bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased expression of platelet IgG Fc receptors in immune heparin- induced thrombocytopenia
Authors: Chong BH , Pilgrim RL , Cooley MA , Chesterman CN 
Published: October 2019

Abstract
Our previous finding that heparin-dependent antibodies in heparin- induced thrombocytopenia (HIT) bind to platelets via platelet IgG Fc receptors (FcRs) prompted this study. Platelet FcRs in 16 patients with HIT, 23 control patients, and 42 normal subjects were studied. Patients with HIT had substantially increased platelet FcRs during the acute illness. Those who suffered serious thrombotic complications or died shortly after diagnosis had significantly more FcRs per platelet than those with milder disease. Consistent with their increased FcRs, platelets of patients with HIT showed increased aggregation reactivity to aggregated IgG and heparin-dependent antibodies. Platelet FcRs in patients with HIT remained elevated for 1 to 3 months after the acute illness then stabilized to a mean value not significantly different from either control group. The increased expression of FcRs on HIT platelets and their increased reactivity to heparin-dependent antibodies may contribute to the pathogenesis of thrombocytopenia and thrombosis in HIT.
A serine/proline-rich protein is fused to HRX in t(4;11) acute leukemias
Authors: Morrissey J , Tkachuk DC , Milatovich A , Francke U , Link M , Cleary ML 
Published: October 2019

Abstract
Translocations involving chromosome band 11q23 in acute leukemias have recently been shown to involve the HRX gene that codes for a protein with significant similarity to Drosophila trithorax. HRX gene alterations are consistently observed in t(4;11) (q21;q23)-carrying leukemias and cell lines by Southern blot analyses and are accompanied by HRX transcripts of anomalous size on Northern blots. HRX-homologous cDNAs were isolated from a library prepared from t(4;11)-carrying acute leukemia cells. cDNAs representative of transcription products from the derivative 11 chromosome were shown to contain HRX sequences fused to sequences derived from chromosome band 4q21. Fragments of the latter were used to clone and analyze cDNAs for wild-type 4q21 transcripts that predicted a 140-Kd basic protein (named FEL) that is rich in prolines, serines, and charged amino acids. FEL contains guanosine triphosphate-binding and nuclear localization consensus sequences and uses one of two possible 5' exons encoding the first 12 or 5 amino acids. After t(4;11) translocations, 913 C-terminal amino acids of FEL are fused in frame to the N-terminal portion of HRX containing its minor groove DNA binding motifs. These features are similar to predicted t(11;19) fusion proteins, suggesting that HRX consistently contributes a novel DNA-binding motif to at least two different chimeric proteins in acute leukemias.
Zinc protoporphyrin in anemia of chronic disorders
Authors: Hastka J , Lasserre JJ , Schwarzbeck A , Strauch M , Hehlmann R 
Published: October 2019

Abstract
Hematofluorometric determination of zinc protoporphyrin (ZPP) is a screening method for the assessment of iron deficiency (ID). Chronic disorders are frequently accompanied by anemias of unclear origin, most probably caused by an impairment of iron metabolism. We investigated the relevance of ZPP for the detection of derangements of iron metabolism in anemias of chronic disorders (ACD). In 19 patients with ACD caused by chronic inflammatory non-neoplastic diseases, ZPP was determined and correlated with ferritin, transferrin saturation, and hemoglobin (Hb). Marrow sideroblast counts and semiquantitative grading of the marrow hemosiderin were performed in all patients to exclude ID and to show the decreased iron bioavailability. In all ACD patients who exhibited the typical laboratory findings of disturbed iron metabolism, such as hypoferremia, decreased transferrin saturation, decreased bone marrow sideroblasts, and increased marrow hemosiderin, strongly elevated ZPP levels were found (131 +/- 23 mumol/mol heme). ZPP returned to normal after successful treatment of the underlying disease. This is shown in three patients with polymyalgia rheumatica. We conclude that the fluorometric determination of ZPP allows detection and quantification of derangements of iron metabolism associated with chronic inflammatory disorders. By recording the derangements quantitatively, ZPP allows monitoring of therapy of chronic inflammatory diseases.
Autoantibodies against platelet glycoproteins in autoimmune thrombocytopenic purpura: their clinical significance and response to treatment
Authors: Berchtold P , Wenger M 
Published: October 2019

Abstract
Autoantibodies against platelet glycoproteins (GP) have been demonstrated in patients with autoimmune thrombocytopenic purpura (ATP). However, their clinical and pathogenetic significance as well as their response to immunosuppressive treatment is unknown. Using an immunobead assay capable of measuring autoantibodies against GPIIb-IIIa and GPIb-IX, we studied 58 adult patients with active ATP (platelet count < 150 x 10(9)/L) and 26 patients with ATP in remission (platelet count > 150 x 10(9)/L and without any therapy at time of investigation). Platelet-associated autoantibodies were detected in 39 of 53 patients with active ATP (73.6%) and in 2 of 26 patients in remission (7.7%). Circulating plasma autoantibodies were noted in 17 of 58 patients in the group with active disease (29.3%) and in none of the patients in remission. Twelve patients with active ATP and autoantibodies against GPIIb-IIIa were studied prospectively during treatment with corticosteroids. Of eight patients whose platelet count normalized during treatment, platelet-associated and plasma antibodies decreased significantly in two or became undetectable in six. In contrast, of four patients whose platelet counts were unchanged or increased moderately, we noted no significant change in antibodies. Moreover, autoantibodies reappeared in two responding patients at the time of relapse. The effect of high-dose intravenous immunoglobulin was studied in six active ATP patients with antiglycoprotein autoantibodies and refractoriness to prednisone. In one patient who developed a sustained remission after IvIgG, platelet-associated and plasma antibodies to GPIIb-IIIa decreased and became undetectable. In contrast, two patients who had only a transient rise of the platelet count after IvIgG showed no significant change in autoantibody. In three unresponsive patients, autoantibodies were without change in two and decreased transiently in one patient. We conclude that in ATP the presence of autoantibodies to GPIIb-IIIa and GPIb-IX is related to the activity of the disease. Corticosteroids may inhibit autoantibody formation in some ATP patients, whereas during the early response to IvIgG, autoantibody production may not be affected.
Kringle glycosylation in a modified human tissue plasminogen activator improves functional properties
Authors: Berg DT , Burck PJ , Berg DH , Grinnell BW 
Published: October 2019

Abstract
Native tissue plasminogen activator (ntPA) has a variable glycosylation site on its kringle-2 domain. We have examined the effects of kringle glycosylation on functional properties by studying the simplified tPA molecule, tPA-6. tPA-6 is composed of kringle-2 and the serine protease domains and, like ntPA, cells expressing tPA-6 process it into two glycoforms: the monoglycosylated tPA-6-primary (tPA-6P, type II) with N- linked glycosylation at Asn-448 in the serine protease domain and diglycosylated tPA-6-variant (tPA-6V, type I) with glycosylation at Asn- 448 and at Asn-184 in kringle-2. When the two glycoforms were separated, we found that purified tPA-6V had reduced fibrin-stimulated plasminogenolytic activity toward Glu-plasminogen when compared to purified tPA-6P. However, in the presence of fibrin, tPA-6V unexpectedly exhibited a sixfold increase in selectivity toward Lys- plasminogen. In addition, tPA-6V was less susceptible than tPA-6P to plasmin-mediated conversion to the two-chain form. By site-directed mutagenesis of tPA-6, we eliminated variable glycosylation at Asn-184 and engineered a new glycosylation signal at a remnant site in the kringle. This derivative, designated tPA-6D, was secreted with complete kringle glycosylation. Like the naturally occurring tPA-6V, tPA-6D had lower rates of fibrin-stimulated Glu-plasminogen activation, increased specificity toward Lys-plasminogen, and greater resistance to plasmin digestion. Although the activity of tPA-6D could be stimulated by fibrin, its activity was not stimulated significantly by fibrinogen, and in human plasma the rate of fibrinogen depletion was reduced threefold. Although fibrin binding to kringle-2 of tPA-6D was slightly improved, there was a substantial increase in the dissociation constant (kd) for lysine binding, demonstrating a lack of correlation between these ligand-binding sites. Overall, our data demonstrate the marked effect of kringle glycosylation on functional properties. In addition, we have generated a derivative with properties that potentially improve clot specificity and single-chain half-life and reduce the potential for plasminogen activation in the plasma.
Type II interleukin-1 receptor is not expressed in cultured endothelial cells and is not involved in endothelial cell activation
Authors: Colotta F , Sironi M , Borre A , Pollicino T , Bernasconi S , Boraschi D , Mantovani A 
Published: October 2019

Abstract
Interleukin-1 (IL-1) profoundly affects a number of functions of endothelial cells (EC). It was previously shown that EC express the type I 80-Kd IL-1 receptor (IL-1 RI). In this study we define the expression and functional significance of the type II IL-1R (IL-1 RII) in EC. Human umbilical vein EC did not express appreciable levels of IL- 1 RII mRNA as assessed by Northern analysis or reverse transcription and polymerase chain reaction. Exposure to various cytokines (including IL-4, which augments IL-1 RII in neutrophils) failed to induce IL-1 RII mRNA. The binding of radiolabeled IL-1 beta to EC was blocked by antitype I (M4) but not by antitype II (M22) monoclonal antibodies (MoAbs). MoAbs directed against the IL-1 RI (M1 and M4) inhibited the induction of IL-6 and adhesion molecules in EC by IL-1, whereas an anti- IL-1 RII (M22) was inactive. The human IL-1 receptor antagonist (IL- 1ra) preferentially interacts with IL-1 RI versus IL-1 RII in the mouse. IL-1 ra inhibited the response of mouse endothelial cells to IL- 1. We conclude that EC selectively express the IL-1 RI and that this is involved in the response of this cell type to IL-1.
Cascade transactivation of growth factor receptors in early human hematopoiesis
Authors: Testa U , Pelosi E , Gabbianelli M , Fossati C , Campisi S , Isacchi G , Peschle C 
Published: October 2019

Abstract
Highly purified progenitors (including erythroid [BFU-E], granulo- monocytic [CFU-GM], multipotent [CFU-GEMM] progenitors, as well as multipotent progenitors with self-renewal capacity [CFU-B]) express high-affinity growth factor receptors (GFRs), with prevalent interleukin-3 receptors (IL-3Rs) (2,700/cell), a > or = 10-fold lower number of IL-6Rs (145/cell) and granulocyte-macrophage colony- stimulating factor receptors (GM-CSFRs) (300/cell), and a barely detectable level of erythropoietin (Ep) receptors (75/cell). Hematopoietic growth factor (HGF) dosages inducing peak clonogenetic effects are associated with partial/subtotal occupancy of the homologous HGF receptor (HGFR). Cross-reactivity between GFRs and heterologous GFs (including IL-6, IL-3, GM-CSF, Ep, and the kit ligand [KL]) was explored by competition experiments on purified progenitors with radiolabeled and excess cold HGFs at +4 degrees C. No cross- reaction was observed between IL-6R, IL-3R, EpR, and the heterologous GFs, whereas the GM-CSFR showed cross-reactivity with IL-3 and, to a lesser extent, KL. Modulation of GFRs was examined after 18 or 40 hours of incubation with GF(s) at 37 degrees C, followed by ligand-binding assay at 20 degrees C. IL-6, IL-3, GM-CSF, and Ep induce a marked down- modulation of their own receptors. Interestingly, each GF induces the transactivation of the R(s) for the “distal” GF(s): (1) IL-6 induces transactivation of IL-3R, but not of GM-CSFR/EpR; (2) IL-3 causes a rapid upmodulation of GM-CSFR/EpR (“pure” progenitors treated with IL-3 show upmodulation of GM-CSFR alpha-chain mRNA by reverse transcriptase- polymerase chain reaction); whereas (3) GM-CSF induces the transactivation of the EpR. This chain upmodulation of HGFRs may underlie the synergistic interactions between the HGFs in clonogenetic culture. It is emphasized that KL does not induce upmodulation of the other GFRs. Finally, Ep, GM-CSF, and IL-3 do not modulate the expression of the “proximal” HGFRs (ie, GM-CSFR/IL-3R/IL-6R, IL-3R/IL- 6R, and IL-6R, respectively). These results allow insight into the cellular basis of hematopoiesis, ie, the complex and coordinate interactions between HGFs and their receptors. They are compatible with a model of cascade transactivation via upmodulation of GFRs in the initial key steps of hematopoietic differentiation, whereby the action of each GF enhances the effect of the distal GF(s) by a multistep chain- potentiation mechanism.
Granulocyte colony-stimulating factor induces hFc gamma RI (CD64 antigen)-positive neutrophils via an effect on myeloid precursor cells
Authors: Kerst JM , van de Winkel JG , Evans AH , de Haas M , Slaper-Cortenbach IC , de Wit TP , von dem Borne AE , van der Schoot CE , van Oers RH 
Published: October 2019

Abstract
In this study we have examined hFc gamma RI expression during myelopoiesis. Normal bone marrow (BM) cells were found to express hFc gamma RI up to the metamyelocyte stage. A different Fc gamma RI expression pattern was observed in an in vitro model of myelopoiesis. Purified CD34-positive BM cells, cultured for 12 to 14 days with granulocyte colony-stimulating factor (G-CSF), differentiate into a population of mature granulocytic cells. In these cultures, in which hFc gamma RI was virtually absent on the initial CD34-positive BM cells, hFc gamma RI was strongly induced by G-CSF after only 5 days. During final maturation the cells remained hFc gamma RI positive. This expression was confirmed functionally by antibody-sensitized erythrocytes (EA)-rosette assays. Moreover, the mature myeloid cells were found to express mRNA encoding for hFc gamma RI, whereas reverse- transcriptase polymerase chain reaction analysis showed that both hFc gamma RIA and hFc gamma RIB genes were expressed. In contrast, on peripheral blood (PB) polymorphonuclear neutrophil leukocytes (PMN) the in vitro effect of G-CSF as to hFc gamma RI induction was limited. Therefore, we conclude that, with respect to hFc gamma RI expression on PMN, G-CSF acts on myeloid precursor cells rather than on mature cells. This conclusion could be strengthened by in vivo administration of a single dose of G-CSF to a healthy volunteer. After a 12-hour lag time, hFc gamma RI expressing PMNs were detected in the peripheral blood. This study shows that hFc gamma RI is an early myeloid differentiation marker that is lost during normal final maturation. However, committed myeloid progenitor cells can be strongly induced by G-CSF to express hFc gamma RI, ultimately resulting in mature granulocytic cells expressing the high-affinity receptor for IgG. This expression may have important consequences for the functional capacity of these cells.
Preclinical analysis of cytokine therapy in the SCID-hu mouse
Authors: Kyoizumi S , Murray LJ , Namikawa R 
Published: October 2019

Abstract
A severe combined immunodeficient (SCID)-hu mouse model implanted with human fetal bone was used to assess the effects of various recombinant human (rh) hematopoietic growth factors, administered either alone or in combination, on human hematopoiesis in vivo. Treatment with rh granulocyte colony-stimulating factor (G-CSF) elicited the expansion of mature neutrophilic granulocyte populations in human marrow. Administration of rh interleukin-3 (IL-3) induced significant increases of eosinophilic granulocyte and burst-forming unit, erythrocyte (BFU-E) activity. The rhIL-6 did not cause significant changes in the subpopulations of human hematopoietic cells within the grafts, but did increase the number of colony-forming unit, granulocyte-macrophage and BFU-E. Pretreatment with rhIL-3 followed by rh erythropoietin (Epo) administration enhanced Epo-induced human erythropoiesis significantly. No synergistic effects on myelopoiesis were observed using sequential treatment with rhIL-3 followed by rhG-CSF. Instead, these factors seemed to work independently, with rhG-CSF increasing the percentage of neutrophils and rhIL-3 increasing the percentage of eosinophils. When administered simultaneously with rhEpo, rhIL-6 showed dose-dependent inhibitory effects on in vivo Epo-induced human erythropoiesis. The rhIL-6 also caused a reduction in the percentage of human neutrophils induced by rhG-CSF. These results suggest that the SCID-hu mouse provides a useful small animal model to assess the in vivo effects of hematopoietic growth factors on human hematopoiesis.
Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia
Authors: Fibach E , Burke LP , Schechter AN , Noguchi CT , Rodgers GP 
Published: October 2019

Abstract
Hydroxyurea (HU), an inhibitor of DNA synthesis, has been shown to increase fetal hemoglobin (HbF) levels in patients with sickle cell anemia and in some patients with beta-thalassemia. However, until now there have not been good in vitro model systems that simulate this effect for study of the molecular and cellular mechanism(s) involved in perturbing the normal ontogeny of the globin genes. We analyzed the cellular effects of HU using a two-phase liquid culture procedure (Fibach et al: Blood 73:100, 1989) in which human peripheral blood- derived progenitor cells undergo proliferation and differentiation. HU was found to have multiple effects on these cultured cells: (1) an increase in the proportion of HbF produced; (2) a decrease in cell number due to inhibition of cell proliferation; (3) an increase in hemoglobin content per cell (mean corpuscular hemoglobin [MCH]); and (4) an increase in cell size (mean corpuscular volume). The extent of these effects was related to the HU dose and time of addition. When added to cell cultures from normal individuals, 4 days following their exposure to erythropoietin (EPO), 100 mumol/L HU caused a 1.3- to 3.5- fold increase in the proportion of HbF, from 0.4% to 5.2% (mean 1.6) in untreated to 1.5% to 8.2% (mean 3.1) in HU-treated cultures and a 45% +/- 10% increase in MCH but only a 25% +/- 7% decrease in cell number on day 13. Cultures of cells derived from five patients with sickle cell anemia have shown a twofold to fivefold increase in the percentage of Hb F following addition of HU while four patients with beta- thalassemia showed a 1.3- to 6.2-fold increase. We believe that this primary cell culture procedure should prove useful in studying the cellular and molecular mechanisms of pharmacologic induction of HbF and might provide a valuable predictive assay system for evaluation of the response of individual patients with hemoglobinopathies to HU and similar agents.
Combination treatment of 2-chlorodeoxyadenosine and type I interferon on hairy cell leukemia-like cells: cytotoxic effect and MHC- unrestricted killer cell regulation
Authors: Reiter Z , Tomson S , Ozes ON , Taylor MW 
Published: October 2019

Abstract
Hairy cell leukemia (HCL) is a lymphoproliferative disorder of B lymphocytes. Interferons (IFNs), especially of the alpha (alpha) subtype, have shown a significant antitumor effect in HCL patients. However, the therapeutic effect of IFN-alpha is still rather limited. The purine analogue 2-chlorodeoxy-adenosine (2-CdA) was reported recently to be an effective agent in the treatment of HCL. In the present study, we find that the HCL cell lines HS-1 and HS-2 as well as Eskol and its IFN-resistant clone (IREs-4) are sensitive to the cytotoxic activity of 2-CdA. Combination treatment of IFN-Con1 and 2- CdA results in a synergistic effect at low doses but an additive inhibitory effect at higher concentrations. IREs-4 cells responded only to 2-CdA treatment. All the HCL cell lines are resistant to natural killer (NK) cell-mediated cytotoxicity (CMC) but are relatively sensitive to IFN-Con1-primed or interleukin-2 (IL-2)-primed NK-CMC activities. No inhibition in killing ability was measured when only the effector cells (NK) were treated with 2-CdA. Pretreatment of the HCL target cells with 2-CdA increases their susceptibility to NK-CMC. Pretreatment with IFN-Con1 can reduce the susceptibility of target cells to NK-CMC in HS-1, HS-2, and Eskol cells but not in the IFN- resistant clone IREs-4. 2-CdA abolished this IFN-induced protection against NK-CMC. Normal fibroblasts only responded to treatment with relatively high doses of 2-CdA, and only a moderate additive cell growth inhibitory effect was seen in combination of 2-CdA with IFN- Con1. Only high doses of 2-CdA increased the susceptibility of fibroblast culture to NK-CMC. Thus, combination of IFN-Con1 and 2-CdA results in an in vitro enhancement of the direct antiproliferative/cytotoxic activity of each treatment alone and increases the efficacy of the NK activity against the HCL cell lines.
Pre-CFU-S quiescence and stem cell exhaustion after cytostatic drug treatment: protective effects of the inhibitory peptide pGlu-Glu-Asp- Cys-Lys (pEEDCK)
Authors: Paukovits WR , Moser MH , Paukovits JB 
Published: October 2019

Abstract
Pre--CFU-S are characterized by their ability to generate spleen colony- forming cells (CFU-S) and by their ability to repopulate the hematopoietic system after damage. We have investigated their response to three consecutive injections of cytosine arabinoside (ara-C), given at t = 0, 12, and 20 hours. Nine hours after treatment, the number of CFU-S and pre--CFU-S was reduced to 10% or 30%, respectively. No pre-- CFU-S were in S-phase at this time, indicating that the pre--CFU-S losses were not caused by direct drug killing. Up to 1 year after treatment, pre--CFU-S were still depleted to 10% of normal, indicating that their proliferative quiescence was permanent. We have previously shown that inhibition of CFU-S recruitment with pGlu-Glu-Asp-Cys-Lys (pEEDCK) makes them ara-C resistant and prevents their decimation. We now found that this also prevented the excessive drainage of the pre-- CFU-S pool, suggesting that pre--CFU-S allocation into active hematopoiesis is triggered by the CFU-S deficit. pEEDCK may thus be applicable as a protector of the hematopoietic repopulation potential against cytostatic drug-induced aplasia. Postchemotherapeutic stimulator treatment with (pEEDCK)2-dimer did not ameliorate pre--CFU-S losses. Long-term culture-initiating cells (LTC-ICs) showed a similar pattern of irreversible reduction after cytostatic drug treatment, which could be prevented by pEEDCK. Our results suggest, that certain subclasses of hematopoietic stem cells (pre--CFU-S) are permanently quiescent and exhaustible and that the capacity for self-renewal is not a necessary property of all stem cell-like cells.