keyword
MENU ▼
Read by QxMD icon Read
search

2 hydroxyglutarate

keyword
https://www.readbyqxmd.com/read/29144447/bcat1-restricts-%C3%AE-kg-levels-in-aml-stem-cells-leading-to-idhmut-like-dna-hypermethylation
#1
Simon Raffel, Mattia Falcone, Niclas Kneisel, Jenny Hansson, Wei Wang, Christoph Lutz, Lars Bullinger, Gernot Poschet, Yannic Nonnenmacher, Andrea Barnert, Carsten Bahr, Petra Zeisberger, Adriana Przybylla, Markus Sohn, Martje Tönjes, Ayelet Erez, Lital Adler, Patrizia Jensen, Claudia Scholl, Stefan Fröhling, Sibylle Cocciardi, Patrick Wuchter, Christian Thiede, Anne Flörcken, Jörg Westermann, Gerhard Ehninger, Peter Lichter, Karsten Hiller, Rüdiger Hell, Carl Herrmann, Anthony D Ho, Jeroen Krijgsveld, Bernhard Radlwimmer, Andreas Trumpp
The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis...
November 16, 2017: Nature
https://www.readbyqxmd.com/read/29126125/highly-specific-determination-of-idh-status-using-edited-in-vivo-magnetic-resonance-spectroscopy
#2
Francesca Branzoli, Anna Luisa Di Stefano, Laurent Capelle, Chris Ottolenghi, Romain Valabrègue, Dinesh K Deelchand, Franck Bielle, Chiara Villa, Bertrand Baussart, Stéphane Lehéricy, Marc Sanson, Malgorzata Marjanska
Background: Mutations in the isocitrate dehydrogenase (IDH) enzyme affects 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG), and to compare performance of these methods with DNA sequencing and tissue 2HG analysis. Methods: Twenty-four subjects with suspected diagnosis of low grade glioma were included prospectively in the study...
November 6, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29097607/adaptive-evolution-of-the-gdh2-allosteric-domain-promotes-gliomagenesis-by-resolving-idh1-r132h-induced-metabolic-liabilities
#3
Matthew S Waitkus, Christopher J Pirozzi, Casey J Moure, Bill H Diplas, Landon J Hansen, Austin B Carpenter, Rui Yang, Zhaohui Wang, Brian O Ingram, Edward D Karoly, Robert P Mohney, Ivan Spasojeic, Roger E McLendon, Henry S Friedman, Yiping He, Darell D Bigner, Hai Yan
Hot-spot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1(R132H) expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1(R132H)-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy...
November 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/29090344/the-role-of-mutant-idh1-and-idh2-inhibitors-in-the-treatment-of-acute-myeloid-leukemia
#4
REVIEW
Samah Nassereddine, Coen J Lap, Faysal Haroun, Imad Tabbara
For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases...
October 31, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29089260/design-synthesis-and-biological-activity-of-3-pyrazine-2-yl-oxazolidin-2-ones-as-novel-potent-and-selective-inhibitors-of-mutant-isocitrate-dehydrogenase-1
#5
Tianfang Ma, Fangxia Zou, Stefan Pusch, Lijun Yang, Qihua Zhu, Yungen Xu, Yueqing Gu, Andreas von Deimling, Xiaoming Zha
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) generating carbon dioxide and NADPH/NADH. Evidence suggests that the specific mutations in IDH1 are critical to the growth and reproduction of some tumor cells such as gliomas and acute myeloid leukemia, emerging as an attractive antitumor target. In order to discovery potent new mutant IDH1 inhibitors, we designed, synthesized and evaluated a series of allosteric mIDH1 inhibitors harboring the scaffold of 3-pyrazine-2-yl-oxazolidin-2-ones...
October 13, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29057925/induction-of-synthetic-lethality-in-idh1-mutated-gliomas-through-inhibition-of-bcl-xl
#6
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Yiru Zhang, Chang Shu, Takashi Tsujiuchi, Matei A Banu, Franklin Garcia, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin
Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29056515/in%C3%A2-vivo-imaging-of-glutamine-metabolism-to-the-oncometabolite-2-hydroxyglutarate-in-idh1-2-mutant-tumors
#7
Lucia Salamanca-Cardona, Hardik Shah, Alex J Poot, Fabian M Correa, Valentina Di Gialleonardo, Hui Lui, Vesselin Z Miloushev, Kristin L Granlund, Sui S Tee, Justin R Cross, Craig B Thompson, Kayvan R Keshari
The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro...
October 16, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/29054837/altered-metabolic-landscape-in-idh-mutant-gliomas%C3%A2-affects-phospholipid-energy-and-oxidative-stress-pathways
#8
Fred Fack, Saverio Tardito, Guillaume Hochart, Anais Oudin, Liang Zheng, Sabrina Fritah, Anna Golebiewska, Petr V Nazarov, Amandine Bernard, Ann-Christin Hau, Olivier Keunen, William Leenders, Morten Lund-Johansen, Jonathan Stauber, Eyal Gottlieb, Rolf Bjerkvig, Simone P Niclou
Heterozygous mutations in NADP-dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D-2-hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient-derived xenografts of IDH-mutant versus IDH wild-type glioma to profile the distribution of metabolites at high anatomical resolution in situ This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography-mass spectrometry (LC-MS) analysis...
October 20, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29038145/oncometabolites-a-new-paradigm-for-oncology-metabolism-and-the-clinical-laboratory
#9
REVIEW
Rebecca R J Collins, Khushbu Patel, William C Putnam, Payal Kapur, Dinesh Rakheja
BACKGROUND: Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic acidurias. In the past decade, the same tricarboxylic acid cycle metabolites have been implicated and studied in cancer. The accumulation of these metabolites in certain cancers not only serves as a biomarker but also directly contributes to cellular transformation, therefore earning them the designation of oncometabolites...
October 16, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/29031613/pathogenic-mutations-of-the-human-mitochondrial-citrate-carrier-slc25a1-lead-to-impaired-citrate-export-required-for-lipid-dolichol-ubiquinone-and-sterol-synthesis
#10
Homa Majd, Martin S King, Anthony C Smith, Edmund R S Kunji
Missense mutations of the human mitochondrial citrate carrier, encoded by the SLC25A1 gene, lead to an autosomal recessive neurometabolic disorder characterised by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development, often resulting in early death. Here, we have measured the effect of all twelve known pathogenic mutations on the transport activity. The results show that nine mutations abolish transport of citrate completely, whereas the other three reduce the transport rate by >70%, indicating that impaired citrate transport is the most likely primary cause of the disease...
October 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29028423/2016-updates-to-the-who-brain-tumor-classification-system-what-the-radiologist-needs-to-know
#11
Derek R Johnson, Julie B Guerin, Caterina Giannini, Jonathan M Morris, Lawrence J Eckel, Timothy J Kaufmann
Radiologists play a key role in brain tumor diagnosis and management and must stay abreast of developments in the field to advance patient care and communicate with other health care providers. In 2016, the World Health Organization (WHO) released an update to its brain tumor classification system that included numerous significant changes. Several previously recognized brain tumor diagnoses, such as oligoastrocytoma, primitive neuroectodermal tumor, and gliomatosis cerebri, were redefined or eliminated altogether...
November 2017: Radiographics: a Review Publication of the Radiological Society of North America, Inc
https://www.readbyqxmd.com/read/28986582/assessing-inhibitors-of-mutant-isocitrate-dehydrogenase-using-a-suite-of-pre-clinical-discovery-assays
#12
Daniel J Urban, Natalia J Martinez, Mindy I Davis, Kyle R Brimacombe, Dorian M Cheff, Tobie D Lee, Mark J Henderson, Steven A Titus, Rajan Pragani, Jason M Rohde, Li Liu, Yuhong Fang, Surendra Karavadhi, Pranav Shah, Olivia W Lee, Amy Wang, Andrew McIver, Hongchao Zheng, Xiaodong Wang, Xin Xu, Ajit Jadhav, Anton Simeonov, Min Shen, Matthew B Boxer, Matthew D Hall
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that are mutated in a variety of cancers to confer a gain-of-function activity resulting in the accumulation of an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG can result in epigenetic dysregulation and a block in cellular differentiation, suggesting these mutations play a role in neoplasia. Based on its potential as a cancer target, a number of small molecule inhibitors have been developed to specifically inhibit mutant forms of IDH (mIDH1 and mIDH2)...
October 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28984323/analysis-of-human-gliomas-by-swab-touch-spray-mass-spectrometry-applications-to-intraoperative-assessment-of-surgical-margins-and-presence-of-oncometabolites
#13
Valentina Pirro, Raquel Sero Llor, Alan K Jarmusch, Clint M Alfaro, Aaron A Cohen-Gadol, Eyas M Hattab, R Graham Cooks
Touch spray mass spectrometry using medical swabs is an ambient ionization technique (ionization of unprocessed sample in the open air) that has potential intraoperative application in quickly identifying the disease state of tissue and in better characterizing the resection margin. To explore this potential, we studied 29 human brain tumor specimens and obtained evidence that this technique can provide diagnostic molecular information that is relevant to brain cancer. Touch spray using medical swabs involves the physical sampling of tissue using a medical swab on a spatial scale of a few mm(2) with subsequent ionization occurring directly from the swab tip upon addition of solvent and application of a high voltage...
October 23, 2017: Analyst
https://www.readbyqxmd.com/read/28978422/the-burgeoning-world-of-immunometabolites-th17-cells-take-center-stage
#14
Glenn R Bantug, Christoph Hess
Dysregulation of the Th17/Treg balance is a key driver of autoimmunity. A new study by Xu et al. (2017) has revealed that small-molecule inhibition of 2-hydroxyglutarate synthesis skews Th17 differentiation to the Treg lineage, which is protective against autoimmune inflammation.
October 3, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28956184/reliable-diagnosis-of-idh-mutant-glioblastoma-by-2-hydroxyglutarate-detection-a-study-by-3-t-magnetic-resonance-spectroscopy
#15
Manabu Natsumeda, Kunio Motohashi, Hironaka Igarashi, Takanori Nozawa, Hideaki Abe, Yoshihiro Tsukamoto, Ryosuke Ogura, Masayasu Okada, Tsutomu Kobayashi, Hiroshi Aoki, Hitoshi Takahashi, Akiyoshi Kakita, Kouichirou Okamoto, Tsutomu Nakada, Yukihiko Fujii
We have previously reported that reliable detection of 2-hydroxyglutarate (2HG) in isocitrate dehydrogenase (IDH)-mutant WHO grade 2 and 3 gliomas is possible utilizing 3.0-T single-voxel magnetic resonance spectroscopy (SVMRS). We set out to determine whether the same method could be applied to detect 2HG in IDH-mutant glioblastoma. Forty-four patients harboring glioblastoma underwent pre-operative MRS evaluation to detect 2HG and other metabolites. Presence of IDH-mutations was determined by IDH1 R132H immunohistochemical analysis and DNA sequencing of surgically obtained tissues...
September 27, 2017: Neurosurgical Review
https://www.readbyqxmd.com/read/28939851/isomers-identification-of-2-hydroxyglutarate-acid-disodium-salt-2hg-by-terahertz-time-domain-spectroscopy
#16
Wanqing Chen, Yan Peng, Xiankai Jiang, Jiayu Zhao, Hongwei Zhao, Yiming Zhu
2-Hydroxyglutaric acid disodium salt (2HG) is a unique biomarker existing in glioma, which can be used for recognizing cancer development stage and identifying the boundary between the ordinary tissue and cancer tissue. However, the most efficient detection method for 2HG now is Magnetic Resonance Spectroscopy (MRS), whose testing time is at least twenty minutes and the variability of 2HG (continuous synthesis and decomposition) determines it cannot be used as the real-time image in medical surgery. In this paper, by using the Terahertz Time-domain Spectroscopy (THz-TDS) System, we investigate the vibration spectra of 2HG isomers and further distinguish their physical properties by using Density Functional Theory...
September 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28916733/clonal-expansion-and-epigenetic-reprogramming-following-deletion-or-amplification-of-mutant-idh1
#17
Tali Mazor, Charles Chesnelong, Aleksandr Pankov, Llewellyn E Jalbert, Chibo Hong, Josie Hayes, Ivan V Smirnov, Roxanne Marshall, Camila F Souza, Yaoqing Shen, Pavithra Viswanath, Houtan Noushmehr, Sabrina M Ronen, Steven J M Jones, Marco A Marra, J Gregory Cairncross, Arie Perry, Sarah J Nelson, Susan M Chang, Andrew W Bollen, Annette M Molinaro, Henrik Bengtsson, Adam B Olshen, Samuel Weiss, Joanna J Phillips, H Artee Luchman, Joseph F Costello
IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28833542/echo-planar-spectroscopic-imaging-with-dual-readout-alternated-gradients-drag-epsi-at-7-t-application-for-2-hydroxyglutarate-imaging-in-glioma-patients
#18
Zhongxu An, Vivek Tiwari, Sandeep K Ganji, Jeannie Baxter, Michael Levy, Marco C Pinho, Edward Pan, Elizabeth A Maher, Toral R Patel, Bruce E Mickey, Changho Choi
PURPOSE: To develop echo-planar spectroscopic imaging (EPSI) with large spectral width and accomplish high-resolution imaging of 2-hydroxyglutarate (2HG) at 7 T. METHODS: We designed a new EPSI readout scheme at 7 T. Data were recorded with dual-readout alternated gradients and combined according to the gradient polarity. Following validation of its performance in phantoms, the new readout scheme, together with previously reported 2HG-optimized magnetic resonance spectroscopy (point-resolved spectroscopy echo time of 78 ms), was used for time-efficient and high-resolution imaging of 2HG and other metabolites in five glioma patients before treatment...
August 22, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/28827360/coupling-between-d-3-phosphoglycerate-dehydrogenase-and-d-2-hydroxyglutarate-dehydrogenase-drives-bacterial-l-serine-synthesis
#19
Wen Zhang, Manman Zhang, Chao Gao, Yipeng Zhang, Yongsheng Ge, Shiting Guo, Xiaoting Guo, Zikang Zhou, Qiuyuan Liu, Yingxin Zhang, Cuiqing Ma, Fei Tao, Ping Xu
l-Serine biosynthesis, a crucial metabolic process in most domains of life, is initiated by d-3-phosphoglycerate (d-3-PG) dehydrogenation, a thermodynamically unfavorable reaction catalyzed by d-3-PG dehydrogenase (SerA). d-2-Hydroxyglutarate (d-2-HG) is traditionally viewed as an abnormal metabolite associated with cancer and neurometabolic disorders. Here, we reveal that bacterial anabolism and catabolism of d-2-HG are involved in l-serine biosynthesis in Pseudomonas stutzeri A1501 and Pseudomonas aeruginosa PAO1...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28827149/studies-on-the-interaction-of-the-histone-demethylase-kdm5b-with-tricarboxylic-acid-cycle-intermediates
#20
Hanna Tarhonskaya, Radosław P Nowak, Catrine Johansson, Aleksandra Szykowska, Anthony Tumber, Rebecca L Hancock, Pauline Lang, Emily Flashman, Udo Oppermann, Christopher J Schofield, Akane Kawamura
Methylation of lysine-4 of histone H3 (H3K4men) is an important regulatory factor in eukaryotic transcription. Removal of the transcriptionally activating H3K4 methylation is catalyzed by histone demethylases, including the Jumonji C (JmjC) KDM5 subfamily. The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, some of which are associated with cancer. Altered levels of tricarboxylic acid (TCA) cycle intermediates and the associated metabolites D- and L-2-hydroxyglutarate (2HG) can cause changes in chromatin methylation status...
September 15, 2017: Journal of Molecular Biology
keyword
keyword
34152
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"