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https://www.readbyqxmd.com/read/29202474/adhfe1-is-a-breast-cancer-oncogene-and-induces-metabolic-reprogramming
#1
Prachi Mishra, Wei Tang, Vasanta Putluri, Tiffany H Dorsey, Feng Jin, Fang Wang, Donewei Zhu, Lauren Amable, Tao Deng, Shaofei Zhang, J Keith Killian, Yonghong Wang, Tsion Z Minas, Harry G Yfantis, Dong H Lee, Arun Sreekumar, Michael Bustin, Wei Liu, Nagireddy Putluri, Stefan Ambs
Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG-producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival...
November 27, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29167927/new-diagnostic-criteria-for-gestational-diabetes-mellitus-and-their-impact-on-the-number-of-diagnoses-and-pregnancy-outcomes
#2
Sarah H Koning, Jelmer J van Zanden, Klaas Hoogenberg, Helen L Lutgers, Alberdina W Klomp, Fleurisca J Korteweg, Aren J van Loon, Bruce H R Wolffenbuttel, Paul P van den Berg
AIMS/HYPOTHESIS: Detection and management of gestational diabetes mellitus (GDM) are crucial to reduce the risk of pregnancy-related complications for both mother and child. In 2013, the WHO adopted new diagnostic criteria for GDM to improve pregnancy outcomes. However, the evidence supporting these criteria is limited. Consequently, these new criteria have not yet been endorsed in the Netherlands. The aim of this study was to determine the impact of these criteria on the number of GDM diagnoses and pregnancy outcomes...
November 22, 2017: Diabetologia
https://www.readbyqxmd.com/read/29162362/prediabetes-is-associated-with-lower-brain-gray-matter-volume-in-the-general-population-the-study-of-health-in-pomerania-ship
#3
M R P Markus, T Ittermann, K Wittfeld, S Schipf, U Siewert-Markus, M Bahls, R Bülow, N Werner, D Janowitz, S E Baumeister, S B Felix, M Dörr, W Rathmann, H Völzke, H J Grabe
BACKGROUND AND AIMS: We investigated the associations of fasting (FG) and 2-h postload (2HG) plasma glucose from oral glucose tolerance test (OGTT) with gray (GMV) and white (WMV) matter volume. METHODS AND RESULTS: We analyzed data from 1330 subjects without known diabetes mellitus, aged 21 to 81, from the second cohort (SHIP-Trend-0) of the population-based Study of Health in Pomerania (SHIP). Following the OGTT, individuals were classified in five groups (according to the American Diabetes Association criteria): normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT) and unknown type 2 diabetes mellitus (UDM)...
December 2017: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
https://www.readbyqxmd.com/read/29126125/highly-specific-determination-of-idh-status-using-edited-in-vivo-magnetic-resonance-spectroscopy
#4
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/29079473/discovery-and-structure-activity-relationship-study-of-novel-conformationally-restricted-indane-analogues-for-mutant-isocitric-dehydrogenase-1-idh1-inhibitors
#5
Qiangang Zheng, Shuai Tang, Xianlei Fu, Ziqi Chen, Yan Ye, Xiaojing Lan, Lei Jiang, Ying Huang, Jian Ding, Meiyu Geng, Min Huang, Huixin Wan
The discovery and optimization of various of indane amides as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1(R132H) enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, favorable PK properties and great selectivity against IDH1(wt) and IDH2(R140Q).
October 16, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29076421/seizures-and-anticonvulsants-in-brain-tumours-frequency-mechanisms-and-anti-epileptic-management
#6
Charles Vecht, Louis Royer-Perron, Caroline Houillier, Gilles Huberfeld
In cancer, epilepsy can be the manifestation of a primary brain tumour, metastatic disease, vascular or surgical complications, opportunistic infection or secondary to anti-tumour therapy. Seizures are frequently the first symptom of a brain tumour. The epilepsy is related to elevated extracellular glutamate stimulating NMDA- and AMPA-receptors and to the formation of D-2HG which resembles glutamate in IDH1 mutated gliomas. Epilepsy as presenting sign is associated with a longer survival in low- and high- grade gliomas, particularly with the IDH1 mutation...
October 27, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28956184/reliable-diagnosis-of-idh-mutant-glioblastoma-by-2-hydroxyglutarate-detection-a-study-by-3-t-magnetic-resonance-spectroscopy
#7
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/28952723/activation-of-the-hg-c-bond-of-methylmercury-by-s2-donor-ligands
#8
Ramesh Karri, Mainak Banerjee, Ashish Chalana, Kunal Kumar Jha, Gouriprasanna Roy
Here we report that [S2]-donor ligands Bmm(OH), Bmm(Me), and Bme(Me) bind rapidly and reversibly to the mercury centers of organomercurials, RHgX, and facilitate the cleavage of Hg-C bonds of RHgX to produce stable tetracoordinated Hg(II) complexes and R2Hg. Significantly, the rate of cleavage of Hg-C bonds depends critically on the X group of RHgX (X = BF4(-), Cl(-), I(-)) and the [S2]-donor ligands used to induce the Hg-C bonds. For instance, the initial rate of cleavage of the Hg-C bond of MeHgI induced by Bme(Me) is almost 2-fold higher than the initial rate obtained by Bmm(OH) or Bmm(Me), indicating that the spacer between the two imidazole rings of [S2]-donor ligands plays a significant role here in the cleavage of Hg-C bonds...
September 27, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28939851/isomers-identification-of-2-hydroxyglutarate-acid-disodium-salt-2hg-by-terahertz-time-domain-spectroscopy
#9
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
#10
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
#11
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/28827149/studies-on-the-interaction-of-the-histone-demethylase-kdm5b-with-tricarboxylic-acid-cycle-intermediates
#12
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
https://www.readbyqxmd.com/read/28810750/the-metal-insulator-transition-in-the-organic-conductor-%C3%AE-%C3%A2-bedt-ttf-2hg-scn-2cl
#13
Weiwu Li, Eva Rose, Minh Vu Tran, Ralph Hübner, Andrzej Łapiński, Roman Świetlik, Svetlana A Torunova, Elena I Zhilyaeva, Rimma N Lyubovskaya, Martin Dressel
We explore the nature of the metal-insulator transition in the two-dimensional organic compound β(″)-(BEDT-TTF)2Hg(SCN)2Cl by x-ray, electrical transport, ESR, Raman, and infrared investigations. Magnetic and vibrational spectroscopy concurrently reveal a gradual dimerization along the stacking direction (a-b), setting in already at the crossover temperature of 150 K from the metallic to the insulating state. A spin gap of Δσ=47 meV is extracted. From the activated resistivity behavior below T = 55 K, a charge gap of Δρ=60 meV is derived...
August 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28717097/plasma-2-hydroxyglutarate-and-hexanoylcarnitine-levels-are-potential-biomarkers-for-skeletal-muscle-toxicity-in-male-fischer-344-rats
#14
Hisakuni Obayashi, Naoko Kobayashi, Yoshikazu Nezu, Takashi Yamoto, Mitsuyuki Shirai, Fumitoshi Asai
To identify new candidate biomarkers for skeletal muscle toxicity, an unbiased metabolomic analysis was performed in rats treated with two distinct myotoxicants, cerivastatin (CER) and tetramethyl-p-phenylenediamine (TMPD). Skeletal muscle toxicity was induced in male Fischer 344 rats by administering CER or TMPD and monitored using established endpoints, such as increased plasma creatine kinase (CK) activity and histopathology, and a metabolomic analysis of skeletal muscle and plasma samples. Plasma CK levels in CER-treated rats were markedly elevated at Day 11; however, those in TMPD-treated rats showed a statistically significant decrease at 24 hr after dosing...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28711227/oncogenic-activities-of-idh1-2-mutations-from-epigenetics-to-cellular-signaling
#15
REVIEW
Laurence M Gagné, Karine Boulay, Ivan Topisirovic, Marc-Étienne Huot, Frédérick A Mallette
Gliomas and leukemias remain highly refractory to treatment, thus highlighting the need for new and improved therapeutic strategies. Mutations in genes encoding enzymes involved in the tricarboxylic acid (TCA) cycle, such as the isocitrate dehydrogenases 1 and 2 (IDH1/2), are frequently encountered in astrocytomas and secondary glioblastomas, as well as in acute myeloid leukemias; however, the precise molecular mechanisms by which these mutations promote tumorigenesis remain to be fully characterized. Gain-of-function mutations in IDH1/2 have been shown to stimulate production of the oncogenic metabolite R-2-hydroxyglutarate (R-2HG), which inhibits α-ketoglutarate (αKG)-dependent enzymes...
October 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28705010/isocitrate-dehydrogenase-mutation-as-a-therapeutic-target-in-gliomas
#16
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/28653623/replication-study-the-common-feature-of-leukemia-associated-idh1-and-idh2-mutations-is-a-neomorphic-enzyme-activity-converting-alpha-ketoglutarate-to-2-hydroxyglutarate
#17
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/28601826/study-protocol-of-a-phase-ib-ii-clinical-trial-of-metformin-and-chloroquine-in-patients-with-idh1-mutated-or-idh2-mutated-solid-tumours
#18
Remco J Molenaar, Robert Js Coelen, Mohammed Khurshed, Eva Roos, Matthan Wa Caan, Myra E van Linde, Mathilde Kouwenhoven, Jos Am Bramer, Judith Vmg Bovée, Ron A Mathôt, Heinz-Josef Klümpen, Hanneke Wm van Laarhoven, Cornelis Jf van Noorden, W Peter Vandertop, Hans Gelderblom, Thomas M van Gulik, Johanna W Wilmink
INTRODUCTION: High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine...
June 10, 2017: BMJ Open
https://www.readbyqxmd.com/read/28573160/quantification-of-2-hydroxyglutarate-enantiomers-by-liquid-chromatography-mass-spectrometry
#19
William M Oldham, Joseph Loscalzo
Two enantiomers of 2-hydroxyglutarate (2HG), L (L2HG) and D (D2HG), are metabolites of unknown function in mammalian cells that were initially associated with separate and rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012). More recently, investigators have shown that D2HG is produced by mutant isocitrate dehydrogenase enzymes associated with a variety of human malignancies, such as acute myeloid leukemia, glioblastoma multiforme, and cholangiocarcinoma (Cairns and Mak, 2013; Dang et al...
August 20, 2016: Bio-protocol
https://www.readbyqxmd.com/read/28536419/the-long-non-coding-rna-linc00152-is-essential-for-cell-cycle-progression-through-mitosis-in-hela-cells
#20
Linda Nötzold, Lukas Frank, Minakshi Gandhi, Maria Polycarpou-Schwarz, Matthias Groß, Manuel Gunkel, Nina Beil, Holger Erfle, Nathalie Harder, Karl Rohr, Jakob Trendel, Jeroen Krijgsveld, Thomas Longerich, Peter Schirmacher, Michael Boutros, Sylvia Erhardt, Sven Diederichs
In recent years, long non-coding RNA (lncRNA) research has identified essential roles of these transcripts in virtually all physiological cellular processes including tumorigenesis, but their functions and molecular mechanisms are poorly understood. In this study, we performed a high-throughput siRNA screen targeting 638 lncRNAs deregulated in cancer entities to analyse their impact on cell division by using time-lapse microscopy. We identified 26 lncRNAs affecting cell morphology and cell cycle including LINC00152...
May 23, 2017: Scientific Reports
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