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2 hydroxyglutarate

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https://www.readbyqxmd.com/read/29773892/metabolite-cycled-density-weighted-concentric-rings-k-space-trajectory-dw-crt-enables-high-resolution-1-h-magnetic-resonance-spectroscopic-imaging-at-3-tesla
#1
Adam Steel, Mark Chiew, Peter Jezzard, Natalie L Voets, Puneet Plaha, Michael Albert Thomas, Charlotte J Stagg, Uzay E Emir
Magnetic resonance spectroscopic imaging (MRSI) is a promising technique in both experimental and clinical settings. However, to date, MRSI has been hampered by prohibitively long acquisition times and artifacts caused by subject motion and hardware-related frequency drift. In the present study, we demonstrate that density weighted concentric ring trajectory (DW-CRT) k-space sampling in combination with semi-LASER excitation and metabolite-cycling enables high-resolution MRSI data to be rapidly acquired at 3 Tesla...
May 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29773061/development-of-novel-therapeutics-targeting-isocitrate-dehydrogenase-mutations-in-cancer
#2
Horrick Sharma
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH 1 and IDH2 regulate several cellular processes, including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumor types, including gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and IDH2 mutations involve a gain in neomorphic activity that catalyze αKG conversion to (R)-2-hydroxyglutarate ((R)-2HG)...
May 17, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29772792/metabolic-regulation-of-hypoxia-inducible-transcription-factors-the-role-of-small-molecule-metabolites-and-iron
#3
REVIEW
Peter S J Bailey, James A Nathan
Hypoxia-inducible transcription factors (HIFs) facilitate cellular adaptations to low-oxygen environments. However, it is increasingly recognised that HIFs may be activated in response to metabolic stimuli, even when oxygen is present. Understanding the mechanisms for the crosstalk that exists between HIF signalling and metabolic pathways is therefore important. This review focuses on the metabolic regulation of HIFs by small molecule metabolites and iron, highlighting the latest studies that explore how tricarboxylic acid (TCA) cycle intermediates, 2-hydroxyglutarate (2-HG) and intracellular iron levels influence the HIF response through modulating the activity of prolyl hydroxylases (PHDs)...
May 17, 2018: Biomedicines
https://www.readbyqxmd.com/read/29769206/targeting-the-idh2-pathway-in-acute-myeloid-leukemia
#4
Maria L Amaya, Daniel A Pollyea
Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. A large percentage of patients succumb to this disease, in spite of aggressive treatments with chemotherapy. Recent advances with mutational analysis led to the discovery of isocitrate dehydrogenase (IDH) mutations in AML. IDH2 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate; its mutated version leads to the accumulation of the oncometabolite (R)-2 hydroxyglutarate, which disrupts several cell processes and leads to a blockage in differentiation...
May 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29744569/widespread-and-debilitating-hemangiomas-in-a-patient-with-enchondromatosis-and-d-2-hydroxyglutaric-aciduria
#5
Patra Yeetong, Teerasak Phewplung, Wuttichart Kamolvisit, Kanya Suphapeetiporn, Vorasuk Shotelersuk
Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) (OMIM 614875) is a severe chondrodysplasia combined with a urinary excretion of D-2-hydroxyglutaric acid. Here, we reported the tenth case of this disease. A 15-year-old boy had symmetric radiolulencies in the metaphyses of the long bones suggesting enchondromatosis and platyspondyly. Remarkably, he manifested widespread cavernous hemangiomas including scalp, lips, tongue, larynx, and prepuce, with the onset of 3 years of age. Hemangiomas at the larynx had caused dyspnea and those in the oral cavity led to recurrent bleeding, requiring several surgical removals...
May 10, 2018: Skeletal Radiology
https://www.readbyqxmd.com/read/29719265/mutant-idh1-promotes-glioma-formation-in-vivo
#6
Beatrice Philip, Diana X Yu, Mark R Silvis, Clifford H Shin, James P Robinson, Gemma L Robinson, Adam E Welker, Stephanie N Angel, Sheryl R Tripp, Joshua A Sonnen, Matthew W VanBrocklin, Richard J Gibbons, Ryan E Looper, Howard Colman, Sheri L Holmen
Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III glioma and secondary glioblastoma (GBM). A causal role for IDH1R132H in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated. In this study, we assessed the role of IDH1R132H in glioma development in the context of clinically relevant cooperating genetic alterations in vitro and in vivo. Immortal astrocytes expressing IDH1R132H exhibited elevated (R)-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth...
May 1, 2018: Cell Reports
https://www.readbyqxmd.com/read/29671246/rapid-detection-of-mutation-in-isocitrate-dehydrogenase-1-and-2-genes-using-mass-spectrometry
#7
Masayuki Kanamori, Masamitsu Maekawa, Ichiyo Shibahara, Ryuta Saito, Masashi Chonan, Miki Shimada, Yukihiko Sonoda, Toshihiro Kumabe, Mika Watanabe, Nariyasu Mano, Teiji Tominaga
The 2016 World Health Organization classification of tumors of the central nervous system was recently revised. Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and chromosome 1p/19q codeletion are especially important for both the integrated diagnosis and the determination of surgical strategy. To establish a method for intraoperative molecular diagnosis, a simple, rapid method was developed for the measurement of 2-hydroxyglutarate (2-HG), a specific oncometabolite formed in the presence of IDH gene mutation, using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS)...
April 18, 2018: Brain Tumor Pathology
https://www.readbyqxmd.com/read/29670690/discovery-of-ag-120-ivosidenib-a-first-in-class-mutant-idh1-inhibitor-for-the-treatment-of-idh1-mutant-cancers
#8
Janeta Popovici-Muller, René M Lemieux, Erin Artin, Jeffrey O Saunders, Francesco G Salituro, Jeremy Travins, Giovanni Cianchetta, Zhenwei Cai, Ding Zhou, Dawei Cui, Ping Chen, Kimberly Straley, Erica Tobin, Fang Wang, Muriel D David, Virginie Penard-Lacronique, Cyril Quivoron, Véronique Saada, Stéphane de Botton, Stefan Gross, Lenny Dang, Hua Yang, Luke Utley, Yue Chen, Hyeryun Kim, Shengfang Jin, Zhiwei Gu, Gui Yao, Zhiyong Luo, Xiaobing Lv, Cheng Fang, Liping Yan, Andrew Olaharski, Lee Silverman, Scott Biller, Shin-San M Su, Katharine Yen
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo...
April 12, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29662077/pharmacodynamics-of-mutant-idh1-inhibitors-in-glioma-patients-probed-by-in-vivo-3d-mrs-imaging-of-2-hydroxyglutarate
#9
Ovidiu C Andronesi, Isabel C Arrillaga-Romany, K Ina Ly, Wolfgang Bogner, Eva M Ratai, Kara Reitz, A John Iafrate, Jorg Dietrich, Elizabeth R Gerstner, Andrew S Chi, Bruce R Rosen, Patrick Y Wen, Daniel P Cahill, Tracy T Batchelor
Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0...
April 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29660019/modeling-the-diffusion-of-d-2-hydroxyglutarate-from-idh1-mutant-gliomas-in-the-central-nervous-system
#10
Andreas Linninger, Grant A Hartung, Benjamin P Liu, Snezana Mirkov, Kevin Tangen, Rimas V Lukas, Dusten Unruh, C David James, Jann N Sarkaria, Craig Horbinski
Background: 20-30% of diffusely infiltrative gliomas in adults contain a point mutation in isocitrate dehydrogenase 1 (IDH1mut), which increases production of D-2-hydroxyglutarate (D2HG). This is so efficient that D2HG often reaches 30 mM within IDH1mut gliomas. Yet, while up to 100 µM D2HG can be detected in the circulating cerebrospinal fluid of IDH1mut glioma patients, the exposure of nonneoplastic cells within and surrounding an IDH1mut glioma to D2HG is unknown and difficult to measure directly...
April 5, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29651790/novel-insights-for-inhibiting-mutant-heterodimer-idh1-wt-r132h-in-cancer-an-in-silico-approach
#11
Ezequiel Iván Juritz, Juan Pablo Bascur, Daniel Eduardo Almonacid, Fernando Danilo González-Nilo
BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) is a dimeric enzyme responsible for supplying the cell's nicotinamide adenine dinucleotide phosphate (NADPH) reserves via dehydrogenation of isocitrate (ICT) and reduction of NADP+. Mutations in position R132 trigger cancer by enabling IDH1 to produce D-2-hydroxyglutarate (2-HG) and reduce inhibition by ICT. Mutant IDH1 can be found as a homodimer or a heterodimer. OBJECTIVE: We propose a novel strategy to inhibit IDH1 R132 variants as a means not to decrease the concentration of 2-HG but to provoke a cytotoxic effect, as the cell malignancy at this point no longer depends on 2-HG...
April 12, 2018: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/29643764/the-idh1-mutation-induced-oncometabolite-2-hydroxyglutarate-may-affect-dna-methylation-and-expression-of-pd-l1-in-gliomas
#12
Luyan Mu, Yu Long, Changlin Yang, Linchun Jin, Haipeng Tao, Haitao Ge, Yifan E Chang, Aida Karachi, Paul S Kubilis, Gabriel De Leon, Jiping Qi, Elias J Sayour, Duane A Mitchell, Zhiguo Lin, Jianping Huang
Background: Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas. Methods: Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29619216/mutant-idh1-gliomas-downregulate-phosphocholine-and-phosphoethanolamine-synthesis-in-a-2-hydroxyglutarate-dependent-manner
#13
Pavithra Viswanath, Marina Radoul, Jose Luis Izquierdo-Garcia, Hema Artee Luchman, J Gregory Cairncross, Russell O Pieper, Joanna J Phillips, Sabrina M Ronen
Background: Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study was to determine the molecular mechanism underlying this unusual metabolic reprogramming in IDHmut gliomas...
2018: Cancer & Metabolism
https://www.readbyqxmd.com/read/29603663/separation-and-determination-of-the-enantiomers-of-lactic-acid-and-2-hydroxyglutaric-acid-by-chiral-derivatization-combined-with-gc-ms
#14
Xuemei Ding, Shuhai Lin, Hongbo Weng, Jianying Liang
Lactic acid and 2-hydroxyglutaric acid are chiral metabolites that have two distinct d and l enantiomers with distinct biochemical properties. Perturbations of single enantiomeric form have been found to be closely related to certain diseases. The ability to differentiate the d and l enantiomers is therefore important for these disease studies. Herein, we describe a method for the separation and determination of lactic acid and 2-hydroxyglutaric acid enantiomers by chiral derivatization (with l-menthol and acetyl chloride) combined with gas chromatography and mass spectrometry...
March 30, 2018: Journal of Separation Science
https://www.readbyqxmd.com/read/29564224/the-role-of-mitochondrial-h-atp-synthase-in-cancer
#15
REVIEW
Pau B Esparza-Moltó, José M Cuezva
Cancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H+ -ATP synthase-the core hub of oxidative phosphorylation-is downregulated in human carcinomas when compared with its expression in normal tissues. Moreover, some prevalent carcinomas also upregulate the ATPase inhibitory factor 1 (IF1), which is the physiological inhibitor of the H+ -ATP synthase...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29549529/isocitrate-dehydrogenase-2-mutations-correlate-with-leukemic-transformation-and-are-predicted-by-2-hydroxyglutarate-in-myelodysplastic-syndromes
#16
Peipei Lin, Yingwan Luo, Shuanghong Zhu, Dominic Maggio, Haiyang Yang, Chao Hu, Jinghan Wang, Hua Zhang, Yanling Ren, Xinping Zhou, Chen Mei, Liya Ma, Weilai Xu, Li Ye, Zhengping Zhuang, Jie Jin, Hongyan Tong
PURPOSE: The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut ) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS...
June 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29548050/radiomics-metabolic-and-molecular-mri-for-brain-tumors
#17
Philipp Kickingereder, Ovidiu Cristian Andronesi
Magnetic resonance imaging plays a key role in diagnosis and treatment monitoring of brain tumors. Novel imaging techniques that specifically interrogate aspects of underlying tumor biology and biochemical pathways have great potential in neuro-oncology. This review focuses on the emerging role of 2-hydroxyglutarate-targeted magnetic resonance spectroscopy, as well as radiomics and radiogenomics in establishing diagnosis for isocitrate dehydrogenase mutant gliomas, and for monitoring treatment response and predicting prognosis of this group of brain tumor patients...
February 2018: Seminars in Neurology
https://www.readbyqxmd.com/read/29547090/prognostic-role-of-mitochondrial-pyruvate-carrier-in-isocitrate-dehydrogenase-mutant-glioma
#18
Michael Karsy, Jian Guan, L Eric Huang
OBJECTIVE Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis...
March 16, 2018: Journal of Neurosurgery
https://www.readbyqxmd.com/read/29545476/d-2-hydroxyglutarate-is-necessary-and-sufficient-for-isocitrate-dehydrogenase-1-mutant-induced-mir148a-promoter-methylation
#19
Tie Li, Christopher D Cox, Byram H Ozer, Nhung T Nguyen, HuyTram N Nguyen, Thomas J Lai, Sichen Li, Fei Liu, Harley I Kornblum, Linda M Liau, Phioanh L Nghiemphu, Timothy F Cloughesy, Albert Lai
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG-dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP) and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated...
March 15, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29544107/prediction-of-platinum-based-chemotherapy-efficacy-in-lung-cancer-based-on-lc-ms-metabolomics-approach
#20
Feng Peng, Yingzi Liu, Chenjie He, Yi Kong, Qianying Ouyang, Xiaonv Xie, Tong Liu, Zhaoqian Liu, Jingbo Peng
Lung cancer is the common cause of cancer-related death worldwide. Platinum-based chemotherapy is the cornerstone of treatment for lung cancer. Platinum sensitivity is a major possibility for effective cancer treatment. In this study, several potential biomarkers were identified for evaluating and predicting the response to platinum-based chemotherapy. LC-MS-based metabolomics was performed on plasma samples from 43 lung cancer patients with different chemotherapy efficacy. By combing multivariate statistical analysis, pathway analysis with correlation analysis, 8 potential biomarkers were significantly associated with platinum chemotherapy response...
May 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
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