contain anti-FVIII IgG. Depletion of mixtures of plasma or rFVIII and (II):6 with immobilized Protein A, reduced FVIII activity by 42.8% and 68.8%, respectively. In addition, adsorption of (II):6 with immobilized Protein A, eliminated its ability to block FVIII inhibition by (I):1. The co-existence of these antibodies in "acquired hemophiliac" plasma would contribute to the complex kinetics seen in these patients. If a sufficiently diverse panel of such blocking IgGs occurred naturally, or could be produced in the laboratory, and their interaction with the target antigen did not adversely affect the half-life, then these blocking antibodies might prove useful to alleviate the effects of inhibitory antibodies in hemophilia and other diseases.