bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet adhesion to collagen in healthy volunteers is influenced by variation of both α2β1 density and von Willebrand factor
Authors: Roest Mark , Sixma Jan J. , Wu Ya-Ping , Ijsseldijk Martin J. W. , Tempelman Mariëlle , Slootweg Pieter J. , de Groot Philip G. , van Zanten G. Henrita 
Published: October 2019

Abstract
Platelet thrombus formation on collagen is initiated by platelet GPIb interaction with von Willebrand factor (vWF) bound to collagen, followed by firm attachment of the platelet to collagen by the integrin α2β1. Platelet and plasma vWF levels and α2β1 density on the platelet surface are highly variable among normal subjects; however, little is known about the consequences of this variability on platelet adhesion to collagen. A population of 32 normal subjects was studied to evaluate the relation between genetic and phenotypic variations of α2β1 density on the platelet surface, plasma vWF levels, platelet vWF levels, and adenosine diphosphate and adenosine triphosphate concentrations on the one hand and platelet adhesion to collagen under flow on the other hand. Platelet adhesion to collagen types I and III under flow was correlated with plasma levels of vWF (r2 = 0.45 and 0.42, respectively) and α2β1 density on the platelet surface (r2 = 0.35 and 0.17, not significant). Platelet adhesion to collagen type IV under flow was significantly correlated with platelet vWF levels (r2 = 0.34) and α2β1 density on the platelet surface (r2 = 0.42). Platelet adhesion to collagen types I and III depends on both plasma levels of vWF and α2β1 density on the platelet surface, whereas platelet adhesion to collagen type IV is mediated by both platelet vWF levels and α2β1 density on the platelet surface.
SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization
Authors: Carver Deborah Jeannean , Aman Mohammad Javad , Ravichandran Kodimangalam S. 
Published: October 2019

AbstractActivation of the serine/threonine kinase Akt and the regulation of its activation are recognized as critical in controlling proliferative/survival signals via many hematopoietic receptors. In B lymphocytes, the B-cell receptor (BCR)-mediated activation of Akt is attenuated by co–cross-linking of BCR with the inhibitory receptor FcγRIIB1, and the binding of the SH2 domain-containing inositol phosphatase, SHIP, to FcγRIIB1. Because SHIP dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3) and activation of Akt requires PIP3, the destruction of this phospholipid has been proposed as the mechanism for Akt inhibition. However, upstream kinases that activate Akt, such as PDK1, also require PIP3 for activation. In this report, we addressed whether SHIP inhibits Akt directly at the level of Akt recruitment to the membrane, indirectly through PDK recruitment/phosphorylation of Akt, or both. We generated stable B-cell lines expressing a regulatable, but constitutively membrane-bound Akt that still required PDK-dependent phosphorylation for activation. Several lines of evidence suggested that activation of this membrane-targeted Akt is not inhibited by FcγRIIB1/SHIP and that PDK is not a target for SHIP-mediated inhibition. These data demonstrate that SHIP inhibits Akt primarily through regulation of Akt membrane localization. We also observed during these studies that FcγRIIB1/SHIP does not inhibit p70S6k activation, even though several other PIP3-dependent events were down-regulated. Because the enhanced activation of Akt in the absence of SHIP correlates with hyperproliferation in the myeloid lineage, our data have implications for SHIP and Akt-dependent regulation of proliferation in the hematopoietic lineage.
Immunity to WT1 in the animal model and in patients with acute myeloid leukemia
Authors: Gaiger Alexander , Reese Valerie , Disis Mary L. , Cheever Martin A. 
Published: October 2019

AbstractThe Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpressed in most types of leukemia in humans. WT1 is also detectable in many types of lung, thyroid, breast, testicular, and ovarian cancers and melanoma in humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse models might lead to resolution of many of the critical issues for developing WT1 vaccines. C57/BL6 (B6) mice were injected with synthetic peptides from the natural sequence of WT1 containing motifs for binding to major histocompatibility (MHC) class II molecules. Immunization induced helper T-cell responses specific for the immunizing WT1 peptides and antibody responses specific for WT1 protein. Screening of multiple murine cancer cell lines identified 2 murine cancers, TRAMP-C and BLKSV40, that “naturally” overexpress WT1. Immunization with MHC class I binding peptides induced WT1 peptide-specific cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40. WT1 specificity of lysis was confirmed by cold target inhibition. No toxicity was noted by histopathologic evaluation in the WT1 peptide-immunized animals. WT1 peptide immunization did not show any effect on TRAMP-C tumor growth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-specific antibody, demonstrating that WT1 can be immunogenic in the context of cancer cells. To evaluate whether WT1 might be similarly immunogenic in humans, serum from patients with leukemia was evaluated for pre-existing antibody responses. Western blot analyses showed WT1-specific antibodies directed against the N-terminus portion of the WT1 protein in the sera of 3 of 18 patients with acute myeloid leukemia (AML).
Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC)
Authors: Dawson Tracey C. , Lentsch Alex B. , Wang Zixuan , Cowhig John E. , Rot Antal , Maeda Nobuyo , Peiper Stephen C. 
Published: October 2019

AbstractDuffy antigen/receptor for chemokines (DARC) is a promiscuous receptor for chemokines that is required for Plasmodium vivax infection of erythroid cells. This receptor is expressed by subsets of endothelial, as well as erythroid cells. Selection for protection from malaria infection resulted in an erythroid-specific defect, suggesting that DARC may play a critical role in endothelial biology. Mice with targeted disruption of this gene were generated, and the function of DARC in inflammation was explored. RNA from spleens of homozygous mutant mice lacked DARC transcripts, which were abundant in wild-type (+/+) and heterozygote (+/−) mice. DARC−/− mice lacked developmental abnormalities and were healthy at 1 year. Whereas hematologic parameters were within normal ranges, erythrocytes from nullizygous mice lacked CXC and CC chemokine-binding activity. Challenge with lipopolysaccharide resulted in significantly increased inflammatory infiltrates in lung and liver of nullizygous mice. These results suggest that DARC modulates the intensity of inflammatory reactions as a sink for chemokines.
Effect of active prenatal management on pregnancy outcome in sickle cell disease in an African setting
Authors: Rahimy Mohamed C. , Gangbo Annick , Adjou Roslyn , Deguenon Chantal , Goussanou Stephanie , Alihonou Eusebe 
Published: October 2019

AbstractSickle cell disease (SCD) is associated with an increased risk of medical complications during pregnancy. In sub-Saharan Africa, fetal and maternal mortality rates are particularly high. This study evaluated the effect of an active prenatal management program on pregnancy outcome in patients with SCD in an African setting. Pregnant women with SCD attending the National Teaching Hospital in Cotonou (The Republic of Benin, West Africa) were recruited before the 28th week of gestation. Management was based on providing information and education about SCD and improving nutritional status, malaria prevention, early detection of bacterial infections, and restricted use of blood transfusion. Maternal and fetal mortality rates and SCD-related morbidity were the principal variables assessed. One hundred and eight patients (42 SS and 66 SC) with 111 fetuses were included in the study. Thirteen fetal deaths (from 9 SS and 4 SC mothers) were recorded and 2 deaths of SC mothers. The maternal mortality rate of 1.8% was comparable with the overall maternal mortality rate for this maternity unit (1.2%). Few SCD-related events were recorded. Plasmodium falciparum malaria infection was the major cause of morbidity. Sixty-three patients (19 SS and 44 SC) successfully completed their pregnancy (58.3%) without requiring transfusion. Providing pregnant SCD patients with relevant medical care based on simple cost-effective approaches can have a positive impact on SCD-associated morbidity and mortality in an otherwise difficult setting in Africa.
Pyk2 and Syk participate in functional activation of granulocytic HL-60 cells in a different manner
Authors: Miura Yasuo , Tohyama Yumi , Hishita Terutoshi , Lala Amitabha , De Nardin Ernesto , Yoshida Yataro , Yamamura Hirohei , Uchiyama Takashi , Tohyama Kaoru 
Published: October 2019

AbstractThe roles of the protein tyrosine kinases Pyk2 (also called RAFTK or CAK β) and Syk in the process of functional activation of human myeloid cells were examined. During granulocytic differentiation of HL-60 cells with dimethyl sulfoxide (DMSO), the amounts of Pyk2 and β2 integrin increased, whereas the amount of Syk was abundant before differentiation and did not change during differentiation. When the granulocytic cells were stimulated withN-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), tyrosine phosphorylation of Pyk2 occurred promptly and subsequent association of Pyk2 with β2 integrin was detected. In contrast, Syk was not tyrosine phosphorylated by fMLP stimulation but constitutively associated with β2 integrin. Stimulation with fMLP also caused the alteration of β2 integrin to an activated form, a finding that was confirmed by the observation of fMLP-induced cell attachment on fibrinogen-coated dishes and inhibition of this attachment by pretreatment with anti-β2 integrin antibody. Cell attachment to fibrinogen caused the enhanced tyrosine phosphorylation of Pyk2 and the initial tyrosine phosphorylation of Syk, which was also inhibited by pretreatment with anti-β2 integrin antibody. In vitro kinase assays revealed that Pyk2 and Syk represented kinase activities to induce tyrosine phosphorylation of several molecules in the anti-β2 integrin immunoprecipitates of the attached cells. These results showed that Pyk2 is involved in the functional activation of granulocytic cells in 2 signaling pathways: an fMLP receptor–mediated “inside-out” signaling pathway that might cause β2 integrin activation and a subsequent β2 integrin–mediated “outside-in” signaling pathway. Syk was activated in relation to cell attachment to fibrinogen as a result of “outside-in” signaling, although it was already associated with β2 integrin before fMLP stimulation.
Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells
Authors: Moulding Dale A. , Giles Richard V. , Spiller David G. , White Michael R. H. , Tidd David M. , Edwards Steven W. 
Published: October 2019

Abstract
Mcl-1 is a member of the Bcl-2 protein family, which has been shown to delay apoptosis in transfection and/or overexpression experiments. As yet no gene knockout mice have been engineered, and so there is little evidence to show that loss of Mcl-1 expression is sufficient to trigger apoptosis. U937 cells constitutively express the antiapoptotic protein Bcl-2; but during differentiation, in response to the phorbol ester PMA (phorbol 12 β-myristate 13 α-acetate), Mcl-1 is transiently induced. The purpose of this investigation was to determine the functional role played by Mcl-1 in this differentiation program. Mcl-1 expression was specifically disrupted by chimeric methylphosphonate/phosphodiester antisense oligodeoxynucleotides to just 5% of control levels. The depletion of Mcl-1 messenger RNA (mRNA) and protein was both rapid and specific, as indicated by the use of control oligodeoxynucleotides and analysis of the expression of otherBCL2 family members and PMA-induced tumor necrosis factor–α (TNF-α). Specific depletion of Mcl-1 mRNA and protein, in the absence of changes in cellular levels of Bcl-2, results in a rapid entry into apoptosis. Levels of the proapoptotic protein Bax remained unchanged during differentiation, while Bak expression doubled within 24 hours. Apoptosis was detected within 4 hours of Mcl-1 antisense treatment by a variety of parameters including a novel live cell imaging technique allowing correlation of antisense treatment and apoptosis in individual cells. The induction of Mcl-1 is required to prevent apoptosis during differentiation of U937 cells, and the constitutive expression of Bcl-2 is unable to compensate for the loss of Mcl-1.
Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice
Authors: Liyanage Marek , Weaver Zoë , Barlow Carrolee , Coleman Allen , Pankratz Daniel G. , Anderson Stacie , Wynshaw-Boris Anthony , Ried Thomas 
Published: October 2019

AbstractAtm-deficient mice (Atm−/−) recapitulate many aspects of the ataxia telangiectasia (AT) syndrome, including the susceptibility to tumors of lymphoid origin. To investigate the mechanism of tumorigenesis, we have examined a panel of 8 thymic lymphomas from Atm−/− mice. AllAtm−/− tumors are of thymic lymphoblastoid origin, display an immature CD3− and CD4+/CD8+ phenotype, and arise coincident with V(D)J recombination. Cytogenetically, all tumors are diploid or near diploid but exhibit multiple chromosome aberrations with an average of 4 abnormal chromosomes per tumor. All the tumors revealed chromosome 14 rearrangements precisely at the T-cell receptorα/δ(Tcrα/δ) locus, suggesting the involvement of V(D)J recombination in these translocations. In addition, 11.5% ofAtm−/− peripheral T cells showed chromosome 14 translocations, suggesting that rearrangements at theTcrα/δ locus occur early during tumor development in the absence of ATM. However, additional genetic aberrations are required for tumorigenesis. For example, translocations involving chromosome 12, often with chromosome 14 (more than 60%), and partial or complete trisomy of chromosome 15, with copy number increases of the c-myc oncogene were frequently observed. These observations suggest that ATM is required for normal rearrangement of the Tcrα/δ locus but not for V(D)J recombination at other loci. The mechanisms that lead to tumorigenesis may be due to the involvement of ATM in monitoring double-stranded DNA breaks.
A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans
Authors: Kohn Michael H. , Pelz Hans-Joachim 
Published: October 2019

AbstractThe locus underlying hereditary resistance to the anticoagulant warfarin (symbol in the rat, Rw) was placed in relation to 8 positionally mapped gene-anchored microsatellite loci whose positions were known in the genome maps of the rat, mouse, and human.Rw segregated with the markers Myl2 (zero recombinants) and Itgam, Il4r, andFgf2r (one recombinant each) during linkage analysis in a congenic warfarin- and bromadiolone-resistant laboratory strain of rats. Comparative ortholog mapping between rat, mouse, and human placedRw onto mouse chromosome 7 at about 60 to 63 cM and onto one of the human chromosomes 10q25.3-26, 12q23-q24.3, and 16p13.1-p11.
Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury
Authors: Iversen Per Ole , Hjeltnes Nils , Holm Bjørn , Flatebø Torun , Strøm-Gundersen Inger , Rønning Wenche , Stanghelle Johan , Benestad Haakon B. 
Published: October 2019

AbstractThe bone marrow is supplied with both sensory and autonomic neurons, but their roles in regulating hematopoietic and immunocompetent cells are unknown. Leukocyte growth and activity in patients with stable and complete spinal cord injuries were studied. The innervation of the bone marrow below the injury level lacked normal supraspinal activity, that is, a decentralized bone marrow. Lymphocyte functions were markedly decreased in injured patients. Long-term colony formation of all hematopoietic cell lineages, including dendritic cells, by decentralized bone marrow cells was substantially reduced. It was concluded that nonspecific and adaptive lymphocyte-mediated immunity and growth of early hematopoietic progenitor cells are impaired in patients with spinal cord injuries. Possibly, this reflects cellular defects caused by the malfunctioning neuronal regulation of immune and bone marrow function.
Financial analysis of chronic transfusion for stroke prevention in sickle cell disease
Authors: Wayne Alan S. , Schoenike Steve E. , Pegelow Charles H. 
Published: October 2019

AbstractChronic red blood cell transfusion can prevent many of the manifestations of sickle cell disease. The medical costs of chronic transfusion and management of associated side effects, especially iron overload, are considerable. This study was undertaken to evaluate the financial impact of chronic transfusion for stroke prevention in patients with sickle cell anemia. Outpatient charges pertaining to hospital-based Medicare uniform bill (UB-92) codes, professional fees, and iron chelation were evaluated. Data were collected on 21 patients for a total of 296 patient months (mean, 14; median, 14 months/patient). Charges ranged from $9828 to $50 852 per patient per year. UB-92, chelation, and physician-related charges accounted for 53%, 42%, and 5% of total charges, respectively. Of UB-92 charges, 58% were associated with laboratory fees and 16% were related to the processing and administration of blood. Charges for patients who required chelation therapy ranged from $31 143 to $50 852 per patient per year (mean, $39 779; median, $38 607). Deferoxamine accounted for 71% of chelation-related charges, which ranged from $12 719 to $24 845 per patient per year (mean, $20 514; median, $21 381). The financial impact of chronic transfusion therapy for sickle cell disease is substantial with charges approaching $400 000 per patient decade for patients who require deferoxamine chelation. These data should be considered in reference to cost and efficacy analyses of alternative therapies for sickle cell disease, such as allogeneic bone marrow transplantation.
Afibrinogenemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation
Authors: Asselta Rosanna , Duga Stefano , Simonic Tatjana , Malcovati Massimo , Santagostino Elena , Giangrande Paul L. F. , Mannucci Pier Mannuccio , Tenchini Maria Luisa 
Published: October 2019

AbstractCongenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of plasma fibrinogen and by a bleeding tendency ranging from mild to moderately severe. Beside a deletion of the almost entire Aα-chain gene, only 2 missense mutations in the C-terminal domain of the Bβ-chain have been very recently described as being associated with afibrinogenemia. We studied a Pakistani patient with unmeasurable plasma levels of functional and immunoreactive fibrinogen. Sequencing of the fibrinogen genes revealed a homozygous G→A transition at position +5 of intron 1 of the γ-chain gene. The predicted mutant fibrinogen γ-chain would contain the signal peptide, followed by a short stretch of aberrant amino acids, preceding a premature stop codon. To demonstrate the causal role of the identified mutation, we prepared expression vectors containing a region of the fibrinogen γ-chain gene spanning from exon 1 to intron 4 and carrying either a G or an A at position +5 of intron 1. Transient transfection of the mutated plasmid in HeLa cells, followed by RNA extraction and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, allowed us to demonstrate the production of an erroneously spliced messenger RNA (mRNA), retaining intron 1, as shown by direct sequencing. A normal splicing occurred in HeLa cells transfected with the wild-type plasmid. This is the first report of a mutation in the fibrinogen γ-chain gene causing afibrinogenemia and indicates that, in addition to the Aα and Bβ-chain genes, the γ-chain gene must also be considered in mutation screening for afibrinogenemia.
Syk-deficient eosinophils show normal interleukin-5–mediated differentiation, maturation, and survival but no longer respond to FcγR activation
Authors: Lach-Trifilieff Estelle , Menear Keith , Schweighoffer Edina , Tybulewicz Victor L. J. , Walker Christoph 
Published: October 2019

AbstractThe tyrosine kinase Syk has been proposed to play a critical role in the antiapoptotic effect of interleukin (IL)-5 in human eosinophils. However, little is known about the involvement of Syk in other IL-5–mediated activation events. To further address these questions, the role of Syk in IL-5–induced eosinophil differentiation, activation, and survival was analyzed using cells obtained from Syk-deficient mice. We could demonstrate that Syk-deficient fetal liver cells differentiate into mature eosinophils in response to IL-5 at the same rate as wild-type fetal liver cells and generate the same total number of eosinophils. Moreover, no difference in IL-5–induced survival of mature eosinophils between Syk−/− and wild-type eosinophils could be demonstrated, suggesting that the antiapoptotic effect of IL-5 does not require Syk despite the activation of this tyrosine kinase upon IL-5 receptor ligation. In contrast, eosinophils derived from Syk-deficient but not wild-type mice were incapable of generating reactive oxygen intermediates in response to Fcγ receptor (FcγR) engagement. Taken together, these data clearly demonstrate no critical role for Syk in IL-5–mediated eosinophil differentiation or survival but underline the importance of this tyrosine kinase in activation events induced by FcγR stimulation.
An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus
Authors: Foster Charles B. , Lehrnbecher Thomas , Samuels Susan , Stein Steven , Mol Femke , Metcalf Julie A. , Wyvill Kathleen , Steinberg Seth M. , Kovacs Joseph , Blauvelt Andrew , Yarchoan Robert , Chanock Stephen J. 
Published: October 2019

AbstractKaposi sarcoma (KS) is an angioproliferative inflammatory condition that occurs commonly in patients infected with human immunodeficiency virus (HIV). Inflammatory cytokines and growth factors promote the development of KS. Because physiologically important cytokine polymorphisms modulate host inflammatory responses, we investigated the association between KS and common regulatory polymorphisms in 5 proinflammatory cytokine genes encoding interleukin (IL) IL-1α, IL-1β, tumor necrosis factor (TNF) α, TNF-β, and IL-6 and in the IL-1 receptor antagonist (IL1RN). We also examined the contribution of stromal-derived factor 1 and chemokine receptor 5 (Δ32) polymorphisms to KS development. The population consisted of 115 HIV-infected men with KS and 126 deceased HIV-infected men without KS. The only strong association was observed between an IL6promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected men (P = .0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P = .0046), whereas allele C homozygotes were underrepresented (P = .0062). Substantial in vitro evidence indicates that IL-6 contributes to the pathogenesis of KS. Our results show thatIL6 promoter genotypes associated with altered gene expression are risk factors for development of KS. Identification of a genetic risk factor for development of KS has important clinical implications for prevention and therapy.