bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products
Authors: van Hinsbergh VW , Bauer KA , Kooistra T , Kluft C , Dooijewaard G , Sherman ML , Nieuwenhuizen W 
Published: October 2019

Abstract
Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI- 1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion, whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were slightly decreased, 5% on average, suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products, and separately of fibrin degradation products and fibrinogen degradation products, was found. This indicates that fibrinolysis persisted, at least partly, in the presence of high levels of PAI activity. Whereas PAI-1 production increased, t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore, it is possible that thrombin, not TNF, is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients.
Transformation-associated alterations in interactions between pre-B cells and fibronectin
Authors: Lemoine FM , Dedhar S , Lima GM , Eaves CJ 
Published: October 2019

Abstract
Marrow stromal elements produce as yet uncharacterized soluble growth factors that can stimulate the proliferation of murine pre-B cells, although close contact between these two cell types appears to ensure a better pre-B cell response. We have now shown that freshly isolated normal pre-B cells (ie, the B220+, surface mu- fraction of adult mouse bone marrow) adhere to fibronectin (FN) via an RGD cell-attachment site, as shown in a serum-free adherence assay, and they lose this functional ability on differentiation in vivo into B cells (ie, the B220+, surface mu+ fraction). Similarly, cells from an immortalized but stromal cell-dependent and nontumorigenic murine pre-B cell line originally derived from a Whitlock-Witte culture were also found to adhere to fibronectin (FN) via an RGD cell-attachment site. Moreover, in the presence of anti-FN receptor antibodies, the ability of this immortalized pre-B cell line to proliferate when co-cultured with a supportive stromal cell line (M2–10B4 cells) was markedly reduced (down to 30% of control). This suggests that pre-B cell attachment to FN on stromal cells may be an important component of the mechanism by which stromal cells stimulate normal pre-B cell proliferation and one that is no longer operative to control their more differentiated progeny. Two differently transformed pre-B cell lines, both of which are autocrine, stromal-independent, tumorigenic in vivo, and partially or completely differentiation-arrested at a very early stage of pre-B cell development, did not bind to FN. In addition, anti-FN receptor antibodies were much less effective in diminishing the ability of these tumorigenic pre-B cells to respond to M2–10B4 cell stimulation, which could still be demonstrated when the tumorigenic pre-B cells were co- cultured with M2–10B4 cells at a sufficiently low cell density. Analysis of cell surface molecules immunoprecipitated from both the nontumorigenic and tumorigenic pre-B cell lines by an anti-FN receptor antibody showed an increase in very late antigen (VLA) alpha chain(s) in both tumorigenic pre-B cell lines and a decrease in the beta 1 chain in one. Interestingly, all of the pre-B cell lines expressed similar amounts of messenger RNA for the beta 1 chain of the FN receptor. These results suggest that alteration of FN receptor expression on pre-B cells may represent a mechanism contributing to the outgrowth of leukemic pre-B cells with an autocrine phenotype and capable of stromal cell-independent, autonomous growth.
Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment
Authors: Clauss IM , Vandenplas B , Wathelet MG , Dorval C , Delforge A , Content J , Stryckmans P , Huez GA 
Published: October 2019

Abstract
Recombinant human interferon-alpha (IFN-alpha) can induce a hematologic remission in patients with chronic myeloid leukemia. However, some patients are resistant and others develop late resistance to the IFN- alpha treatment. To understand the molecular mechanism of this resistance, we have analyzed the expression of 10 IFN-inducible genes in the cells of three resistant patients, two responsive patients, and six healthy controls. Northern blot hybridizations showed that all the genes were induced in in vitro IFN-alpha treated peripheral blood cells of the patients and healthy controls. These genes were also inducible in peripheral blood and bone marrow cells of two out of two resistant patients administered an injection of IFN-alpha. We conclude that the resistance to the IFN-alpha treatment of the chronic myeloid leukemia patients we studied is not due to (1) the absence of induction of any of the 10 IFN-inducible genes we studied, including the low-molecular- weight 2′-5′oligoadenylate synthetase; (2) the presence of an antagonist of IFN-alpha in the peripheral blood or bone marrow cells; and (3) the presence of neutralizing anti-IFN-alpha antibodies.
Interleukin-8 production in red blood cell incompatibility
Authors: Davenport RD , Strieter RM , Standiford TJ , Kunkel SL 
Published: October 2019

Abstract
Hemolytic transfusion reactions (HTR) are characterized by fever, shock, organ system failure, intravascular coagulation, and possibly death. The same findings may be associated with sepsis. Neutrophils have been implicated in the pathogenesis of HTR, although a mechanism for neutrophil activation has not been shown. In addition, the possible role that cytokines may play in HTR has not been investigated. We show that interleukin-8 (IL-8), a cytokine with chemotactic and neutrophil- activation properties, is produced in whole blood following addition of ABO-incompatible red blood cells, in a dose- and time-dependent manner related to the degree of hemolysis, and is inhibited by inactivation of complement. IL-8 production is accompanied by increased gene expression in the buffy coat. This observation has implications for the understanding of the pathogenesis of and for the treatment of HTR.
Immunity against Pseudomonas aeruginosa adoptively transferred to bone marrow transplant recipients
Authors: Gottlieb DJ , Cryz SJ Jr , Furer E , Que JU , Prentice HG , Duncombe AS , Brenner MK 
Published: October 2019

Abstract
Infection is a common problem for bone marrow transplant (BMT) recipients during the period of neutropenia that immediately follows the procedure. Gram-negative infections present a particular hazard in these immunocompromised hosts. To augment host defenses against one such pathogen, Pseudomonas aeruginosa, we immunized bone marrow transplant donors and/or recipients with a polyvalent O-polysaccharide- toxin A conjugate vaccine. When either donor or recipient alone was vaccinated before transplant, no increase in specific antibody titers to any of the vaccine components was observed in the recipient. However, when both donor and recipient were vaccinated before transplant, increases in antibody titers to all polysaccharide components occurred to levels shown to be protective in animal models of gram-negative sepsis. Specific antibodies were primarily of the IgG1 and IgG2 subclass even though IgG2 subclass deficiency is common after BMT. The requirement for both donor and recipient immunization reflects the need for primed donor B lymphocytes in the marrow inoculum to be transferred into an antigen-containing environment so that maximum B- cell proliferation and antibody secretion can occur. Adoptive transfer of antibody responses to Pseudomonas aeruginosa and other common bacterial pathogens has the potential to reduce infection-related morbidity and mortality after allogeneic bone marrow transplantation.
Oxidants, ATP depletion, and endothelial permeability to macromolecules
Authors: Wilson J , Winter M , Shasby DM 
Published: October 2019

Abstract
Oxidants can reversibly increase the permeability of endothelium to ions and macromolecules. Oxidants also deplete ATP in cultured endothelial cells. We asked if oxidant-mediated ATP depletion, alone, accounted for the effects of oxidants on endothelial permeability to macromolecules. When porcine pulmonary artery endothelial cells were exposed to 2.5 mmol/LH2O2, ATP was depleted to 31.7% +/- 1.8% of control within 15 minutes and was reduced to 23.1% +/- 2.0% of control after 30 minutes. To determine if this magnitude of ATP depletion could account for the oxidant-induced increase in endothelial permeability to macromolecules, we measured ATP in endothelial cells exposed to metabolic inhibitors of ATP production. We then measured the effects of these metabolic inhibitors on endothelial monolayer permeability to macromolecules. ATP levels were reduced to 44% +/- 4% of control by 12 mmol/L deoxyglucose (DOG) in the absence of glucose and to 2% +/- 1.3% of control by DOG with 25 nmol/L antimycin A in the absence of glucose. Reduction of endothelial cell ATP to these levels with the metabolic inhibitors did not alter the flux of albumin or dextran across the endothelial monolayers. Thus ATP depletion, by itself, does not explain oxidant-induced changes in endothelial permeability to macromolecules.
Relationship between globin mRNA accumulation and commitment to terminal cell differentiation in inducer sensitive and resistant erythroleukemia variants
Authors: Weich N , Marks PA , Rifkind RA 
Published: October 2019

Abstract
The relationship between the kinetics of commitment to terminal cell differentiation and the rates of accumulation of globin mRNA has been examined during the induction of erythroid differentiation by polar/apolar chemical inducers in murine erythroleukemia cells (MELC), under conditions of more and less rapid commitment. Two differentiation inducers and three MELC variants have been studied. Hexamethylene bisacetamide (HMBA) initiates more rapid commitment than does dimethylsulfoxide (Me2SO). MELC variant DR10 is resistant to induction by Me2SO and responds sluggishly to HMBA, in comparison with the DS19- Sc9 variant. V3.17, an MELC variant resistant to low concentrations of vincristine, shows increased sensitivity to the inducers and an accelerated rate of commitment to terminal differentiation compared with DS19-Sc9. It is demonstrated that commitment and the actual expression of differentiation, as measured by the accumulation of alpha- , beta maj-, and beta min-globin mRNA, are temporally coordinated functions during induced differentiation of a transformed cell line by exposure to polar/apolar agents.
Interleukin-1 alpha also induces granulocyte-macrophage colony- stimulating factor in immature normal bone marrow cells
Authors: Bot FJ , Schipper P , Broeders L , Delwel R , Kaushansky K , Lowenberg B 
Published: October 2019

Abstract
The cytokine interleukin-1 (IL-1) plays a role in the regulation of normal as well as leukemic hematopoiesis. In acute myeloid leukemia (AML), IL-1 induces autocrine granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) production, and these factors may then synergistically induce proliferation in AML blast cells. In this report, we show that IL-1 stimulates DNA synthesis of highly enriched normal bone marrow blast cells (CD34 positive, adherent cell depleted, CD3/CD14/CD15 negative). The stimulative effect of IL-1 can be blocked with neutralizing anti-TNF alpha and anti-GM-CSF antibodies and, most efficiently, by the combination of anti-TNF alpha and anti-GM-CSF, but not with anti-G-CSF antibody, suggesting that IL-1- induced proliferation was initiated through TNF and GM-CSF release. Concentrations of TNF and GM-CSF increased in the culture medium of normal bone marrow blast cells after IL-1 induction. Of the IL-1- induced cells, 12% were positive for GM-CSF mRNA by in situ hybridization, as opposed to 6% of non-induced cells. Thus, in addition to its effect on leukemic blast cells, IL-1 also acts on normal marrow blast cells. We propose a scheme where IL-1 stimulation of normal bone marrow blast cells leads to the induction of TNF alpha and GM-CSF, which in association stimulate DNA synthesis efficiently according to a paracrine or autocrine mechanism within the marrow blast cell compartment.
Effects of recombinant human G-CSF, GM-CSF, IL-3, and IL-1 alpha on the growth of purified human peripheral blood progenitors
Authors: Takaue Y , Kawano Y , Reading CL , Watanabe T , Abe T , Ninomiya T , Shimizu E , Ogura T , Kuroda Y , Yokobayashi A 
Published: October 2019

Abstract
The effects of recombinant products of granulocyte colony-stimulating factors (G-CSF), granulocyte/macrophage CSF (GM-CSF), human interleukin- 3 (IL-3), and interleukin-1 (IL-1) were studied using purified target cell populations from patients undergoing peripheral blood stem cell transplantation after myeloablative therapy. Cells were subjected to combined purification procedures including negative selection with a panel of monoclonal antibodies (CD2, 3, 5, 10, and 20). The purified cells were enriched for HLA-DR+ (51% to 71%) and My-10+ (CD34; 37% to 54%) and had a plating efficiency of up to 20%. In the liquid- suspension limiting dilution clonal assay (LDA), purified progenitors responded directly to IL-3 by proliferation with single-hit kinetics. The ability of GM-CSF to support progenitor growth was inferior to that of IL-3, and the cells were virtually unresponsive when cultured with G- CSF, supporting the notion that these blood-derived progenitors belong to a primitive population of hematopoietic progenitor cells. The results obtained in simultaneous methycellulose cultures (MC) showed the same trend and provided additional information on the ability of GM- CSF and IL-3 to support erythroid progenitor growth. The combination of IL-3 plus G-CSF, but not IL-3 plus GM-CSF, resulted in a synergistic increase in colony number. IL-1 alpha increased both the size and number of colonies when added to IL-3 or G-CSF. Study of this enriched progenitor cell population in MC and LDA represents an excellent model for the investigation of myeloid and erythroid differentiation and for evaluating the influence of various cytokines on human hematopoiesis.
Structural and functional comparison of the genes for human platelet factor 4 and PF4alt
Authors: Eisman R , Surrey S , Ramachandran B , Schwartz E , Poncz M 
Published: October 2019

Abstract
Platelet factor 4 (PF4) is a 70 amino acid heparin-binding protein released from the alpha-granules of activated platelets. Its exact biologic function is not known, although PF4 is a member of a multigene family involved in chemotaxis, coagulation, inflammation, and cell growth. We previously cloned the cDNA for human PF4 from a human erythroleukemic (HEL) cell expression library. We now report the isolation and sequence determination of the gene for human PF4. This gene contains three exons and spans approximately 1,000 basepairs (bp). Concurrently, we have cloned a highly homologous gene that we have called PF4alt. We show that PF4 and PF4alt are non-allelic genes: the human PF4 gene is encoded on a 10 kilobasepairs (kb) EcoRI fragment, and its DNA sequence agrees with protein and cDNA data for PF4, while PF4alt is encoded in a polymorphic 3 or 5 kb EcoRI fragment. Compared with PF4, this gene has 14% DNA and 38% amino acid divergence in the signal peptide region, and 2.6% DNA and 4.3% amino acid divergence in the coding region of the mature protein. PF4alt contains three amino acid substitutions (P58----L, K66----E, and L67----H) near the C- terminus, in a region known to be critical for PF4 function. Primer extension studies show the 5′-untranslated region of PF4 is 73 bp long. A TATA box is present 30 bp 5′ to the transcription start site. A 90 bp stretch of pyrimidines (including 53 consecutive thymidine residues) begins at -227 bp and is analogous to a similar region of 30 residues 5′ to the rodent PF4 gene. This pyrimidine-rich region is absent from the PF4alt gene; however, DNA homology exists between the two human genes in the 5′- and 3′-flanking regions and extends for over 3.6 kb. Alternating purine/pyrimidine tracts occur both 5′ and 3′ to PF4 and PF4alt but do not define the endpoints of the gene duplication, which extend beyond these sequences at least at the 5′ end. Northern blot analysis using gene-specific oligonucleotides and platelet RNA showed an 800 or 900 nucleotide (n) message for PF4 and PF4alt, respectively. Northern blot and primer extension studies show that steady-state platelet PF4 mRNA levels are approximately one magnitude greater than PF4alt mRNA levels. Thus, these studies demonstrate that PF4alt mRNA is expressed in platelets. Whether PF4alt protein is expressed remains to be determined, and the nature of its biologic function needs to be studied.
Diminished A-LAK cytotoxicity and proliferation accompany disease progression in chronic myelogenous leukemia
Authors: Verfaillie C , Kay N , Miller W , McGlave P 
Published: October 2019

Abstract
We have compared the proliferative and cytotoxic capacities of a highly purified population of recombinant interleukin-2 (rIL-2)-activated peripheral blood mononuclear cells (PBMNC), termed adherent lymphokine- activated killer cells (A-LAK), in 15 chronic phase (CP) and 10 advanced disease (AD) Ph-positive chronic myelogenous leukemia (CML) patients. The selective enrichment of CML A-LAK cells depended on their propensity to adhere to plastic and to proliferate when cultured in the presence of rIL-2 for 14 days. In both CP and AD patients, 14-day culture resulted in growth of a uniform population of large granular lymphocytes. While less than 10% of the A-LAK cells were CD56-/CD3+ (mature T lymphocytes), 82% +/- 12% of A-LAK cells from early CP patients (diagnosed less than 1 year from study), 84% +/- 3% of A-LAK cells from late CP patients (studied greater than 1 year after diagnosis), and 87% +/- 3% of A-LAK cells from AD patients were CD56+/CD3- (activated natural killer [NK] cells). No bcr gene rearrangement could be found in A-LAK cells from 13 CP and six AD CML patients studied. A-LAK cells from seven early CP CML patients displayed similar cytotoxicity against K562 (80% +/- 7% lysis at effector:target ratio of 20:1) and against Raji (80% +/- 12% lysis) compared with A-LAK from 17 normal individuals (72% +/- 3% K562 lysis, P = .21; 74% +/- 5% Raji lysis, P = .39). However, the cytotoxicity of A-LAK cells from eight late CP patients (59% +/- 5% K562 lysis, P = .02; 52% +/- 8% Raji lysis, P = .02) and that of 10 AD patients studied at any point after diagnosis (31% +/- 3% K562 lysis, P less than .001; 25% +/- 6% Raji lysis, P less than .001) was significantly lower than that of seven early CP CML patients and 17 normals. The proliferative potential of A-LAK cells from seven early CP CML patients (291 +/- 191- fold) was significantly greater than that of A-LAK cells from 17 normal individuals (23 +/- 3-fold, P = .03), eight late CP patients (46 +/- 17- fold, P = .02), and 10 AD patients (5.4 +/- 1.9-fold, P = .01). In contrast to CML A-LAK, K562 cytotoxicity of unstimulated mature peripheral blood NK cells was significantly lower in early CP CML patients than in normals and remained low at all stages of disease.
Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes
Authors: Ganser A , Seipelt G , Lindemann A , Ottmann OG , Falk S , Eder M , Herrmann F , Becher R , Hoffken K , Buchner T 
Published: October 2019

Abstract
In a phase I-II study, nine patients with myelodysplastic syndromes and concomitant severe transfusion-dependent cytopenias were treated with recombinant human interleukin-3 (rhIL-3) to improve hematopoietic function. Doses of rhIL-3 ranged from 250 micrograms/m2 to 500 micrograms/m2 and were given as daily subcutaneous bolus injections for 15 days. Blood leucocyte counts increased 1.3- to 3.6-fold in all nine patients, including neutrophils, eosinophils, lymphocytes, basophils, and monocytes. The mean absolute neutrophil counts increased from 1,350/microL (range, 150 to 2,420) to 2,660/microL (range, 300 to 9,380) (P less than .05) immediately after the end of rhIL-3 therapy and to a maximum count of 4,096/microL (range, 350 to 10,820) (P less than .01). Platelet responses were seen in two of four profoundly thrombocytopenic patients, resulting in discontinuation of platelet transfusion. The requirements for red blood cell transfusion temporarily improved in one patient. Stimulation of plasma cells was evident by a significant increase in serum IgM and IgA levels. Mild side effects (fever, headache, local erythema, and bone pain) were observed in some patients, while transient thrombocytopenia developed in two patients. Disease progression with an increase in blast cells was seen in one patient. These results suggest that rhIL-3 is effective in stimulating hematopoiesis of all lineages in patients with myelodysplastic syndromes and may produce at least short-term hematologic improvement.
High-dose chemotherapy and autologous bone marrow transplantation in acute myeloid leukemia
Authors: McMillan AK , Goldstone AH , Linch DC , Gribben JG , Patterson KG , Richards JD , Franklin I , Boughton BJ , Milligan DW , Leyland MM 
Published: October 2019

Abstract
For younger patients with acute myeloid leukemia (AML), an allogeneic transplant from a matched sibling may afford the best chance of cure. In patients who are older or without a matched sibling donor, dose intensification can be achieved with an autologous bone marrow transplant (ABMT). We report here the results of a high-dose chemotherapy regime with nonpurged ABMT in 82 adult patients in first remission of AML with a median follow-up of 31 months. The median age was 40 years (range 16 to 57 years). The median interval between remission and ABMT was 5 months (range 1 to 12 months). Twenty-eight of these patients received a second course of the same high-dose chemotherapy and ABMT. The procedure related mortality rate was 6%. The projected leukemia-free survival (LFS) at 5 years is 48% for all 82 patients and 50% for the 76 patients with no known preceding myelodysplastic syndrome. For those patients with primary AML who received a double ABMT the projected LFS is 67%. The interval between remission and ABMT did not predict for either relapse or LFS. ABMT using a multidrug chemotherapy protocol is less toxic than allogeneic BMT yet results in a similar LFS.