bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-4 receptor regulation in human monocytic cells
Authors: de Wit H , Hendriks DW , Halie MR , Vellenga E 
Published: October 2019

Abstract
The regulation of the interleukin-4 receptor (IL-4R) was studied at mRNA and protein level in monocytic cells on stimulation with activators of different intracellular signaling pathways and IL-4. Activation of protein kinase C-dependent pathways with phorbol myristate acetate (PMA) or activation of protein kinase A-dependent pathways with DBcAMP and prostaglandin E2 resulted in an augmented IL- 4R expression at mRNA and protein level. Transcriptional and posttranscriptional mechanisms seemed to be involved in the promotive effect of DBcAMP because the transcription rate increased 1.8-fold, and the half-life of IL-4R mRNA was prolonged to 150 minutes compared with 120 minutes in unstimulated cells. In contrast, the effect of PMA could only be ascribed to changes at transcriptional level. However, activation of Ca(2+)-dependent pathways with A23187 or stimulation with IL-4 had no effect on the IL-4R expression. The unresponsiveness to IL- 4 could not be ascribed to a nonfunctional receptor because IL-4 did modulate the CD14, CD23, and HLA-DR antigen expression. These results are in contrast with IL-4R regulation in T cells, which is affected by IL-4- and Ca(2+)-dependent pathways. The discrepancy might be caused by the presence of the common IL-2 receptor gamma chain (gamma c) in T cells and the absence of the gamma c in monocytic cells, as has been shown by polymerase chain reaction. These data indicate that IL-4Rs are differentially regulated, depending on the cell type studied.
2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders
Authors: O'Brien S , Kurzrock R , Duvic M , Kantarjian H , Stass S , Robertson LE , Estey E , Pierce S , Keating MJ 
Published: October 2019

Abstract
Mature T-cell lymphoproliferative disorders comprise a heterogenous group of diseases for which there is no standard therapy. These disorders are uncommon, and are usually treated similarly to their B- cell counterparts, but with less success. Nucleoside analogues have proven effective in indolent B-cell disorders but have been less well explored in T-cell malignancies. We treated 22 patients with mature T- cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days. Nineteen of the patients had received prior therapy with a median number of prior regimens of three. Eleven patients had leukemia or large granular lymphocytosis, eight patients had mycosis fungoides, and three had T-cell lymphoma. Nine patients (41%) responded to 2-CDA. Four of the patients had responses that were complete remissions, and three of these four patients remain in remission at 23, 24, and 23 months. The only important toxic effects were fever or infection, seen during 38% of courses. In conclusion, 2-CDA appears to be an effective therapy in T-cell lymphoproliferative disorders and deserves wider evaluation in this subset of patients.
Expression of the G-protein--coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells
Authors: Forster R , Emrich T , Kremmer E , Lipp M 
Published: October 2019

Abstract
The G-protein-coupled receptor BLR1 related to receptors for chemokines and neuropeptides has been identified as the first lymphocyte-specific member of the gene family characterized by seven transmembrane-spanning regions. Using a high-affinity anti-BLR1 monoclonal antibody (MoAb) and three-color flow cytometry it is shown that BLR1 expression on peripheral blood cells is limited to B cells and to a subset of CD4+ (14%) and CD8+ (2%) lymphocytes. T cells expressing BLR1 were positive for CD45R0, were negative for interleukin-2 receptors, show high levels of CD44, and show low levels of L-selectin. The majority of CD4+ cells originating from secondary lymphatic tissue, but none of cord blood- derived T cells, express BLR1. These observations suggest that BLR1 is a marker for memory T cells. Furthermore, BLR1 expression was detected on all CD19+ peripheral or tonsillar B lymphocytes, but only on a fraction of cord blood cells and bone marrow cells expressing CD19, sIgM, or sIgD. Interestingly, activation of both mature B and T cells by CD40 MoAb and CD3 MoAb, respectively, led to complete downregulation of BLR1. These data suggest that the G-protein-coupled receptor BLR1 is involved in functional control of mature recirculating B cells and T- helper memory cells participating in cell migration and cell activation.
Clinical importance of extraordinary integration patterns of human T- cell lymphotropic virus type I proviral DNA in adult T-cell leukemia/lymphoma [see comments]
Authors: Shimamoto Y , Suga K , Shibata K , Matsuzaki M , Yano H , Yamaguchi M 
Published: October 2019

Abstract
The proviral DNA of human T-cell lymphotrophic virus type I (HTLV-I) is known to be integrated monoclonally in the malignant cells of adult T- cell leukemia/lymphoma (ATL), which is a peripheral T-cell malignancy caused by this virus. We studied the relationship between the integration patterns of HTLV-I and clinical characteristics in 89 patients with ATL. The proviral DNA of HTLV-I was examined by the standard Southern blot analysis using the endonucleases EcoRI and Pst I. One clear band of greater than 9 kb was detected in most of the patients (83 case) when cellular DNA was digested with EcoRI. On the other hand, extraordinary integration patterns of HTLV-I proviral DNA were detected in 6 patients; 3 of them showed two bands, while the other 3 showed one band smaller than 9 kb. When cellular DNA was digested with PstI, the band patterns of these patients were quite different from those of typical patients. The patients with the extraordinary integration patterns had clinical characteristics dissimilar to those of the other 83 patients with the ordinary integration pattern. The patients with two bands by EcoRI digestion always had severe hypoxemia with extremely high levels of serum lactate dehydrogenase at first presentation and showed peculiar organ infiltrations, such as retina and muscle, which were less frequent in the other ordinary 83 patients. They all died within 8 months after the onset. In contrast, the patients with one smaller band by EcoRI digestion always had small and mature T lymphocytes with bilobulated nuclei without lymphadenopathy and showed a favorable clinical course, which was uncommon in the ordinary cases. They were alive 20 to 38 months after diagnosis. Rearranged bands of the T-cell receptor gene were detected in all patients with unusual integration. These findings indicate that the integration patterns of HTLV-I proviral DNA have a clinical implication and may be one of the explanations for heterogeneity in the behavior of this disease.
Hairy cell interactions with extracellular matrix: expression of specific integrin receptors and their role in the cell's response to specific adhesive proteins
Authors: Burthem J , Baker PK , Hunt JA , Cawley JC 
Published: October 2019

Abstract
Integrin/extracellular-matrix interactions are central to the migration, localization, and subsequent function of lymphocytes within tissues. In hairy cell leukemia (HCL) the malignant cells display a highly characteristic tissue distribution in which interactions with extracellular matrix (ECM) are often prominent. Therefore, we used HCL as a model in which to investigate the poorly understood integrin/ECM interactions that underlie the migratory behavior of malignant B lymphocytes. Using a combined approach involving immunocytochemistry, flow cytometry, and immunoprecipitation analysis, hairy cells (HCs) were shown to have a consistent and distinctive phenotype (mainly alpha 4 beta 1, alpha 5 beta 1, alpha v beta 1, and alpha v beta 3). Furthermore, functional studies utilising adhesion assays, time-lapse video-microscopy and image analysis showed that the HCs displayed very specific adhesive behaviour in response to relevant adhesive protein ligands. HCs were able to adhere to different extents on all the adhesive proteins examined, but, on laminin and collagen, binding was weak with little cytoplasmic spreading. In contrast, the cells showed strong adhesion both to fibronectin (FN) and to vitronectin (VN). On FN, the cells spread extensively with nonpolarized cytoplasmic projections, whereas on VN cytoplasmic projections were markedly polarized. This polarized morphology was shown to reflect cell motility. Investigation of the role of individual integrin receptors in the cell movement response suggested that alpha v beta 3 is the major integrin responsible for this motile behavior. These results are discussed in relation to the limited previous data on leukemic and activated B-cell integrins, and we suggest that the HC integrins play a significant role in the characteristic behavior of HCs within tissues.
Progression of the myeloid differentiation program is dominant to transforming growth factor-beta 1-induced apoptosis in M1 myeloid leukemic cells
Authors: Selvakumaran M , Reed JC , Liebermann D , Hoffman B 
Published: October 2019

Abstract
Hematopoiesis is a profound example of cell homeostasis that is regulated throughout life. This process requires the participation of many factors, including positive and negative regulators of growth and differentiation, that determine survival, growth stimulation, differentiation, functional activation, and programmed cell death. Understanding the effects of multiple stimuli on specific cells at the molecular and cellular level is crucial towards understanding how the population of blood cells maintains a homeostatic state. Two appropriate stimuli for analysis, both of which are found in bone marrow, are differentiation-inducing cytokines, which induce terminal differentiation associated with growth arrest, ultimately culminating in programmed cell death, and transforming growth factor-beta 1 (TGF- beta 1), which induces rapid growth arrest and apoptosis of hematopoietic cells. Previously, we have shown, using M1 myeloblastic leukemic cells as a model system, that differentiation-inducing cytokines induce terminal differentiation associated with growth arrest and, only after 5 to 7 days, apoptosis, whereas TGF-beta 1 induces rapid growth arrest and apoptosis. In this report, we show that M1 myeloid leukemic cells treated concomitantly with the differentiation inducer interleukin-6 and TGF-beta 1 undergo terminal differentiation, in which modulators of the MyD118 gene product, previously shown to be a positive regulator of TGF-beta 1-induced apoptosis, are implicated to play a role in protecting the cells from TGF-beta 1-induced apoptosis. Furthermore, using M1 cell variants blocked at different stages after induction of differentiation, including M1myb and M1myc, as well as conditionally blocked M1mycer, it has been shown that the dominance of interleukin-6 to TGF-beta 1-induced apoptosis is dependent on the progression of the differentiation program. Further studies with M1 and the genetically engineered M1 cell variants will be instrumental towards molecularly dissecting the interaction of hematopoietic differentiation with a variety of apoptotic pathways.
Transcription factor GATA-2 is expressed in erythroid, early myeloid, and CD34+ human leukemia-derived cell lines
Authors: Nagai T , Harigae H , Ishihara H , Motohashi H , Minegishi N , Tsuchiya S , Hayashi N , Gu L , Andres B , Engel JD 
Published: October 2019

Abstract
To understand the functional roles that the GATA factors may play during hematopoietic cell differentiation, we examined the expression of GATA factor mRNAs and protein products in various human cell lines. Blot hybridization analyses demonstrated that GATA-1 and GATA-2 mRNAs are expressed abundantly in a set of cell lines established from human myelogenous leukemia cells, but the expression pattern of each factor is distinct. GATA-2 mRNA is expressed in all cell lines tested that express erythroid markers, and, in addition, the mRNA is also expressed in three CD34+ cell lines and two early myeloid cell lines. In contrast, the expression of GATA-1 mRNA showed tight correlation to that of the erythroid/megakaryocytic lineage markers. We also found that the GATA-2 probe identifies two types of mRNA. Structural analysis of genomic DNA clones encoding human GATA-2 coupled with RNA blot analysis demonstrated that there exists an alternative use of polyadenylation consensus sequences in a single exon and this causes the molecular heterogeneity among GATA-2 mRNAs. Through immunochemical and immunohistochemical analyses using anti-GATA-1- and anti-GATA-2- specific antibodies, GATA-2 protein was clearly shown to be present in the nuclei of leukemia-derived early myeloid and CD34+ cell lines, whereas both GATA-1 and GATA-2 proteins are expressed in erythroid/megakaryocytic cell lines. Thus, the expression profile of GATA-2 is consistent with the hypothesis that GATA-2 plays unique roles for the transcriptional activation of genes in cells at an early stage of hematopoietic differentiation and in developing cells of the erythroid and myeloid lineages.
Clustering of vitronectin and RGD peptides on microspheres leads to engagement of integrins on the luminal aspect of endothelial cell membrane
Authors: Zanetti A , Conforti G , Hess S , Martin-Padura I , Ghibaudi E , Preissner KT , Dejana E 
Published: October 2019

Abstract
In previous work (Conforti et al, Blood 80:437, 1992), we have shown that integrins in endothelial cells (EC) are not polarized to the basal cell membrane, but are also exposed on the apical cell surface, in contact with blood. Therefore, endothelial integrins might be available for binding circulating plasma proteins. However soluble plasma vitronectin (vn) bound very poorly to EC apical surface and this interaction was unaffected by Arg-Gly-Asp (RGD) peptides or an anti- alpha v beta 3 serum. In contrast, beads (diameter, 4.5 microns) coupled with plasma vn associated to EC apical surface in a time- and concentration-dependent way. Addition of antibodies directed to vn, alpha v beta 3, and RGD-containing peptides blocked the interaction of vn beads with EC. In contrast, heparin and antibodies directed to alpha v beta 5 and beta 1 integrin chain had no effect. Beads coupled with Gly-Arg-Gly-Asp-Ser-Pro bound to the EC surface, but not those coupled with Gly-Arg-Gly-Glu-Ser-Pro. This interaction was blocked by alpha v beta 3 antibodies and RGD peptides, but not by alpha v beta 5 antibody. Overall, these results indicate that luminal alpha v beta 3 retains its binding capacity for surface-linked vn and RGD-containing ligands, but binding is observed only when the ligand is offered in a clustered, multivalent form. We propose that when vn or RGD-containing proteins are bound to circulating cells, they can act as bridging molecules by promoting adhesion of the cells to the endothelium via apical integrins.
Complete hematologic remissions induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia
Authors: Santana VM , Hurwitz CA , Blakley RL , Crom WR , Luo X , Roberts WM , Ribeiro R , Mahmoud H , Krance RA 
Published: October 2019

Abstract
The majority of children with acute myeloid leukemia (AML) who are treated exclusively with chemotherapy die of progressive disease. Improvement in outcome will likely require new active drugs capable of eradicating resistant blast cells early in the clinical course. We therefore assessed the cytoreductive potential of 2- chlorodeoxyadenosine (2-CdA), a halogenated purine analogue, in 22 consecutive children with newly diagnosed AML. The drug was administered as a single 120-hour continuous infusion (8.9 mg/m2 of body surface area per day) before the introduction of standard remission induction therapy. Six patients (27%) had complete hematologic remissions by a median of 21 days after treatment with the nucleoside (range, 14 to 33 days). Seven others had partial responses, yielding a total response rate of 59%. The drug also eliminated leukemic cells from cerebrospinal fluid in 4 of the 6 patients tested. Concentrations of 2-CdA in cerebrospinal fluid on day 5 after the initiation of treatment ranged from 12.4% to 38.0% (mean, 22.7%) of the steady-state plasma concentrations. Severe but reversible myelosuppression and thrombocytopenia developed in all patients. Analysis of factors that may have influenced the complete remission rate suggested a better outcome in patients with myeloblastic leukemia (M0-M2 subtypes in the revised French-American-British classification system). These results demonstrate clinically significant activity by 2- CdA against previously untreated AML in children, including leukemic blast cells in the central nervous system. Its use in combination chemotherapy may improve the outlook for patients with this often fatal hematologic cancer.
Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor
Authors: Anasetti C , Hansen JA , Waldmann TA , Appelbaum FR , Davis J , Deeg HJ , Doney K , Martin PJ , Nash R , Storb R 
Published: October 2019

Abstract
Humanized anti-Tac is a genetically engineered human IgG1 monoclonal antibody specific for Tac, the alpha subunit of the interleukin-2 (IL- 2) receptor, and blocks IL-2-dependent activation of human T lymphocytes. The safety, pharmacokinetics, and immunosuppressive activity of humanized anti-Tac were evaluated in 20 patients who developed acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Patients had developed acute GVHD at 5 to 26 (median, 14) days after transplantation and had failed to respond to primary therapy with glucocorticoids. Sequential groups of 4 patients each received a single 1-hour infusion of antibody in escalating doses of 0.5, 1.0, or 1.5 mg/kg; 8 additional patients were then treated with 1.5 mg/kg. A second infusion of antibody was administered after 11 to 48 (median, 16) days in 8 patients who had transient improvement of GVHD after the first infusion. Acute side effects, limited to chills in 1 patient and diaphoresis in another, were observed during or shortly after the antibody infusion. Overall improvement of acute GVHD occurred in 8 patients, 6 of whom were treated with a single antibody infusion and 2 with two infusions. Four responses were complete and 4 were partial. Three additional patients had improvement in one organ but progression in another. Responses occurred in 9 of 16 cases with skin disease, 3 of 15 with liver disease, and 6 of 12 with gastrointestinal disease. Two patients survive at 529 and 645 days after antibody treatment. Two patients died after relapse of leukemia. Sixteen patients died of infection or organ failure between 5 and 211 (median, 55) days. The terminal elimination half-life of the antibody was 44 to 363 hours, with a harmonic mean of 79, 88, and 94 hours, respectively, for the three doses studied. Absolute peripheral blood T-lymphocyte counts remained unchanged during the 56 days after infusion of the antibody. A fraction of circulating T cells expressed the alpha chain of the IL-2 receptor that, in some patients, was bound by antibody in vivo up to 28 days after treatment. No patient developed a measurable antibody response to humanized anti-Tac. Humanized anti-Tac has a long half-life after intravenous injection in humans, superior to any rodent monoclonal antibody specific for human T cells, and does not appear to induce antibody formation in recipients of marrow transplants. Improvement of steroid-refractory GVHD in 40% of patients after only one or two antibody infusions indicates that humanized anti-Tac is immunosuppressive.
Positively selected autologous blood CD34+ cells and unseparated peripheral blood progenitor cells mediate identical hematopoietic engraftment after high-dose VP16, ifosfamide, carboplatin, and epirubicin
Authors: Brugger W , Henschler R , Heimfeld S , Berenson RJ , Mertelsmann R , Kanz L 
Published: October 2019

Abstract
To investigate the feasibility of peripheral blood CD34+ cell selection and to analyze CD34+ cell-mediated engraftment after high-dose chemotherapy, we performed a phase I/II trial in 21 patients with advanced malignancies. The rationale for the selection of CD34+ cells from peripheral blood progenitor cell (PBPC) collections is based on the observation that contaminating tumor cells can be depleted approximately 3 logs using this procedure. CD34+ cells from chemotherapy+granulocyte colony-stimulating factor-mobilized PBPCs were positively selected with an avidin-biotin immunoadsorption column (CEPRATE SC system). One leukapheresis product with a median number of 2.8 x 10(6) CD34+ cells/kg was labeled with a biotinylated anti-CD34 monoclonal antibody and subsequently processed over the column. The yield of selected CD34+ cells was 73% +/- 24.6%. The purity of the CD34+ cell fraction was 61.4% +/- 19.7%. CD34+ cells were shown to represent predominantly committed progenitors coexpressing CD33, CD38, and HLA-DR molecules (lin+). They gave rise to myeloid as well as erythroid and multilineage colonies in vitro. In addition, positively selected CD34+ cells also comprised early hematopoietic progenitor cells, as shown by the presence of CD34+/lin- cells. Transfusion of positively selected CD34+ cells (2.5 x 10(6) CD34+/kg; range, 0.45 to 5.1) after high-dose VP16 (1,500 mg/m2), ifosfamide (12 g/m2), carboplatin (750 mg/m2), and epirubicin (150 mg/m2) (VIC-E) in 15 patients resulted in a rapid and stable engraftment of hematopoiesis without any adverse events. As compared with 13 historical control patients reconstituted with a comparable number of unseparated PBPCs, time to neutrophil and platelet recovery was identical in both groups (absolute neutrophil count > 500/microL, day + 12; platelet count > 50,000/microL, day + 15). These data indicate that autologous peripheral blood CD34+ cells and unseparated PBPCs mediate identical reconstitution of hematopoiesis after high-dose VIC-E chemotherapy. Because positive selection of CD34+ cells from mobilized blood results in a median 403-fold depletion of T cells, allogeneic CD34+ cells from mobilized blood should be investigated as an alternative to bone marrow cells for allotransplantation.