Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-kit proto-oncogene encodes a 145- to 160-Kd transmembrane tyrosine kinase, which is a member of the platelet-derived growth factor receptor family and is allelic with the murine white spotting locus (W). W mutations affect several aspects of hematopoiesis, most notably erythroid progenitors and mast cells. A monoclonal antibody, YB5.B8, had been raised against the leukemic blasts of a patient with M1-type acute myelocytic leukemia (AML) and it precipitates a 150-Kd cell surface glycoprotein from leukemic cells. The YB5.B8 epitope is expressed on mast cells, on up to 3% of normal mononuclear bone marrow cells, and it identifies a sub-group of AML patients with a poor prognosis. In view of similarities noted between the cell surface antigen identified by YB5.B8 and the c-kit protein product, we performed experiments to determine whether they are identical. c-kit RNA expression in the cell lines HEL (human erythroleukemia) and A172 (glioblastoma) was shown to parallel the expression of the YB5.B8 epitope in these lines as measured by flow cytometry. Immunoprecipitation analysis with anti-kit serum and YB5.B8 antibody indicated that the two antibodies identified proteins of identical size in HEL (155 Kd) and A172 (145 Kd) cells, and sequential immunoprecipitations with the kit and the YB5.B8 antibodies demonstrated that the two antibodies recognize the same molecule. The proteins identified by both the anti-kit and YB5.B8 antibodies displayed in vitro autophosphorylation activity in immune complex kinase assays. In addition, YB5.B8 was able to inhibit the binding of the kit ligand to HEL cells. These studies provide evidence that the YB5.B8 antigen and the c-kit protein product are identical and raise certain hypotheses regarding the role of c-kit in AML.
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PMID:Monoclonal antibody YB5.B8 identifies the human c-kit protein product. 170 91

Structural features of v-kit, the oncogene of HZ4 feline sarcoma virus, suggested that this gene arose by transduction and truncation of cellular sequences. Complementary DNA cloning of the human proto-oncogene coding for a receptor tyrosine kinase confirmed this possibility: c-kit encodes a transmembrane glycoprotein that is structurally related to the receptor for macrophage growth factor (CSF-1) and the receptor for platelet-derived growth factor. The c-kit gene is widely expressed as a single, 5-kb transcript, and it is localized to human chromosome 4 and to mouse chromosome 5. A c-kit peptide antibody permitted the identification of a 145,000 dalton c-kit gene product that is inserted in the cellular plasma membrane and is capable of self-phosphorylation on tyrosine residues in both human glioblastoma cells and transfected mouse fibroblasts. Our results suggest that p145c-kit functions as a cell surface receptor for an as yet unidentified ligand. Furthermore, carboxy- and amino-terminal truncations that occurred during the viral transduction process are likely to have generated the transformation potential of v-kit.
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PMID:Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. 244 37

IFN-gamma induces the production of N-formyl-kynurenine from L-tryptophan in various cell types by the induction of the enzyme indoleamine 2,3-dioxygenase (IDO). The IFN-gamma induced IDO activity in the glioblastoma cell line 86HG39 and cells of clone 2D9 derived from this cell line was found to be greater than that in Hela cells and U373MG cells. Consequently 2D9 cells were used in all subsequent experiments. The determination of kynurenine in the supernatant of IFN-gamma activated cells was performed photometrically using a microplate reader. It was found that the amount of kynurenine produced was directly proportional to the amount of IFN-gamma used to activate cells. The detection limit for IFN-gamma of this assay was 20 U/ml. The induction of L-tryptophan degradation was specific for IFN-gamma since neither IFN-alpha, IFN-beta, IL-1, IL-2, IL-6, GM-CSF nor TNF alpha induced the production of detectable amounts of kynurenine by 86HG39 and 2D9 cells. Furthermore, a mab directed against IFN-gamma was able to completely block the IFN-gamma induced IDO activation. This bioassay was used to determine the IFN-gamma content of supernatants harvested from toxoplasma antigen specific human T cell lines and clones. This assay gave reproducible results which correlated well with the IFN-gamma content detected in the same samples using a commercially available ELISA kit. Furthermore in the case of T cell supernatant stimulated 2D9 cells a mab directed against IFN-gamma was able to completely block IDO induction. We conclude that the measurement of kynurenine production induced by IFN-gamma can be used to determinate IFN-gamma content. This is a simple bioassay which can be performed with standard laboratory equipment.
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PMID:A new, simple, bioassay for human IFN-gamma. 828 93

Thymidine phosphorylase (TP) has been implicated as a potent angiogenic factor and a prognostic factor in various human solid tumors. We investigated the expression of TP in a series of human astrocytic tumors using immunohistochemistry, enzyme-linked immunosorbent assay, and reverse transcriptase/polymerase chain reaction (RT-PCR) analysis. A total of 63 astrocytic tumors [27 glioblastomas (GBM), 19 anaplastic astrocytomas (AA), 17 low-grade astrocytomas (LGA)] and 5 normal brain tissues were immunohistochemically stained with antibodies to TP, vascular endothelial growth factor (VEGF), p53, MIB-1, and factor-VIII-related antigen. They were also evaluated for the degree of apoptosis by a ApopTag kit. Ten tumors (5 GBM, 2 AA, 3 LGA) and 3 normal brain tissues were evaluated for their expression of VEGF and TP by RT-PCR analysis. TP was constantly localized in the cytoplasm of astrocytic tumor cells, less intensely in the cytoplasm of vascular endothelial cells, but not in the normal brain. Some of the TP-positive cells were of macrophage origin, but most positive cells were the tumor cells themselves. Vascular density, MIB-1 positivity, p53 positivity, VEGF expression, and the apoptotic index were significantly higher in the TP-positive tumors than in TP-negative tumors. There was a significant correlation between TP and VEGF mRNA expression. In a limited number of glioblastoma cases, the apoptotic index was significantly higher in TP-positive glioblastomas than in TP-negative glioblastomas. In human astrocytic tumors, TP was expressed in the tumor, macrophage, and endothelial cells. TP was a potent angiogenic factor closely associated with cell proliferation and tumor apoptosis.
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PMID:Expression of the angiogenic factor thymidine phosphorylase in human astrocytic tumors. 1074 8

The inhibitor of apoptosis protein, XIAP, is frequently overexpressed in chemoresistant human tumours. An antisense oligonucleotide (AEG 35156/GEM 640) that targets XIAP has recently entered phase I trials in the UK. Method validation data are presented on three pharmacodynamic assays that will be utilised during this trial. Quantitative RT-PCR was based on a Taqman assay and was confirmed to be specific for XIAP. Assay linearity extended over four orders of magnitude. MDA-MB-231/U6-E1 cells and clone X-G4 stably expressing an RNAi vector against XIAP were chosen as high and low XIAP expression quality controls (QCs). Within-day and between-day coefficients of variation (CVs) in precision for cycle threshold (CT) and delta CT values (employing GAPDH and beta 2 microglobulin as housekeepers) were always less than 10%. A Western blotting technique was validated using a GST-XIAP fusion protein as a standard and HeLa cells and SF268 (human glioblastoma) cells as high and low XIAP expression QCs. Specificity of the final choice of antibody for XIAP was evaluated by analysing a panel of cell lines including clone X-G4. The assay was linear over a 29-fold range of protein concentration and between-day precision was 29% for the low QC and 23% for the high QC when normalised to GAPDH. XIAP protein was also shown to be stable at -80 degrees C for at least 60 days. M30-Apoptosense plasma Elisa detects a caspase-cleaved fragment of cytokeratin 18 (CK18), believed to be a surrogate marker for tumour cell apoptosis. Generation of an independent QC was achieved through the treatment of X-G4 cells with staurosporine and collection of media. Measurements on assay precision and kit-to-kit QC were always less than 10%. The M30 antigen (CK18-Asp396) was stable for 3 months at -80 degrees C, while at 37 degrees C it had a half-life of 80-100 h in healthy volunteer plasma. Results from the phase I trial are eagerly awaited.
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PMID:Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. 1568 40

C-kit is a proto-oncogene involved in normal growth and development and neoplastic processes, and its product, CD117, is a highly specific immunohistochemical diagnostic marker for gastrointestinal stromal tumors (GISTs). Because GISTs that express immunohistochemically-detectable CD117 respond dramatically to treatment with tyrosine kinase inhibitors, identification of central nervous system tumors that express CD117 might open new therapeutic approaches for treatment of brain tumors. Specimens from 52 glial tumors of various histologic types and grades were assayed for CD117 immunoreactivity, and about 75% of the tumors were positive for CD117 expression; all except a few exhibited strong cytoplasmic and membranous staining. The proportion of high grade tumors of all tumor types with detectable CD117 immunoreactivity was statistically significantly greater than low grade tumors, and glioblastoma and anaplastic oligodendroglioma showed the highest staining grade. These findings support further investigation into the possibility that CD117 has an important role in growth of glial tumors and that patients with brain tumors expressing CD117 might benefit from treatment with receptor tyrosine kinase inhibitors.
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PMID:CD117 expression in glial tumors. 1613 4

EGF receptor (EGFR) became a useful target for several recently introduced therapies of various cancer types including colorectal, lung, head and neck cancers and glioblastoma. The successful clinical application of these novel molecularly targeted therapies requires the expression of their target, EGFR, determined by nucleic acid based or immunohistochemical techniques. However, until now, immunohistochemistry has not become a reliable diagnostic approach for this purpose. The golden standard for the determination of EGFR protein expression in paraffin-embedded cancer tissues is the EGFR pharmDxTM kit. Here we show that the recommended protocol may not be optimal for EGFR immunodetection. Microwave antigen retrieval and extended primary antibody incubation time converted four out of eight EGFR-negative tumors into EGFR-positive in a study of 50 lung adenocarcinoma cases. Accordingly, we recommend retesting cases negative for EGFR with EGFR pharmDxTM using protocol modifications optimizing antigen retrieval and the incubation periods.
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PMID:Protocol modifications influence the result of EGF receptor immunodetection by EGFR pharmDx in paraffin-embedded cancer tissues. 1718 89

Herpes simplex virus infections are encountered often due to their ubiquitous nature. Common sites involved include skin, mucous membrane, genitalia, eye and the nervous system. HSV infection of the central nervous system can be life threatening. Little is known about the pathogenesis of this cataclysmic disease, at the cellular level. Virus induced apoptosis may play a role in the molecular pathogenesis of encephalitis. This study aims to detect the presence of apoptosis: a) In the brain tissue obtained at autopsy from a patient who succumbed to Herpes simplex virus - 1 encephalitis (HSE) and b) In a human glioblastoma cell line (SNB 19). Wedge tissue samples were obtained from the inferior surface of the frontal lobe and fixed in buffered formalin. Tissue sections were stained with haematoxylin and eosin for histopathological analysis. An indirect immunoperoxidase assay was performed for the detection of HSV -1 antigen in the tissue sections. Apoptosis in the brain tissue was detected employing the TUNEL assay (Terminal deoxynucleotidyl Transferase (TdT) mediated deoxy Uridine Triphosphate Nick End Labeling) using a commerically available kit (TdT Fragel DNA fragmentation detection kit, Oncogene Research Products, CA). HSV-1 induced apoptosis of SNB 19 cells were detected in-vitro by: a) Membrane blebbing assay and b) Hoechst 33258 staining. Classical features of viral encephalitis including the presence of intranuclear inclusions, neuronal loss and perivascular cuffing were seen in the tissue sections. The immunoperoxidase assay revealed the presence of abundant viral antigen in the neurons, microglial and satellite cells. TUNEL assay revealed many apoptotic neurons, microglial and satellite cells. In-vitro assays showed evidence of HSV-1 induced apoptosis in the SNB 19 cell line. These results suggest that virus induced apoptosis may play a role in the molecular pathogenesis of HSE. Further studies are warranted to elucidate the role of HSV-1 induced apoptosis, especially employing cell lines of neuronal origin.
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PMID:Neuronal apoptosis in herpes simplex virus - 1 encephalitis (HSE). 1766 14

It has been hypothesized that cancer stem cell is responsible for the refractoriness of glioblastoma therapy. This study is to observe the influence of Etoposide on anti-apoptotic and multidrug resistance-associated protein genes in glioblastoma stem-like cells. U251 glioblastoma cells were cultured and CD133 positive cancer stem-like cells were isolated and identified. Cell counting kit-8 assay, cell morphology and flow cytometry were employed for assaying cell survival condition. Real-time quantitative PCR was chosen for detecting mRNA expression of livin, livinalpha, livinbeta, survivin, MRP1 and MRP3. As results, after Etoposide intervention, the U251 stem-like cells showed more resistant property, more intact morphology and lower apoptotic rate than that in U251 cells (p<0.05). It could be found that the expression of livinbeta in U251 stem-like cells was significantly higher (p<0.05). After Etoposide intervention, only livinalpha was suppressed markedly (p<0.05), while livin expression was not notably decreased with livinbeta increased on the contrary (p<0.05). MRP1 and MRP3 in U251 stem-like cells were significantly higher than that in cancer cells, and after chemotherapy, the expression of MRP1 increased notably (p<0.05). But the expression of survivin and MRP3 did not show these features. In conclusion, after Etoposide intervention glioblastoma stem-like cells showed a stronger resistance to apoptosis and death, and the anti-apoptotic gene livinbeta was more related with the high survival rate and MRP1 appeared to be more related with transporting chemotherapeutics out of glioblastoma stem-like cells.
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PMID:Influence of Etoposide on anti-apoptotic and multidrug resistance-associated protein genes in CD133 positive U251 glioblastoma stem-like cells. 2038 2

Myxopapillary ependymoma (MPE) is a rare tumor of the distal spinal cord. Despite benign histopathology, local recurrences occur in ~30 % of patients and distant metastases have been described in few cases. MPE tumor cells typically express glial fibrillary acidic protein (GFAP), which could be released to the circulation. In this current report, we investigated circulating plasma-GFAP in a series of MPE patients. We analyzed circulating plasma-GFAP using a commercially available ELISA kit in 3 patients with completely resected MPE, 1 patient with locally advanced MPE and 2 patients with pleuropulmonary metastases of MPE. As controls we used blood samples of age and gender-matched healthy volunteers (n = 3), 6 glioblastoma patients with known plasma-GFAP status (positive for 3 and negative for 3 patients) and 3 brain metastases patients with known plasma-GFAP negativity. We found very high concentrations of plasma-GFAP in two MPE patients with pleuropulmonary metastases, while in none of the other MPE patients circulating plasma-GFAP was detectable. Circulating GFAP could be useful as marker for early detection or follow-up of distant metastases in MPE patients.
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PMID:High plasma-GFAP levels in metastatic myxopapillary ependymoma. 2362 79


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