bluuebunny/crossref_metadata_2025_split huggingface dataset:
High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura
Authors: Cortelazzo S , Finazzi G , Buelli M , Molteni A , Viero P , Barbui T 
Published: October 2019

Abstract
The purpose of this study was to estimate the incidence and to establish which factors were associated with an increased risk of hemorrhagic complications in an historic cohort of 117 consecutive and unselected patients with chronic idiopathic thrombocytopenic purpura (ITP). Sixty-eight patients (58%) underwent medical treatment and/or splenectomy and 33 (48% of treated) achieved a complete stable remission. At equivalent platelet count the incidence of major hemorrhagic complications was significantly higher in aged (greater than 60 years) than in younger (less than 40 years) patients (10.4% v 0.4%/pt-y, relative risk = 28.9, P less than .01). A previous hemorrhagic event was identified as another major risk factor for hemorrhage (relative risk = 27.5, P less than .0005), while hypertension and underlying disorders had no influence. We conclude that age more than 60 years and a previous history of bleeding are major risk factors for severe hemorrhages in adults with ITP.
Stimulation of megakaryocytopoiesis in mice by human recombinant interleukin-6
Authors: Hill RJ , Warren MK , Stenberg P , Levin J , Corash L , Drummond R , Baker G , Levin F , Mok Y 
Published: October 2019

Abstract
The in vivo effects of purified human recombinant interleukin-6 (IL-6) on murine megakaryocytopoiesis were examined. IL-6 was administered subcutaneously to Swiss Webster mice, followed by evaluation of bone marrow megakaryocyte ploidy, size and frequency, and median platelet volume 24, 48, and 72 hours after the initiation of IL-6 administration. In addition, bone marrow megakaryocyte morphology was examined using electron microscopy at 72 hours. IL-6 (10,000 U per subcutaneous injection) was administered three times during the first 24 hours, three times during the second 24 hours, and twice during the last 24-hour period. IL-6 bioactivity (10 U/ng) was determined using the IL-6-dependent murine hybridoma cell line B9. Megakaryocyte ploidy distribution, measured by two-color flow cytometry, demonstrated a shift in the modal ploidy class from 16N to 32N and a significant increase in the relative frequency of 64N megakaryocytes 48 and 72 hours (but not 24 hours) after initiation of IL-6 administration (cumulative doses of 60,000 and 80,000 U at 48 and 72 hours, respectively). In addition, ploidy levels were increased in animals that received a cumulative IL-6 dose of only 40,000 U (evaluated after 72 hours). The size of recognizable bone marrow megakaryocytes, determined by the cross-sectional areas of plastic embedded bone marrow megakaryocytes, was increased at the 48-hour (60,000 U IL-6) and 72- hour (80,000 U IL-6) time points. Megakaryocyte frequency, measured by flow cytometry, was unaffected at all time points and doses of IL-6. Median platelet volume, measured by electrical impedance, was not consistently altered by administration of IL-6. Electron microscopic examination of bone marrow megakaryocytes showed an increase in the proportion of megakaryocytes with a wide, peripheral, organelle- deficient zone from 20% +/- 9% (SD) in control animals to 50% +/- 7% (SD) (P less than .02) in animals that received IL-6. No changes were observed in the distribution of the demarcation membranes. IL-6 is a potent stimulator of murine megakaryocytopoiesis, in vivo, and appears to act early in megakaryocyte differentiation.
Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro
Authors: Metcalf D , Hilton D , Nicola NA 
Published: October 2019

Abstract
Receptors for murine leukemia inhibitory factor (LIF) were demonstrated on immature and mature murine megakaryocytes. LIF alone had no effects in culture on the survival or proliferation of normal murine megakaryocytes or their precursors. However, combination of LIF with multipotential-colony-stimulating factor (Multi-CSF) (interleukin-3) enhanced the megakaryocyte colony formation able to be stimulated by Multi-CSF; the enhancement involved all types of megakaryocyte colony and resulted in the formation of increased numbers of megakaryocytes. These observations provide a possible basis for the observation that, when LIF is injected in vivo, elevations are observed in megakaryocyte numbers and platelet levels.
Myeloid cell kinetics in mice treated with recombinant interleukin-3, granulocyte colony-stimulating factor (CSF), or granulocyte-macrophage CSF in vivo
Authors: Lord BI , Molineux G , Pojda Z , Souza LM , Mermod JJ , Dexter TM 
Published: October 2019

Abstract
Myeloid cell kinetics in mice treated with pure hematopoietic growth factors have been investigated using tritiated thymidine labeling and autoradiography. Mice were injected subcutaneously with 125 micrograms/kg granulocyte colony-stimulating factor (G-CSF) (in some cases 5 micrograms/kg), or 10 micrograms/kg of granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3) every 12 hours for 84 hours. 3HTdR labeling was performed in vivo after 3 days of treatment. G-CSF increased the peripheral neutrophil count 14-fold and increased the proportion and proliferation rate of neutrophilic cells in the marrow, suppressing erythropoiesis at the same time. Newly produced mature cells were released into the circulation within 24 hours of labeling, compared with a normal appearance time of about 96 hours. By contrast, GM-CSF and IL-3 had little effect on either marrow cell kinetics or on the rate of release of mature cells, although GM-CSF did stimulate a 50% increase in peripheral neutrophils. Monocyte production was also increased about eightfold by G-CSF and 1.5-fold by GM-CSF, but their peak release was only slightly accelerated. While the peripheral half- lives of the neutrophilic granulocytes were normal, those of the monocytes were dramatically reduced, perhaps due to sequestration in the tissues for functional purposes. The stimulated monocyte production in the case of G-CSF required an additional five cell cycles, a level that might have repercussions on the progenitor compartments.
Antithrombin-III-Hamilton, Ala 382 to Thr: an antithrombin-III variant that acts as a substrate but not an inhibitor of alpha-thrombin and factor Xa
Authors: Austin RC , Rachubinski RA , Ofosu FA , Blajchman MA 
Published: October 2019

Abstract
Antithrombin-III-Hamilton has been shown to be a structural variant of antithrombin-III (AT-III) with normal heparin affinity but impaired protease inhibitory activity. The molecular defect of AT-III-Hamilton is the substitution of Thr for Ala at amino acid residue 382. The plasma of affected individuals contains approximately equal quantities of normal AT-III and AT-III-Hamilton. When AT-III was isolated from the plasma of the propositus by heparin-Sepharose chromatography, it had identical mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to normal plasma-derived AT-III, under both reducing and nonreducing conditions. However, the AT-III-Hamilton species, separated from the propositus' normal AT-III by a combination of heparin-Sepharose and thrombin-Sepharose chromatography, had increased mobility on reductive SDS-PAGE compared with AT-III from the propositus isolated by heparin-Sepharose chromatography alone. Under nonreducing conditions this AT-III-Hamilton species had decreased mobility compared with AT-III from the propositus (or normal AT-III) isolated only by heparin-Sepharose chromatography. When incubated with either human alpha-thrombin or human factor Xa, this AT-III-Hamilton species was unreactive. Approximately 50% of the AT-III from the propositus isolated by heparin-Sepharose chromatography, when incubated with either human alpha-thrombin or factor Xa, did not form complex but was cleaved, presumably at the reactive center Arg393-Ser394. To further substantiate the biological behavior of this variant, AT-III- Hamilton polypeptides were synthesized in a cell-free system. This recombinantly produced AT-III-Hamilton, when incubated with either human alpha-thrombin or factor Xa, was cleaved by both these proteases, but did not show any complex formation. The results indicate that AT- III-Hamilton does not form a stable covalent inhibitory complex with these serine proteases but can be cleaved at the reactive center. Thus, the inhibition of serine proteases by their natural inhibitors (the serpins) involves at least two separate, but interrelated events; hydrolysis at the reactive center followed by complex formation. AT-III- Hamilton is capable of only the first of these events.
High-dose cyclophosphamide, carmustine, and etoposide followed by autologous peripheral stem cell transplantation for patients with relapsed Hodgkin's disease [published erratum appears in Blood 1991 Dec 15;78(12):3330]
Authors: Kessinger A , Bierman PJ , Vose JM , Armitage JO 
Published: October 2019

Abstract
Between February 1986 and March 1990, 56 patients with relapsed Hodgkin's disease treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) received an autologous peripheral stem cell transplantation (PSCT) rather than an autologous bone marrow transplantation (ABMT) because each patient had a marrow abnormality, either hypocellularity or tumor involvement. At least 6.5 x 10(8) [corrected] mononuclear cells/kg patient weight were collected from the peripheral blood of each patient, cyropreserved, and returned intravenously following CBV administration. Three patients had an early death 2, 22, and 25 days after PSCT. The actuarial event-free survival for these 56 patients at 3 years was 37% and was at least as good as that reported for relapsed Hodgkin's disease patients treated with CBV and ABMT. The 30 patients who had no marrow metastases at the time of PSC harvesting had an actuarial event-free survival of 47%, while those 26 patients with marrow metastases had a significantly different actuarial event-free survival of 27% (P = .02). CBV and PSCT for patients with relapsed Hodgkin's diseases who have marrow hypocellularity in traditional harvest sites or histopathologic evidence of BM metastases can result in long-term event-free survival.
Proliferative responses to interleukin-3 and granulocyte colony- stimulating factor distinguish a minor subpopulation of CD34-positive marrow progenitors that do not express CD33 and a novel antigen, 7B9
Authors: Litzow MR , Brashem-Stein C , Andrews RG , Bernstein ID 
Published: October 2019

Abstract
Human hematopoietic colony-forming cells (CFC) express the CD34 antigen (CD34+) as well as differentiation antigens such as CD33 and HLA-DR. CD34+ cells that do not express these latter differentiation antigens have been shown to contain few CFC in direct culture, but generate increasing numbers of CFC when cultured over a marrow stromal cell layer in the long-term culture system. In this study we determined if CD34+ cells with low or absent expression of CD33 and a novel antigen, 7B9 (CD34+CD33–7B9-), could be distinguished from CD34+ cells expressing these antigens (CD34+CD33+7B9+) based on their proliferative responses to interleukin-3 (IL-3) and granulocyte colony-stimulating factor (G-CSF) in a short-term liquid culture system. These two populations were separated by fluorescence-activated cell sorting, cultured with IL-3 (10 ng/mL), G-CSF (100 ng/mL), or IL-3 and G-CSF, and 3H-thymidine uptake was measured. CD34+CD33–7B9- cells proliferated in the presence of IL-3, but not G-CSF. However, a synergistic response to the combination of IL-3 and G-CSF was seen in most experiments. In contrast, CD34+CD33+7B9+ cells proliferated in the presence of either IL-3 or G-CSF but did not display an additive or synergistic response to the combination of IL-3 and G-CSF. In colony-forming assays performed before and after liquid culture, the CD34+CD33–7B9- cells in two experiments contained 0.3% and 2.2% of all sorted marrow CFC before liquid culture and generated 40-fold and ninefold increases in the number of granulocyte-macrophage colony-forming units (CFU-GM), respectively, after liquid culture with IL-3 and G-CSF. In contrast, the CD34+CD33+7B9+ cells contained 99.7% and 97.8% of all sorted marrow CFC before liquid culture and had no change or a threefold increase in the number of CFU-GM, respectively, after liquid culture with IL-3 and G-CSF. Single-cell liquid cultures containing IL-3 and G-CSF with cells that were either CD34+CD33–7B9- and depleted of mature lymphoid cells (CD34+lin-) or were CD34+lin+ showed that a higher proportion of wells containing a CD34+lin- cell gave rise to one or more CFC (8.7%) than did wells containing a CD34+lin+ cell (2.9%), with the responding cells in the former population giving rise to an average of 2.9 +/- 0.6 CFC and in the latter population, 2.0 +/- 1.0 CFC.(ABSTRACT TRUNCATED AT 400 WORDS)
Comparative analysis of the in vivo radioprotective effects of recombinant granulocyte colony-stimulating factor (G-CSF), recombinant granulocyte-macrophage CSF, and their combination
Authors: Waddick KG , Song CW , Souza L , Uckun FM 
Published: October 2019

Abstract
The purpose of the present study was to evaluate and compare the in vivo radioprotective effects of pre-total body irradiation (TBI) conditioning with recombinant granulocyte colony-stimulating factor (rG- CSF) and recombinant granulocyte-macrophage CSF (rGM-CSF) in a large series of lethally and supralethally irradiated mice. Also analyzed were the radioprotective effects of simultaneous as well as sequential combinations of rG-CSF and rGM-CSF. Our findings in 1,180 mice provide direct evidence that in vivo administration of rG-CSF or rGM-CSF before TBI protects a significant fraction of mice from the lethal effects of LD100/30 TBI. At equivalent doses, rG-CSF displayed a more potent radioprotective activity than rGM-CSF. Not only was rG-CSF radioprotective at much smaller doses than rGM-CSF, the survival rate after lethal TBI was also significantly higher in mice receiving optimally radioprotective doses of rG-CSF as compared with mice receiving optimally radioprotective doses of rGM-CSF. Pretreatment of mice with rGM-CSF markedly attenuated the radioprotective affects of rG- CSF in lethally as well as supralethally irradiated mice. Pretreatment with rG-CSF followed by rGM-CSF was slightly more effective than rG-CSF alone in supralethally irradiated mice but not in lethally irradiated mice. Notably, marked differences among different strains of mice were noted regarding the optimally radioprotective doses of rG-CSF or rGM- CSF as well as probability of survival and median survival time after lethal or supralethal TBI. This report confirms and extends previous studies concerning the potential of cytokines in prevention or therapy of lethal radiation injury.
Abnormal methylation of the calcitonin gene marks progression of chronic myelogenous leukemia
Authors: Nelkin BD , Przepiorka D , Burke PJ , Thomas ED , Baylin SB 
Published: October 2019

Abstract
The clinical aspects of disease progression in chronic myelogenous leukemia (CML) are well established, but the nature of the molecular events responsible is not known. We have previously reported a consistent pattern of novel sites of methylation in the 5′ region of the calcitonin (CT) gene and other chromosome 11p loci in acute myelogenous and and lymphoid leukemias. In the present study, CT gene methylation patterns were investigated in peripheral blood from 51 patients with CML. Abnormal patterns were found in only 2 of 31 patients in chronic phase, but in 5 of 8 patients in accelerated phase, and in 11 of 12 patients in blast crisis (P less than .005). For one patient studied in blast crisis, abnormal CT gene methylation was found in the peripheral blast cells but not in the granulocytes. In two of three patients studied with CML and having normal peripheral cell patterns, abnormal patterns were found in marrow blast cells. In one patient, only partial normalization of the CT gene methylation pattern was seen after chemotherapy induction of a second chronic phase and the patient relapsed 5 months later. Our findings indicate that abnormal methylation of the 5′ region of the CT gene is regularly a marker of disease progression in CML which may prove clinically useful. This abnormal methylation site is part of an imbalance in DNA methylation that may play a role in the progressive genetic instability which characterizes the advancing stages of CML.
Interleukin-7 differentiates a subgroup of acute lymphoblastic leukemias
Authors: Skjonsberg C , Erikstein BK , Smeland EB , Lie SO , Funderud S , Beiske K , Blomhoff HK 
Published: October 2019

Abstract
The bone marrow stromal cell-derived growth factor interleukin-7 (IL-7) is known to stimulate growth of normal human B-cell precursors. In the present report, we have examined the effect of IL-7 on neoplastic B- cell precursors. Leukemic cells from 20 patients with common acute lymphoblastic leukemia (ALL) were highly purified by removing contaminating T cells and monocytes by rosetting with immunomagnetic beads. IL-7 markedly reduced the DNA synthesis in leukemic cells from three patients. This inhibition of DNA synthesis was accompanied by maturation of the cells, as demonstrated by the induced expression of the differentiation antigens CD19, CD20, CDw75, and surface mu-chain, and a decreased expression of terminal deoxynucleotidyl transferase. By examining G1 parameters, such as MYC, 4F2, and transferrin-receptor levels analyzed by flow cytometry as well as RNA and the cell cycle regulated antigen Ki67, it appeared that the cells were inhibited late in G1. Leukemic cells from the majority of the cases (12 of the 20 patients) responded to IL-7 with enhanced DNA synthesis without detectable maturation, as has been reported for their normal counterparts. Low molecular weight B-cell growth factor greatly potentiated the IL-7-induced growth stimulation of these cells. Thus, we have shown that IL-7 is capable of inhibiting proliferation of leukemic cells isolated from a subgroup of ALLs, and that this growth inhibition is accompanied by maturation of the cells.
Homing and progression patterns of childhood acute lymphoblastic leukemias in severe combined immunodeficiency mice
Authors: Cesano A , O'Connor R , Lange B , Finan J , Rovera G , Santoli D 
Published: October 2019

Abstract
The aim of this study was to analyze the homing and progression patterns of childhood acute lymphoblastic leukemias (ALL) in mice with severe combined immunodeficiency (SCID). Upon intraperitoneal (IP) transfer, cells from relapse samples of three children with T-lineage ALL spread hematogenously and infiltrated the non-lymphoid and/or lymphoid organs with a pattern reminiscent of the human clinical disease. These mice either died or were killed in extremis at a mean of 9 weeks. Moreover, cell lines established in vitro from two of these samples manifested identical homing and progression in the SCID mouse as compared with the original patients' cells. Thus, long-term culture of the primary leukemic T cells did not alter their invasive potential and migration pattern. When engrafted IP, three cell lines established from pre-B-ALL cases displayed primarily a lymphatic spread with induction of local tumor masses and kidney/liver nodules. Mice were killed at 11 to 13 weeks, but had not developed imminently fatal leukemia. However, when transferred intravenously, one pre-B ALL cell line was able to spread hematogenously and to infiltrate both lymphoid and non-lymphoid tissues. Overall, these data demonstrate that the SCID mouse provides an efficient and reproducible model to study the pathogenesis of childhood ALL, and may be a suitable system for evaluating therapy.
Localization of cells producing erythropoietin in murine liver by in situ hybridization [see comments]
Authors: Koury ST , Bondurant MC , Koury MJ , Semenza GL 
Published: October 2019

Abstract
In situ hybridization using antisense RNA probes was used to localize cells that produce erythropoietin (EPO) in the livers of anemic transgenic mice expressing the human EPO gene and in livers of anemic nontransgenic mice. In transgenic mice bled from a hematocrit of 55% to one of 10%, hepatocytes surrounding central veins synthesized large amounts of human EPO mRNA. EPO-producing cells were very rare in the area of portal triads. In transgenic mice bled to a hematocrit of 20%, a similar number and distribution of cells contained human EPO mRNA as was found with a 10% hematocrit, but the cells were less heavily labeled, indicating increased EPO production per cell at 10% hematocrit as compared with 20% hematocrit. No human EPO mRNA was detected in the kidneys of anemic transgenic mice, although endogenous murine EPO mRNA was strongly expressed in cortical interstitial cells. In sections of livers from nontransgenic mice bled from a hematocrit of 45% to one of 10%, only isolated cells produced EPO. When the types of cells could clearly be identified, approximately 80% of these cells were hepatocytes, while 20% had a nonepithelial morphology and were located in or adjacent to the sinusoidal spaces. When the sense strand was used as the RNA probe for in situ hybridization, no labeled cells were seen in normal or anemic livers. These results demonstrate that hepatocytes are responsible for production of EPO in both transgenic and nontransgenic mice and that a second cell type that is similar in morphology to EPO-producing interstitial cells in the kidney also produces EPO in the livers of nontransgenic mice.
Expression of c-jun during macrophage differentiation of HL-60 cells
Authors: Gaynor R , Simon K , Koeffler P 
Published: October 2019

Abstract
Cellular transcription factors are important in the regulation of cellular genes. Recent studies have indicated that a class of cellular genes known as early response genes are important in the control of cellular growth properties. Two of these genes, c-jun and c-fos, play an important role in the control of cellular differentiation. Because the acute myelogenous leukemia cell line, HL-60, is capable of differentiating to either macrophages or granulocytes, it provides a good model to understand differential gene expression. To determine if the modulation of c-jun was important in the differentiation of HL-60 cells to either macrophages or granulocytes, expression of c-jun mRNA was determined by Northern analysis at various times following treatment with a variety of differentiating agents, including 12- tetradeconyl-phorbol 13-acetate (TPA), retinoic acid (RA), dimethyl sulfoxide (DMSO), or 1,25 dihydroxyvitamin D3 [1,25 (OH)2 D3]. Both TPA and 1,25(OH)2D3, which induce HL-60 cells to differentiate to macrophages, resulted in marked increases in c-jun mRNA; while RA and DMSO, which induce HL-60 cells to differentiate to granulocytes, did not greatly alter c-jun mRNA expression. HL-60 cell lines resistant to macrophage differentiation after exposure to either 1,25(OH)2D3 or TPA did not result in increases in c-jun mRNA. These results suggest that elevation of c-jun mRNA in HL-60 cells correlated temporally with differentiation to macrophages. Thus, c-jun may be a critical cellular transcription factor involved in macrophage differentiation.