bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-Idiotype Antibodies Can Induce Long-Term Complete Remissions in Non-Hodgkin’s Lymphoma Without Eradicating the Malignant Clone
Authors: Davis Thomas A. , Maloney David G. , Czerwinski Debra K. , Liles Tina-Marie , Levy Ronald 
Published: October 2019

AbstractThe immunoglobulin on the surface of B-cell lymphomas can be a tumor-specific target for monoclonal antibody therapy. Between 1981 and 1993, 45 individuals with low grade B-cell lymphoma were treated with 52 courses of custom-made anti-idiotype antibodies. The antibodies were used either alone or in combination with -interferon, chlorambucil, or interleukin-2 (IL-2). The majority of these patients responded to treatment, with a 66% overall and 18% complete response rate. Six patients (13%) experienced prolonged complete remissions, five of which are ongoing from 4 to 10 years after therapy and are the subject of this report. We asked whether residual lymphoma could be found in these patients with prolonged remissions. We performed enzyme-linked immunosorbent assay (ELISA) assays for idiotype protein or anti-idiotype antibodies in serum. Blood and bone marrow samples were examined by flow cytometry for idiotype positive cells, and by polymerase chain reaction (PCR) for clonal gene rearrangements of immunoglobulin CDR3 sequences or t(14;18) translocations. Using these sensitive and specific tests it was possible to detect very low levels of residual lymphoma in five of these patients who had been in clinical remission for 3 to 8 years before this evaluation. These five have continued without recurrence for up to 3 years since. Thus, we have found a pattern of residual inactive disease in patients treated with anti-idiotype antibodies. The biology of follicular lymphoma evidently includes the potential for tumor dormancy after therapies with varied mechanisms of action, resulting in clinical inactivity for many years. Thus, long-term control of the disease is possible at a clinical level despite persistence of the malignant clone.© 1998 by The American Society of Hematology.
Expression of Protein Kinase C Isozymes in Human Basophils: Regulation by Physiological and Nonphysiological Stimuli
Authors: Miura Katsushi , Jr Donald W. MacGlashan 
Published: October 2019

AbstractThe expression of protein kinase C (PKC) isozymes in human basophils and the regulation of PKC isozymes during basophil activation by phorbol 12-myristate 13-acetate (PMA) ± ionomycin, f-met-leu-phe (FMLP), and anti-IgE antibody were examined. In human basophils (&gt; 98% purity), PKCβΙ, βΙΙ, δ, and  were expressed, PKC was difficult to detect, and PKCγ and η were undetectable. In unstimulated basophils, PKCβI and βII were found primarily in the cytosol fraction (95% ± 3% of total and 98% ± 1%, respectively). Within 5 minutes of stimulation with PMA (100 ng/mL), both PKCβI and βII were translocated to the membrane fraction (85% ± 4% and 83% ± 6%, respectively). In resting cells, 48% ± 3% and 61% ± 10% of PKCδ and , respectively, existed in the membrane fraction. Within 1 minute of stimulation with PMA, 90% ± 6% of PKC was found in the membrane fraction, however, no translocation of PKCδ was apparent. Stimulation with FMLP caused modest translocation (≈20%) of all PKC isozymes by 1 minute, whereas stimulation with anti-IgE antibody led to no detectable changes in PKC location throughout a 15-minute period of measurement. However, concentrations of PMA and ionomycin that alone caused no PKC translocation and little histamine release, together caused significant histamine release but no apparent PKC translocation. Studies with bis-indolylmaleimide analogs showed inhibition of PMA-induced, but not anti–IgE-induced, histamine release. These pharmacological studies suggest that PKC does not play a prodegranulatory role in human basophil IgE-mediated secretion.© 1998 by The American Society of Hematology.
The Distal Cytoplasmic Domain of the Erythropoietin Receptor Induces Granulocytic Differentiation in 32D Cells
Authors: Harris Kevin W. , Hu Xian-Jue , Schultz Suzanne , Arcasoy Murat O. , Forget Bernard G. , Clare Nanette 
Published: October 2019

AbstractThe role of hematopoietic growth factors in lineage commitment and differentiation is unclear. We present evidence that heterologous expression of an erythroid specific receptor allows granulocytic differentiation of a myeloid cell line. We have previously characterized a truncation mutant of the erythropoietin receptor (EpoR), which is associated with familial erythrocytosis (Blood89:4628, 1997). This truncated EpoR lacks the distal 70 amino acids of the cytoplasmic domain. To study the functional role of this distal receptor domain, 32D cells, a murine interleukin-3 (IL-3)–dependent myeloid line, were transfected with the wild-type EpoR (32D/EpoR WT) or the truncated EpoR (32D/EpoR FE). 32D cells expressing either the full-length or truncated EpoR display equivalent proliferative rates in saturating concentrations of Epo. There is a dramatic difference in maturational phenotype between the two cell lines, however. The 32D/EpoR FE cells and mock transfected 32D cells have an immature, monoblastic morphology and do not express the primary granule protein myeloperoxidase. The 32D/EpoR WT cells, on the other hand, demonstrate granulocytic differentiation with profuse granulation, mature, clumped chromatin, and myeloperoxidase expression. There is no evidence of erythroid differentiation in 32D cells transfected with either the full-length or truncated EpoR. Treatment of the cells with the specific Jak2 inhibitor tyrphostin AG 490 inhibits myeloid differentiation driven by the distal EpoR. We conclude that: (1) the distal cytoplasmic domain of the EpoR is able to induce a specific myeloid differentiation signal distinct from mitogenic signaling, and (2) these data extend to myelopoiesis the growing body of evidence that the cellular milieu, not the specific cytokine receptor, determines the specificity of differentiation after cytokine receptor activation.© 1998 by The American Society of Hematology.
Thrombin-Activated Human Endothelial Cells Support Monocyte Adhesion In Vitro Following Expression of Intercellular Adhesion Molecule-1 (ICAM-1; CD54) and Vascular Cell Adhesion Molecule-1 (VCAM-1; CD106)
Authors: Kaplanski Gilles , Marin Valérie , Fabrigoule Martine , Boulay Vera , Benoliel Anne-Marie , Bongrand Pierre , Kaplanski Solange , Farnarier Catherine 
Published: October 2019

AbstractThrombin, a central molecule in coagulation, is also involved in inflammation. Notably, thrombin induces endothelial neutrophil adhesion, P- and E-selectin expression, and chemokine production. We show here that thrombin induces expression of intercellular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106) on human umbilical vein endothelial cells (HUVECs) associated with increased adhesion of monocytes. Thrombin increased mRNA steady-state levels and expression of ICAM-1 over 24 hours. Thrombin-induced VCAM-1 expression exhibited unusual kinetics, reaching maximum levels after 6 to 12 hours, but decreasing to near baseline after 24 hours. Thrombin activity on HUVECs was mediated through interaction with its specific receptor, because ICAM-1 and VCAM-1 expression were similarly induced by the 14-amino acid thrombin receptor-activating peptide. Thrombin-induced ICAM-1 and VCAM-1 expression was significantly inhibited by hirudin, but not by interleukin-1 receptor antagonist or anti-tumor necrosis factor  monoclonal antibody (MoAb). Thrombin-activated HUVECs significantly increased greater numbers of adhering THP-1 macrophagic cells, peripheral blood mononuclear cells, or purified monocytes than unstimulated HUVECs. This adhesion was inhibited by anti-CD18 and anti-CD49d MoAb, demonstrating that thrombin-induced ICAM-1 and VCAM-1 were functional. These results show that, in addition to selectins, thrombin directly induces a cytokine-independent expression of adhesion molecules of the Ig superfamily on HUVECs that may support firm leukocyte attachment during inflammation.© 1998 by The American Society of Hematology.
Outside-In Signaling of Soluble and Solid-Phase Fibrinogen Through Integrin ΙΙbβ3 Is Different and Cooperative With Each Other in a Megakaryoblastic Leukemia Cell Line, CMK
Authors: Tohyama Yumi , Tohyama Kaoru , Tsubokawa Misao , Asahi Momoyo , Yoshida Yataro , Yamamura Hirohei 
Published: October 2019

AbstractThe function and the outside-in signaling pathways of IIbβ3 were examined in relation to cell adhesion using a megakaryoblastic leukemia cell line, CMK. After 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, the cells adhered to the culture plate and underwent megakaryocytic differentiation with expression of IIbβ3. Binding of soluble fibrinogen to the cells via IIbβ3 was dependent on cell adhesion. Cell detaching reduced the affinity of this integrin for soluble fibrinogen, although its surface expression was almost unchanged. In contrast, detached cells became tightly adherent to the fibrinogen-coated plate (solid-phase fibrinogen). The same ligand, fibrinogen, present either in soluble or solid-phase form, triggered differential signaling pathways mediated by IIbβ3. By the stimulation with soluble fibrinogen, Syk was tyrosine-phosphorylated but FAK was dephosphorylated, whereas solid-phase fibrinogen promptly caused tyrosine phosphorylation of FAK followed by delayed phosphorylation of Syk. In addition, the binding of soluble fibrinogen to the cells adherent to fibrinogen-coated plate resulted in tyrosine phosphorylation of integrin β3 and a complex formation of integrin β3 with Syk. This implies the cooperation of both soluble and solid-phase fibrinogen-mediated signaling pathways.© 1998 by The American Society of Hematology.
Neutrophil Elastase Cleavage of Human Factor IX Generates an Activated Factor IX-Like Product Devoid of Coagulant Function
Authors: Samis John A. , Kam Eunice , Nesheim Michael E. , Giles Alan R. 
Published: October 2019

AbstractIn preliminary studies, the generation of thrombin in vivo was found to induce a 92% loss of functional activity of factor IX (F.IX) despite the detection by Western blotting of a product resembling activated F.IX (F.IXa) and a 25% increase in F.IX antigen levels (Hoogendoorn et al, Thromb Haemost 69:1127, 1993 [abstr]). These changes were associated with evidence of increased elastase availability. To study the possibility that these two observations were related, a detailed physical and functional characterization of the hydrolysis of purified human F.IX by human neutrophil elastase (HNE) was performed in vitro. An activated partial thromboplastin time (aPTT) clotting assay demonstrated that, although HNE eliminated the potential of F.IX to be activated, it only marginally reduced the F.IXa activity. Reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) indicated that HNE treatment of F.IX generated cleavage products of 30 and 20 kD that could not be distinguished from the respective heavy and light chain peptides that were identified in parallel studies when F.IX was activated by activated bovine F.XI (F.XIa), one of its physiological activators. In addition, nonreducing SDS-PAGE demonstrated that HNE-treated F.IX formed no complexes with antithrombin III (ATIII) in the presence of heparin. Furthermore, HNE-treated F.IX was unable to (1) bind the active site probe p-aminobenzamidine; (2) hydrolyze the synthetic peptide substrate CH3SO2-Leu-Gly-Arg-p-nitroanilide; and (3) activate human factor X (F.X). In contrast to dansyl-Glu-Gly-Arg-chloromethyl ketone (dEGR)-inactivated F.IXa, HNE-treated F.IX (0.01 to 10,000 pmol/L) failed to inhibit the clotting activity of F.IXa (10 pmol/L) in the aPTT. NH2-terminal sequencing indicated that HNE cleaved human F.IX at Thr140, Thr144, Ile164, Thr172, and Val181. The cleavages at Thr140/Thr144 and at Thr172/Val181 are both very close to the normal F.XIa -(Arg145) and β-(Arg180) cleavage sites, respectively. In summary, the results suggest that the activatability of F.IX is eliminated after cleavage by HNE and that the inability of HNE-treated F.IX to support F.IXa-like coagulant function is a consequence of improper active site formation. These in vitro observations support the possibility that increased HNE cleavage of F.IX in vivo may contribute to the disregulation of hemostasis that occurs in conditions such as disseminated intravascular coagulation (DIC).© 1998 by The American Society of Hematology.
Distinct Regulation of T-Cell Death by CD28 Depending on Both Its Aggregation and T-Cell Receptor Triggering: A Role for Fas-FasL
Authors: Collette Y. , Benziane A. , Razanajaona D. , Olive D. 
Published: October 2019

AbstractCD28 is a major coreceptor that regulates cell proliferation, anergy, and viability of T cells. The negative selection by T-cell receptor (TCR)-induced cell death of immature thymocytes as well as of activated human antigen-specific T-cell clone, requires a costimulatory signal that can be provided by CD28. Conversely, CD28-mediated signals increase expression of Bcl-XL, a survival gene, and promote survival of naive T cells cultured in the absence of antigen or costimulation. Because CD28 appears to both protect from, or induce T-cell death, one important question is to define the activation and cellular parameters that dictate the differential role of CD28 in T-cell apoptosis. Here, we compared different CD28 ligands for their ability to regulate TCR-induced cell death of a murine T-cell hybridoma. In these cells, TCR triggering induced expression of Fas and FasL, and cell death was prevented by anti-Fas blocking monoclonal antibody (MoAb). When provided as a costimulus, both CD28 MoAb and the B7.1 and B7.2 counter receptors downregulated, yet did not completely abolish T-cell receptor–induced apoptosis. This CD28 cosignal resulted in both upregulation of Bcl-XL and prevention of FasL expression. In marked contrast, when given as a single signal, CD28 MoAb or B7.1 and B7.2 induced FasL expression and resulted in T-cell death by apoptosis, which was dependent on the level of CD28 ligation. Furthermore, triggering of CD28 upregulated FasL and induced a marked T-cell death of previously activated normal peripheral T cells. Our results identify Fas and FasL as crucial targets of CD28 in T-cell death regulation and show that within the same cell population, depending on its engagement as a single signal or as a costimulus together with the TCR, CD28 can either induce a dose-dependent death signal or protect from cell death, respectively. These data provide important insights into the role of CD28 in T-cell homeostasis and its possible implication in neoplastic disorders.© 1998 by The American Society of Hematology.
Heparin-Induced Thrombocytopenia: New Insights Into the Impact of the FcγRIIa-R-H131 Polymorphism
Authors: Carlsson Lena E. , Santoso Sentot , Baurichter Gudrun , Kroll Hartmut , Papenberg Stephanie , Eichler Petra , Westerdaal Nomdo A.C. , Kiefel Volker , van de Winkel Jan G.J. , Greinacher Andreas 
Published: October 2019

AbstractHeparin-induced thrombocytopenia (HIT), a severe complication of heparin treatment, can be associated with new thrombotic complications. HIT antibodies activate platelets via the platelet Fcγ-receptor (FcγRIIa), which carries a functionally relevant polymorphism (FcγRIIa-R-H131). The effect of this polymorphism on the clinical manifestations of HIT is controversial. We determined prospectively the FcγRIIa-R-H131 genotypes in 389 HIT patients, in 351 patients with thrombocytopenia or thrombosis due to causes other than HIT and without detectable HIT antibodies, and in 256 healthy blood donors. For this purpose, a novel nested sequence-specific primer-polymerase chain reaction (SSP-PCR) was developed. FcγRIIa-R/R131 was found to be overrepresented in the HIT patients (27%) compared with the control groups (non-HIT patients [21%] and blood donors [20%]). In a subgroup of 122 well-characterized HIT patients, the genotype distribution in patients presenting with thrombocytopenia only was compared with that of patients who developed thromboembolic complications. The frequency of FcγRIIa-R/R131 among patients with thrombotic events was significantly elevated (37% v 17%;P = .036). Our results indicate that genotype distribution can be correlated to the clinical outcome of patients with HIT. We speculate that the reduced clearance of immune complexes in patients with the FcγRIIa-R/R131 allotype causes prolonged activation of endothelial cells and platelets, thus increasing the risk for thrombotic complications.© 1998 by The American Society of Hematology.
Proliferation in Monocyte-Derived Dendritic Cell Cultures Is Caused by Progenitor Cells Capable of Myeloid Differentiation
Authors: Cavanagh Lois L. , Saal Russell J. , Grimmett Karen L. , Thomas Ranjeny 
Published: October 2019

AbstractDendritic cells (DC) can be generated by culture of adherent peripheral blood (PB) cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). There is controversy as to whether these DC arise from proliferating precursors or simply from differentiation of monocytes. DC were generated from myeloid-enriched PB non-T cells or sorted monocytes. DC generated from either population functioned as potent antigen-presenting cells. Uptake of [3H]-thymidine was observed in DC cultured from myeloid-enriched non-T cells. Addition of lipopolysaccharide or tumor necrosis factor- led to maturation of the DC, but did not inhibit proliferation. Ki67+ cells were observed in cytospins of these DC, and by double staining were CD3−CD19−CD11c−CD40−and myeloperoxidase+, suggesting that they were myeloid progenitor cells. Analysis of the starting population by flow cytometry demonstrated small numbers of CD34+CD33−CD14− progenitor cells, and numerous granulocyte-macrophage colony-forming units were generated in standard assays. Thus, production of DC in vitro from adherent PB cells also enriches for progenitor cells that are capable of proliferation after exposure to GM-CSF. Of clinical importance, the yield of DC derived in the presence of GM-CSF and IL-4 cannot be expanded beyond the number of starting monocytes.© 1998 by The American Society of Hematology.
Severe Factor VII Deficiency Due to a Mutation Disrupting an Sp1 Binding Site in the Factor VII Promoter
Authors: Carew Josephine A. , Pollak Eleanor S. , High Katherine A. , Bauer Kenneth A. 
Published: October 2019

AbstractWe have identified a point mutation in the promoter of the factor VII gene responsible for a severe bleeding disorder in a patient from a large French-Canadian family with known consanguinity. The proband has an extremely low plasma level of factor VII antigen and factor VII coagulant activity (&lt;1 percent of normal) and suffers from hemarthroses and chronic arthropathy. Sequencing of the patient’s factor VII 5′ flanking region, intron/exon junctions, and coding regions showed a homozygous point mutation, a C to G transversion at position −94 relative to the translation start site. We show here that this mutation prevented binding of transcription factor Sp1 and of other nuclear proteins to this region of the factor VII promoter and resulted in a 20-fold reduction in reporter gene expression in HepG2 cells. These data underscore the importance of this region of the factor VII promoter for in vivo expression of the factor VII gene.© 1998 by The American Society of Hematology.
A Janus Kinase Inhibitor, JAB, Is an Interferon-γ–Inducible Gene and Confers Resistance to Interferons
Authors: Sakamoto Hiroshi , Yasukawa Hideo , Masuhara Masaaki , Tanimura Shyu , Sasaki Atsuo , Yuge Kentaro , Ohtsubo Motoaki , Ohtsuka Akira , Fujita Takasi , Ohta Tsunetaka , Furukawa Yusuke , Iwase Satsuki , Yamada Hisashi , Yoshimura Akihiko 
Published: October 2019

AbstractIt has been shown that interferons (IFNs) exert their signals through receptor-associated Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). However, molecular mechanism of regulation of IFN signaling has not been fully understood. We have reported novel cytokine-inducible SH2 protein (CIS) and JAK binding protein (JAB) family genes that can potentially modulate cytokine signaling. Here we report that JAB is strongly induced by IFN-γ but not by IFN-β in mouse myeloid leukemia M1 cells and NIH-3T3 fibroblasts. NIH-3T3 cells ectopically expressing JAB but not CIS3 lost responsiveness to the antiviral effect of IFN-β and IFN-γ. M1 leukemic cells stably expressing JAB were also resistant to IFN-γ and IFN-β–induced growth arrest. In both NIH-3T3 and M1 transformants expressing JAB, IFN-γ did not induce tyrosine phosphorylation and DNA binding activity of STAT1. Moreover, IFN-γ–induced activation of JAK1 and JAK2 and IFN-β–induced JAK1 and Tyk2 activation were inhibited in NIH-3T3 JAB transformants. These results suggest that JAB inhibits IFN signaling by blocking JAK activity. We also found that IFN-resistant clones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation. In IFN-resistant Daudi cells, IFN-induced STAT1 and JAK phosphorylation was partially reduced. Therefore, overexpression of JAB could be, at least in part, a mechanism of IFN resistance.© 1998 by The American Society of Hematology.
Cytogenetic Abnormalities in Primary Myelodysplastic Syndrome Are Highly Predictive of Outcome After Allogeneic Bone Marrow Transplantation
Authors: Nevill Thomas J. , Fung Henry C. , Shepherd John D. , Horsman Douglas E. , Nantel Stephen H. , Klingemann Hans-G. , Forrest Donna L. , Toze Cynthia L. , Sutherland Heather J. , Hogge Donna E. , Naiman Sheldon C. , Le Alan , Brockington Daphne A. , Barnett Michael J. 
Published: October 2019

AbstractAllogeneic bone marrow transplantation (BMT) is the only curative therapy available for patients with myelodysplastic syndrome (MDS). In an attempt to identify prognostic factors influencing outcome, we collected data retrospectively on 60 consecutive adult patients who had undergone BMT at our center for primary MDS or acute myelogenous leukemia evolving from preexisting primary MDS (sAML). Patients were divided into subgroups according to cytogenetic abnormalities based on a recently described International MDS Workshop categorization system. The 7-year actuarial event-free survival (EFS), relapse rate, and nonrelapse mortality (NRM) for all patients were 29% (95% confidence interval [CI], 16% to 43%), 42% (CI, 24% to 67%), and 50% (CI, 37% to 64%), respectively. The EFS for the good-, intermediate-, and poor-risk cytogenetic subgroups were 51% (CI, 30% to 69%), 40% (CI, 16% to 63%), and 6% (CI, 0% to 24%), respectively (P= .003). The corresponding actuarial relapse rates were 19% (CI, 6% to 49%), 12% (CI, 2% to 61%), and 82% (CI, 48% to 99%), respectively (P = .002) with no difference in NRM between the subgroups. Univariate analysis showed cytogenetic category, French-American-British (FAB) subtype, and graft-versus-host disease (GVHD) prophylaxis used to be predictive of relapse and EFS. In multivariate analysis, only the cytogenetic category was predictive of EFS, with the relative risk of treatment failure for the good-, intermediate-, and poor-risk cytogenetic subgroups being 1.0, 1.5, and 3.5, respectively (P = .004). For adults with primary MDS and sAML, even after BMT, poor-risk cytogenetics are predictive of an unfavorable outcome; novel treatment strategies will be required to improve results with allogeneic BMT in this patient population.© 1998 by The American Society of Hematology.