FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W984969756> ?p ?o ?g. }

• W984969756 abstract "The main subject of my thesis is the investigation of mechanisms of glioma tumorigenesis associated with the recently identified mutations in isocitrate dehydrogenase. Gliomas account for 80% of primary brain cancers. They represent a diverse group of tumours, and are graded from I-IV based on histopathological features. Whilst grade I tumours may be curable with surgery alone, grade II and III gliomas inevitably progress to glioblastoma multiforme (GBM), which is highly resistant to current therapies and carries a very poor prognosis. Despite an improved understanding of the pathways and mechanisms involved in the development of glioma and its progression to grade IV disease, current and novel treatments have so far failed to significantly improve outcome. Isocitrate dehydrogenase (IDH) enzymes catalyse the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Somatic mutations in genes encoding IDH1 and IDH2 were first identified in glioma and subsequently in acute myeloid leukemia and other solid tumours. These heterozygous point mutations occur at the arginine residue of the enzymes active site and cause both loss of normal enzyme function and gain-of-function, causing the reduction of α-KG to D-2-hydroxyglutarate (D-2HG), which accumulates. D-2HG may act as an oncometabolite through the inhibition of various α-KG dependent enzymes, stimulating angiogenesis, histone modifications and aberrant DNA methylation. Possibly, IDH1/2 mutations may also cause oncogenic effects through dysregulation of the tricarboxylic acid (TCA) cycle, or by increasing susceptibility to oxidative stress. The exact role of mutant IDH1/2 in tumorigenesis however remains unclear. In the work outlined in this thesis, I have demonstrated that the expression of mutant IDH1/2 in glioma cell lines leads to 2-HG accumultation and a reduction in α-KG production and results in HIF1α accumulation and a reduction in 5hmC production. Furthermore, the brain-specific expression of mutant Idh1 in mice also results in 2-HG accumulation and reduced α-KG production, whilst a reduction in 5hmC levels are also seen. This data appears to support the theory that IDH1/2 mutant activity results in the inhibition of α-KG dependent enzymes, either through the accumulation of 2-HG or due to a reduction in α-KG levels. The brain-specific expression of mutant Idh1 in mice also results in increased cellular proliferation and an increase in the expression of the neural stem cell marker, nestin. However gliomas do not develop, perhaps suggesting that additional mutations are required in conjunction with those occuring in IDH1/2 in order to initiate tumourigenesis. Clinically, IDH1/2 mutations may represent a novel therapeutic target in glioma and may also serve as useful diagnostic, prognostic and predictive biomarkers. However, a better understanding of the pathogenesis of mutant IDH is required, to enable effective IDH1/2 directed therapies to be developed in the future." @default.
• W984969756 created "2016-06-24" @default.
• W984969756 creator A5033611186 @default.
• W984969756 date "2014-01-01" @default.
• W984969756 modified "2023-09-23" @default.
• W984969756 title "Functional analysis of mutations in isocitrate dehydrogenase involved in gliomagenesis" @default.
• W984969756 hasPublicationYear "2014" @default.
• W984969756 type Work @default.
• W984969756 sameAs 984969756 @default.
• W984969756 citedByCount "0" @default.
• W984969756 crossrefType "dissertation" @default.
• W984969756 hasAuthorship W984969756A5033611186 @default.
• W984969756 hasConcept C104317684 @default.
• W984969756 hasConcept C121608353 @default.
• W984969756 hasConcept C127848430 @default.
• W984969756 hasConcept C181199279 @default.
• W984969756 hasConcept C2776059313 @default.
• W984969756 hasConcept C2777150147 @default.
• W984969756 hasConcept C2778227246 @default.
• W984969756 hasConcept C501734568 @default.
• W984969756 hasConcept C502942594 @default.
• W984969756 hasConcept C54355233 @default.
• W984969756 hasConcept C55493867 @default.
• W984969756 hasConcept C555283112 @default.
• W984969756 hasConcept C86803240 @default.
• W984969756 hasConceptScore W984969756C104317684 @default.
• W984969756 hasConceptScore W984969756C121608353 @default.
• W984969756 hasConceptScore W984969756C127848430 @default.
• W984969756 hasConceptScore W984969756C181199279 @default.
• W984969756 hasConceptScore W984969756C2776059313 @default.
• W984969756 hasConceptScore W984969756C2777150147 @default.
• W984969756 hasConceptScore W984969756C2778227246 @default.
• W984969756 hasConceptScore W984969756C501734568 @default.
• W984969756 hasConceptScore W984969756C502942594 @default.
• W984969756 hasConceptScore W984969756C54355233 @default.
• W984969756 hasConceptScore W984969756C55493867 @default.
• W984969756 hasConceptScore W984969756C555283112 @default.
• W984969756 hasConceptScore W984969756C86803240 @default.
• W984969756 hasLocation W9849697561 @default.
• W984969756 hasOpenAccess W984969756 @default.
• W984969756 hasPrimaryLocation W9849697561 @default.
• W984969756 hasRelatedWork W2117996853 @default.
• W984969756 hasRelatedWork W2137131553 @default.
• W984969756 hasRelatedWork W2566625964 @default.
• W984969756 hasRelatedWork W2766580779 @default.
• W984969756 hasRelatedWork W2797541558 @default.
• W984969756 hasRelatedWork W2801958156 @default.
• W984969756 hasRelatedWork W2884536184 @default.
• W984969756 hasRelatedWork W2899083722 @default.
• W984969756 hasRelatedWork W2901681483 @default.
• W984969756 hasRelatedWork W2949220971 @default.
• W984969756 hasRelatedWork W2955391481 @default.
• W984969756 hasRelatedWork W2970423639 @default.
• W984969756 hasRelatedWork W2982496885 @default.
• W984969756 hasRelatedWork W2990572193 @default.
• W984969756 hasRelatedWork W3081135066 @default.
• W984969756 hasRelatedWork W3087738194 @default.
• W984969756 hasRelatedWork W3100312252 @default.
• W984969756 hasRelatedWork W3157902236 @default.
• W984969756 hasRelatedWork W3165568336 @default.
• W984969756 hasRelatedWork W3197821151 @default.
• W984969756 isParatext "false" @default.
• W984969756 isRetracted "false" @default.
• W984969756 magId "984969756" @default.
• W984969756 workType "dissertation" @default.