Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tocols are a family of eight isomers consisting of four tocopherols and four tocotrienols that exist in four isomeric forms: alpha (alpha), beta (beta), gamma (gamma), and delta (delta). Recently, tocols were found to have important and unique biological effects on nutrition and health other than antioxidant properties and are, therefore, now receiving increased attention. We have demonstrated the radioprotective efficacy of various tocol analogs and some of their esters. Three forms of tocols - alpha-tocopherol, alpha-tocopherol succinate, and gamma-tocotrienol - significantly protected mice against lethal gamma irradiation when administered subcutaneously 24 h before irradiation. The radioprotective effects of tocols on survival were associated with peripheral blood cell recovery after radiation induced cytopenia. Hematopoietic cytokines are known to promote the proliferation and differentiation of blood cell progenitors. Therefore, we hypothesized that peripheral blood cell recovery is preceded by hematopoietic cytokine induction. To test this hypothesis and compare the various radioprotective and non-radioprotective analogs, we measured serum cytokines using a sandwich ELISA, Luminex, and cytokine array in mice treated with various tocols (alpha-tocopherol succinate, alpha-tocopherol, delta-tocopherol, gamma- tocopherol, gamma-tocotrienol, and tocopherol acetate). Among the serum cytokines measured, ELISA and Luminex studies indicated that alpha-tocopherol, alpha-tocopherol succinate, and gamma-tocotrienol increased G-CSF levels in mice. Alpha-tocopherol succinate was most effective in stimulating G-CSF. IL-6 was detected by Luminex in sera samples from mice treated with the above three analogs. The results of the cytokine array suggest that other cytokines and chemokines in addition to G-CSF and IL-6 are induced. Since G-CSF, IL-6, and certain chemokines are important hematopoietic factors, these results support our hypothesis that the protection of mice from radiation-induced hematopoietic death is mediated by cytokines and chemokines. These studies may indicate that alpha-tocopherol succinate can be used as an adjunct in cancer chemotherapy, where neutropenia is a serious problem with threatening infectious complications.
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PMID:Induction of cytokines by radioprotective tocopherol analogs. 1642 3

Variability in the efficacies and toxicities of anticancer agents is a major problem. We hypothesized that polymorphisms in cytokine gene promoters may underlie genetic susceptibility to chemotherapy-induced toxicities in the Japanese. DNA was extracted from 100 patients undergoing 5-fluorouracil plus cisplatin chemotherapy. We used a case-only design to evaluate the relation between toxicities and cytokine promoter gene polymorphisms. The following polymorphisms were genotyped: tumor necrosis factor (TNF)-alpha-1031T/C, interleukin (IL)-1beta-511C/T, IL-6-634C/G, IL-10-819T/C, IL-18-137G/C, macrophage migration inhibitory factor -173G/C, and 86-basepair variable numbers of tandem repeat in intron 2 of the IL-1 receptor antagonist. The frequency of the IL-6-634 GC and GG genotypes was significantly higher in patients with grades 1-4 leukopenia (P=0.003; Crude-odds ratios (Cr-OR) =4.0), neutropenia (P=0.0051; Cr-OR=3.6), or thrombocytopenia (P<0.0001; Cr-OR=6.1) than in patients without these toxicities. Similarly, the frequency of the IL-1beta-511 TC and TT genotypes and the frequency of the TNF-alpha-1031 TT genotype were significantly higher in patients with grades 1-4 thrombocytopenia (P=0.015; Cr-OR=2.9) and stomatitis (P=0.02; Cr-OR=3.1), respectively. Multivariate analysis of factors such as age, sex, disease type, purpose of the chemotherapy, use of radiotherapy, and cytokine promoter gene polymorphisms showed polymorphisms to be significant predictors of toxicity. Our results suggest that polymorphisms in cytokine gene promoters may be associated with susceptibilities to leukopenia, neutropenia, thrombocytopenia and stomatitis in patients treated with 5-fluorouracil plus cisplatin.
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PMID:Relation between cytokine promoter gene polymorphism and toxicity of 5-fluorouracil plus cisplatin chemotherapy. 1682 Sep 19

The levels of interleukin-10 (IL-10) were evaluated in long-term bone marrow (BM) culture supernatants from 54 patients with chronic idiopathic neutropenia (CIN) and 30 healthy volunteers using enzyme-linked immunoabsorbent assay. Cytokine levels were significantly reduced in patients, compared with controls, and strongly correlated with peripheral blood neutrophil counts. Low levels of supernatant IL-10 were associated with increased values of supernatant IL-1beta, tumour necrosis factor-alpha, IL-6 and transforming growth factor-beta(1). We suggest that the pro-inflammatory milieu in the BM of CIN patients may be causatively related to the impaired production of IL-10, a cytokine normally displaying strong anti-inflammatory properties.
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PMID:Pro-inflammatory bone marrow milieu in patients with chronic idiopathic neutropenia is associated with impaired local production of interleukin-10. 1705 69

Systemic inflammatory stimuli, such as infection, increase the risk of stroke and are associated with poorer clinical outcome. The mechanisms underlying the impact of systemic inflammatory stimuli on stroke are not well defined. We investigated the impact of systemic inflammation on experimental stroke and potential mechanisms involved. Focal cerebral ischemia was induced by intraluminal filament occlusion of the middle cerebral artery (MCAo). Brain damage and neurological deficit 24 h after MCAo were exacerbated by systemic lipopolysaccharide (LPS) administration. This exacerbation was critically dependent on interleukin (IL)-1, because coadministration of IL-1 receptor antagonist abolished the effect of LPS on brain damage. Systemic administration of IL-1 increased ischemic damage to a similar extent as LPS and also exacerbated brain edema. IL-1 markedly potentiated circulating levels of the acute phase proteins, serum amyloid A and IL-6, and the neutrophil-selective CXC chemokines, KC and macrophage inflammatory protein-2. Neutrophil mobilization and cortical neutrophil infiltration were aggravated by IL-1 before changes in ischemic damage. Neutropenia abolished the damaging effects of systemic IL-1. These data show for the first time that an acute systemic inflammatory stimulus is detrimental to outcome after experimental stroke and highlight IL-1 as a critical mediator in this paradigm. Our data suggest IL-1-induced potentiation of neutrophil mobilization via CXC chemokine induction is a putative mechanism underlying this effect. Our results may help to explain the poorer outcome in stroke patients presenting with infection and may have implications for neurodegenerative diseases involving neurovascular alterations, such as Alzheimer's disease, in which systemic inflammation can modulate disease progression.
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PMID:Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. 1744 25

The primary objective of the study was to compare the predictive potential of procalcitonin (PCT), C-reactive protein (CRP), serum amyloid A (SAA), and interleukin (IL)-1beta, IL-6, IL-8, and IL-10, with that of the Multinational Association of Supportive Care in Cancer (MASCC) risk-index score in cancer patients on presentation with chemotherapy-induced febrile neutropenia (FN). Seventy-eight consecutive FN episodes in 63 patients were included, and MASCC scores, as well as concentrations of CRP, SAA, PCT, and IL-1beta, IL-6, IL-8 and IL-10, and haematological parameters were determined on presentation, 72 h later and at outcome. Multivariate analysis of data revealed the MASCC score, but none of the laboratory parameters, to be an accurate, independent variable (P < 0.0001) for prediction of resolution with or without complications and death. Of the various laboratory parameters, PCT had the strongest association with the MASCC score (r = -0.51; P < 0.0001). In cancer patients who present with FN, the MASCC risk-index score is a useful predictor of outcome, while measurement of PCT, CRP, SAA, or IL-1beta, IL-6, IL-8 and IL-10, is of limited value.
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PMID:Prediction of outcome in cancer patients with febrile neutropenia: comparison of the Multinational Association of Supportive Care in Cancer risk-index score with procalcitonin, C-reactive protein, serum amyloid A, and interleukins-1beta, -6, -8 and -10. 1794 61

Infectious complications in neutropenic patients are a major cause of morbidity and mortality. Clinical signs are unspecific and fever can be attributed to other causes. Inflammatory biomarkers have emerged as potentially useful in diagnosis of bacterial and fungal infection. Levels of several biomarkers were measured in patients with hematological malignancy at diagnosis and at the beginning of neutropenia due to cytostatic treatment or after hematopoietic stem cell transplantation, and daily until 6 days after presenting fever. Procalcitonin (PCT) and neopterin levels were not elevated at diagnosis or at the beginning of neutropenia. C-reactive protein (CRP) was moderately elevated. PCT levels were significantly higher in patients with Gram-negative bacteremia at 24-48 h after the onset of fever. Patients with probable fungal infection presented elevated PCT values when fever persisted for more than 4-5 days. CRP was more sensitive to predict bacteremia (both Gram-positive and Gram-negative) but the specificity was low. Neither neopterin, IL-6 nor IL-8 presented significant differences according to the origin or etiology of fever. Since it showed a high negative predictive value of Gram-negative bacteremia, clinical prediction rules that attempt to predict a high risk of severe infection might be improved by including measurement of PCT.
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PMID:Evaluation of procalcitonin, neopterin, C-reactive protein, IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia. 1866 97

Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and class A bioterror bacterial pathogens, and the fungal pathogen, Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-kappaB, type I and II IFN, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly up-regulated. Taken together, stimulated innate resistance appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection.
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PMID:Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. 1932 54

VAMP8, a member of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) family of fusion proteins, initially characterized in endosomal and endosomal-lysosomal fusion, may also function in regulated exocytosis. VAMP8 physiological function in inflammation has not been elucidated. In this paper, we show that deficiency of VAMP8 protects mice from anaphylatoxin (C5a)-induced neutropenia, peritonitis, and systemic inflammation. We show that, in vivo, VAMP8 deletion inhibits neutropenia and phagocyte recruitment. We also show that in macrophages, VAMP8 localizes on secretory granules and degranulation is inhibited in VAMP8-deficient macrophages. Moreover, VAMP8(-/-) mice show reduced systemic inflammation with inhibition of serum TNF-alpha levels, whereas IL-1beta, IL-6, and MIP1alpha release are not affected. In wild-type macrophages, TNF-alpha colocalizes with VAMP8-positive vesicles, and in VAMP8-deficient macrophages, the TNF-alpha release is inhibited. Furthermore, VAMP8 regulates the release of TNF-alpha and beta-hexosaminidase triggered by fMLP, and VAMP8(-/-) mice are protected from fMLP-induced peritonitis. These data demonstrate that the VAMP8 vesicle-associated-SNARE is required for the proper trafficking of secretory lysosomal granules for exocytosis in macrophages and for the release of the potent proinflammatory cytokine, TNF-alpha.
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PMID:VAMP8 is essential in anaphylatoxin-induced degranulation, TNF-alpha secretion, peritonitis, and systemic inflammation. 2345 3

Primary autoimmune neutropenia (AIN) is more common in newborns, and usually benign or self-limiting, so most cases require no specific therapy. In adults, however, for little tendency toward spontaneous remission, they require certain treatments and careful managements. Here we report a successful management of primary AIN patient by estimating the granulopoiesis according to CRP levels without administration of G-CSF or increase of prednisolone when peripheral neutrophil counts dropped down. Transient elevation of CRP associated with severe drop down in neutrophil count, and subsequent dramatic neutrophil increase was occasionally observed during the follow up with minimal dose of prednisolone. Coexistence of decreased neutrophil counts and elevated CRP levels was accompanied by increase of serum levels of IL-6 and IL-8. Although this is the report of only one patient, these elevated CRP levels combined with severe drop down and subsequently spontaneous rapid recovery in neutrophil count, were repetitively observed, suggesting the preceding CRP elevation before neutrophil recovery. We propose the important part of CRP as a predictor of granulopoiesis in patients with neutropenia.
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PMID:C reactive protein as a predictor of neutrophil recovery in autoimmune neutropenia. 2131 4

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


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