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Shigeo Ohba, Joydeep Mukherjee, Tor-Christian Johannessen, Andrew Mancini, Tracy T Chow, Matthew Wood, Lindsey Jones, Tali Mazor, Roxanne E Marshall, Pavithra Viswanath, Kyle M Walsh, Arie Perry, Robert J A Bell, Joanna J Phillips, Joseph F Costello, Sabrina M Ronen, Russell O Pieper
Mutations in the isocitrate dehydrogenase gene IDH1 are common in lower-grade glioma where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation and gliomagenesis. IDH1 mutations also co-segregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine if and how this may occur, we investigated the phenotype of pRb/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H mutant (IDH1mut) genes as they progressed through their lifespan...
October 6, 2016: Cancer Research
Anne Marie Greenhalgh, Leticia Gonzalez-Blanco, Clemente Garcia-Rizo, Emilio Fernandez-Egea, Brian Miller, Miguel Bernardo Arroyo, Brian Kirkpatrick
BACKGROUND: Some studies have suggested that antipsychotic-naïve patients with nonaffective psychosis (NAP) have glucose intolerance. AIMS: To conduct a systematic review and meta-analysis of fasting glucose (FG), two hour values in the oral glucose tolerance test (2HG), fasting insulin concentration (INS), and insulin resistance (IR). METHOD: We identified possibly relevant studies, then selected studies, following usual guidelines, with two authors reviewing the manuscripts...
October 13, 2016: Schizophrenia Research
Gaurav Verma, Suyash Mohan, MacLean P Nasrallah, Steven Brem, John Y K Lee, Sanjeev Chawla, Sumei Wang, Rajakumar Nagarajan, M Albert Thomas, Harish Poptani
BACKGROUND: Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the "oncometabolite" 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism...
2016: Journal of Translational Medicine
Mélissa Carbonneau, Laurence M Gagné, Marie-Eve Lalonde, Marie-Anne Germain, Alena Motorina, Marie-Christine Guiot, Blandine Secco, Emma E Vincent, Anthony Tumber, Laura Hulea, Jonathan Bergeman, Udo Oppermann, Russell G Jones, Mathieu Laplante, Ivan Topisirovic, Kevin Petrecca, Marc-Étienne Huot, Frédérick A Mallette
The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases...
2016: Nature Communications
Johanna Mondesir, Christophe Willekens, Mehdi Touat, Stéphane de Botton
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis...
2016: Journal of Blood Medicine
Yu Cho Woo, Chi Ho Lee, Carol Hy Fong, Aimin Xu, Annette Wk Tso, Bernard My Cheung, Karen Sl Lam
OBJECTIVE: Fibroblast growth factor 21 (FGF21) improves glucose and lipid metabolism but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2-hour plasma glucose (2hG) during the oral glucose tolerance test (OGTT)...
September 9, 2016: Clinical Endocrinology
Hyeonjin Kim, Sungjin Kim, Hyeong Hun Lee, Hwon Heo
The diagnostic and prognostic potential of an onco-metabolite, 2-hydroxyglutarate (2HG) as a proton magnetic resonance spectroscopy (1H-MRS) detectable biomarker of the isocitrate dehydrogenase (IDH)-mutated (IDH-MT) gliomas has drawn attention of neuroradiologists recently. However, due to severe spectral overlap with background signals, quantification of 2HG can be very challenging. In this technical review for neuroradiologists, first, the biochemistry of 2HG and its significance in the diagnosis of IDH-MT gliomas are summarized...
September 2016: Korean Journal of Radiology: Official Journal of the Korean Radiological Society
Jing-Yi Chen, You-Syuan Lai, Hui-Jen Tsai, Cheng-Chin Kuo, B Linju Yen, Su-Peng Yeh, H Sunny Sun, Wen-Chun Hung
Mutations of isocitrate dehydrogenase 1 (IDH1) and IDH2 in acute myeloid leukemia (AML) cells produce the oncometabolite R-2-hydroxyglutarate (R-2HG) to induce epigenetic alteration and block hematopoietic differentiation. However, the effect of R-2HG released by IDH-mutated AML cells on the bone marrow microenvironment is unclear. Here, we report that R-2HG induces IκB kinase-independent activation of NF-κB in bone marrow stromal cells. R-2HG acts via a reactive oxygen species/extracellular signal-regulated kinase (ERK)-dependent pathway to phosphorylate NF-κB on the Thr254 residue...
2016: Scientific Reports
Elena Anghileri, Nicola Bertolino, Ettore Salsano, Luigi Antelmi, Patrizia Carpinelli, Barbara Castellotti, Ileana Zucca, Cinzia Gellera, Raffaele Bisogno, Claudio Caccia, Valeria Cuccarini
UNLABELLED: L-2-Hydroxyglutaric aciduria (L2HGA) is an extremely rare hereditary neurometabolic disease, characterized by increased L-2-hydroxyglutarate (L2HG) levels in the brain and biological fluids. 24-h urine 2HG level remains the biochemical hallmark for the diagnosis of L2HGA, whereas it is unknown the feasibility to measure in vivo the intracerebral levels of 2HG by using magnetic resonance spectroscopy (MRS). PATIENTS AND METHODS: We used at 3T H(1)-MRS Single-Voxel (SV) PRESS sequences tailored to detect 2HG, in three adult patients with the diagnosis of L2HGA and in healthy controls...
October 1, 2016: Brain Research
Fang Wang, Jeremy Travins, Zhizhong Lin, Yaguang Si, Yue Chen, Josh Powe, Stuart Murray, Dongwei Zhu, Erin Artin, Stefan Gross, Stephanie Santiago, Mya Steadman, Andrew Kernytsky, Kimberly Straley, Chenming Lu, Ana Pop, Eduard A Struys, Erwin E W Jansen, Gajja S Salomons, Muriel D David, Cyril Quivoron, Virginie Penard-Lacronique, Karen S Regan, Wei Liu, Lenny Dang, Hua Yang, Lee Silverman, Samuel Agresta, Marion Dorsch, Scott Biller, Katharine Yen, Yong Cang, Shin-San Michael Su, Shengfang Jin
D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus...
November 2016: Journal of Inherited Metabolic Disease
Zhongxu An, Sandeep K Ganji, Vivek Tiwari, Marco C Pinho, Toral Patel, Samuel Barnett, Edward Pan, Bruce E Mickey, Elizabeth A Maher, Changho Choi
PURPOSE: To test the efficacy of triple-refocusing MR spectroscopy (MRS) for improved detection of 2-hydroxyglutarate (2HG) in brain tumors at 3T in vivo. METHODS: The triple-refocusing sequence parameters were tailored at 3T, with density-matrix simulations and phantom validation, for enhancing the 2HG 2.25-ppm signal selectivity with respect to the adjacent resonances of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA). In vivo MRS data were acquired from 15 glioma patients and analyzed with LCModel using calculated basis spectra...
July 25, 2016: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
Joanne M Kingsbury, Nachiketha Shamaprasad, R Blake Billmyre, Joseph Heitman, Maria E Cardenas
A major advance in understanding the progression and prognostic outcome of certain cancers, such as low-grade gliomas, acute myeloid leukemia, and chondrosarcomas, has been the identification of early-occurring mutations in the NADP(+)-dependent isocitrate dehydrogenase genes IDH1 and IDH2 These mutations result in the production of the onco-metabolite D-2-hydroxyglutarate (2HG), thought to contribute to disease progression. To better understand the mechanisms of 2HG pathophysiology, we introduced the analogous glioma-associated mutations into the NADP(+) isocitrate dehydrogenase genes (IDP1, IDP2, IDP3) in Saccharomyces cerevisiae Intriguingly, expression of the mitochondrial IDP1(R148H) mutant allele results in high levels of 2HG production as well as extensive mtDNA loss and respiration defects...
July 17, 2016: Human Molecular Genetics
Kourosh Jafari-Khouzani, Franziska Loebel, Wolfgang Bogner, Otto Rapalino, Gilberto R Gonzalez, Elizabeth Gerstner, Andrew S Chi, Tracy T Batchelor, Bruce R Rosen, Jan Unkelbach, Helen A Shih, Daniel P Cahill, Ovidiu C Andronesi
BACKGROUND: Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning...
July 5, 2016: Neuro-oncology
Juliya Kalinina, Jun Ahn, Narra S Devi, Liya Wang, Yuancheng Li, Jeffrey J Olson, Michael Glantz, Thomas Smith, Ella Kim, Alf Giese, Randy L Jensen, Clark Chen, Bob Carter, Hui Mao, Miao He, Erwin G Van Meir
PURPOSE: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene. EXPERIMENTAL DESIGN: We developed a Mass Spectroscopy (MS)-based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients...
June 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Xin Teng, Matthew J Emmett, Mitchell A Lazar, Erwin Goldberg, Joshua D Rabinowitz
Metabolomics is a valuable tool for studying tissue- and organism-specific metabolism. In normal mouse testis, we found 70 μM S-2-hydroxyglutarate (2HG), more than 10-fold greater than in other tissues. S-2HG is a competitive inhibitor of α-ketoglutarate-dependent demethylation enzymes and can alter histone or DNA methylation. To identify the source of testis S-2HG, we fractionated testis extracts and identified the fractions that actively produced S-2HG. Through a combination of ion exchange and size exclusion chromatography, we enriched a single active protein, the lactate dehydrogenase isozyme LDHC, which is primarily expressed in testis...
September 16, 2016: ACS Chemical Biology
Sofi Jonsson, Nashaat M Mazrui, Robert P Mason
Underlying formation pathways of dimethylmercury ((CH3)2Hg) in the ocean are unknown. Early work proposed reactions of inorganic Hg (Hg(II)) with methyl cobalamin or of dissolved monomethylmercury (CH3Hg) with hydrogen sulfide as possible bacterial mediated or abiotic pathways. A significant fraction (up to 90%) of CH3Hg in natural waters is however adsorbed to reduced sulfur groups on mineral or organic surfaces. We show that binding of CH3Hg to such reactive sites facilitates the formation of (CH3)2Hg by degradation of the adsorbed CH3Hg...
2016: Scientific Reports
Vidya Rajendran
Arginine to histidine mutation at position 132 (R132H) in isocitrate dehydrogenase 1 (IDH1) led to reduced affinity of the respective enzymes for isocitrate and increased affinity for α-ketoglutarate (AKG) and NADPH. This phenomenon retarded oxidative decarboxylation of isocitrate to AKG and conferred a novel enzymatic activity that facilitated the reduction of AKG to d-2-hydroxyglutarate (d-2HG). The loss of isocitrate utilization and gain of 2HG production from IDH1 R132H had been taken up as a fundamental problem and to solve this, structural biology approaches were adopted...
June 21, 2016: Molecular BioSystems
Hiroaki Nagashima, Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Naoko Sato, Yukiko Takeuchi, Katsusuke Kyotani, Akitake Mukasa, Katsu Mizukawa, Junichi Sakata, Yusuke Yamamoto, Kohkichi Hosoda, Tomoo Itoh, Ryohei Sasaki, Eiji Kohmura
BACKGROUND: Mutations in the isocitrate dehydrogenase 1 (IDH1) gene that are frequently observed in low-grade glioma are strongly associated with the accumulation of 2-hydroxyglutarate (2HG), which is a valuable diagnostic and prognostic biomarker of IDH1 mutant glioma. However, conventional MR spectroscopy (MRS)-based noninvasive detection of 2HG is challenging. In this study, we aimed to determine the additional value of other metabolites in predicting IDH1 mutations with conventional MRS...
May 5, 2016: Neuro-oncology
A Chaturvedi, M M Araujo Cruz, N Jyotsana, A Sharma, R Goparaju, A Schwarzer, K Görlich, R Schottmann, E A Struys, E E Jansen, C Rohde, C Müller-Tidow, R Geffers, G Göhring, A Ganser, F Thol, M Heuser
Canonical mutations in IDH1 and IDH2 produce high levels of the R-enantiomer of 2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of α-ketoglutarate (αKG)-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We used two mouse models and a patient-derived acute myeloid leukemia xenotransplantation (PDX) model to evaluate the in vivo transforming potential of R-2HG, S-2HG and αKG independent of the mutant IDH1 protein. We show that R-2HG, but not S-2HG or αKG, is an oncometabolite in vivo that does not require the mutant IDH1 protein to induce hyperleukocytosis and to accelerate the onset of murine and human leukemia...
August 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Min Sik Eom, Jieun Noh, Han-Sung Kim, Soyeon Yoo, Min Su Han, Sunwoo Lee
Mercury complex of 4-(2-pyridylazo)resorcinol (PAR-2Hg(2+)), a halide-ion chemosensor, was prepared and its efficiency as a tool for high-throughput screening (HTS) of transition-metal-catalyzed coupling reactions was investigated. It showed a high selectivity for halide ions. When the PAR-2Hg(2+) complex was used in the Suzuki coupling reaction and C-H activated coupling reaction with aryl bromides, the quantitative and qualitative conversions of aryl halides were obtained from the reaction mixture color change...
April 15, 2016: Organic Letters
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