bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and Costs of Granulocyte Colony-Stimulating Factor in Allogeneic T-Cell Depleted Bone Marrow Transplantation
Authors: Lee Stephanie J. , Weller Edie , Alyea Edwin P. , Ritz Jerome , Soiffer Robert J. 
Published: October 2019

Abstract
Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P &lt; .0001) and time from marrow infusion to discharge (23 days v 17 days,P &lt; .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs.
© 1998 by The American Society of Hematology.
Human Integrin β3 Gene Expression: Evidence for a Megakaryocytic Cell-Specific cis-Acting Element
Authors: Jin Ying , Wilhide Calvin C. , Dang Chi , Li Lu , Li Su-Xia , Villa-Garcia Manuel , Bray Paul F. 
Published: October 2019

AbstractThe human integrin β3 participates in a wide range of adhesive biologic functions and is expressed in a selected subset of tissues, but little is known about the cis-acting DNA elements or trans-acting factors responsible for this regulation. Using cell lines characterized for β3 expression, a number of upstream regulatory regions in the β3 gene were identified. (1) The three regions from −1159 to −584, −290 to −146, and −126 to −115 demonstrated positive, negative, and negative activity, respectively. (2) The region from −115 to +29 of the β3 gene was sufficient for cell-specific activity. Deletion of the sequence from −115 to −89 produced a 6- to 40-fold reduction in reporter gene activity in β3-expressing megakaryocytic cell lines (K562, Dami, and HEL), but only a 1.7- and 2.7-fold reduction, respectively, in β3-expressing endothelial and melanoma cell lines, and 1.3- and 2.8-fold reduction, respectively, in non–β3-expressing Chinese hamster ovary and 293 cell lines. This sequence also bound nuclear proteins in a cell-specific manner in electrophoretic mobility shift assays. Mutational analysis indicated that the sequence GAGGGG (positions −113 to −108) is a megakaryocytic cell line-specificcis-acting element. (3) The region from −89 to +29 promoted lower activity in all cell lines. We also provide evidence that a CCCACCC sequence at position −70 has transcriptional activity, most likely through the Sp1 transcription factor. These data supply the first detailed map of the transcriptional regulatory elements of the 5′ region of the β3 gene, define positive regulatory sequences with potent megakaryocyte preferential activity, and indicate that the ubiquitous transcription factor, Sp1, may augment β3 gene expression.© 1998 by The American Society of Hematology.
Expression of Macrophage Inflammatory Protein-1 Receptors in Human CD34+ Hematopoietic Cells and Their Modulation by Tumor Necrosis Factor- and Interferon-γ
Authors: Dürig Jan , de Wynter Erika A. , Kasper Christoph , Cross Michael A. , Chang James , Testa Nydia G. , Heyworth Clare M. 
Published: October 2019

AbstractMacrophage inflammatory protein-1 (MIP-1) can stimulate growth inhibitory and potent chemotactic functions in hematopoietic cells. To investigate whether the action of MIP-1 may be regulated at the cellular receptor level, we studied the expression and modulation of MIP-1 receptors on CD34+ cells isolated from normal bone marrow (NBM), umbilical cord blood (CB), and leukapheresis products (LP). Expression of MIP-1 receptors on CD34+cells was analyzed by two-color flow cytometry using a biotinylated MIP-1 molecule. The mean percentage of LP CD34+ cells expressing the MIP-1 receptors was 67.7 ± 7.2% (mean ± SEM; n = 22) as compared with 89.9 ± 2.6% (n = 10) and 74.69 ± 7.04% (n = 10) in CB and NBM, respectively (P = .4). The expression of the MIP-1 receptor subtypes on LP CD34+ cells was studied by indirect immunofluorescence using specific antibodies for the detection of CCR-1, CCR-4, and CCR-5. Microscopical examination revealed a characteristic staining of the cytoplasmic cell membrane for all three receptor subtypes. Detailed analysis of two LP samples showed that 65.8%, 4.4%, and 30.5% of CD34+ cells express CCR-1, CCR-4, and CCR-5, respectively. Culture of LP CD34+ cells for 24 to 36 hours in the presence of tumor necrosis factor- (TNF-) and interferon-γ (IFN-γ) resulted in a significant increase in MIP-1 receptor expression. TNF- induced MIP-1 receptor upregulation in a time- and concentration-dependent manner. Our results suggest that inhibitory cytokines produced by the bone marrow microenvironment are likely to be involved in the regulation of MIP-1 receptor expression on hematopoietic cells.© 1998 by The American Society of Hematology.
Defining an Antigenic Epitope on Platelet Factor 4 Associated With Heparin-Induced Thrombocytopenia
Authors: Ziporen L. , Li Z.Q. , Park K.S. , Sabnekar P. , Liu W.Y. , Arepally G. , Shoenfeld Y. , Kieber-Emmons T. , Cines D.B. , Poncz M. 
Published: October 2019

AbstractHeparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin therapy. Antibodies to platelet factor 4 (PF4)/heparin complexes have been implicated in the pathogenesis of this disorder, but the antigenic epitope(s) on the protein have not been defined. To address this issue, we studied the binding of HIT antibodies to a series of recombinant proteins containing either point mutations in PF4 or chimeras containing various domains of PF4 and the related protein, neutrophil activating peptide-2 (NAP-2). Serum samples from 50 patients with a positive 14C-serotonin release assay (14C-SRA) and a clinical diagnosis of HIT and 20 normal controls were studied. HIT antibodies reacted strongly with wild-type (WT) PF4/heparin complexes, but reacted little, if at all, with NAP-2/heparin complexes (optical density [OD]405 = 2.5 and 0.2, respectively). Alanine substitutions at three of the four lysine residues implicated in heparin binding, K62, K65, and K66, had little effect on recognition by HIT antibodies (OD405 = 2.2, 2.8, and 2.0, respectively), whereas an alanine substitution at position K61 led to reduced, but still significant binding (OD405 = 1.0). Similar studies involving chimeras between PF4 and NAP-2 localized a major antigenic site to the region between the third and fourth cysteine residues for more than half of the sera tested. This site appears to involve a series of amino acids immediately after the third cysteine residue beginning with P37. Thus our studies suggest that whereas the C-terminal lysine residues of PF4 are important for heparin binding, they do not comprise a critical antigenic site for most HIT antibodies. Rather, we propose that maintaining a region near the third cysteine residue of PF4, distal from the proposed heparin-binding domain, is required to form the epitope recognized by many HIT antibodies.© 1998 by The American Society of Hematology.
Formation of the Human Fibrinogen Subclass Fib420: Disulfide Bonds and Glycosylation in Its Unique (EChain) Domains
Authors: Fu Yiping , Zhang Jian-Zhong , Redman Colvin M. , Grieninger Gerd 
Published: October 2019

AbstractCOS cell transfection has been used to monitor the assembly and secretion of fibrinogen molecules, both those of the subclass containing the novel E chain and those of the more abundant subclass whose  chains lack E’s globular C-terminus. That region, referred to as the EC domain, is closely related to the ends of β and γ chains of fibrinogen (βC and γC). Transfection of COS cells with E, β, and γ cDNAs alone results in secretion of the symmetrical molecule (Eβγ)2, also known as Fib420. Cotransfection with cDNA for the shorter  chain yielded secretion of both (βγ)2 and (Eβγ)2 but no mixed molecules of the structure E(βγ)2. Exploiting the COS cells’ fidelity with regard to Fib420 production, identification was made of the highly conserved Asn667 as the sole site of N-linked glycosylation in the E chain. No evidence from Cys → Ser replacements was found for interchain disulfide bridges involving the four cysteines of the EC domain. However, for fibrinogen secretion, the E, β, and γ subunits do exhibit different requirements for integrity of the two intradomain disulfide bridges located at homologous positions in their respective C-termini, indicating dissimilar structural roles in the process of fibrinogen assembly.© 1998 by The American Society of Hematology.
Identification of Mutations and Polymorphisms in the Factor XI Genes of an African American Family by Dideoxyfingerprinting
Authors: Martincic Danko , Zimmerman Sherri A. , Ware Russell E. , Sun Mao-Fu , Whitlock James A. , Gailani David 
Published: October 2019

AbstractCongenital deficiency of factor XI is a rare condition associated with a mild to moderate bleeding diathesis that is most commonly found in persons of Jewish ancestry. The disorder has been reported sporadically in a number of other ethnic groups, but rarely in the black population. We report on the genetic analysis of the factor XI genes of two African American patients: a 9-year-old boy (the propositus) with mild factor XI deficiency and his mother. Both individuals have lifelong histories of excessive bleeding. Dideoxyfingerprinting, a technique combining components of single-strand conformational polymorphism analysis and dideoxy-chain termination sequencing, was used in the analysis. Both patients were found to be heterozygous for a mutation changing serine 248 to glutamine, whereas the propositus was heterozygous for an additional mutation on the paternal allele changing glutamine 226 to arginine. Both mutations reside in the third apple domain of the factor XI heavy chain, an area that has been shown to contain binding sites for factor IX, platelets, and glycosaminoglycans. Previously reported mutations in the factor XI gene seem to cause deficiency primarily by reducing protein expression. Because both alleles in the propositus contain amino acid substitutions, the significant amount of circulating factor XI in his plasma must be comprised entirely of abnormal molecules. Factor XI circulates as a homodimer, and the presence of mutations in both alleles of the factor XI gene suggests that his bleeding disorder is caused in part by the effect of the two abnormal gene products forming dimers in different combinations. Three neutral (not associated with amino acid changes) DNA polymorphisms were also identified in the two subjects: a C to T change at nucleotide 472 in exon 5, A to G at nucleotide 844 in exon 8, and T to C at nucleotide 1234 in exon 11. Analysis of a random sample of normal volunteers showed that these polymorphisms are relatively common, with allele frequencies of 7.4%, 19%, and 18%, respectively. This suggests that there is considerable genetic heterogeneity in the factor XI gene.© 1998 by The American Society of Hematology.
Ceramide and Cyclic Adenosine Monophosphate (cAMP) Induce cAMP Response Element Binding Protein Phosphorylation via Distinct Signaling Pathways While Having Opposite Effects on Myeloid Cell Survival
Authors: Scheid Michael P. , Foltz Ian N. , Young Peter R. , Schrader John W. , Duronio Vincent 
Published: October 2019

AbstractThe role of ceramide as a second messenger is a subject of great interest, particularly since it is implicated in signaling in response to inflammatory cytokines. Ceramide induces apoptosis in both cytokine-dependent MC/9 cells and factor-independent U937 cells. Elevation of cyclic adenosine monophosphate (cAMP) levels inhibits apoptosis induced by ceramide and several other treatments. One target of cAMP-mediated signaling is the transcription factor CREB (cAMP response element binding protein), and recently CREB phosphorylation at an activating site has been shown to also be mediated by a cascade involving p38 mitogen-activated protein kinase (MAPK), one of the stress-activated MAP kinases. Because no role for p38 MAPK in apoptosis has been firmly established, we examined the relationship between p38 MAPK and CREB phosphorylation under various conditions. Ceramide, or sphingomyelinase, like tumor necrosis factor- (TNF-) or the hematopoietic growth factor, interleukin-3 (IL-3), was shown to activate p38 MAPK, which in turn activated MAPKAP kinase-2. Each of these treatments led to phosphorylation of CREB (and the related factor ATF-1). A selective p38 MAPK inhibitor, SB203580, blocked TNF-– or ceramide-induced CREB phosphorylation, but had no effect on the induction of apoptosis mediated by these agents. The protective agents cAMP and IL-3 also led to CREB phosphorylation, but this effect was independent of p38 MAPK, even though IL-3 was shown to activate both p38 MAPK and MAPKAP kinase-2. Therefore, the opposing effects on apoptosis observed with cAMP and IL-3, compared with ceramide and TNF-, could not be explained on the basis of phosphorylation of CREB. In addition, because SB203580 had no effect of TNF- or ceramide-induced apoptosis, our results strongly argue against a role for p38 MAPK in the induction of TNF-– or ceramide-induced apoptosis.
Nitric Oxide–Mediated Augmentation of Polymorphonuclear Free Radical Generation After Hypoxia-Reoxygenation
Authors: Sethi Sonia , Singh Mahendra Pratap , Dikshit Madhu 
Published: October 2019

AbstractPolymorphonuclear leukocytes (PMNLs), nitric oxide (NO), calcium, and free radicals play an important role in hypoxia/ischemia and reoxygenation injury. In the present study, NO donors, sodium nitroprusside (SNP), and diethylamine-NO (DEA-NO) at low concentrations (10 and 100 nmol/L) potentiated, while higher (10 μmol/L to 10 mmol/L) concentrations inhibited free radical generation response in the rat PMNLs. Free radical generation response was found to be significantly augmented when hypoxic PMNLs were reoxygenated (hypoxia-reoxygenation [H-R]). This increase in free radical generation after reoxygenation or SNP (10 nmol/L) was blocked in the absence of extracellular calcium. SNP (10 nmol/L) or H-R–mediated increases in the free radical generation were prevented by the pretreatment of PMNLs with NO scavenger (hemoglobin), the polyadenine diphosphate (ADP)-ribosylation synthase inhibitor (benzamide) or the calcium channel antagonist (felodipine). A significant augmentation in the nitrite and intracellular calcium levels was observed during hypoxia. Hemoglobin pretreatment also blocked the increase in intracellular calcium levels due to SNP (10 nmol/L) or hypoxia. Thus, increased availability of NO during SNP treatment or H-R, may have led to an ADP-ribosylation–mediated increase in intracellular calcium, thereby increasing the free radical generation from the rat PMNLs.
Etretinate Therapy for Refractory Sclerodermatous Chronic Graft-Versus-Host Disease
Authors: Marcellus D.C. , Altomonte V.L. , Farmer E.R. , Horn T.D. , Freemer C.S. , Grant J. , Vogelsang G.B. 
Published: October 2019

AbstractChronic graft-versus-host disease (GVHD) is the most common late complication of allogeneic bone marrow transplantation (BMT). The sclerodermatous form of the disease is often refractory to standard treatment modalities. Based on reports of response to etretinate, a synthetic retinoid, among patients with scleroderma, we have added etretinate to the treatment regimen of 32 patients with refractory sclerodermatous chronic GVHD. This case series is comprised mainly of patients who had chronic GVHD of long duration (median of 30 months before the initiation of etretinate). Most had failed to respond to three or more agents before etretinate treatment was started. Clinical response was assessed after 3 months of therapy. Five patients did not complete a 3-month trial. Among the 27 patients evaluable for response, 20 showed improvement including softening of the skin, flattening of cutaneous lesions, increased range of motion, and improved performance status. Four showed no response after 3 months of therapy and 3 had progression of their sclerosis. Overall, etretinate has been fairly well tolerated in our patients, with skin breakdown and/or ulceration leading to its discontinuation in 6 patients. We believe the results in our patients are encouraging and suggest that further evaluation of etretinate in the treatment of sclerodermatous chronic GVHD is warranted.
The Apoptosis Inhibitor Gene API2 and a Novel 18q Gene,MLT, Are Recurrently Rearranged in the t(11;18)(q21;q21) Associated With Mucosa-Associated Lymphoid Tissue Lymphomas
Authors: Dierlamm Judith , Baens Mathijs , Wlodarska Iwona , Stefanova-Ouzounova Margarita , Hernandez Jesus Maria , Hossfeld Dieter Kurt , De Wolf-Peeters Christiane , Hagemeijer Anne , Van den Berghe Herman , Marynen Peter 
Published: October 2019

Abstract
Marginal zone cell lymphomas of the mucosa-associated lymphoid tissue (MALT) are the most common subtype of lymphoma arising at extranodal sites. The t(11;18)(q21;q21) appears to be the key genetic lesion and is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphomas. We show that the API2 gene, encoding an inhibitor of apoptosis also known as c-IAP2, HIAP1, andMIHC, and a novel gene on 18q21 characterized by several Ig-like C2-type domains, named MLT, are recurrently rearranged in the t(11;18). In both MALT lymphomas analyzed, the breakpoint inAPI2 occurred in the intron separating the exons coding respectively for the baculovirus IAP repeat domains and the caspase recruitment domain. The breakpoints within MLT differed but the open reading frame was conserved in both cases. In one case, the translocation was accompanied by a cryptic deletion involving the 3′ part of API2. As a result, the reciprocal transcript was not present, strongly suggesting that the API2-MLT fusion is involved in the oncogenesis of MALT lymphoma.
Selective Ablation of Acute Myeloid Leukemia Using Antibody-Targeted Chemotherapy: A Phase I Study of an Anti-CD33 Calicheamicin Immunoconjugate
Authors: Sievers E.L. , Appelbaum F.R. , Spielberger R.T. , Forman S.J. , Flowers D. , Smith F.O. , Shannon-Dorcy K. , Berger M.S. , Bernstein I.D. 
Published: October 2019

Abstract
Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33+ AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3,3’-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic &gt;5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.
CrkL Activates Integrin-Mediated Hematopoietic Cell Adhesion Through the Guanine Nucleotide Exchange Factor C3G
Authors: Arai Ayako , Nosaka Yurika , Kohsaka Hitoshi , Miyasaka Nobuyuki , Miura Osamu 
Published: October 2019

AbstractCrkL is a member of the Crk family of adapter proteins consisting mostly of SH2 and SH3 domains. CrkL is most abundantly expressed in hematopoietic cells and has been implicated in pathogenesis of chronic myelogenous leukemia. However, its function has not been precisely defined. Here, we show that overexpression of CrkL enhances the adhesion of hematopoietic 32D cells to fibronectin. The CrkL-induced increase in cell adhesion was blocked by antibodies against VLA-4 (4β1) and VLA-5 (5β1) but was observed without changes in surface expression levels of these integrins. Studies using CrkL mutants demonstrated that the SH2 domain is partially required for enhancing cell adhesion, whereas the C-terminal SH3 domain as well as the tyrosine phosphorylation site (Y207) is dispensable. In contrast, the N-terminal SH3 domain, involved in binding C3G and other signaling molecules, was showed to play a crucial role, because a mutant defective of this domain showed an inhibitory effect on the cell adhesion to fibronectin. Furthermore, overexpression of C3G also increased the adhesion of hematopoietic cells to fibronectin, whereas a C3G mutant lacking the guanine nucleotide exchange domain abrogated the CrkL-induced increase in cell adhesion. On the other hand, a dominant negative mutant of H-Ras or that of Raf-1 enhanced the basal and CrkL-induced cell adhesion and that of R-Ras modestly decreased the adhesion. Taken together, these results indicate that the CrkL-C3G complex activates VLA-4 and VLA-5 in hematopoietic cells, possibly by activating the small GTP binding proteins, including R-Ras, through the guanine nucleotide exchange activity of C3G.
Vascular Endothelial Cell Growth Factor–Induced Tissue Factor Expression in Endothelial Cells Is Mediated by EGR-1
Authors: Mechtcheriakova Diana , Wlachos Alexander , Holzmüller Harry , Binder Bernd R. , Hofer Erhard 
Published: October 2019

AbstractVascular endothelial cell growth factor (VEGF) is a major regulator of angiogenesis. We report here that treatment of endothelial cells with VEGF leads to upregulation of tissue factor mRNA and protein expression on the cell surface. Reporter gene studies show that transcriptional activation of the tissue factor gene by VEGF is mediated by a GC-rich promoter element containing overlapping binding sites for Sp1 and EGR-1. As shown by immunofluorescence and electrophoretic mobility shift assays, upon VEGF treatment EGR-1 rapidly accumulates in the nucleus and binds to its respective recognition site in the tissue factor promoter. Sp1 occupies this element in unstimulated cells and seems to be partially displaced by increasing amounts of EGR-1. Transfection of endothelial cells with an EGR-1 expression plasmid mimics the upregulation of tissue factor transcription observed after VEGF treatment. In contrast, NFκB, the major transcription factor involved in tissue factor upregulation by inflammatory stimuli, is not activated by VEGF. These data show that VEGF induces a response in endothelial cells largely distinct from inflammatory stimuli, and suggest that EGR-1 is a major mediator of the activation of the tissue factor and possibly other VEGF-responsive genes.