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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by refractory cytopenias in one or more myeloid cell lines and an increased probability of transformation to acute leukemia. Supportive care remains the mainstay of therapy in MDS and frequently includes monotherapy and combination therapy with hematopoietic growth factors, such as erythropoietin, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor. Clinical trials have demonstrated the ability of growth factors to improve neutropenia and anemia in selected patients with MDS, which may have clinical, quality-of-life, and economic benefits for patients even though overall survival has not been improved. This paper reviews the role of hematopoietic growth factors in the treatment of MDS.
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PMID:Hematopoietic growth factors in myelodysplastic syndromes. 1456 88

Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates proliferation of hematopoietic cells of the macrophage and granulocyte lineages and is used clinically to treat neutropenia and other myeloid disorders. Because of its short circulating half-life, GM-CSF is administered to patients by daily injection. We describe here the engineering of highly potent, long-acting human GM-CSF proteins through site-specific modification of GM-CSF cysteine analogues with a cysteine-reactive poly(ethylene glycol) (PEG) reagent. Thirteen cysteine analogues of GM-CSF were constructed, primarily in nonhelical regions of the protein believed to lie away from the major receptor binding sites. The GM-CSF cysteine analogues were properly processed but insoluble following secretion into the Escherichia coli periplasm. The proteins were refolded and purified by column chromatography. Ten of the cysteine analogues could be modified with a 5-kDa maleimide PEG, and seven of the mono-PEGylated proteins were purified by ion-exchange column chromatography. Biological activities of the 13 cysteine analogues and 7 PEGylated cysteine analogues were comparable to that of wild-type GM-CSF in an in vitro cell proliferation assay using human TF-1 cells. One cysteine analogue was modified with larger 10-, 20-, and 40-kDa PEGs, with only minimal loss of in vitro bioactivity. Pharmacokinetic experiments in rats demonstrated that the PEGylated proteins had up to 47-fold longer circulating half-lives than wild-type GM-CSF. These data demonstrate the utility of site-specific PEGylation for creating highly potent, long-acting GM-CSF analogues and provide further evidence that the nonhelical regions of human GM-CSF examined are largely nonessential for biological activity of the protein.
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PMID:Site-specific PEGylation of engineered cysteine analogues of recombinant human granulocyte-macrophage colony-stimulating factor. 1617 10

The human granulocyte macrophage colony-stimulating factor (GM-CSF) is a glycoprotein with important clinical applications for the treatment of neutropenia and aplastic anemia and reducing infections associated with bone marrow transplants. We evaluated the potential for using a potato virus X (PVX) viral vector system for efficient expression of the biologically functional GM-CSF protein in Nicotiana benthamiana leaves. The GM-CSF gene was cloned into PVX viral expression vector, driven with the CaMV 35S promoter. Gene transfer was accomplished by inoculating N. benthamiana leaves with the plasmid DNA of PVX vector containing the GM-CSF gene. The expression level of the recombinant GM-CSF protein was determined with ELISA and its size was confirmed by Western blot analysis. The results showed that: (1) leaf age significantly affects GM-CSF protein concentration with younger leaves accumulating 19.8 mg g(-1) soluble protein which is 2.6 times the concentration in older leaves, (2) recombinant protein accumulation within a given leaf declined slightly over time but was not significantly different between 7 and 11 days post-inoculation (dpi), and (3) the two leaves immediately above the inoculated leaves play an important role for GM-CSF accumulation in the younger leaves. Protein extracts of infected N. benthamiana leaves contained recombinant human GM-CSF protein in concentrations of up to 2% of total soluble protein, but only when the pair of leaves immediately above the inoculated leaves remained intact. The recombinant protein actively stimulated the growth of human TF-1 cells suggesting that the recombinant human GM-CSF expressed via PVX viral vector was biologically active.
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PMID:Efficient transient expression of human GM-CSF protein in Nicotiana benthamiana using potato virus X vector. 1661 40

Cancer chemotherapy is associated with several life threatening complications, including bone marrow suppression and leucopenia. To overcome this problem, colony stimulating factor (CSF), granulocyte colony stimulating factor (GCSF) and granulocyte macrophage colony stimulating factor (GMCSF), can be used, however, these therapeutics are expensive and have several disadvantages, including tumor growth promoting activities. This study attempted to use an immunostimulatory neem (Azadirachta indica) leaf preparation (NLP) to prevent the cyclophosphamide (CYP) induced reduction in the WBC count. Pretreatment of mice with NLP reduced the extent of leucopenia and neutropenia in normal and tumor bearing CYP treated mice. NLP pretreatment enhanced in vitro tumor cell cytotoxicity by peripheral blood mononuclear cells (PBMC) from CYP treated mice in either normal or tumor bearing conditions. Similarly, NLP pretreatment of mice enhanced the CYP mediated in vivo tumor growth inhibition and survivability of the host. Based on these observations, it is concluded that NLP would be an effective tool to reduce CYP-induced hematological complications.
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PMID:Pretreatment with neem (Azadirachta indica) leaf preparation in Swiss mice diminishes leukopenia and enhances the antitumor activity of cyclophosphamide. 1680 77

Human intravenous immunoglobulin (IVIg) preparations are increasingly used for the treatment of autoimmune diseases. Earlier work demonstrated the presence of autoantibodies against Fas in IVIg, suggesting that IVIg might be able to induce caspase-dependent cell death in Fas-sensitive cells. In this study, we demonstrate that sialic acid-binding Ig-like lectin 9 (Siglec) represents a surface molecule on neutrophils that is activated by IVIg, resulting in caspase-dependent and caspase-independent forms of cell death. Neutrophil death was mediated by naturally occurring anti-Siglec-9 autoantibodies present in IVIg. Moreover, the efficacy of IVIg-mediated neutrophil killing was enhanced by the proinflammatory cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma), and this additional cell death required reactive oxygen species (ROSs) but not caspases. Anti- Siglec-9 autoantibody-depleted IVIg failed to induce this caspase-independent neutrophil death. These findings contribute to our understanding of how IVIg preparations exert their immunoregulatory effects under pathologic conditions and may provide a possible explanation for the neutropenia that is sometimes seen in association with IVIg therapy.
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PMID:Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations. 1710 87

In a randomized clinical trial (RCT), we often encounter non-compliance with the treatment protocol for a subset of patients. The intention-to-treat (ITT) analysis is probably the most commonly used method in a RCT with non-compliance. However, the ITT analysis estimates 'the programmatic effectiveness' rather than 'the biological efficacy'. In this paper, we focus attention on the latter index and consider use of the risk difference (RD) to measure the effect of a treatment. Based on a simple additive risk model proposed elsewhere, we develop four asymptotic interval estimators of the RD for repeated binary measurements in a RCT with non-compliance. We apply Monte Carlo simulation to evaluate and compare the finite-sample performance of these interval estimators in a variety of situations. We find that all interval estimators considered here can perform well with respect to the coverage probability. We further find that the interval estimator using a tanh(-1)(x) transformation is probably more precise than the others, while the interval estimator derived from a randomization-based approach may cause a slight loss of precision. When the number of patients per treatment is large and the probability of compliance to an assigned treatment is high, we find that all interval estimators discussed here are essentially equivalent. Finally, we illustrate use of these interval estimators with data simulated from a trial of using macrophage colony-stimulating factor to reduce febrile neutropenia incidence in acute myeloid leukaemia patients.
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PMID:Interval estimation of the risk difference in non-compliance randomized trials with repeated binary measurements. 1717 72

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor, which has been used as a therapeutic agent in clinical cases like neutropenia. In this study, we report the production of recombinant human GM-CSF in the methylotrophic yeast Pichia pastoris through secretory expression using the inducible AOX1 promoter. Recombinant P. pastoris GS115 cells were grown in fed batch cultures to obtain a biomass density of 55.6 gDCW L(-1) and a high volumetric activity of 131 mg L(-1) of GM-CSF. The protein migrated as a diffuse band on SDS-PAGE at the range of 28-35 kDa indicating differential glycosylation. The secreted protein was purified to 95% in two steps using cation exchange and size exclusion chromatography.
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PMID:Production and purification of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) from high cell density cultures of Pichia pastoris. 1745 57

The leukocyte colony stimulating factors (recombinant granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor) have become widely used in hematology and oncology to raise neutrophil levels in patients with neutropenia. They have been used primarily by rheumatologists to treat neutropenia accompanying infections in patients with Felty's syndrome or systemic lupus erythematosus and in infected patients made neutropenic with drug therapy. These factors have been lifesaving. The drugs generally are well tolerated and adverse effects usually are easily treated. Some of the adverse effects of the agents may mimic de novo rheumatic conditions such as vasculitis and Sweet's syndrome. There may be important future roles for these growth factors in treatment protocols for patients with rheumatic disease using more aggressive chemotherapy regimens.
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PMID:Leukocyte colony stimulating factors for rheumatologists. 1907 90

In acute myeloid leukaemia (AML), age has a definite effect on the biology of the disease and also determines the outcome of chemotherapy. AML cells constitutively express mRNA and produce several haematopoietic cytokines. The haematopoietic cytokines: SCF, IL-3, GM-CSF and G-CSF induce leukaemic colonies or activate DNA synthesis in about 80% of AML cases. Both M-CSF and thrombopoietin stimulated AML cell proliferation is seen in vitro in about 50% of cases. Both IL-6 and IL-11 showed little proliferative activity on primary AML cells. The combinations of these cytokines were synergistic in stimulating the proliferation of AML cells. On the other hand, the inhibitory haematopoietic cytokines: TNF-alpha, TGF-beta, IFN-gamma and IL-4 have shown multiple effects on AML blast cell proliferation. In several in vitro systems, haematopoietic cytokines have failed to induce maturation of AML blasts. Only in AML with t(8;21), G-CSF has induced granulocytic maturation of AML blasts in vitro. AML cells with chromosomal abnormalities involving the 21q22 region differentiate in vitro into eosinophils in the presence of IL-5. IL-6 and IFN-alpha have induced megakaryocytic differentiation of blast cells from acute megakaryoblastic leukemia (M7) patients. The haematopoietic cytokines: SCF, IL-3 and GMCSF have protected in vitro AML cells from chemotherapy-induced apoptosis. Many clinical studies have been recently reported evaluating the effect of the haematopoietic cytokines: GM-CSF, G-CSF, IL-3 and PIXY321 as adjuncts to the chemotherapy of AML patients. Most studies have shown these haematopoietic cytokines to be well-tolerated and effective in augmenting neutrophil recovery in elderly AML patients when given after chemotherapy. On the other hand, considerable number of studies using these cytokines before and during chemotherapy to recruit AML cells into cell cycle and thus make them more susceptible to chemotherapy have reaveled no benefit. Several clinical trials have shown promising results after the use of IL-2 either as remission induction therapy in refractory and/or relapsed AML patients or as post-remission consolidative immunotherapy. Haematopoietic cytokines administered after chemotherapy can shorten the duration of neutropenia and hospitalisation without a significant effect on treatment outcome. On the other hand, their use before and during chemotherapy has yielded no benefit, and instead have led to delay of platelet recovery and worse survival rate in some elderly AML patients.
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PMID:Haematopoietic cytokines in the biology and treatment of acute myeloid leukaemia. 2159 Feb 10

Hematopoietic colony-stimulating factors coordinate the proliferation and maturation of bone marrow and peripheral blood cells during normal hematopoiesis. Most of these factors are now available as recombinant human colony-stimulating factors, and preclinical and clinical testing is proceeding rapidly. Granulocyte and granulocyte/macrophage colony-stimulating factors have been the most extensively studied to date. In human clinical trials, granulocyte colony-stimulating factor improves neutrophil counts and function, reduces episodes of febrile neutropenia, improves neutrophil recovery after disease- or treatment-induced myelosuppression, and reduces the number of serious infections in several neutropenic disease states. Granulocyte/macrophage colony-stimulating factor has similar biological properties but may also improve eosinophil proliferation and function, and platelet cell recovery after myelotoxic bone marrow injury, Interleukin-1 boosts the effects of granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor, but also may promote the resolution of established infections in conjunction with antibiotics. The therapeutic realities and future therapeutic implications of these agents for the therapy of infections, cancer and hemopoietic disorders are discussed.
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PMID:The potential role of recombinant hematopoietic colony-stimulating factors in preventing infections in the immunocompromised host. 2252 14


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