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:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphatase and tension homolog located on chromosome ten (PTEN) is a tumor suppressor as it negatively regulates activation of Akt. Mutation or deletion of PTEN has been found in as high as 80% of glioblastomas, which harbor aberrant cell signaling passing through the phosphatidylinositol-3-kinase (PI3K) and Akt (PI3K/Akt) survival pathway. Glioblastoma cells without functional PTEN are not easily amenable to apoptosis. We investigated the possibility of modulation of signal transduction pathways for induction of apoptosis in human glioblastoma T98G (PTEN-harboring) and U87MG (PTEN-deficient) cell lines after treatment with the combination of all-trans retinoic acid (ATRA) and interferon-gamma (IFN-gamma). Treatment with ATRA plus IFN-gamma stimulated PTEN expression and suppressed Akt activation in T98G cells, whereas no PTEN expression but Akt activation in U87MG cells under the same conditions. Pretreatment of U87MG cells with the PI3K inhibitor LY294002 could prevent Akt activation. Interestingly, ATRA plus IFN-gamma could significantly decrease cell viability and increase morphological features of apoptosis in both cell lines. Combination of ATRA and IFN-gamma showed more efficacy than IFN-gamma alone in causing apoptosis that occurred due to increases in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and caspase-3 activity. Luciferase reporter gene assay showed that combination of ATRA and IFN-gamma significantly down regulated transcriptional activity of the nuclear factor kappa B (NF-kappaB), a survival signaling factor, in U87MG cells. Thus, combination of ATRA and IFN-gamma caused significant amounts of apoptosis in T98G cells due to suppression of the PI3K/Akt survival pathway while the same treatment caused apoptosis in U87MG cells due to down regulation of the NF-kappaB activity. Therefore, the combination of ATRA and IFN-gamma could modulate different survival signal transduction pathways for induction of apoptosis and should be considered as an effective therapeutic strategy for controlling the growth of both PTEN-harboring and PTEN-deficient glioblastomas.
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PMID:Combination of all-trans retinoic acid and interferon-gamma suppressed PI3K/Akt survival pathway in glioblastoma T98G cells whereas NF-kappaB survival signaling in glioblastoma U87MG cells for induction of apoptosis. 1761 12

Glioblastoma is the deadliest brain tumor in humans. Current therapies are mostly ineffective and new agents need to be explored for controlling this devastating disease. Inositol hexaphosphate (IP6) is a phytochemical that is widely found in corns, cereals, nuts, and high fiber-content foods. Previous studies demonstrated anti-cancer properties of IP6 in several in vitro and in vivo tumor models. However, therapeutic efficacy of IP6 has not yet been evaluated in glioblastoma. Here, we explored the molecular mechanism of action of IP6 in human malignant glioblastoma T98G cells. The viability of T98G cells decreased following treatment with increasing doses of IP6. T98G cells exposed to 0.25, 0.5, and 1 mM IP6 for 24 h showed morphological and biochemical features of apoptosis. Western blotting indicated changes in expression of Bax and Bcl-2 proteins resulting in an increase in Bax:Bcl-2 ratio and upregulation of cytosolic levels of cytochrome c and Smac/Diablo, suggesting involvement of mitochondria-dependent caspase cascade in apoptosis. IP6 downregulated cell survival factors such as baculovirus inhibitor-of-apoptosis repeat containing-2 (BIRC-2) protein and telomerase to promote apoptosis. Upregulation of calpain and caspase-9 occurred in course of apoptosis. Increased activities of calpain and caspase-3 cleaved 270 kD alpha-spectrin at specific sites generating 145 kD spectrin break down product (SBDP) and 120 kD SBDP, respectively. Increased caspase-3 activity also cleaved inhibitor of caspase-3-activated DNase and poly(ADP-ribose) polymerase. Collectively, our results demonstrated that IP6 down regulated the survival factors BIRC-2 and telomerase and upregulated calpain and caspase-3 activities for apoptosis in T98G cells.
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PMID:Molecular mechanism of inositol hexaphosphate-mediated apoptosis in human malignant glioblastoma T98G cells. 1761 15

Glioblastoma growth is a genetically regulated process. Loss or inactivation of genes - tumor suppressors may give rise to tumors and their progression. Glioblastoma multiforme is followed by a number of genetic breakages. Expression of a number of genes may affect the prognosis of the disease and tumor sensitivity to chemotherapy. Comprehensive studies of glioblastomas showed that there were at least two immunologic phenotypes: 1) that with a picture of pronounced immunodeficiency and 2) that without obvious immunodeficiency. This should be considered when elaborating present-day programs of geno- and immunodiagnosis, as well as clinicoimmunological criteria for the treatment of these tumors.
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PMID:[Glial tumors of the brain: current aspects of the immunopathogenesis and immunogenodiagnosis]. 1764 97

Glioblastoma is a highly malignant tumor, characterized by an unfavorable prognosis even in response to multidisciplinary treatment strategies, owing to its high-invasive phenotype. Ukrain, a semisynthetic thiophosphoric acid derivative of the purified alkaloid chelidonine, has been used in the therapy of several solid tumors, but little is known about its effect on glioblastoma and, in general, about the molecular mechanisms responsible for its effects. In particular, we previously demonstrated that Ukrain modulates the expression of genes and proteins involved in tumor invasion, and here we investigate some unreported effects of Ukrain on human cultured glioblastoma cells. We used morphological and molecular biology methods to analyze the expression and the intracellular distribution pattern of glial fibrillary acidic protein, the expression of the gap junction protein connexin 43 and the apoptotic effect in human glioblastoma cells treated with 0.1, 1 and 10 micromol/l Ukrain for 72 h. After treatment with 10 micromol/l Ukrain, glial fibrillary acidic protein fluorescence increased and a higher number of cells displayed glial fibrillary acidic protein organized into a filamentous state. Western blot analysis of glial fibrillary acidic protein confirmed that Ukrain tended to upregulate the protein. Connexin 43 was not modulated by Ukrain both at the mRNA and at the protein level. Ukrain-induced apoptotic rate was 4.63, 10.9 and 28.9% after 0.1, 1 and 10 micromol/l Ukrain, respectively, likely mediated by cytochrome c release in the cytoplasm. Considered as a whole, these findings provide new information to complete the understanding of the mechanisms of Ukrain antitumor and chemopreventive effect, and support the possible potential of Ukrain for the therapy of brain tumors.
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PMID:Ukrain modulates glial fibrillary acidic protein, but not connexin 43 expression, and induces apoptosis in human cultured glioblastoma cells. 1776 95

Glioblastoma (GBM), a highly aggressive (WHO grade IV) primary brain tumor, is refractory to traditional treatments, such as surgery, radiation or chemotherapy. This study aims at aiding in the design of more efficacious GBM therapies. We constructed a mathematical model for glioma and the immune system interactions, that may ensue upon direct intra-tumoral administration of ex vivo activated alloreactive cytotoxic-T-lymphocytes (aCTL). Our model encompasses considerations of the interactive dynamics of aCTL, tumor cells, major histocompatibility complex (MHC) class I and MHC class II molecules, as well as cytokines, such as TGF-beta and IFN-gamma, which dampen or increase the pro-inflammatory environment, respectively. Computer simulations were used for model verification and for retrieving putative treatment scenarios. The mathematical model successfully retrieved clinical trial results of efficacious aCTL immunotherapy for recurrent anaplastic oligodendroglioma and anaplastic astrocytoma (WHO grade III). It predicted that cellular adoptive immunotherapy failed in GBM because the administered dose was 20-fold lower than required for therapeutic efficacy. Model analysis suggests that GBM may be eradicated by new dose-intensive strategies, e.g., 3 x 10(8) aCTL every 4 days for small tumor burden, or 2 x 10(9) aCTL, infused every 5 days for larger tumor burden. Further analysis pinpoints crucial bio-markers relating to tumor growth rate, tumor size, and tumor sensitivity to the immune system, whose estimation enables regimen personalization. We propose that adoptive cellular immunotherapy was prematurely abandoned. It may prove efficacious for GBM, if dose intensity is augmented, as prescribed by the mathematical model. Re-initiation of clinical trials, using calculated individualized regimens for grade III-IV malignant glioma, is suggested.
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PMID:Improving alloreactive CTL immunotherapy for malignant gliomas using a simulation model of their interactive dynamics. 1782 98

Glioblastoma multiformes (GBMs) express increased aquaporin (AQP) 1 compared to normal brain. AQPs may contribute to edema, cell motility, and shuttling of H(2)O and H(+) from intracellular to extracellular space. We sought to gain insight into AQP1 function in GBM. In cultured 9L gliosarcoma cells, AQP1 expression was induced by dexamethasone, platelet-derived growth factor, NaCl, hypoxia, D-glucose (but not L-glucose), and fructose. Induction of AQP1 expression correlated with the level of glycolysis, maximized by increasing medium D-glucose or fructose and decreasing O(2), and was quantified by measuring lactate dehydrogenase (LDH) activity and medium lactate concentration. Upregulation of the protease cathepsin B was also observed in 9L cells cultured under glycolytic conditions. Immunohistochemical staining of human GBM specimens revealed increased coincident expression of AQP1, LDH, and cathepsin B in glioma cells associated with blood vessels at the tumor periphery. GBMs are known to exhibit aerobic glycolysis. Increased glucose metabolism at the tumor periphery may provide a scenario by which upregulation of AQP1, LDH, and cathepsin B contributes to acidification of the extracellular milieu and to invasive potential of glioma cells in perivascular space. The specific upregulation and metabolic consequences of increased AQP1 in gliomas may provide a therapeutic target, both as a cell surface marker and as a functional intervention.
Neoplasia 2007 Sep
PMID:Regulation and function of aquaporin-1 in glioma cells. 1789 73

Glioblastoma is the most common brain malignancy and is marked by an extremely poor prognosis, despite advances in surgical and clinical neuro-oncology. That is why central nervous system glioblastoma is quite a challenging neoplasm, requiring much further research to understand the molecular and cellular clinical basis. Existing in vivo glioblastoma models are based on the inoculation of glioma cells into rodent brains or the use of transgenic mice. For decades the avian model was the model of choice in developmental biology. However, the reports on chorioallantoic membrane glioblastoma model are quite rare. The objective of these experiments was to evaluate morphological issues of glioblastoma on CAM and the interaction between transplant and CAM. Chicken embryos obtained from a local poultry farm were put in an incubator. Fresh samples of glioblastoma obtained during the operation were grafted on CAM, which is formed on the 7-9 th day of embryo development. The growth and morphological issues of cells were observed with a stereo microscope and the histological preparations were done in particular intervals of time, starting from 24 hours after the transplantation. We observed peritumoral edema, necrotic zones and angiogenesis on the chorioallantoic membrane. This evidence, together with the immunohistological proof, shows that glioblastoma survives on CAM and has its typical morphological features.
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PMID:Evaluation of morphological issues of central nervous system glioblastoma on chicken embryo chorioallantoic membrane. 1793 90

Glioblastoma is the most frequent primary brain tumor in adults. The average survival time of less than 1 year did not improve notably over the last three decades. The dismal prognosis of glioblastoma patients is largely due to the striking radioresistance of this tumor. Here, we attempt a combined view on the genetics, the repair mechanisms and the radioresistance of glioblastoma. Specifically, we address the role of DNA-PKcs and the novel potential end-joining factor KUB3 in maintaining the radioresistant phenotype, the interrelationship between genetic lesions and repair mechanisms, and new perspectives that emerge from the identification of glioblastoma stem cells.
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PMID:Glioblastoma multiforme: the role of DSB repair between genotype and phenotype. 1806 94

Glioblastoma is one of the most lethal central nervous system (CNS) primary tumors. Although significant progress, only few analysis have been made in pediatric glioblastoma, which are less common and have worse prognosis than in adults. To evaluate gender, site, age, survival, and immunohistochemistry to p53, we selected cases of pediatric glioblastoma of "CNS Tumors Database in Curitiba", 1987-2003 and of the Hospital Municipal Jesus, Rio de Janeiro, 1970-1988. Twelve tumors were included. The age ranged from up to 12 years (median 7). There were 7 females and 5 males. The median survival was 7.9 months. Location was: cerebral hemispheres (58.4%), mesencephalon and brainstem (33.3%) and one case in the cerebellum. Immunostained to p53 in 9 (75%) cases. In conclusion, glioblastoma behaves similarly in children and adults. It is rare in children, affects both cerebral hemispheres more than brainstem and cerebellum and shows strong immunohistochemistry to p53.
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PMID:[Pediatric glioblastoma: a clinicopathological study of 12 cases with p53 protein immunohistochemistry]. 1809 77

Glioblastoma is the most malignant and frequent of the glial tumors. A minor fraction of glioblastoma may contain areas showing oligodendroglioma-like tumor cell differentiation. Several authors have described such tumors as glioblastoma with oligodendroglial component (GBMO). GBMO may represent the ultimate level of malignancy in the oligodendroglial lineage. The oligodendroglial component and combined loss of chromosomal arm 1p and 19q in glioblastoma indicate increased survival. In our study, we analyzed 1p and 19q status in a series of 12 glioblastoma and 8 oligodendroglial tumors using fluorescence in situ hybridization (FISH) on paraffin-embedded tissues. In each case, hybridization status was classified as deletion, imbalance, polysomy, amplification, or normal pattern. Other genetic alterations such as CDKN2A (p16), RB, and EGFR were also assessed. On histological review, 2 of 12 glioblastoma (16.7%) were classified as GBMO. Chromosome 1p/19q deletion was detected in 3 of 12 glioblastomas (25%). In contrast, all 8 oligodendroglial tumors showed 1p/19q deletion. All GBMO had 19q deletion with imbalance, whereas 1 of 10 ordinary glioblastoma (10%) demonstrated 19q deletion with imbalance. All but 1 ordinary glioblastoma (90%) showed CDKN2A (p16) deletion, but no GBMO displayed this alteration. Our results indicate that GBMO may be a distinct subtype of glioblastoma harboring a characteristic molecular profile. FISH on paraffin-embedded specimens is a useful method for subclassification of glioblastoma.
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PMID:FISH 1p/19q deletion/imbalance for molecular subclassification of glioblastoma. 1809 37


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