bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant human granulocyte colony-stimulating factor as an activator of human granulocytes: potentiation of responses triggered by receptor- mediated agonists and stimulation of C3bi receptor expression and adherence
Authors: Yuo A , Kitagawa S , Ohsaka A , Ohta M , Miyazono K , Okabe T , Urabe A , Saito M , Takaku F 
Published: October 2019

Abstract
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) enhanced superoxide release and membrane depolarization in parallel in human granulocytes stimulated by the receptor-mediated agonists, N- formyl-methionyl-leucyl-phenylalanine and wheat germ agglutinin, but not by the Ca2+ ionophore ionomycin and phorbol myristate acetate, which bypass the receptors to stimulate the cells. The optimal effect was obtained by pretreatment of cells with 25 to 50 ng/mL (1.3 to 2.6 nmol/L) rhG-CSF for 10 minutes at 37 degrees C. rhG-CSF produced by bacteria and mammalian cells had identical biological effects on a molar basis. rhG-CSF neither affected stimulus-induced increase in cytoplasmic free Ca2+ nor changed the number and affinity of N-formyl- methionyl-leucyl-phenylalanine receptors. The priming effect of rhG-CSF was temperature dependent and did not require new protein synthesis. rhG-CSF increased the expression of C3bi receptors on human granulocytes and enhanced granulocyte adherence to nylon fiber. The optimal effect was obtained by pretreatment of cells with 25 to 50 ng/mL rhG-CSF for 30 minutes at 37 degrees C. rhG-CSF had no effect on human monocytes. These findings demonstrate that rhG-CSF can selectively stimulate mature granulocyte functions.
Defective monocyte-to-macrophage maturation in patients with aplastic anemia
Authors: Andreesen R , Brugger W , Thomssen C , Rehm A , Speck B , Lohr GW 
Published: October 2019

Abstract
Macrophages (MAC) are important effector cells of the immune system but also play an essential role as regulatory cells in hematopoiesis. They originate from circulating monocytes (MO) as immature precursor cells that undergo terminal differentiation upon migration from the capillary bed into the various tissues. In the presence of serum, MAC maturation from blood MO is observed in vitro and can be followed by the expression of maturation-associated antigens (MAX.1, .3, .11, and .26; transferrin receptor, 13C2, CD16). We have tested blood MO from 22 patients with aplastic anemia (AA) for their capacity to undergo terminal maturation in vitro. After isolation, blood MO in six patients expressed CD14 molecules at low density when compared to normals. On culture for 7 days, in 15 patients various abnormalities could be shown by phenotype analysis using cell-enzyme-linked immunosorbent assay (ELISA) and an immunoperoxidase staining technique of single cells. Abnormalities ranged from the distinctive failure of mature MAC to express single surface antigens (eg, gp64-MAX.1) to complete inhibition of the development of a MAC maturation-associated phenotype. In three patients the maturational defect was found to persist in complete remission after successful therapy with antileukocyte globulin (ALG). Neither in other immunosuppressed or multiple-transfused patients nor in those with bone marrow hypoplasia secondary to cancer chemotherapy and during hematologic reconstitution following autologous bone marrow transplantation (BMT), defective MO maturation in vitro was seen. Our data provide evidence for the existence of serious disorders within the MO-MAC lineage in patients with AA. This observation may either reflect the stem-cell defect or indicate a MAC involvement in the pathogenesis of the disease.
Lymphotoxin: stimulation and regulation of colony-stimulating factors in fibroblasts
Authors: Akashi M , Saito M , Koeffler HP 
Published: October 2019

Abstract
Colony-stimulating factors (CSFs) are pivotal for proliferation and function of hematopoietic cells. We found that lymphotoxin, a product of activated lymphocytes, stimulates accumulation of granulocyte- macrophage (GM)-CSF and macrophage (M)-CSF proteins and mRNAs in fibroblasts. An increase in GM- and M-CSF mRNA levels occurred within 2 hours after addition of 1,000 U/mL lymphotoxin and levels plateaued over the next 24 hours. Tumor necrosis factor alpha (TNF alpha) was about five times more potent than lymphotoxin at low concentrations, and was nearly 1.5 to to 2 times more potent at maximally stimulating concentrations of the cytokines. Stimulation by lymphotoxin did not require either new protein synthesis or protein kinase-C stimulation. Stability studies of GM- and M-CSF transcripts in fibroblasts showed that M-CSF mRNA was five times more stable (half-life [t 1/2], 100 minutes) than GM-CSF mRNA (t 1/2, 20 minutes). Stability of these mRNAs was unchanged after stimulation of the cells with lymphotoxin. In addition, exposure of cells to 12-O-tetradecanoylphorbol 13-acetate did not alter stability of M-CSF mRNA but markedly prolonged the stability of GM-CSF mRNA. This is consistent with data showing that the AT-rich consensus region in the 3′ untranslated region of many transiently expressed cytokines including GM-CSF but not M-CSF, play a major role in their mRNA stability. Our results suggest that activated lymphocytes can affect hematopoietic cell function and growth by stimulating production of CSFs by mesenchymal cells.
A role for protein kinase C in the membrane fusion necessary for platelet granule secretion
Authors: Gerrard JM , Beattie LL , Park J , Israels SJ , McNicol A , Lint D , Cragoe EJ 
Published: October 2019

Abstract
The addition of 1-oleoyl-2-acetylglycerol (OAG), or phorbol-12- myristate-13-acetate (PMA) to platelets induced the phosphorylation of a 47,000 dalton protein (47 Kd), fusion of granule membranes with membranes of the surface connected canalicular system, the formation of large vesicles and the secretion of serotonin. 1-(5- isoquinolinesulfonyl)-2-methyl-piperazine (H7), and sphingosine, inhibitors of protein kinase C, significantly inhibited the ultrastructural changes and the phosphorylation of 47 Kd. N-(2- guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), structurally similar to H7, but a weaker inhibitor of protein kinase C, did not attenuate these responses to OAG or to PMA. H7, but not HA1004, also markedly inhibited secretion induced by the synergistic combination of OAG and the calcium ionophore A23187. Amiloride and 5-(N,N dimethyl)- amiloride, inhibitors of the Na+/H+ transporter, did not inhibit the ultrastructural response and the protein phosphorylation induced by OAG, or the secretion induced by the combination of A23187 and OAG. The results link the activation of protein kinase C by diglycerides to the labilization and fusion of granule membranes important for secretion.
Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant
Authors: Marciniak E , Romond EH 
Published: October 2019

Abstract
Lupus anticoagulant (LA), an antibody against anionic phospholipid with anticoagulant laboratory manifestations, is paradoxically associated with a high incidence of thrombosis. In the present study we analyzed the phospholipid- and platelet-dependent degradation of factor Va following clotting in plasma from 15 consecutive patients with LA to provide evidence for a distinct procoagulant effect of the antibody. After clotting with 25 micrograms phospholipid/mL, all samples containing LA showed markedly decreased rates of factor Va degradation (k = 0.01 to 0.14 min-1 v 0.27 to 0.35 min-1 in controls). Also with higher phospholipid concentrations (up to 100 micrograms/mL), as well as in the presence of platelets (5 to 33 x 10(7)/mL), significantly less of the procoagulant activity disappeared per unit of time in samples with LA than in controls. Plasma with LA was to a variable extent capable of decreasing or abolishing factor Va inhibition in normal plasma. Most importantly, exogenous activated protein C failed to correct the ineffective factor Va destruction despite adequate protein S levels. These data suggest that LA prevents the formation of the complex essential for rapid proteolysis of factor Va both on phospholipid and on the platelet membrane, thereby compromising the catalytic function of activated protein C. Our findings offer a new opportunity for a more comprehensive evaluation of patients with antiphospholipid antibody in defining the pathogenesis of thrombosis in this clinical condition.
Cell-type-specific cytotoxicity of anti-CD4 and anti-CD8 ricin immunotoxins against human alloreactive T-cell clones
Authors: Uckun FM , Myers DE , Ledbetter JA , Wee SL , Vallera DA 
Published: October 2019

Abstract
Potent T-cell subset-directed immunotoxins (ITs) were generated by conjugating the anti-CD4 monoclonal antibody (MoAb) G17–2 and the anti- CD8 MoAb G10.1 to the ribosome-inhibitory protein, ricin. The cell-type- specific cytotoxicities of the generated ITs were evaluated at the clonal level using human alloreactive T-cell clones. The kinetics of anti-CD4 ricin-induced inactivation of protein synthesis in target CD4+ cloned T-cells was first order with no detectable lag period and a maximum rate of 0.07 logs per hour (t10 = 13.6 hours; first-order rate constant/K = 0.17 hr-1). The alloantigen specific lytic function of the CD4+ cytolytic T-cell clone JMAC28 was acutely sensitive to anti-CD4 ricin, and no residual lytic activity against allogeneic targets was detectable 24 hours after treatment with as little as 0.5 mmol/L anti- CD4 ricin. Notably, both anti-CD4 ricin and anti-CD8 ricin elicited a selective and dose-dependent inhibition of clonal proliferation of target T-cell clones with a maximum kill of greater than 3 logs at 5 nmol/L. No significant “bystander effects” were observed for non-target cells. Bone marrow progenitor cells CFU-GM, BFU-E, and CFU-GEMM were only minimally affected by either IT. We conclude that these ITs show considerable potential for effective depletion of T-cell subpopulations from allogeneic donor marrow grafts for clinical graft-versus-host disease (GVHD) prophylaxis.
T-lymphoblastic lymphomas expressing the non-disulfide-linked form of the T-cell receptor gamma/delta: characterization with monoclonal antibodies and genotypic analysis
Authors: Falini B , Flenghi L , Fagioli M , Martelli MF , Pileri S , Grignani F , Beltrami A , Novero D , Pelicci PG 
Published: October 2019

Abstract
Three cases of T-lymphoblastic lymphomas (T-LL) expressing the T cell antigen receptor gamma delta (TCR gamma delta) are reported. All of them were CD3+/beta F1-/TCR delta 1+. Moreover, neoplastic cells reacted with the delta TCS1 monoclonal antibody (MoAb) which binds to the non-disulfide-linked form of the TCR gamma delta, but not with the BB3 MoAb which recognizes the disulfide-linked form of the TCR gamma delta. All cases showed a stage II cortical phenotype, eg, TdT+/CD1+/CD3+/CD5+/CD7+; two of them coexpressed CD4/CD8, while the other was CD4+/CD8-. Two cases were positive for CALLA and CD25. Immunogenotypic analysis showed evidence of T beta and C gamma 2 gene rearrangements in all three cases and immunoglobulin (Ig) gene rearrangements in two cases. Two patients presented with an anterior mediastinal mass and the third with a solitary inguinal lymphadenopathy. We suggest that these cases of TCR gamma delta+ T-LL may be derived from the small population (approximately 0.5%) of CD3+ cortical thymocytes which, in the normal human thymus, express the delta TCS1-reactive, non-disulfide-linked form of the TCR gamma delta.
Mutations of the ras protooncogenes in chronic myelogenous leukemia: a high frequency of ras mutations in bcr/abl rearrangement-negative chronic myelogenous leukemia
Authors: Cogswell PC , Morgan R , Dunn M , Neubauer A , Nelson P , Poland-Johnston NK , Sandberg AA , Liu E 
Published: October 2019

Abstract
Seventy cases of chronic myelogenous leukemia (CML) were analyzed for the presence of ras mutations using polymerase chain reaction (PCR), oligonucleotide hybridization, and direct PCR sequencing. All cases had preceding cytogenetic and bcr rearrangement studies. Aberrant ras genes were detected in none of 39 patients with Philadelphia (Ph) chromosome or bcr/abl rearrangement positive chronic-phase CML and in only 1 of 18 patients in blast crisis, suggesting that ras mutations have little or no role in initiation or progression of common CML. Seven of 13, or 54% of patients with bcr/abl rearrangement negative chronic phase CML (atypical CML) harbored mutations in ras, however. This high incidence of ras mutations, together with the absence of bcr/abl rearrangement, provides evidence that atypical CML is an entity that is molecularly distinct from common CML. Moreover, the clinical characteristics and the high frequency of ras mutations suggest that atypical CML may constitute a subset of the myelodysplastic syndrome and may be best classified as a variant of chronic myelomonocytic leukemia (CMML).
In vivo activation of human neutrophil functions by administration of recombinant human granulocyte colony-stimulating factor in patients with malignant lymphoma
Authors: Ohsaka A , Kitagawa S , Sakamoto S , Miura Y , Takanashi N , Takaku F , Saito M 
Published: October 2019

Abstract
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered (50 to 800 micrograms/m2) once daily as a half-hour intravenous (IV) infusion for 14 days to seven patients with malignant lymphoma. In all patients, administration of rhG-CSF not only ameliorated the decrease in absolute neutrophil count after the cytotoxic chemotherapy but also enhanced superoxide (O2-) release in neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP). The priming effect of rhG-CSF on neutrophil O2- release was rapid (evident within 6.5 hours) and sustained at least for 24 hours after a single IV administration of rhG-CSF. The responsiveness to further in vitro challenge of rhG-CSF was lost or reduced in neutrophils isolated after rhG-CSF treatment, indicating that neutrophils already primed in vivo by rhG-CSF are desensitized to this factor. In contrast to the results obtained with FMLP, when phorbol myristate acetate (PMA) was used as stimulus, no consistent enhancement of O2- release was observed, suggesting that rhG-CSF modulates the signal transduction pathways linked to FMLP receptors rather than increases the components of the O2- producing enzyme complexes. Administration of rhG-CSF also rapidly (evident within 15 minutes) caused an increase in expression of neutrophil C3bi-receptors that was sustained for at least 24 hours after a single IV administration of rhG- CSF. Pharmacokinetic study of rhG-CSF showed a half-life (t1/2) of 114 min. These findings show that rhG-CSF is a potent activator for neutrophil functions both in vivo and in vitro.
Recurrent acute splenic sequestration crisis due to interacting genetic defects: hemoglobin SC disease and hereditary spherocytosis
Authors: Warkentin TE , Barr RD , Ali MA , Mohandas N 
Published: October 2019

Abstract
A 14-year-old boy with hemoglobin SC disease and alpha-thalassemia-2 experienced five episodes of acute splenic sequestration crisis (ASSC), while two of his siblings with identical globin genotypes (SC and - alpha/alpha alpha) had no such experience. To determine if an additional red blood cell (RBC) defect was responsible for the unusual occurrence of frequent ASSCs, we performed detailed rheologic characterization and membrane protein analysis on RBCs from the proband and other members of his family. Reduced surface area, increased mechanical instability, and decreased spectrin content of the membrane, distinguishing features of RBCs in hereditary spherocytosis, were observed in cells from the proband and his mother, but not in cells from other family members. These findings are consistent with the dominant inheritance of spherocytosis by the proband. We suggest that the combined effects of SC disease and spherocytosis in the proband resulted in decreased RBC deformability and led to increased splenic trapping, intrasplenic sickling, and consequently, recurrent sequestration crisis. Marked clinical and hematologic improvement occurred from splenectomy. Thus, inheritance of interacting genetic defects, sickling hemoglobinopathy, and hereditary spherocytosis appear to be responsible for the unusual clinical manifestation of recurrent ASSC in this patient.
Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia
Authors: Beutler E , Moroose R , Kramer L , Gelbart T , Forman L 
Published: October 2019

Abstract
gamma-Glutamylcysteine synthetase is one of the enzymes of glutathione (GSH) synthesis. A deficiency of this enzyme has been found only once previously in humans: it was associated with spinocerebellar degeneration and hemolytic anemia. We report the case of a woman, daughter of fifth cousins, who was gamma-glutamylcysteine-synthetase- deficient. Modest decreases in the amount of GSH in cultured lymphoblasts and fibroblasts could be documented. The amount of residual enzyme was insufficient to permit detailed studies of the characteristics of the mutant enzymes, but no major abnormality in its Km for cysteine and glutamic acid or in its heat stability were found. In contrast to the earlier report, the only manifestation of the enzyme deficiency was hemolytic anemia. This leads us to conclude that either the occurrence of neurologic symptoms in the other reported family was a chance association or that the clinical expression of this rare defect is pleomorphic.
Pure red cell aplasia of long duration complicating major ABO- incompatible bone marrow transplantation [see comments]
Authors: Gmur JP , Burger J , Schaffner A , Neftel K , Oelz O , Frey D , Metaxas M 
Published: October 2019

Abstract
In 3 of 15 consecutive patients receiving a human leukocyte antigen (HLA)-identical but major ABO incompatible bone marrow transplant (BMT), pure red cell aplasia (PRA) lasting 5 to 8 months was observed. Titers of the incompatible anti-A agglutinin before infusion of the red blood cell (RBC)-depleted BMT was very high in one, and in the usual range in two patients. Decrease of agglutinin titers during the first 4 weeks after BMT were comparable between PRA patients and those of ABO- incompatible BMT recipients with timely RBC recovery. However, in PRA patients, agglutinin titers rose again and remained elevated for 19 to 28 weeks. RBC engraftment and reticulocyte recovery ultimately occurred spontaneously and coincided with the decrease of agglutinin titers below 16. These observations indicate that PRA is antibody-dependent in this setting. Furthermore, it is conceivable that cyclosporine facilitates recipient-derived antibody synthesis after major ABO- incompatible BMT.
Acute and subacute hematologic effects of multi-colony stimulating factor in combination with granulocyte colony-stimulating factor in vivo
Authors: Ulich TR , del Castillo J , McNiece IK , Yin SM , Irwin B , Busser K , Guo KZ 
Published: October 2019

Abstract
Multi-colony stimulating factor (Multi-CSF, interleukin-3, IL-3) and granulocyte-CSF (G-CSF) administered concurrently as an intravenous (IV) injection induce a peripheral neutrophilia that is approximately additive in comparison with the neutrophilia induced by IL-3 and G-CSF individually. The bone marrow (BM) at 12 hours is depleted of mature neutrophils and shows a left-shifted myeloid hyperplasia, consistent with the neutrophil-releasing and myeloproliferative activities of both IL-3 and G-CSF individually. The BM at 24 hours shows a replenished reserve of mature neutrophils and a synergistic left-shifted myeloid hyperplasia as compared with IL-3 and G-CSF alone. Daily IV injections of IL-3 plus G-CSF for 1 week also induce an approximately additive daily peripheral neutrophilia. The BM after a week's administration of IL-3 plus G-CSF shows a generalized myeloid hyperplasia with a synergistic increase in mature neutrophils as compared with IL-3 or G- CSF alone. Daily injection of IL-3 plus G-CSF induced a significant decrease in erythroid, lymphoid, and eosinophilic marrow precursors, possibly owing to a myelophthisic effect of the myeloid hyperplasia and despite the fact that IL-3 alone induced a significant erythroid hyperplasia.
Proliferation of early human myeloid precursors induced by interleukin- 1 and recombinant soluble CD23
Authors: Mossalayi MD , Arock M , Bertho JM , Blanc C , Dalloul AH , Hofstetter H , Sarfati M , Delespesse G , Debre P 
Published: October 2019

Abstract
Low affinity Fc epsilon receptors (Fc epsilon RII/CD23) or their soluble fragments have various biologic effects on B- and T-cell lineages. In this study, we have assessed the effect of recombinant soluble CD23 (rsCD23) on the proliferation of human bone marrow (BM)- derived myeloid precursors with or without recombinant interleukin-1 (rIL-1) addition. Non-adherent CD2- or CD34+ BM cell subsets were used as target cells. Our results show that rsCD23 in synergy with rIL-1 displays an interleukin-3-like activity as it promotes the proliferation of multipotential marrow precursors. This effect was abolished by anti-CD23 addition to these cultures, but was not affected by anti-IL-3 monoclonal antibody. Furthermore, sequential study indicates that rIL-1 induces bone marrow cell responsiveness to rsCD23.
Characterization of two types of fetal hemoglobin: alpha 2G gamma 2 and alpha 2A gamma 2
Authors: Adachi K , Kim J , Asakura T , Schwartz E 
Published: October 2019

Abstract
The effect of differences in G gamma and A gamma fractions of fetal hemoglobin (HbF) on the kinetics of polymerization of HbS-HbF mixtures was studied. We also examined their effect on oxygen affinity, surface hydrophobicity, mechanical stability, and solubility of HbF. Differences in G gamma:A gamma ratio did not affect the polymerization of mixtures of HbF and HbS, suggesting that the inhibitory effect of HbF on the polymerization of HbS is independent of the G gamma:A gamma ratio of HbF and is totally dependent on the fraction of HbF in the mixture. The oxygen equilibrium curve of HbF was not affected by differences in the ratios of G gamma and A gamma in HbF. In contrast, surface hydrophobicity, mechanical stability, and solubility of HbF were affected by differences in the G gamma:A gamma ratio. The higher the G gamma:A gamma ratio, the smaller the elution volume on a TSK Gel SW hydrophobic column in high phosphate buffer. The mechanical stability of HbF was also dependent on the ratio of G gamma:A gamma; stability was greater at higher fractions of A gamma. Differences in the G gamma:A gamma ratio also affected solubility of HbF: HbF containing the higher fraction of G gamma was the more soluble. These data indicate that although alanine at the 136th position of the gamma chains has a stronger surface hydrophobicity than does glycine, this difference does not affect either the polymerization of HbS or the oxygen affinity of HbF.