Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oligodendrocytes (OLs) and their myelin membranes are the apparent injury targets in the putative human autoimmune disease multiple sclerosis. The basis for this selective injury remains to be defined. OLs in vitro have been shown to be susceptible to both tumor necrosis factor (TNF) and non-TNF-dependent immune effector mechanisms. The former involves initial nuclear injury (apoptosis); the latter, when mediated by activated T cells, involves initial cell membrane injury (lysis). In the current study, we determined whether human adult CNS-derived OLs could be protected from the above immune effector mechanisms by selected neurotrophic factors (CNTF, BDNF, NGF, NT-3, and NT-4/5) or cytokines demonstrated to protect from human or experimental autoimmune demyelinating diseases (beta-interferon [IFN], IL-10, and TGF-beta). Nuclear injury was assessed in terms of DNA fragmentation using a DNA nick-end-labelling technique; cell membrane injury was assessed by lactate dehydrogenase or chromium 51 release. MTT and cell counting assays were used to assess cell viability and cell loss, respectively. Amongst the neurotrophic factors and cytokines tested, only CNTF significantly protected the OLs from TNF-mediated injury. CNTF also protected the OLs from serum deprivation-induced apoptosis. CNTF, however, did not protect the OLs from injury induced by activated CD4+ T cells. CNTF also did not protect human fetal cortical neurons from serum deprivation or TNF-induced DNA fragmentation, nor did it protect the U251 human glioma cell line from DNA fragmentation induced by a combination of TNF and reduced serum concentration in the culture media. Our results indicate that potential protective effects of neurotrophic factors or cytokines on neural cell populations can be selective both for cell type involved and mechanism of immune-mediated injury. CNTF is the protective factor selective for nuclear-directed injury of OLs.
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PMID:Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury. 871 18

A 50-year-old Chinese woman with a chronic 20-year history of ataxic gait associated with dry eyes and mouth, was admitted to hospital after a single episode of syncope. Magnetic resonance imaging scans showed a large left frontal hypodense lesion suggestive of a glioma. Craniotomy was performed and the lesion excised, with histology showing only infarcted tissue and no malignant cells. Further diagnostic evaluation revealed that the patient had primary Sjogren's syndrome, with demyelinating polyneuropathy. In the absence of risk factors for stroke, it was considered likely that the cerebral infarct was secondary to autoimmune-related vasculitis. Functional neuroimaging, such as magnetic resonance spectroscopy, should be considered in evaluating doubtful or unusual brain lesions in patients with autoimmune disease.
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PMID:Cerebral infarct mimicking glioma in Sjogren's syndrome. 1216 35

The primary goal of this Phase I study was to assess the safety and bioactivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed DCs was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quantitative PCR-based assay. Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-gamma expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. Using HLA-restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones against one or more of tumor-associated antigens MAGE-1, gp100, and HER-2 after DC vaccination in four of nine patients. A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. The median survival for patients with recurrent glioblastoma multiforme in this study (n = 8) was 133 weeks. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients.
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PMID:Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. 1525 71

In spite of preclinical efficacy and recent randomized, controlled studies with adenoviral vectors expressing herpes simplex virus-1 thymidine kinase (HSV1-TK) showing statistically significant increases in survival, most clinical trials using single therapies have failed to provide major therapeutic breakthroughs. Because glioma is a disease with dismal prognosis and rapid progression, it is an attractive target for gene therapy. Preclinical models using microscopic brain tumor models (e.g., < or =0.3 mm3) may not reflect the pathophysiology and progression of large human tumors. To overcome some of these limitations, we developed a syngeneic large brain tumor model. In this model, administration of single therapeutic modalities, either conditional cytotoxicity or immunostimulation, fail. However, when various immunostimulatory therapies were delivered in combination with conditional cytotoxicity (HSV1-TK), only the combined delivery of fms-like tyrosine kinase ligand (Flt3L) and HSV1-TK significantly prolonged the survival of large tumor-bearing animals (> or =80%; P < or = 0.005). When either macrophages or CD4+ cells were depleted before administration of viral therapy, TK + Flt3L therapy failed to prolong survival. Meanwhile, depletion of CD8+ cells or natural killer cells did not affect TK + Flt3L efficacy. Spinal cord of animals surviving 6 months after TK + Flt3L were evaluated for the presence of autoimmune lesions. Whereas macrophages were present within the corticospinal tract and low levels of T-cell infiltration were detected, these effects are not indicative of an overt autoimmune disorder. We propose that combined Flt3L and HSV1-TK adenoviral-mediated gene therapy may provide an effective antiglioma treatment with increased efficacy in clinical trials of glioma.
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PMID:Combined immunostimulation and conditional cytotoxic gene therapy provide long-term survival in a large glioma model. 1610 70

A role of immunological factors in glioma etiology is suggested by reports of an inverse relationship with history of allergy or autoimmune disease. To test whether single-nucleotide polymorphisms (SNPs) in cytokine genes were related to risk of adult glioma, we genotyped 11 SNPs in seven cytokine genes within a hospital-based study conducted by the National Cancer Institute and an independent, population-based study by the National Institute for Occupational Safety and Health (overall 756 cases and 1190 controls with blood samples). The IL4 (rs2243248, -1098T>G) and IL6 (rs1800795, -174G>C) polymorphisms were significantly associated with risk of glioma in the pooled analysis (P trend = 0.006 and 0.04, respectively), although these became attenuated after controlling for the false discovery rate (P trend = 0.07 and 0.22, respectively). Our results underscore the importance of pooled analyses in genetic association studies and suggest that SNPs in cytokine genes may influence susceptibility to glioma.
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PMID:Single-nucleotide polymorphisms in selected cytokine genes and risk of adult glioma. 1791

Glioma still remains a major health problem in the world. Celastrol has been proved to be an effective natural proteasome inhibitor and was used for treatment of autoimmune disease, chronic inflammation and neurodegenerative disease. However, its effect on glioma is unclear. In this study, we investigated the therapeutic effects of celastrol on C6 glioma cells. The results demonstrated that celastrol inhibited cell proliferation in a time- and dose-dependent manner, suppressed proteasome chymotrypsin-like activity and induced apoptosis and cell cycle arrest at G2/M phase in C6 cells. Proapoptosis proteins bax and caspase-3 were up-regulated, as well as cell cycle G2/M-related proteins cyclin B(1), p21 and p27. Conversely, anti-apoptosis proteins bcl-2 and XIAP and cell cycle regulator cyclin-dependent kinase 2 were down-regulated. Taken together, our data suggest that celastrol can suppress proteasome activity and induce apoptosis and cell cycle arrest in C6 glioma cells, which make it be a potential drug for glioma.
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PMID:Celastrol causes apoptosis and cell cycle arrest in rat glioma cells. 1990 82

While studying the brain function of the human partial epilepsy gene, leucine-rich glioma-inactivated 1 (LGI1), a new mechanism of human epileptogenesis was revealed-persistent immaturity of glutamatergic circuitries. LGI1, a novel secreted protein, was found to be increased during the postnatal period; when glutamatergic synapses both downregulate their presynaptic vesicular release probability and reduce their postsynaptic NMDA-receptor subunit NR2B. During this same period, the dendritic arbor and spines are pruned and remodeled. Using bacterial artificial chromosome transgenic mouse techniques, excess wild-type LGI1 was shown to magnify these critical brain developmental events in the hippocampal dentate gyrus; while an epilepsy-associated, truncated, dominant-negative form of LGI1 blocked them. By contrast, the hippocampal dentate granule neuron GABAergic synapses and intrinsic excitability were unaltered. A role for LGI1 in downregulating glutamate synapse function was confirmed by germline gene deletion; this intervention also revealed a selective increase of glutamatergic synaptic transmission with unaltered GABAergic synapses and intrinsic excitability of hippocampal CA1 pyramidal neurons. Interestingly, the role of LGI1 in neurological disease was further expanded when a subset of patients with limbic encephalitis (an autoimmune disorder with memory loss in 100% and seizures in 80% of individuals) were discovered to carry autoantibodies to LGI1.
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PMID:Arrested glutamatergic synapse development in human partial epilepsy. 2115 44

The development and function of the vertebrate nervous system depend on specific interactions between different cell types. Two examples of such interactions are synaptic transmission and myelination. LGI1-4 (leucine-rich glioma inactivated proteins) play important roles in these processes. They are secreted proteins consisting of an LRR (leucine-rich repeat) domain and a so-called epilepsy-associated or EPTP (epitempin) domain. Both domains are thought to function in protein-protein interactions. The first LGI gene to be identified, LGI1, was found at a chromosomal translocation breakpoint in a glioma cell line. It was subsequently found mutated in ADLTE (autosomal dominant lateral temporal (lobe) epilepsy) also referred to as ADPEAF (autosomal dominant partial epilepsy with auditory features). LGI1 protein appears to act at synapses and antibodies against LGI1 may cause the autoimmune disorder limbic encephalitis. A similar function in synaptic remodelling has been suggested for LGI2, which is mutated in canine Benign Familial Juvenile Epilepsy. LGI4 is required for proliferation of glia in the peripheral nervous system and binds to a neuronal receptor, ADAM22, to foster ensheathment and myelination of axons by Schwann cells. Thus, LGI proteins play crucial roles in nervous system development and function and their study is highly important, both to understand their biological functions and for their therapeutic potential. Here, we review our current knowledge about this important family of proteins, and the progress made towards understanding their functions.
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PMID:LGI proteins in the nervous system. 2371 23

Down's syndrome (DS; also known as trisomy 21; T21) is caused by a triplication of all or part of human chromosome 21 (chr21). DS is the most common genetic cause of intellectual disability attributable to a naturally-occurring imbalance in gene dosage. DS incurs huge medical, healthcare, and socioeconomic costs, and there are as yet no effective treatments for this incapacitating human neurogenetic disorder. There is a remarkably wide variability in the 'phenotypic spectrum' associated with DS; the progression of symptoms and the age of DS onset fluctuate, and there is further variability in the biophysical nature of the chr21 duplication. Besides the cognitive disruptions and dementia in DS patients other serious health problems such as atherosclerosis, altered lipogenesis, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), autoimmune disease, various cancers including lymphoma, leukemia, glioma and glioblastoma, status epilepticus, congenital heart disease, hypotonia, manic depression, prostate cancer, Usher syndrome, motor disorders, Hirschsprung disease, and various physical anomalies such as early aging occur at elevated frequencies, and all are part of the DS 'phenotypic spectrum.' This communication will review the genetic link between these fore-mentioned diseases and a small group of just five stress-associated microRNAs (miRNAs)-that include let-7c, miRNA-99a, miRNA-125b, miRNA-155, and miRNA-802-encoded and clustered on the long arm of human chr21 and spanning the chr21q21.1-chr21q21.3 region.
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PMID:Chromosome 21-Encoded microRNAs (mRNAs): Impact on Down's Syndrome and Trisomy-21 Linked Disease. 2868 76

We report a case of moyamoya disease (MMD), which developed after non-herpetic acute limbic encephalitis (NHALE) associated with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody. The patient's mother had a history of MMD. No vascular lesions were identified at the time of the NHALE. Nine years later, the patient visited our hospital due to memory disturbances and repeated transient ischemic attacks affecting the right limb. Diffusion-weighted magnetic resonance imaging revealed scattered areas of signal hyperintensity, and the patient was ultimately diagnosed with MMD based on angiography. Revascularization surgery was performed on the left side, where cerebral blood flow was impaired on 123I-N-isopropyl-p-iodoamphetamine single photon emission computed tomography. Postoperatively, the patient was discharged with a normal neurological examination. NHALE associated with LGI1 antibodies is an autoimmune disease. Although autoimmune disease is the most frequent finding other than atherosclerosis in quasi-MMD, this is the first report of NHALE associated with anti-LGI1 antibodies mimicking quasi-MMD. Inflammation and angiogenesis may contribute to the development of MMD, in addition to genetic background.
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PMID:Development of moyamoya disease after non-herpetic acute limbic encephalitis: A case report. 2973 Dec 74


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