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https://www.readbyqxmd.com/read/29662077/pharmacodynamics-of-mutant-idh1-inhibitors-in-glioma-patients-probed-by-in-vivo-3d-mrs-imaging-of-2-hydroxyglutarate
#1
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/29568832/neutral-and-cationic-cyclic-alkyl-amino-carbene-mercury-caac-hg-ii-complexes-scope-of-hydroamination-of-alkynes-with-organomercury-compounds
#2
Deependra Bawari, Bhupendra Goswami, Sabari V R, Sandeep Kumar Thakur, R V Varun Tej, Angshuman Roy Choudhury, Sanjay Singh
This study demonstrates the first synthesis of cyclic (alkyl)(amino)carbene (cAAC) adducts of Hg(ii), [cAACMe·HgBr(μ-Br)]2 (1a) and [cAACcy·HgBr(μ-Br)]2 (1b). Adduct 1b catalyzes intermolecular hydroamination of aromatic alkynes and amines under mild conditions to afford aromatic imines. The quest to prepare an electrophilic Hg(ii) complex resulted in the synthesis of cationic [(cAACcy)2Hg(H2O)]2+2[NO3]- (3) by reacting 1b with AgNO3.
March 23, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/29528543/samarium-polystibides-derived-from-highly-activated-nanoscale-antimony
#3
Peter Werner Roesky, Christoph Schoo, Sebastian Bestgen, Alexander Egeberg, Svetlana Klementieva, Claus Feldmann, Sergey N Konchenko
Zintl-ions in molecular compounds are of fundamental interest for basic research and application. However, in contrast to the lighter group 15 elements, elemental antimony has never been applied as reagent for the preparation of molecular polystibides. Herein, we report for the first time two reactive antimony sources, which allow the direct access to molecular polystibide compounds. These are Sb amalgam (Sb/Hg) and ultrasmall Sb0 nanoparticles (d = 6.6±0.8 nm), which were used independently as precursors for the synthe-sis of the largest f-element polystibide, [(Cp*2Sm)4Sb8]...
March 12, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29522955/validation-of-a-routine-gas-chromatography-mass-spectrometry-method-for-2-hydroxyglutarate-quantification-in-human-serum-as-a-screening-tool-for-detection-of-idh-mutations
#4
Esther Fernández-Galán, Núria Massana, Marina Parra-Robert, Susana Hidalgo, Gregori Casals, Jordi Esteve, Wladimiro Jiménez
High circulating levels of 2-hydroxyglutarate (2HG) have been reported in patients with determinate isocitrate dehydrogenase (IDH) mutated tumors. Recent studies indicate that in malignancies such as acute myeloid leukemia (AML), measurements of 2HG in serum provide useful diagnostic and prognostic information and improve patient selection and monitoring of IDH-targeted treatments. In the current study, we validated a sensitive and specific gas chromatography mass spectrometry (GC-MS) method specifically intended to quantify serum levels of 2HG in routine clinical laboratories...
February 28, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29499756/rapid-detection-of-2-hydroxyglutarate-in-frozen-sections-of-idh-mutant-tumors-by-maldi-tof-mass-spectrometry
#5
Rémi Longuespée, Annika K Wefers, Elena De Vita, Aubry K Miller, David E Reuss, Wolfgang Wick, Christel Herold-Mende, Mark Kriegsmann, Peter Schirmacher, Andreas von Deimling, Stefan Pusch
All isocitrate dehydrogenase (IDH) mutant solid neoplasms exhibit highly elevated levels of D-2-hydroxyglutarate (D-2HG). Detection of 2HG in tumor tissues currently is performed by gas or liquid chromatography-mass spectrometry (GC- or LC-MS) or biochemical detection. While these methods are highly accurate, a considerable amount of time for tissue preparation and a relatively high amount of tissue is required for testing. We here present a rapid approach to detect 2HG in brain tumor tissue based on matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF)...
March 2, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29479068/mutational-profiling-of-isolated-myeloid-sarcomas-and-utility-of-serum-2hg-as-biomarker-of-idh1-2-mutations
#6
Christophe Willekens, Aline Renneville, Sophie Broutin, Véronique Saada, Jean-Baptiste Micol, Julia Delahousse, Vianney Poinsignon, Claire Bories, Céline Berthon, Raphael Itzykson, Nicolas Boissel, Cyril Quivoron, Marie Terroir-Cassou-Mounat, Jacques Bosq, Claude Preudhomme, Angelo Paci, Virginie Penard-Lacronique, Stéphane De Botton
No abstract text is available yet for this article.
February 26, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29459295/the-link-between-insulin-resistance-parameters-and-serum-uric-acid-is-mediated-by-adiposity
#7
Mohsen Mazidi, Niki Katsiki, Dimitri P Mikhailidis, Maciej Banach
BACKGROUND AND AIMS: Conflicting results suggest a link between serum uric acid (SUA), inflammation and glucose/insulin homeostasis; however, the role of adiposity in this relationship is not clear. Therefore, we evaluated the role of different adiposity factors, including central body mass index (BMI), peripheral waist circumference (WC), and visceral adiposity [visceral adipose tissue (apVAT)], on the association between SUA, inflammation and glucose/insulin homeostasis among US adults...
December 26, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/29438510/diagnostic-accuracy-of-2-hydroxyglutarate-magnetic-resonance-spectroscopy-in-newly-diagnosed-brain-mass-and-suspected-recurrent-gliomas
#8
Min Zhou, Yue Zhou, Huijun Liao, Benjamin C Rowland, Xiangquan Kong, Nils D Arvold, David A Reardon, Patrick Y Wen, Alexander P Lin, Raymond Y Huang
Background: Isocitrate dehydrogenase (IDH) mutations result in abnormal accumulation of 2-hydroxyglutarate (2HG) in gliomas that can be detected by MRS. We examined the diagnostic accuracy of 2HG single-voxel spectroscopy (SVS) and chemical shift imaging (CSI) in both newly-diagnosed and post-treatment settings. Methods: Long-TE (97 ms) SVS and CSI were acquired in 85 subjects, including a discovery cohort of 39 patients who had postoperative residual or recurrent glioma with confirmed IDH-mutation status and 6 normal volunteers, a prospective preoperative validation cohort of 24 patients with newly-diagnosed brain mass, and a prospective recurrent-lesion validation cohort of 16 previously-treated IDH-mutant glioma patients with suspected tumor recurrence...
February 9, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29337019/prediabetes-is-associated-with-microalbuminuria-reduced-kidney-function-and-chronic-kidney-disease-in-the-general-population-the-kora-cooperative-health-research-in-the-augsburg-region-f4-study
#9
M R P Markus, T Ittermann, S E Baumeister, C Huth, B Thorand, C Herder, M Roden, U Siewert-Markus, W Rathmann, W Koenig, M Dörr, H Völzke, S Schipf, C Meisinger
BACKGROUND AND AIMS: We investigated the associations of serum fasting (FG) and 2-h postload (2HG) glucose from an oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), fasting insulin and the homeostasis model assessment-insulin resistance index (HOMA-IR) with urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). METHODS AND RESULTS: We performed cross-sectional analyses of 2713 subjects (1429 women; 52.7%) without known type 2 diabetes, aged 31-82 years, from the KORA (Cooperative Health Research in the Augsburg Region) F4-Study...
March 2018: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
https://www.readbyqxmd.com/read/29287025/2-hydroxyglutarate-detection-by-short-echo-time-magnetic-resonance-spectroscopy-in-routine-imaging-study-of-brain-glioma-at-3-0-t
#10
Girolamo Crisi, Silvano Filice, Maria Michiara, Pellegrino Crafa, Silvia Lana
OBJECTIVE: The objective of this study was to assess the effective performance of short echo time magnetic resonance spectroscopy (short TE MRS) for 2HG detection as biomarker of isocitrate dehydrogenase (IDH) status in all grade glioma (GL). METHODS: A total of 82 GL patients were prospectively investigated by short TEMRS at 3.0 T as part of a multimodal magnetic resonance imaging study protocol. Spectral analysis was performed using linear combination model. Tumor specimens were diagnosed as IDH mutant or wild type according to the 2016 World Health Organization (WHO) classification of brain tumors...
December 28, 2017: Journal of Computer Assisted Tomography
https://www.readbyqxmd.com/read/29274619/circulating-oncometabolite-d-2-hydroxyglutarate-enantiomer-is-a-surrogate-marker-of-isocitrate-dehydrogenase-mutated-intrahepatic-cholangiocarcinomas
#11
Julia Delahousse, Loic Verlingue, Sophie Broutin, Clémence Legoupil, Mehdi Touat, Ludovic Doucet, Samy Ammari, Ludovic Lacroix, Michel Ducreux, Jean-Yves Scoazec, David Malka, Angelo Paci, Antoine Hollebecque
Therapeutic resources are limited for advanced biliary tract cancers and prognosis remains poor. Somatic mutations in isocitrate dehydrogenase (IDH)1/2 gene are found in 5-36% of patients with intrahepatic cholangiocarcinoma (ICC). The mutant forms of IDH1/2 catalyse the non-reversible accumulation of 2-hydroxyglutarate (2HG). Increasing numbers of indirect or direct-targeted therapies are developed to IDH1/2 mutations and could be assisted by a routinely feasible, rapid and inexpensive serum 2HG measurement by liquid chromatography coupled to tandem mass spectrometry...
February 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29249359/r-2hg-exhibits-anti-tumor-activity-by-targeting-fto-m-6-a-myc-cebpa-signaling
#12
Rui Su, Lei Dong, Chenying Li, Sigrid Nachtergaele, Mark Wunderlich, Ying Qing, Xiaolan Deng, Yungui Wang, Xiaocheng Weng, Chao Hu, Mengxia Yu, Jennifer Skibbe, Qing Dai, Dongling Zou, Tong Wu, Kangkang Yu, Hengyou Weng, Huilin Huang, Kyle Ferchen, Xi Qin, Bin Zhang, Jun Qi, Atsuo T Sasaki, David R Plas, James E Bradner, Minjie Wei, Guido Marcucci, Xi Jiang, James C Mulloy, Jie Jin, Chuan He, Jianjun Chen
R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N6 -methyladenosine (m6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways...
January 11, 2018: Cell
https://www.readbyqxmd.com/read/29202474/adhfe1-is-a-breast-cancer-oncogene-and-induces-metabolic-reprogramming
#13
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...
January 2, 2018: 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
#14
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
#15
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
#16
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
#17
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 IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, favorable PK properties and great selectivity against IDH1wt and IDH2R140Q .
December 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29076421/seizures-and-anticonvulsants-in-brain-tumours-frequency-mechanisms-and-anti-epileptic-management
#18
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
#19
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-s-2-donor-ligands
#20
Ramesh Karri, Mainak Banerjee, Ashish Chalana, Kunal Kumar Jha, Gouriprasanna Roy
Here we report that [S2 ]-donor ligands BmmOH , BmmMe , and BmeMe 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 R2 Hg. 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 BmeMe is almost 2-fold higher than the initial rate obtained by BmmOH or BmmMe , 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...
October 16, 2017: Inorganic Chemistry
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