bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral Blood Stem Cell Transplantation From Unrelated Donors: A Comparison With Marrow Transplantation
Authors: Ringdén O. , Remberger M. , Runde V. , Bornhäuser M. , Blau I.W. , Basara N. , Hölig K. , Beelen D.W. , Hägglund H. , Basu O. , Ehninger G. , Fauser A.A. 
Published: October 2019

AbstractPeripheral blood stem cell (PBSC) transplants from HLA-A, -B, and -DR compatible unrelated donors (n = 45) were compared with bone marrow (BM; BM group, n = 45). Eighteen patients received CD34-selected PBSC (CD34 group). The PBSCs contained more mononuclear cells, CD34+, CD3+, and CD56+cells compared with marrow (P &lt; .001). Engraftment was achieved in all 45 patients in the BM group, in 43 of 45 (95%) in the PBSC group, and in 14 of 18 (78%) in the CD34 group (P &lt; .01). In multivariate analysis, a short time to absolute neutrophil count (ANC) equal to 0.5 × 109/L was associated with the PBSC/CD34 groups (P &lt; .001) and granulocyte colony-stimulating factor (G-CSF) treatment (P = .017). A short time to platelets equal to 50 × 109/L was associated with PBSC (P = .003) and no methotrexate (P = .015). Grades II-IV acute graft-versus-host disease (GVHD) was 20% in the BM controls, 30% in the PBSC group, and 18% in the CD34 group (not significant [NS]). The probability of chronic GVHD was 85% in the BM group, 59% in the PBSC group, and 0% in the CD34 group (P &lt; .01). One-year transplant-related mortality was 21% and 27% and survival was 53% and 54% in the BM and PBSC groups, respectively (NS). The 2-year relapse-free survival was 41% and 46% in the two groups, respectively.
Acute Systemic Reaction and Lung Alterations Induced by an Antiplatelet Integrin gpIIb/IIIa Antibody in Mice
Authors: Nieswandt Bernhard , Echtenacher Bernd , Wachs Frank-Peter , Schröder Josef , Gessner J. Engelbert , Schmidt Reinhold E. , Grau Georges E. , Männel Daniela N. 
Published: October 2019

AbstractShock is frequently accompanied by thrombocytopenia. To investigate the pathogenic role of platelets in shock, we examined the in vivo effects of monoclonal antibodies (MoAbs) against mouse platelet membrane proteins. Injection of the platelet-specific MoAb MWReg30 to the fibrinogen receptor (gpIIb/IIIa) rendered mice severely hypothermic within minutes. Isotype-matched control antibodies, even if they also recognized platelet surface antigens, did not induce comparable signs. MWReg30 induced early signs of acute lung injury with increased cellularity in the lung interstitium and rapid engorgement of alveolar septal vessels. Despite this in vivo activity, MWReg30 inhibited rather than stimulated platelet aggregation in vitro. MWReg30-binding to platelets led to phosphorylation of gpIIIa, but did not induce morphological signs of platelet activation. The MWReg30-induced reaction was abolished after treatment with MoAbs 2.4G2 to FcγRII/III and was absent in FcγRIII-deficient mice, clearly demonstrating the requirement for FcγRIII on involved leukocytes. Simultaneous administration of tumor necrosis factor exacerbated, whereas a tolerizing regimen of tumor necrosis factor or bacterial lipopolysaccharide completely prevented the reaction. These data suggest that platelet surface-deposited MWReg30-immune complexes lead to an acute Fc-mediated reaction with pulmonary congestion and life-threatening potential that could serve as an in vivo model of acute lung injury.
Dyskeratosis Congenita Caused by a 3′ Deletion: Germline and Somatic Mosaicism in a Female Carrier
Authors: Vulliamy T.J. , Knight S.W. , Heiss N.S. , Smith O.P. , Poustka A. , Dokal I. , Mason P.J. 
Published: October 2019

Abstract
X-linked dyskeratosis congenita (DC) is a bone marrow failure syndrome caused by mutations in the DKC1 gene located at Xq28. By 20 years of age, most affected boys develop bone marrow failure, whereas female carriers show a skewed pattern of X-chromosome inactivation. The gene product, dyskerin, is homologous to a yeast protein involved in ribosomal RNA biogenesis, providing a unique insight into a cause of aplastic anemia. Whereas most causative mutations are single amino acid substitutions, and nonsense or frameshift mutations have not been observed, we present here a case of DC caused by a 2-kb deletion that removes the last exon of the gene. Normal levels of mRNA are produced from the deleted gene, with the transcripts using a cryptic polyadenylation site in the antisense strand of the adjacent MPP1 gene, normally located 1 kb downstream of DKC1 in a tail to tail orientation. The predicted truncated protein lacks a lysine-rich peptide that is less conserved than the rest of the dyskerin molecule and is dispensable in yeast, supporting the contention that it may retain some activity and that null mutations at this locus may be lethal. The affected boy had an unaffected brother with the same haplotype around the DKC1 gene and a sister who was heterozygous for the deletion. We conclude therefore that the mother must be a germline mosaic with respect to this deletion. Investigation of her blood cells and other somatic tissues showed that a small proportion of these cells also carried the deletion, making her a somatic mosaic and indicating that the deletion took place early in development.
Inheritance of Chromosomally Integrated Human Herpesvirus 6 DNA
Authors: Daibata Masanori , Taguchi Takahiro , Nemoto Yuiko , Taguchi Hirokuni , Miyoshi Isao 
Published: October 2019

Abstract
Human herpesvirus 6 (HHV-6) genome has been detected in several human lymphoproliferative disorders with no signs of active viral infection, and found to be integrated into chromosomes in some cases. We previously reported a woman with HHV-6–infected Burkitt’s lymphoma. Fluorescence in situ hybridization showed that the viral genome was integrated into the long arm of chromosome 22 (22q13). The patient’s asymptomatic husband also carried HHV-6 DNA integrated at chromosome locus 1q44. To assess the possibility of chromosomal transmission of HHV-6 DNA, we looked for HHV-6 DNA in the peripheral blood of their daughter. She had HHV-6 DNA on both chromosomes 22q13 and 1q44, identical to the site of viral integration of her mother and father, respectively. The findings suggested that her viral genomes were inherited chromosomally from both parents. The 3 family members were all seropositive for HHV-6, but showed no serological signs of active infection. To confirm the presence of HHV-6 DNA sequences, we performed polymerase chain reaction (PCR) with 7 distinct primer pairs that target different regions of HHV-6. The viral sequences were consistently detected by single-step PCR in all 3 family members. We propose a novel latent form for HHV-6, in which integrated viral genome can be chromosomally transmitted. The possible role of the chromosomally integrated HHV-6 in the pathogenesis of lymphoproliferative diseases remains to be explained.
Hydroxyurea as an Alternative to Blood Transfusions for the Prevention of Recurrent Stroke in Children With Sickle Cell Disease
Authors: Ware Russell E. , Zimmerman Sherri A. , Schultz William H. 
Published: October 2019

AbstractChildren with sickle cell disease (SCD) and stroke receive chronic transfusions to prevent stroke recurrence. Transfusion risks including infection, erythrocyte allosensitization, and iron overload suggest a need for alternative therapies. We previously used hydroxyurea (HU) and phlebotomy in two young adults with SCD and stroke as an alternative to transfusions. We have now prospectively discontinued transfusions in 16 pediatric patients with SCD and stroke. Reasons to discontinue transfusions included erythrocyte alloantibodies or autoantibodies, recurrent stroke on transfusions, iron overload, noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d based on hematologic toxicity. Patients with iron overload underwent phlebotomy. The children have been off transfusions 22 months, (range, 3 to 52 months). Their average HU dose is 24.9 ± 4.2 mg/kg/d, hemoglobin concentration is 9.4 ± 1.3 g/dL, and mean corpuscular volume (MCV) is 112 ± 9 fL. Maximum percentage fetal hemoglobin (%HbF) is 20.6% ± 8.0% and percentage HbF-containing erythrocytes (%F cells) is 79.3% ± 14.7%. Fourteen patients underwent phlebotomy with an average of 8,993 mL (267 mL/kg) removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4 children have normal ferritin values. Three patients (19%) had neurological events considered recurrent stroke, each 3 to 4 months after discontinuing transfusions, but before maximal HU effects. These preliminary data suggest some children with SCD and stroke may discontinue chronic transfusions and use HU therapy to prevent stroke recurrence. Phlebotomy is well-tolerated and significantly reduces iron overload. Modifications in HU therapy to raise HbF more rapidly might increase protection against stroke recurrence.
Pathophysiology of Thrombocytopenia and Anemia in Mice Lacking Transcription Factor NF-E2
Authors: Levin Jack , Peng Jin-Peng , Baker Georgiann R. , Villeval Jean-Luc , Lecine Patrick , Burstein Samuel A. , Shivdasani Ramesh A. 
Published: October 2019

Abstract
Expression of the p45 subunit of transcription factor NF-E2 is restricted to selected blood cell lineages, including megakaryocytes and developing erythrocytes. Mice lacking p45 NF-E2 show profound thrombocytopenia, resulting from a late arrest in megakaryocyte differentiation, and a number of red blood cell defects, including anisocytosis and hypochromia. Here we report results of studies aimed to explore the pathophysiology of these abnormalities. Mice lacking NF-E2 produce very few platelet-like particles that display highly disorganized ultrastructure and respond poorly to platelet agonists, features consistent with the usually lethal hemorrhage in these animals. Thrombocytopenia was evident during fetal life and was not corrected by splenectomy in adults. Surprisingly, fetal NF-E2–deficient megakaryocyte progenitors showed reduced proliferation potential in vitro. Thus, NF-E2 is required for regulated megakaryocyte growth as well as for differentiation into platelets. All the erythroid abnormalities were reproduced in lethally irradiated wild-type recipients of hematopoietic cells derived from NF-E2-null fetuses. Whole blood from mice lacking p45 NF-E2 showed numerous small red blood cell fragments; however, survival of intact erythrocytes in vivo was indistinguishable from control mice. Considered together, these observations indicate a requirement for NF-E2 in generating normal erythrocytes. Despite impressive splenomegaly at baseline, mice lacking p45 NF-E2 survived splenectomy, which resulted in increased reticulocyte numbers. This reveals considerable erythroid reserve within extra-splenic sites of hematopoiesis and suggests a role for the spleen in clearing abnormal erythrocytes. Our findings address distinct aspects of the requirements for NF-E2 in blood cell homeostasis and establish its roles in proper differentiation of megakaryocytes and erythrocytes.
DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms
Authors: Yin Hong , Blanchard K. L. 
Published: October 2019

AbstractThe human erythropoietin gene is expressed predominantly in the kidney and liver in response to hypoxia. Although the signaling cascade for hypoxia is present in many different cell types, the expression of erythropoietin is restricted to only a few tissues. The authors show that the promoter and 5′-untranslated region (5′-UTR) of the erythropoietin gene comprise a CpG island and that methylation of the CpG island correlates inversely with expression. Methylation represses the expression of the erythropoietin gene in 2 ways: high-density methylation of the 5′-UTR recruits a methyl-CpG binding protein to the promoter, and methylation of CpGs in the proximal promoter blocks the association of nuclear proteins. (Blood. 2000;95:111-119)
A naturally occurring mutation near the amino terminus of αIIb defines a new region involved in ligand binding to αIIbβ3
Authors: Basani Ramesh B. , French Deborah L. , Vilaire Gaston , Brown Deborah L. , Chen Fangping , Coller Barry S. , Derrick Jerry M. , Gartner T. Kent , Bennett Joel S. , Poncz Mortimer 
Published: October 2019

AbstractDecreased expression of functional IIbβ3 complexes on the platelet surface produces Glanzmann thrombasthenia. We have identified mutations of IIbP145 in 3 ethnically distinct families affected by Glanzmann thrombasthenia. Affected Mennonite and Dutch patients were homozygous and doubly heterozygous, respectively, for a P145A substitution, whereas a Chinese patient was doubly heterozygous for a P145L substitution. The mutations affect expression levels of surface IIbβ3 receptors on their platelets, which was confirmed by co-transfection of IIbP145A and β3 cDNA constructs in COS-1 cells. Each mutation also impaired the ability of IIbβ3 on affected platelets to interact with ligands. Moreover, when IIbP145A and β3 were stably coexpressed in Chinese hamster ovary cells, IIbβ3 was readily detected on the cell surface, but the cells were unable to adhere to immobilized fibrinogen or to bind soluble fluorescein isothiocyanate–fibrinogen after IIbβ3 activation by the activating monoclonal antibody PT25-2. Nonetheless, incubating affected platelets with the peptide LSARLAF, which binds to IIb, induced PF4 secretion, indicating that the mutant IIbβ3 retained the ability to mediate outside-in signaling. These studies indicate that mutations involving IIbP145 impair surface expression of IIbβ3 and that the IIbP145A mutation abrogates ligand binding to the activated integrin. A comparative analysis of other IIb mutations with a similar phenotype suggests that these mutations may cluster into a single region on the surface of the IIb and may define a domain influencing ligand binding. (Blood. 2000;95:180188)
Outpatient penile aspiration and epinephrine irrigation for young patients with sickle cell anemia and prolonged priapism
Authors: Mantadakis Elpis , Ewalt David H. , Cavender Joe Don , Rogers Zora R. , Buchanan George R. 
Published: October 2019

AbstractThe optimal management of prolonged priapism for patients with sickle cell anemia (SCA) has not been established. We prospectively studied in an outpatient setting the efficacy and safety of a procedure that employs aspiration of blood from the corpora cavernosa and irrigation with a dilute epinephrine solution under local anesthesia to relieve priapism in young patients with SCA. If hydration and analgesics failed to produce detumescence or if priapism had lasted &gt;4 hours, the protocol was activated in the emergency room or clinic. Fifteen patients with homozygous SCA (Hb SS) were treated on 39 occasions; 10 patients were treated once, 1 patient twice, 2 patients 3 times, 1 patient 6 times, and 1 patient 15 times. Median age of patients at first treatment was 14.3 years (range, 3.9-18.3 years). The procedure was successful in producing immediate detumescence on 37 of 39 occasions (95% efficacy, 95% confidence intervals (CI): 81%-99%). No serious immediate or long-term side effects were observed. None of the patients who demonstrated detumescence required hospitalization. The 2 patients whose priapism persisted after aspiration and irrigation presented with episodes lasting &gt;24 hours. All evaluable patients whose priapism resolved after aspiration and irrigation self-reported normal erectile function at a median of 40 months (range, 3-58 months) after the last procedure. Thus, aspiration of the corpora cavernosa followed by irrigation with dilute epinephrine is effective in producing immediate and sustained detumescence and should be the initial therapy employed for patients with SCA and prolonged priapism. (Blood, 2000; 95:78-82)
Interleukin-13 induces PSGL-1/P–selectin–dependent adhesion of eosinophils, but not neutrophils, to human umbilical vein endothelial cells under flow
Authors: Woltmann Gerrit , McNulty Claire A. , Dewson Grant , Symon Fiona A. , Wardlaw Andrew J. 
Published: October 2019

AbstractSelective eosinophil accumulation is a hallmark of diseases such as asthma. In a model of chronic eosinophilic inflammation, we have previously shown that the tethering step in eosinophil adhesion is mediated by PSGL-1 binding to P-selectin. The Th2-associated cytokine IL-13 is of potential importance in allergic disease. We have therefore investigated whether IL-13 can mediate eosinophil binding to human umbilical vein endothelial cells (HUVEC) through P-selectin. IL-13 caused dose- and time-dependent increases of P-selectin expression, as assessed by flow and laser scanning cytometry. A similar degree of expression was observed with IL-4. There was no effect on E-selectin or ICAM-1 expression. Tumor necrosis factor- induced the expression of VCAM-1, E-selectin, and ICAM-1 but had no effect on P-selectin expression. IL-13 increased the production of mRNA for surface and soluble variants of P-selectin. Under flow conditions, eosinophils, but not neutrophils, showed enhanced binding to IL-13 and to IL-4–stimulated HUVEC compared to medium-cultured cells. Eosinophil adhesion was completely inhibited by a blocking monoclonal antibody against PSGL-1 and P-selectin. Anti–VLA-4 and anti–VCAM-1 antibodies inhibited binding to a lesser extent. Thus, at physiologic levels of expression induced by Th2 cytokines, P-selectin/PSGL-1 supported eosinophil but not neutrophil adhesion. This mechanism is likely to be a key event leading to the selective accumulation of eosinophils in allergic inflammation.
Identification and characterization of a new human ETS-family transcription factor, TEL2, that is expressed in hematopoietic tissues and can associate with TEL1/ETV6
Authors: Potter Mark D. , Buijs Arjan , Kreider Brent , van Rompaey Luc , Grosveld Gerard C. 
Published: October 2019

Abstract
The ETS family of proteins is a large group of transcription factors implicated in many aspects of normal hematopoietic development, as well as oncogenesis. For example, the TEL1/ETV6 (TEL1) gene is required for normal yolk sac angiogenesis, adult bone marrow hematopoiesis, and is rearranged or deleted in numerous leukemias. This report describes the cloning and characterization of a novelETS gene that is highly related to TEL1 and is therefore called TEL2. The TEL2 gene consists of 8 exons spanning approximately 21 kilobases (kb) in human chromosome 6p21. Unlike the ubiquitously expressed TEL1 gene, however,TEL2 appears to be expressed predominantly in hematopoietic tissues. Antibodies raised against the C-terminus of the TEL2 protein were used to show that TEL2 localizes to the nucleus. All ETS proteins can bind DNA via the highly conserved ETS domain, which recognizes a purine-rich DNA sequence with a GGAA core motif. DNA binding assays show that TEL2 can bind the same consensus DNA binding sequence recognized by TEL1/ETV6. Additionally, the TEL2 protein is capable of associating with itself and with TEL1 in doubly transfected Hela cells, and this interaction is mediated through the pointed (PNT) domain of TEL1. The striking similarities ofTEL2 to the oncogenic TEL1, its expression in hematopoietic tissues, and its ability to associate withTEL1 suggest that TEL2 may be an important hematopoietic regulatory protein.
Vitamin A deficiency in mice causes a systemic expansion of myeloid cells
Authors: Kuwata Takeshi , Wang I-Ming , Tamura Tomohiko , Ponnamperuma Roshini M. , Levine Rachel , Holmes Kevin L. , Morse Herbert C. , De Luca Luigi M. , Ozato Keiko 
Published: October 2019

AbstractTo examine the role of retinoids in hematopoietic cell growth in vivo, we studied female SENCAR mice made vitamin A deficient by dietary restriction. Deficient mice exhibited a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. The abnormal expansion of myeloid cells was detected from an early stage of vitamin A deficiency and contrasted with essentially normal profiles of T and B lymphocytes. This abnormality was reversed on addition of retinoic acid to the vitamin A–deficient diet, indicating that the myeloid cell expansion is a direct result of retinoic acid deficiency. TUNEL analysis indicated that spontaneous apoptosis, a normal process in the life cycle of myeloid cells, was impaired in vitamin A–deficient mice, which may play a role in the increased myeloid cell population. Quantitative reverse transcriptase-polymerase chain reaction analysis of purified granulocytes showed that expression of not only RAR, but RXRs, 2 nuclear receptors that mediate biologic activities of retinoids, was significantly reduced in cells of deficient mice. This work shows that retinoids critically control the homeostasis of myeloid cell population in vivo and suggests that deficiency in this signaling pathway may contribute to various myeloproliferative disorders.
Intramedullary and extramedullary B lymphopoiesis in osteopetrotic mice
Authors: Tagaya Hisashi , Kunisada Takahiro , Yamazaki Hidetoshi , Yamane Toshiyuki , Tokuhisa Takeshi , Wagner Erwin F. , Sudo Tetsuo , Shultz Leonard D. , Hayashi Shin-Ichi 
Published: October 2019

AbstractAdult bone marrow is a major site for hematopoiesis, and reduction of the bone marrow cavity induces hematopoiesis in extramarrow tissues. To investigate the rudimentary intramarrow and the compensatory extramarrow hematopoiesis, particularly B lymphopoiesis, we used 3 osteopetrotic mouse strains [op/op, mi/mi, and Fos(−/−)], which are severely deficient in functional osteoclasts and therefore form inadequate bone marrow cavities. We found that bone marrow in these osteopetrotic mice supports myelopoiesis but not B lymphopoiesis, although cells that have the potential to differentiate into B lineage cells are present in the bone marrow. Although B lymphopoiesis normally occurs both in the spleen and liver of newborn mice, compensatory B lymphopoiesis in adultop/op and mi/mi mice is observed only in the liver, while myelopoiesis is enhanced in both organs. Interestingly, mice lacking the Fos proto-oncogene exhibit B lymphopoiesis in the spleen as well as liver. The amounts of expression of steel factor, Flt3/Flk-2 ligand, and interleukin-7 in the bone marrow, spleen, or liver were not significantly affected in these osteopetrotic mutants. These findings suggest that the volume of the bone marrow cavity regulates B lymphopoiesis without affecting the production of certain hematopoietic growth factors. The splenic microenvironments that support both myelopoiesis and B lymphopoiesis in the neonatal stage are lost in adults and are not reactivated even in the osteopetrotic adults unless the Fos gene is disrupted.