Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of interleukin 8 (IL-8), a neutrophil chemotactic factor, and its amino acid sequence were examined in glioblastoma cell lines in vitro. Neutrophil chemotactic activity was demonstrated in 9 conditioned media of 15 human glioblastoma cell lines. Tumor necrosis factor (TNF)-alpha stimulated secretion of the activity in 7 lines and induced secretion in 4 other lines. ELISA quantification disclosed that the conditioned media contained interleukin 8 (IL-8) in an amount equivalent to the chemotactic activity. The IL-8 secretion increased with the stimulation by TNF-alpha. Northern blot analysis and the RT-PCR method confirmed expression of mRNA in the glioblastoma cells and its augmentation by TNF-alpha and/or IL-beta. Reversed-phase HPLC following ion-exchange chromatography revealed that the chemotactic activity was a single peptide, which was determined to be IL-8 by the retention time and ELISA. Furthermore, amino acid analysis disclosed that a major part of the glioblastoma-cell derived IL-8 peptide was 77 amino acid IL-8 (IL-8(77); with the N-terminal sequence AVLPRSAKELRCQCI-).
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PMID:Human glioblastoma cells produce 77 amino acid interleukin-8 (IL-8(77)). 841 Jan 39

In order to investigate the antiproliferative and anti-invasive effects of tumor necrosis factor (TNF)-alpha on human glioblastoma cells, an in vitro three-dimensional (anchorage-independent) assay was performed using Matrigel, a mixture of extracellular matrix proteins. Four glioblastoma-derived cell lines, including one cloned line, were cultured in Matrigel with or without TNF-alpha. In the Matrigel containing TNF-alpha, three of the four cell lines, including the cloned line, showed significant growth inhibition in a dose-dependent manner. Dramatic three-dimensional morphological differences were observed between TNF-treated and untreated glioblastoma cells cultured in Matrigel. Untreated cells formed large and highly branched colonies throughout the gel. In contrast, the majority of TNF-treated cells demonstrated truncated branching processes and, at a high TNF-alpha dose, an increasing number of cells remained in relatively small spherical aggregates, their cell processes being significantly reduced. Quantitative invasion assay using a micro-Boyden chamber system confirmed that TNF-treated cells lost invasiveness in a dose-dependent manner. These results suggest that TNF-alpha exerts not only antiproliferative but also anti-invasive effects on human glioblastoma cells in vitro. It is believed that this is the first report showing the anti-invasive effect of TNF-alpha on tumor cells.
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PMID:Effect of recombinant tumor necrosis factor-alpha on three-dimensional growth, morphology, and invasiveness of human glioblastoma cells in vitro. 848 78

Toxoplasma gondii, an obligate intracellular parasite, is able to replicate in human brain cells. We recently showed that interferon (IFN)-gamma-activated cells from glioblastoma line 86HG39 were able to restrict Toxoplasma growth. The effector mechanism responsible for this toxoplasmostatic effect was shown by us to be the IFN-gamma-mediated activation of indolamine 2,3-dioxygenase (IDO), resulting in the degradation of the essential amino acid tryptophan. In contrast, glioblastoma 87HG31 was unable to restrict Toxoplasma growth after IFN-gamma activation, and IFN-gamma-mediated IDO activation was weak. We observed that tumor necrosis factor (TNF)-alpha alone is unable to activate IDO or to induce toxoplasmostasis in any glioblastoma cell line tested. Interestingly, we found that TNF-alpha and IFN-gamma were synergistic in the activation of IDO in glioblastoma cells 87HG31, 86HG39 and U373MG and in native astrocytes. This was shown by the measurement of enzyme activity as well as by the detection of IDO mRNA in TNF-alpha + IFN-gamma activated cells. This IDO activity results in a strong toxoplasmostatic effect mediated by glioblastoma cells activated simultaneously by both cytokines. Antibodies directed against TNF-alpha or IFN-gamma were able to inhibit IDO activity as well as the induction of toxoplasmostasis in glioblastoma cells stimulated with both cytokines. Furthermore, it was found that the addition of L-tryptophan to the culture medium completely blocks the antiparasitic effect. We therefore conclude that both TNF-alpha and IFN-gamma may be involved in the defense against cerebral toxoplasmosis by inducing IDO activity as an antiparasitic effector mechanism in brain cells.
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PMID:Anti-parasitic effector mechanisms in human brain tumor cells: role of interferon-gamma and tumor necrosis factor-alpha. 861 21

Severe immunodysregulation on lymphocyte level has been described in patients with glioblastoma and is likely involved into its unfavorable prognosis. Although the major importance of monocytic cells for immunoregulation is well established, only very limited data exist regarding the monocyte status in glioblastoma patients. Here we demonstrate a markedly diminished monocytic HLA-DR expression and ex vivo cytokine secretion capacity (TNF-alpha, IL-1beta, IL-10) as signs for monocyte deactivation in glioblastoma patients but not in patients with astrocytoma. As known in immunocompromised patients from other reasons, monocyte deactivation indicate global immunodepression associated with an enhanced risk of infectious complications. Interestingly, tumor resection resulted in partial recovery from the monocytic deactivation. This suggests that the glioblastoma itself contributed to this phenomenon. However, IL-10 and the active forms of transforming growth factor-beta2 and -beta1, which are produced by glioblastoma cells and known to inhibit monocyte function, were not detectable in plasma in our patients. Moreover, low levels of the adrenocorticotropic hormone and cortisol excluded hypothalamo-pituitary-adrenal axis involvement. So, further investigations are necessary to clarify the mechanism. The demonstrated severe glioblastoma-associated monocytic deactivation may contribute to its unfavorable prognosis. Therefore, monocytes may represent target cells for new adjuvant immunotherapies in glioblastoma.
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PMID:Diminished monocytic HLA-DR expression and ex vivo cytokine secretion capacity in patients with glioblastoma: effect of tumor extirpation. 962 59

The ICAM-1 molecule plays a role in the interaction of NK cells with a variety of tumor cells, including carcinoma, melanoma and glioblastoma cells. In the present study, we analyzed the effect of IFN-gamma and TNF-alpha on both the expression of HLA-DR and ICAM-1 molecules on HGCN (Germa-2), and on their susceptibility to lysis by LAK cells. Our results show that 1,000 U/ml IFN-gamma induced a substantial increase in the expression of both ICAM-1 molecules and HLA-DR on the cell surface, while the effect of TNF-alpha on the expression of these molecules was substantially less prominent. When Germa-2 cells, previously exposed to 1,000 U/ml IFN-gamma, were employed as target cells in a 4-hour 51Cr release assay, a statistically significant increase in the lysis by LAK cells was noted. These results show that in the presence of IFN-gamma, Germa-2 tumor cells undergo modulation which affects both the expression of ICAM-1 and HLA-DR molecules as well as their susceptibility to lysis by LAK cells.
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PMID:The effect of interferon-gamma and tumor necrosis factor-alpha on the expression of ICAM-1 and HLA-DR molecules on cells of a human germ cell neoplasm and their susceptibility to lysis by lymphokine-activated killer cells. 973 34

We present our experience with a combination chemotherapy regimen consisting of ranimustine (MCNU) and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for malignant astrocytomas. The initial regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. Newly diagnosed patients were treated with up to four cycles of this regimen (TNF-SAM2, MCNU, and radiotherapy: TMR group). Seventeen patients (11 men and 6 women) aged 24 to 68 years (median 54.6 years) were eligible and evaluated for response and toxicity. The estimated median survival time was 354 weeks with anaplastic astrocytomas, and 76 weeks with glioblastomas. One- and 2-year survival rates were 100% and 100% with anaplastic astrocytomas, and 69.2% and 29.7% with glioblastomas. Grade 3 and 4 hematological toxicities were not experienced. None of the patients experienced a treatment delay due to toxicity. All other acute toxicities were anticipated and manageable. Twenty three patients (11 men and 12 women) aged 22 to 66 years (median 50.7 years) were evaluated as a historical control of patients who received chemotherapy with MCNU alone in conjunction with radiotherapy following standard surgical treatment (MCNU and radiotherapy: MR group). The estimated median survival time was 205 weeks with anaplastic astrocytomas, and 62 weeks with glioblastomas. One- and 2-year survival rates were 88.9% and 66.7% with anaplastic astrocytomas, and 71.4% and 7.1% with glioblastomas in this group. There were no significant differences in survival rates between patients in the TMR and MR groups with either anaplastic astrocytoma or glioblastoma. However, despite the small number of patients, those with anaplastic astrocytoma in the TMR group tended to survive longer than those in the MR group. These results suggest that combined chemotherapy with mutant TNF-alpha may benefit those with anaplastic astrocytoma, and thus warrants further evaluation. On the other hand, the lack of activity does not warrant any further study of this schedule of TNF-SAM2 for the treatment of glioblastoma.
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PMID:Treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2). 985 11

Tumor necrosis factor (TNF) genes map on the short arm of chromosome 6 and have been described to contain several polymorphic regions, the most informative of which are TNFa (13 alleles) and TNFb (8 alleles) microsatellites. We analyze TNFa and TNFb microsatellite polymorphisms in 58 Italian patients with glioblastoma (GBL) and 95 unrelated healthy controls. At the TNFb locus, we detected a statistically significant decrease in the TNFb4 allele in GBL patients compared with the controls (P = 0.002; Pcorr = 0.015). Among the patients, 8 were homozygous TNFb4 (+/+), 23 were TNFb4 heterozygous (+/-), and 27 were negative for TNFb4 (-/-). In a comparison with the controls, we detected a statistically significant difference (P = 0.017). In fact, although no difference was detected in +/-, statistically significant differences were detected both for an increase in -/- and for a decrease in +/+ in the patient groups (P = 0.006 and P = 0.047, respectively). These data suggest that TNFb4-negative individuals might preferentially develop a Th2-type immune response that could lead to a reduction in antitumor activity.
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PMID:Tumor necrosis factor microsatellite polymorphisms in Italian glioblastoma patients. 1008 55

Patients with gliomas exhibit deficient in vitro and in vivo T cell immune activity, and human glioblastoma culture supernatants (GCS) inhibit in vitro T lymphocyte responses. Because APC are essential for initiating and regulating T cell responses, we investigated whether GCS would affect cytokines produced by monocytes and T cells from healthy donors of PBMC. Incubation of PBMC with GCS decreased production of IL-12, IFN-gamma, and TNF-alpha, and increased production of IL-6 and IL-10. The GCS-induced changes in IL-12 and IL-10 occurred in monocytes, and involved changes in IL-12 p40 and IL-10 mRNA expression. Incubation with GCS also resulted in reduced expression of MHC class II and of CD80/86 costimulatory molecules on monocytes. The immunosuppressive effects were not the result of IL-6 or TGF-beta1 that was detected in GCS. However, it was due to a factor(s) that is resistant to pH extremes, differentially susceptible to temperature, susceptible to trypsin, and has a minimum molecular mass of 40 kDa. Our findings show that glioblastoma-generated factors that are known to suppress T cell responses alter the cytokine profiles of monocytic APC that, in turn, inhibit T cell function. This model indicates that monocytes can serve as an intermediate between tumor-generated immune-suppressive factors and the T cell responses that are suppressed in gliomas.
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PMID:Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. 1020 33

Adoptive immunotherapy using tumor-specific killer cells can be beneficial in inducing regression of advanced cancer. The roles of cytokines on effector cells in inducing maximal killing activity and the accompanying side-effects should be investigated in vitro and fully understood prior to their clinical use. The present study indicates that the gammadeltaT cells involved in autologous tumor-specific killing consist of several populations in terms of their T cell receptor (TCR) repertoire, but predominantly express the products of the Vgamma9/Vdelta2 gene locus of the TCR. We then examined the effect of TNF-alpha and IFN-gamma on these tumor-specific gammadeltaT cells for possible clinical use in cancer patients. TNF-alpha alone, at concentrations of 0.01-1.0 microg/ml, caused increased gammadeltaT cell cytotoxicity against autologous glioblastoma cells, whereas IFN-gamma alone had no effect. The combination of TNF-alpha (1 microg/ml) with IL-2 (50 units/ml) resulted in further enhancement of cytotoxicity. TNF-alpha, but not IFN-gamma, marginally inhibited the proliferative response of gammadeltaT cells; a similar result was seen when the cytokines were combined. TNF-alpha may, therefore, be one cytokine capable of inducing increased autologous tumor-specific activity in gammadeltaT cells, bearing mainly Vgamma9/Vdelta2 chains, which can be enhanced when combined with other cytokines.
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PMID:Enhancing effect of tumor necrosis factor (TNF)-alpha, but not IFN-gamma, on the tumor-specific cytotoxicity of gammadeltaT cells from glioblastoma patients. 1040 55

FHL-1/reconectin and factor H are two human complement regulators which are encoded by a single gene. FHL-1/reconectin contains the first 7 of 20 SCR protein domains of factor H and has four unique residues attached to its C-terminal end. The overlapping region of 445 amino acids explains the related complement regulatory functions of the two proteins. However, unique biological functions have also been reported for FHL-1/reconectin, such as cell adhesion and binding to microbial surfaces. Both proteins are synthesised and secreted by the liver. Extrahepatic synthesis occurs in a wide variety of cells, e.g. in monocytes, fibroblasts or neuronal cells. Unexpectedly, FHL-1/reconectin and factor H exhibit distinct expression patterns. This is also observed in disease situations such as in rheumatoid arthritis or malignancies. In rheumatoid arthritis a potentially protective role is suggested by the local synthesis of both FHL-1/reconectin and factor H in synovial fibroblasts and their induction by the anti-inflammatory agent dexamethasone and the cytokine IFN-gamma, but not by TNF-alpha. FHL-1/reconectin is overexpressed in certain tumor cells such as glioblastoma, conferring an exceptional resistance to such cells against complement mediated lysis. Although FHL-1/reconectin and factor H are encoded by a single gene, regulated by the same gene promoter and initiate transcription at the same start site, their transcripts are differently regulated. The putative control levels, which are responsible for this complex regulation, include transcript elongation, RNA processing, alternative splicing and differential poly(A) site selection.
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PMID:FHL-1/reconectin and factor H: two human complement regulators which are encoded by the same gene are differently expressed and regulated. 1069 34


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