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https://www.readbyqxmd.com/read/28735490/measurement-of-oncometabolites-d-2-hydroxyglutaric-acid-and-l-2-hydroxyglutaric-acid
#1
Patricia M Jones, Richard Boriack, Eduard A Struys, Dinesh Rakheja
We describe a liquid chromatography-tandem mass spectrometry assay for measurement of D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid. These metabolites are increased in specific inborn errors of metabolism and are now recognized as oncometabolites. The measurement of D-2-hydroxyglutarate in peripheral blood may be used as a biomarker for screening and follow-up of patients with IDH-mutated acute myeloid leukemia.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28729418/myc-regulated-mevalonate-metabolism-maintains-brain-tumor-initiating-cells
#2
Xiuxing Wang, Zhi Huang, Qiulian Wu, Briana C Prager, Stephen C Mack, Kailin Yang, Leo J Y Kim, Ryan C Gimple, Yu Shi, Sisi Lai, Qi Xie, Tyler E Miller, Christopher G Hubert, Anne Song, Zhen Dong, Wenchao Zhou, Xiaoguang Fang, Zhe Zhu, Vaidehi Mahadev, Shideng Bao, Jeremy N Rich
Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wildtype IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor initiating cells (BTICs) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment...
July 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28714279/predicting-idh-mutation-status-in-grade-ii-gliomas-using-amide-proton-transfer-weighted-aptw-mri
#3
Shanshan Jiang, Tianyu Zou, Charles G Eberhart, Maria A V Villalobos, Hye-Young Heo, Yi Zhang, Yu Wang, Xianlong Wang, Hao Yu, Yongxing Du, Peter C M van Zijl, Zhibo Wen, Jinyuan Zhou
PURPOSE: To assess the amide proton transfer-weighted (APTw) MRI features of isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant grade II gliomas and to test the hypothesis that the APTw signal is a surrogate imaging marker for identifying IDH mutation status preoperatively. METHODS: Twenty-seven patients with pathologically confirmed low-grade glioma, who were previously scanned at 3T, were retrospectively analyzed. The Mann-Whitney test was used to evaluate relationships between APTw intensities for IDH-mutant and IDH-wildtype groups, and receiver operator characteristic (ROC) analysis was used to assess the diagnostic performance of APTw...
July 16, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/28705010/isocitrate-dehydrogenase-mutation-as-a-therapeutic-target-in-gliomas
#4
Catherine H Han, Tracy T Batchelor
Isocitrate dehydrogenases (IDH) are important enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH in the process. More than 80% of low-grade gliomas and secondary glioblastoma (GBM) harbor an IDH mutation. IDH mutations involve the catalytic pocket of the enzyme and lead to a neomorphic ability to produce 2-hydroxyglutarate (2HG) while oxidizing NADPH to NADP+. 2HG is considered as an 'oncometabolite' which is thought to be responsible for many, if not all, biologic effects of IDH mutations...
June 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28704501/reduced-susceptibility-of-clinical-strains-of-mycobacterium-tuberculosis-to-reactive-nitrogen-species-promotes-survival-in-activated-macrophages
#5
Jonna Idh, Blanka Andersson, Maria Lerm, Johanna Raffetseder, Daniel Eklund, Hanna Woksepp, Jim Werngren, Mikael Mansjö, Tommy Sundqvist, Olle Stendahl, Thomas Schön
BACKGROUND: Drugs such as isoniazid (INH) and pretomanid (PRT), used against Mycobacterium tuberculosis are active partly through generation of reactive nitrogen species (RNS). The aim of this study was to explore variability in intracellular susceptibility to nitric oxide (NO) in clinical strains of M. tuberculosis. METHOD: Luciferase-expressing clinical M. tuberculosis strains with or without INH resistance were exposed to RNS donors (DETA/NO and SIN-1) in broth cultures and bacterial survival was analysed by luminometry...
2017: PloS One
https://www.readbyqxmd.com/read/28696020/complete-durable-response-of-a-pediatric-anaplastic-oligodendroglioma-to-temozolomide-alone-case-report-and-review-of-literature
#6
Caryn Sorge, Rong Li, Sumit Singh, Alyssa T Reddy, David A Solomon, Arie Perry, Gregory K Friedman
Anaplastic oligodendroglioma (AO) is rare in children. Treatment typically consists of varying combinations of surgery, chemotherapy, and radiotherapy. We present a pediatric case of frontal lobe AO with periventricular subcallosal extension and local leptomeningeal involvement. The isocitrate dehydrogenase (IDH) wild-type tumor was MGMT methylated and contained an ATRX mutation, BRAF alteration, and 1p/19q co-deletion; a combination of alterations mostly encountered in pediatric oligodendrogliomas. The patient underwent a near total resection and had a complete, durable response to temozolomide alone, suggesting that conservative management without radiation may be appropriate in some cases...
July 11, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28679024/multi-pronged-proteomic-analysis-to-study-the-glioma-pathobiology-using-cerebrospinal-fluid-samples
#7
Nikita Gahoi, Darpan Malhotra, Aliasgar Moiyadi, Santosh G Varma, Mayuri N Gandhi, Sanjeeva Srivastava
PURPOSE: Gliomas are one of the most aggressive and lethal brain tumors arising from neoplastic transformation of astrocytes and oligodendrocytes. In this study, we have carried out a comprehensive quantitative analysis of proteome level differences in cerebrospinal fluid (CSF) across different grades of gliomas for a better understanding of glioma pathobiology. EXPERIMENTAL DESIGN: Glioma patients were diagnosed by radiology and histochemistry- based analyses. Differential proteomic analysis of high (n = 12) and low (n = 8) grade gliomas, and control (n = 3) samples was performed by using two complementary quantitative proteomic approaches; 2D-DIGE and iTRAQ...
July 5, 2017: Proteomics. Clinical Applications
https://www.readbyqxmd.com/read/28674742/characterization-of-gliomas-from-morphology-to-molecules
#8
Sean P Ferris, Jeffrey W Hofmann, David A Solomon, Arie Perry
This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma)...
July 4, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28673962/potential-mechanisms-linking-sirt-activity-and-hypoxic-2-hydroxyglutarate-generation-no-role-for-direct-enzyme-de-acetylation
#9
Sergiy M Nadtochiy, Yves T Wang, Jimmy Zhang, Keith Nehrke, Xenia Schafer, Kevin Welle, Sina Ghaemmaghami, Joshua Munger, Paul S Brookes
2-hydroxyglutarate (2-HG) is a hypoxic metabolite with potentially important epigenetic signaling roles. The mechanisms underlying 2-HG generation are poorly understood, but evidence suggests a potential regulatory role for the sirtuin family of lysine deacetylases. Thus, we hypothesized that the acetylation status of the major 2-HG-generating enzymes (lactate dehydrogenase (LDH), isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH)) may govern their 2-HG generating activity. In-vitro acetylation of these enzymes, with confirmation by western blotting, mass spectrometry, reversibility by recombinant sirtuins, and an assay for global lysine occupancy, yielded no effect on 2-HG generating activity...
July 3, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28673671/relationship-among-clinical-pathological-and-bio-molecular-features-in-low-grade-epilepsy-associated-neuroepithelial-tumors
#10
Gianfranco Vornetti, Gianluca Marucci, Corrado Zenesini, Dario de Biase, Roberto Michelucci, Paolo Tinuper, Giovanni Tallini, Marco Giulioni
The aim of this study was to evaluate the relationship between molecular markers and clinicopathological features in patients operated on for low-grade epilepsy-associated neuroepithelial tumors. Molecular-genetic signatures are becoming increasingly important in characterizing these lesions, which represent the second most common cause of focal epilepsy in patients undergoing epilepsy surgery. Data from 22 patients operated on for histopathologically confirmed low-grade epilepsy-associated neuroepithelial tumors were retrospectively collected...
June 30, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28672945/o-6-methyl-guanine-dna-methyltransferase-methylation-and-idh1-2-mutation-in-small-cell-lung-cancer
#11
Hongyang Lu, Jing Qin, Haimiao Xu, Na Han, Fajun Xie, Weimin Mao
Small cell lung cancer (SCLC) is sensitive to first-line chemotherapy and radiotherapy, but frequently recurs. Temozolomide is a chemotherapeutic drug suitable for the treatment of relapsed SCLC, particularly when brain metastases are present. The response of SCLC to temozolomide may be associated with the methylation status of O(6)-methyl-guanine-DNA methyltransferase (MGMT). Isocitrate dehydrogenase (IDH) mutation is an independent prognostic factor of good outcome in gliomas and appears to be a significant marker of positive chemosensitivity in secondary glioblastoma...
July 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28665599/importance-of-r-cf3%C3%A2-%C3%A2-%C3%A2-o-tetrel-bonding-interactions-in-biological-systems
#12
Xavier García-LLinás, Antonio Bauzá, Saikat K Seth, Antonio Frontera
In this article, ab initio calculations have been combined with a search in the Protein Data Bank (PDB) to demonstrate the importance of σ-hole tetrel bonding interactions in biological systems. In particular, we focus our attention on the ability of the -CF3 group to participate in noncovalent interactions as Lewis acids, and we show the importance of this interaction in the inhibition mechanism of a NADP(+)-dependent isocitrate dehydrogenase (IDH) enzyme that converts isocitrate to α-ketoglutarate. IDH mutations are found in multiple hematologic and solid tumors, inducing premalignant disorders...
July 11, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28663574/vitamin-c-induced-epigenomic-remodelling-in-idh1-mutant-acute-myeloid-leukaemia
#13
M Mingay, A Chaturvedi, M Bilenky, Q Cao, L Jackson, T Hui, M Moksa, A Heravi-Moussavi, R K Humphries, M Heuser, M Hirst
The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating ten-eleven translocation 2 (TET2) mutations and neomorphic isocitrate dehydrogenase (IDH) mutations are recurrent and mutually exclusive in acute myeloid leukaemia genomes. Ascorbic acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukaemic model expressing IDH1(R132H). Vitamin C treatment induced an IDH1(R132H)-dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation...
June 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28653623/replication-study-the-common-feature-of-leukemia-associated-idh1-and-idh2-mutations-is-a-neomorphic-enzyme-activity-converting-alpha-ketoglutarate-to-2-hydroxyglutarate
#14
Megan Reed Showalter, Jason Hatakeyama, Tomas Cajka, Kacey VanderVorst, Kermit L Carraway, Oliver Fiehn
In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fiehn et al., 2016), that described how we intended to replicate selected experiments from the paper "The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate" (Ward et al., 2010). Here, we report the results of those experiments. We found that cells expressing R172K mutant IDH2 did not display isocitrate-dependent NADPH production above vector control levels, in contrast to the increased production observed with wild-type IDH2...
June 27, 2017: ELife
https://www.readbyqxmd.com/read/28640702/diffuse-infiltrating-oligodendroglioma-and-astrocytoma
#15
Martin J van den Bent, Marion Smits, Johan M Kros, Susan M Chang
The new 2016 WHO brain tumor classification defines different diffuse gliomas primarily according to the presence or absence of IDH mutations ( IDH-mt) and combined 1p/19q loss. Today, the diagnosis of anaplastic oligodendroglioma requires the presence of both IDH-mt and 1p/19q co-deletion, whereas anaplastic astrocytoma is divided into IDH wild-type ( IDH-wt) and IDH-mt tumors. IDH-mt tumors have a more favorable prognosis, and tumors with low-grade histology especially tend evolve slowly. IDH-wt tumors are not a homogeneous entity and warrant further molecular testing because some have glioblastoma-like molecular features with poor clinical outcome...
July 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28638988/same-day-genomic-and-epigenomic-diagnosis-of-brain-tumors-using-real-time-nanopore-sequencing
#16
Philipp Euskirchen, Franck Bielle, Karim Labreche, Wigard P Kloosterman, Shai Rosenberg, Mailys Daniau, Charlotte Schmitt, Julien Masliah-Planchon, Franck Bourdeaut, Caroline Dehais, Yannick Marie, Jean-Yves Delattre, Ahmed Idbaih
Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making...
June 21, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28629182/magnetic-resonance-spectroscopy-for-detection-of-2-hydroxyglutarate-as-a-biomarker-for-idh-mutation-in-gliomas
#17
REVIEW
Thomas Leather, Michael D Jenkinson, Kumar Das, Harish Poptani
Mutations in the isocitrate dehydrogenase (IDH)1/2 genes are highly prevalent in gliomas and have been suggested to play an important role in the development and progression of the disease. Tumours harbouring these mutations exhibit a significant alteration in their metabolism resulting in the aberrant accumulation of the oncometabolite 2-hydroxygluarate (2-HG). As well as being suggested to play an important role in tumour progression, 2-HG may serve as a surrogate indicator of IDH status through non-invasive detection using magnetic resonance spectroscopy (MRS)...
June 19, 2017: Metabolites
https://www.readbyqxmd.com/read/28621624/use-of-telomerase-promoter-mutations-to-mark-specific-molecular-subsets-with-reciprocal-clinical-behavior-in-idh-mutant-and-idh-wild-type-diffuse-gliomas
#18
Cemaliye B Akyerli, Şirin Yüksel, Özge Can, E Zeynep Erson-Omay, Yavuz Oktay, Erdal Coşgun, Ege Ülgen, Yiğit Erdemgil, Aydın Sav, Andreas von Deimling, Murat Günel, M Cengiz Yakıcıer, M Necmettin Pamir, Koray Özduman
OBJECTIVE Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade...
June 16, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28588020/enasidenib-in-mutant-idh2-relapsed-or-refractory-acute-myeloid-leukemia
#19
Eytan M Stein, Courtney D DiNardo, Daniel A Pollyea, Amir T Fathi, Gail J Roboz, Jessica K Altman, Richard M Stone, Daniel J DeAngelo, Ross L Levine, Ian W Flinn, Hagop M Kantarjian, Robert Collins, Manish R Patel, Arthur E Frankel, Anthony Stein, Mikkael A Sekeres, Ronan T Swords, Bruno C Medeiros, Christophe Willekens, Paresh Vyas, Alessandra Tosolini, Qiang Xu, Robert D Knight, Katharine E Yen, Sam Agresta, Stéphane de Botton, Martin S Tallman
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies...
June 6, 2017: Blood
https://www.readbyqxmd.com/read/28575485/adult-idh-wild-type-lower-grade-gliomas-should-be-further-stratified
#20
Aibaidula Abudumijiti, Aden Ka-Yin Chan, Zhifeng Shi, Yanxi Li, Ruiqi Zhang, Rui Yang, Kay Ka-Wai Li, Nellie Yuk-Fei Chung, Yu Yao, Liangfu Zhou, Jinsong Wu, Hong Chen, Ho-Keung Ng
Background: IDH wild-type astrocytoma is described as a provisional entity within the new WHO classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be sub-stratified prognostically. Methods: 718 adult WHO Grade II and III gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations...
May 27, 2017: Neuro-oncology
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