bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized study of erythropoietin and granulocyte colony-stimulating factor (G-CSF) versus placebo and G-CSF for patients with Hodgkin's and non-Hodgkin's lymphoma undergoing autologous bone marrow transplantation
Authors: Chao NJ , Schriber JR , Long GD , Negrin RS , Catolico M , Brown BW , Miller LL , Blume KG 
Published: October 2019

Abstract
Anemia is a universal finding in patients undergoing autologous bone marrow transplantation (BMT). Effective therapies to increase the number of autologous red blood cells could result in a lower morbidity and mortality associated with red blood cell transfusions. We examined whether the addition of erythropoietin (Epo) to intensive therapy supported by progenitor cell transplantation and granulocyte colony- stimulating factor (G-CSF) would result in a lower requirement for red blood cell transfusions. Thirty-five patients with lymphoma were randomized to receive Epo versus placebo. Epo (600 U/kg three times per week) or placebo was begun 3 weeks before administration of high-dose therapy. Epo was held during the week of the preparatory regimen, and restarted on the day after BMT. All patients also received G-CSF following BMT. No significant differences were noted between the two groups in terms of patient characteristics at pretreatment or post-BMT evaluation. There were no differences in the total number of red blood cell units transfused (median Epo: 8 v placebo: 6, P = .22) nor the number of platelet transfusions given (median Epo: 12 v placebo 5, P = .14). Engraftment of granulocytes (absolute neutrophil count > or = 500/microL) occurred in a median of 12 days (range, 9 to 33) for the patients receiving Epo and G-CSF, compared with a median of 10 days (range, 8 to 22) for those receiving placebo and G-CSF (P = .70). Likewise, there were no differences in the time to platelet count > or = 20,000/microL without further transfusions with a median of 22 days (range, 15 to 150+) for those receiving Epo and G-CSF compared with a median of 20 days (range, 11 to 54) for those patients receiving placebo and G-CSF (P = .28). The combination of G-CSF and Epo as administered in this study appears to be safe but does not result in an improvement in the total number of red blood cell transfusions or total number of single donor platelet units transfused.
Differential regulation of stem cell factor mRNA expression in human endothelial cells by bacterial pathogens: an in vitro model of inflammation
Authors: Koenig A , Yakisan E , Reuter M , Huang M , Sykora KW , Corbacioglu S , Welte K 
Published: October 2019

Abstract
Production of hematopoietic growth factors by endothelial cells plays a pivotal role during inflammatory processes. Stem cell factor (SCF) is known to be expressed constitutively in endothelial cells. To investigate the regulation of this cytokine expression by inflammatory stimuli, we cocultured human umbilical vein endothelial cells (HUVEC) with various gram-negative bacterial strains (Escherichia coli, Yersinia enterocolitica, Chlamydia trachomatis, and Neisseria meningitidis, respectively). Experiments were performed with bacterial concentrations ranging from 10(2) to 10(7) bacteria/mL for 3 hours. SCF- specific mRNA expression was studied using Northern blot analysis. Stimulation with the enteropathogenic bacterial strains Y enterocolitica and E coli resulted in a significant concentration- dependent increase of SCF mRNA expression. Similar results were obtained in coculture experiments with N meningitidis. As shown in experiments with E coli, the accumulation of SCF transcripts was also time-dependent. In contrast, coculture of HUVEC with the intracellular gram-negative strain C trachomatis had no effect on SCF mRNA expression. To elucidate the role of the gram-negative bacterial cell wall components, we stimulated HUVEC with bacterial lipopolysaccharide (LPS). LPS induced a maximal SCF mRNA accumulation within 2 hours followed by decrease of SCF-specific transcripts to the basal level after 24 hours. In addition, we exposed HUVEC to the classical inflammatory cytokine interleukin-1 alpha (IL-1 alpha). Kinetic experiments showed a similar pattern of regulation with an increase of SCF mRNA within 2 hours, persisting up to 12 hours, and a decrease to basal transcription after 24 hours. From these data, we conclude that SCF expression is regulated by inflammatory stimuli, such as IL-1 alpha and bacterial pathogens, suggesting an important role of SCF during inflammation.
Identification of a critical regulatory site in the human interleukin-3 promoter by in vivo footprinting
Authors: Cameron S , Taylor DS , TePas EC , Speck NA , Mathey-Prevot B 
Published: October 2019

Abstract
Interleukin-3 (IL-3) is involved in proliferation and differentiation of hematopoietic progenitor cells. Its expression is subject to precise, tissue-specific regulation, and has been studied extensively in the gibbon T-cell line MLA 144 by a combination of functional assays and DNA binding experiments. To extend these studies, the gibbon IL-3 promoter was cloned and in vivo footprinting of the gibbon and human IL- 3 proximal promoters was performed. The gibbon IL-3 promoter was found to be highly homologous to its human counterpart and both promoters yielded identical in vivo footprints after induction of IL-3 synthesis. In particular, we observed specific protection of three guanines over a core sequence TGTGGTTT (IF-1IL3) that had not been recognized in previous studies. IF-1IL3 is not found in other cytokine promoters, but it is conserved in the IL-3 promoter of several species and is similar to a recurring motif in viral and T-cell-specific cellular enhancers. IF-1IL3 binds a specific complex in MLA 144 and Jurkat nuclear extracts in vitro, which shares the same specificity as the complex bound by the polyoma virus and T-cell receptor delta enhancers. Mutation of the three guanines in IF-1IL3 core sequence disrupts binding in vitro and abrogates the ability of the IL-3 promoter to mediate inducible expression in T cells. Although IF-1IL3 is necessary for IL-3 expression, it is not sufficient: a truncated IL-3 promoter with an intact IF-1IL3 site but no other activator sites is transcriptionally silent. These studies describe a new regulatory element within the IL-3 promoter that is essential for expression and conserved between species.
Circulating tumor gangliosides enhance platelet activation
Authors: Valentino LA , Ladisch S 
Published: October 2019

Abstract
Gangliosides enhance tumor formation in experimental animals, and high circulating concentrations of gangliosides shed by tumor cells are associated with rapid progression of human neuroblastoma. We studied these shed molecules for effects on platelet function, because platelet activation may play a role in the metastatic process. Preincubation of normal platelets in patient (tumor ganglioside-containing) serum resulted in their aggregation upon exposure to a subthreshold concentration (1 microgram/mL) of collagen (up to 34% v < 10% in normal serum) and ATP release (up to 1.1 nmol/2.5 x 10(7) platelets v < 0.2 in normal serum). Because circulating shed tumor gangliosides are lipoprotein-associated, we next assessed the effects of the serum lipoprotein fraction on platelet ATP release. The patient serum lipoprotein fraction (d > 1.210) enhanced ATP release (up to 3.1 nmol ATP), whereas the same fraction of normal serum, and both patient and control lipoprotein-depleted serum fractions (d > 1.210), were inactive (< 0.2 nmol ATP released). Finally, as little as 0.5 mumol/L patient serum gangliosides (purified from the lipoprotein fraction) caused significantly greater ATP release than did normal serum gangliosides (P < .01) and caused maximal release at 50 mumol/L (up to 3.0 nmol ATP released v < or = 0.3 nmol released by platelets exposed to normal serum gangliosides). Purified total human neuroblastoma tumor gangliosides, detected in the patient serum and isolated from LA-N5 cells, were highly active; preincubation of platelets with only 5 mumol/L of these gangliosides resulted in release of 2.5 +/- 0.1 nmol ATP. Thus, neuroblastoma patient serum, the lipoprotein fraction, and, specifically, the serum gangliosides enhance platelet activation. This activity appears to reside particularly in the tumor cell gangliosides, which are shed in vivo.
Two types of genomic rearrangements create alternative E2A-HLF fusion proteins in t(17;19)-ALL
Authors: Hunger SP , Devaraj PE , Foroni L , Secker-Walker LM , Cleary ML 
Published: October 2019

Abstract
The t(17;19)(q21-q22;p13.3) in acute lymphoblastic leukemia results in creation of an E2A-HLF fusion protein with structural and functional properties of a chimeric transcription factor. Two types of genomic rearrangements underlie fusion of E2A with HLF. In type I rearrangements, an insertion that codes for a portion of the chimera not found in either wild type protein occurs between E2A exon 13- and HLF exon 4-encoded sequences. This insertion is derived from a cryptic exon created at the junction between chromosomes 17 and 19, and includes intronic portions of both E2A and HLF with intervening nontemplated N nucleotides. Type II rearrangements arise from more 5′ breakpoints in E2A and result in fusion cDNAs with E2A exon 12 spliced directly to HLF exon 4. Analysis of the genomic structure of HLF shows that these different modes of protein fusion result from selective constraints to maintain the proper HLF reading frame, because a direct E2A exon 13 to HLF exon 4 splice would lead to translation of a truncated E2A protein lacking any contribution from HLF. These features underscore the requirement for DNA binding and/or dimerization conferred by the bZIP portion of the E2A-HLF chimera in t(17;19)-ALL.
Mutation His322Asn in human acetylcholinesterase does not alter electrophoretic and catalytic properties of the erythrocyte enzyme
Authors: Masson P , Froment MT , Sorenson RC , Bartels CF , Lockridge O 
Published: October 2019

Abstract
The YT blood group antigen is located on human red blood cell (RBC) acetylcholinesterase. Wild-type acetylcholinesterase, YT1, has histidine at codon 322, whereas the genetic variant of acetylcholinesterase, YT2, has asparagine. This mutation is located within exon 2 of the ACHE gene, an exon that is present in all alternatively spliced forms of acetylcholinesterase. Therefore, acetylcholinesterase in brain and muscle has the same mutation as RBC acetylcholinesterase. We compared the electrophoretic and kinetic properties of RBC acetylcholinesterases having His 322 or Asn 322. We found no differences in the isoelectric point, mobility on non- denaturing gel electrophoresis, affinity for acetylthiocholine, activity per milligram of RBC ghost protein, substrate inhibition constants, binding to the peripheral site ligand (propidium), and binding to active site ligands (tetrahydroaminoacridine and edrophonium). Thus, although the point mutation elicits antibody production in nonmatching blood transfusion recipients, it has no effect on the enzymatic properties of acetylcholinesterase.
Clonogenicity of circulating neuroblastoma cells: implications regarding peripheral blood stem cell transplantation
Authors: Moss TJ , Cairo M , Santana VM , Weinthal J , Hurvitz C , Bostrom B 
Published: October 2019

Abstract
Peripheral blood stem cells (PBSCs) are being used as an alternative to autologous marrow rescue for hematopoietic reconstitution after high- dose chemotherapy in patients with neuroblastoma and other solid malignancies. Use of PBSCs is preferred by some because of the belief that there is less risk of tumor contamination. Because tumor stem cell contamination is thought to be one contributing cause of relapse after myeloablative therapy and autologous reconstitution, we examined the potential risk of reinfusing circulating neuroblastoma cells by in vitro evaluation of their clonogenicity. Immunocytologic and tumor cell clonogenic analyses were performed on 74 blood samples obtained from 56 children with advanced-stage neuroblastoma. Concurrently drawn bone marrow specimens were evaluated in 30 instances. Circulating neoplastic cells were detected in 19 of 74 (26%) for all specimens and by immunologic techniques (26%). Using a clonogenic assay, 13 grew identifiable tumor colonies. Comparing results with the two techniques showed tumor colony growth in 10 of the 19 positive specimens by immunocytology. However, 3 of 53 samples (6%) that were negative by immunocytology were positive by the clonogenic assay. Of the 11 positive blood samples, 9 concurrent marrows contained neuroblastoma cells; of the 19 negative blood specimens, 3 concurrent marrows had metastatic disease. We conclude that circulating neuroblastoma cells are present in peripheral blood and have clonogenic properties in vitro. This supports the view that tumor cell contamination may well be one cause of relapse after autologous reconstitution. Consequently, PBSC collections should also undergo meticulous monitoring for tumor contamination before autologous reinfusion.
A Clinical Evaluation of the International Lymphoma Study Group Classification of Non-Hodgkin's Lymphoma
Authors:   The Non-Hodgkin's Lymphoma Classification Project
Published: October 2019

Abstract
The recognition of several new types of non-Hodgkin's lymphoma (NHL) in recent years has led to proposals for changing lymphoma classifications, including a new proposal put forth by the International Lymphoma Study Group (ILSG). However, the clinical significance of the new entities and the practical utility of this new proposal have not been studied. Therefore, we performed a clinical evaluation of the ILSG classification. A cohort of 1,403 cases of NHL was organized at nine study sites around the world and consisted of consecutive patients seen between 1988 and 1990 who were previously untreated. A detailed protocol for histologic and clinical analysis was followed at each site, and immunologic characterization as to T- or B-cell phenotype was required. Five expert hematopathologists visited the sites and each classified each case using the ILSG classification. A consensus diagnosis was also reached in each case, and each expert rereviewed a 20% random sample of the cases. Clinical correlations and survival analyses were then performed. A diagnosis of NHL was confirmed in 1,378 (98.2%) of the cases. The most common lymphoma types were diffuse large B-cell lymphoma (31%) and follicular lymphoma (22%), whereas the new entities comprised 21% of the cases. Diagnostic accuracy was at least 85% for most of the major lymphoma types, and reproducibility of the diagnosis was 85%. Immunophenotyping improved the diagnostic accuracy by 10% to 45% for a number of the major types. The clinical features of the new entities were distinctive. Both the histologic types and the patient characteristics as defined by the International Prognostic Index predicted for patient survival. In conclusion we found that the ILSG classification can be readily applied and identifies clinically distinctive types of NHL. However, for clinical application, prognostic factors as defined by the International Prognostic Index must be combined with the histologic diagnosis for appropriate clinical decisions.
Cytokine Production Regulating Th1 and Th2 Cytokines in Hemophagocytic Lymphohistiocytosis
Authors: Osugi Yuko , Hara Junichi , Tagawa Shinichi , Takai Kenji , Hosoi Gaku , Matsuda Yoshiko , Ohta Hideaki , Fujisaki Hiroyuki , Kobayashi Michiko , Sakata Naoki , Kawa-Ha Keisei , Okada Shintaro , Tawa Akio 
Published: October 2019

AbstractHemophagocytic lymphohistiocytosis (HLH) is caused by the hyperactivation of T cells and macrophages. The clinical characteristics associated with this disease result from overproduction of Th1 cytokines including interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α). In this study, we analyzed the production of IL-12 and IL-4, which determine Th1 and Th2 response, respectively, and IL-10, which antagonizes Th1 cytokines, in 11 patients with HLH. IL-12 was detected in plasma in all patients (mean peak value, 30.0 ± 5.0 pg/mL), while IFN-γ was massively produced in nine patients (mean peak value, 79.2 ± 112.0 U/mL). IL-4 was not detected in any of the patients. Plasma IL10 levels were elevated in all patients (mean peak value, 2,698.0 ± 3,535.0 pg/mL). There was a positive correlation between the levels of IFN-γ and IL-10 (P < .01). The plasma concentrations of these cytokines were initially high, before decreasing after the acute phase. However, the decrease in IL-10 levels was slower than that of IFN-γ. Although the concentration of IL-12 was high at the acute phase, in some patients, a peak in the level was delayed until the chronic phase. Thus, in HLH, production of cytokines that promote development of Th1 cells appears to be predominant over that for Th2 cell development. Overproduction of IL-10 was also observed indicating that a mechanism suppressing hyperactivation of Th1 cells and monocytes/macrophages functions in patients with this disease.
Retinoid Induced Apoptosis in Leukemia Cells Through a Retinoic Acid Nuclear Receptor-Independent Pathway
Authors: Hsu C. Alex , Rishi Arun K. , Su-Li Xiao , Gerald Tonya M. , Dawson Marcia I. , Schiffer Charles , Reichert Uwe , Shroot Braham , Poirer Guy C. , Fontana Joseph A. 
Published: October 2019

AbstractTrans retinoic acid (RA) has proven to be a potent therapeutic agent in the treatment of acute promyelocytic leukemia. Unfortunately, other subtypes of acute myelogenous leukemia are resistant to the antiproliferative and differentiating effects of RA. In this report, we describe a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN; CD437) that not only totally inhibits the proliferation of RA-resistant leukemic cell lines HL-60R and K562 but also induces apoptosis in these cells. Exposure of HL-60R to CD437 results in the rapid (within 30 minutes) increase of the cyclin-dependent kinase inhibitor p21waf1/cip1 as well as GADD45 mRNA. Manifestations of CD437-mediated programmed cell death are noted within 2 hours, as indicated by both the cleavage and activation of the CPP32 protease and cleavage of poly (ADP-ribose) polymerase. This is followed by cleavage of bcl-2 and internucleosomal DNA degradation. HL-60R cells do not express the retinoid nuclear receptor RARβ and RARγ and express a truncated RARα. Thus, CD437 induction of p21waf1/cip1 and GADD45 mRNAs and apoptosis occurs through a unique mechanism not involving the retinoid nuclear receptors. CD437 represents a unique retinoid with therapeutic potential in the treatment of myeloid leukemia.
Spectrin St Claude, a Splicing Mutation of the Human α-Spectrin Gene Associated With Severe Poikilocytic Anemia
Authors: Fournier Catherine M. , Nicolas Gaël , Gallagher Patrick G. , Dhermy Didier , Grandchamp Bernard , Lecomte Marie-Christine 
Published: October 2019

AbstractAn α-spectrin variant with increased susceptibility to tryptic digestion, αII/47, was previously observed in a child with severe, recessively inherited, poikilocytic anemia. The molecular basis of this variant, spectrin St Claude, has now been identified as a splicing mutation of the α-spectrin gene due to a T → G mutation in the 3′ acceptor splice site of exon 20. This polypyrimidine tract mutation creates a new acceptor splice site, AT → AG, and leads to the production of two novel mRNAs. One mRNA contains a 12 intronic nucleotide insertion upstream of exon 20. This insertion introduces a termination codon into the reading frame and is predicted to encode a truncated protein (108 kD) that lacks the nucleation site and thus cannot be assembled in the membrane. In the other mRNA, there is in-frame skipping of exon 20, predicting a truncated (277 kD) α-spectrin chain. The homozygous propositus has only truncated 277 kD α-spectrin chains in his erythrocyte membranes. His heterozygous parents are clinically and biochemically normal. This allele was identified in 3% of asymptomatic individuals from Benin, Africa.
Apoptosis of Late-Stage Erythroblasts in Megaloblastic Anemia: Association With DNA Damage and Macrocyte Production
Authors: Koury Mark J. , Horne Donald W. , Brown Zoe A. , Pietenpol Jennifer A. , Blount Benjamin C. , Ames Bruce N. , Hard Robert , Koury Stephen T. 
Published: October 2019

Abstract
An in vitro model of folate-deficient erythropoiesis has been developed using proerythroblasts isolated from the spleens of Friend virus-infected mice fed an amino acid-based, folate-free diet. Control proerythroblasts were obtained from Friend virus-infected mice fed the same diet plus 2 mg folic acid/kg diet. Our previous studies showed that, after 20 to 32 hours of culture in folate-deficient medium with 4 U/mL of erythropoietin, the folate-deficient proerythroblasts underwent apoptosis, whereas control erythroblasts survived and differentiated into reticulocytes over a period of 48 hours. The addition of folic acid or thymidine to the folate-deficient medium prevented the apoptosis of the folate-deficient erythroblasts, thereby implicating decreased thymidylate synthesis as the main cause of apoptosis in the folate-deficient erythroblasts. In the study reported here, we examined intracellular folate levels, uracil misincorporation into DNA, p53 and p21 proteins, and reticulocyte formation in erythroblasts cultured in folate-deficient or control medium. In all experiments, the folate-deficient erythroblasts cultured in folate-deficient medium gave results that varied significantly from folate-deficient erythroblasts cultured in control medium or control erythroblasts cultured in either folate-deficient or control media. Folate-deficient erythroblasts cultured in folate-deficient medium had marked decreases in all coenzyme forms of folate that persisted throughout culture, increased uracil misincorporation into DNA, persistent accumulations of p53 and p21, and decreased reticulocyte production but increased size of individual reticulocytes. A model of folate-deficient erythropoiesis based on apoptosis of late stage erythroblasts is presented. This model provides explanations for the clinical findings in megaloblastic anemia.
Molecular Analysis of Eight Biochemically Unique Glucose-6-Phosphate Dehydrogenase Variants Found in Japan
Authors: Hirono Akira , Fujii Hisaichi , Takano Toshikuni , Chiba Yasuko , Azuno Yoichi , Miwa Shiro 
Published: October 2019

Abstract
We analyzed the molecular mutations of eight known Japanese glucose-6-phosphate dehydrogenase (G6PD) variants with unique biochemical properties. Three of them were caused by novel missense mutations: G6PD Musashino by 185 C→T, G6PD Asahikawa by 695 G→A, and G6PD Kamiube by 1387 C→T. Predicted amino acid substitutions causing asymptomatic variants G6PD Musashino (62 Pro→Phe) and G6PD Kamiube (463 Arg→Cys) were located in regions near the amino or carboxyl end of the polypeptide chain, whereas an amino acid change 232 Cys→Tyr causing a class 1 variant G6PD Asahikawa was located in the region where amino acid alterations in some class 1 variants were clustered. The other five variants had known missense mutations, namely, G6PD Fukushima, 1246 G→A, G6PD Morioka, 1339 G→A, and G6PD Iwate, G6PD Niigata and G6PD Yamaguchi, 1160 G→A, which cause variants, G6PD Tokyo, G6PD Santiago de Cuba, and G6PD Beverly Hills, respectively.