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https://www.readbyqxmd.com/read/28956184/reliable-diagnosis-of-idh-mutant-glioblastoma-by-2-hydroxyglutarate-detection-a-study-by-3-t-magnetic-resonance-spectroscopy
#1
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
#2
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
#3
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
#4
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...
September 15, 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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
https://www.readbyqxmd.com/read/28506858/accuracy-of-1h-magnetic-resonance-spectroscopy-for-quantification-of-2-hydroxyglutarate-using-linear-combination-and-j-difference-editing-at-9-4t
#15
Ulf Neuberger, Philipp Kickingereder, Xavier Helluy, Manuel Fischer, Martin Bendszus, Sabine Heiland
Non-invasive detection of 2-hydroxyglutarate (2HG) by magnetic resonance spectroscopy is attractive since it is related to tumor metabolism. Here, we compare the detection accuracy of 2HG in a controlled phantom setting via widely used localized spectroscopy sequences quantified by linear combination of metabolite signals vs. a more complex approach applying a J-difference editing technique at 9.4T. Different phantoms, comprised out of a concentration series of 2HG and overlapping brain metabolites, were measured with an optimized point-resolved-spectroscopy sequence (PRESS) and an in-house developed J-difference editing sequence...
May 12, 2017: Zeitschrift Für Medizinische Physik
https://www.readbyqxmd.com/read/28504706/the-mitochondrial-respiratory-chain-is-essential-for-haematopoietic-stem-cell-function
#16
COMPARATIVE STUDY
Elena Ansó, Samuel E Weinberg, Lauren P Diebold, Benjamin J Thompson, Sébastien Malinge, Paul T Schumacker, Xin Liu, Yuannyu Zhang, Zhen Shao, Mya Steadman, Kelly M Marsh, Jian Xu, John D Crispino, Navdeep S Chandel
Adult and fetal haematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron-sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anaemia and prenatal death. RISP-null fetal HSCs displayed impaired respiration resulting in a decreased NAD(+)/NADH ratio...
June 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28423525/the-combination-of-circulating-long-noncoding-rnas-ak001058-inhba-as1-mir4435-2hg-and-cebpa-as1-fragments-in-plasma-serve-as-diagnostic-markers-for-gastric-cancer
#17
Dong Ke, Hanwei Li, Yi Zhang, Yinghong An, Hanjiang Fu, Xuedong Fang, Xiaofei Zheng
BACKGROUND: Suitable diagnostic markers for cancers are urgently required in clinical practice. Long non-coding RNAs, which have been reported in many cancer types, are a potential new class of biomarkers for tumor diagnosis. RESULTS: Five lncRNAs, including AK001058, INHBA-AS1, MIR4435-2HG, UCA1 and CEBPA-AS1 were validated to be increased in gastric cancer tissues. Furthermore, we found that plasma level of these five lncRNAs were significantly higher in gastric cancer patients compared with normal controls...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28327577/metabolic-profiling-of-idh-mutation-and-malignant-progression-in-infiltrating-glioma
#18
Llewellyn E Jalbert, Adam Elkhaled, Joanna J Phillips, Evan Neill, Aurelia Williams, Jason C Crane, Marram P Olson, Annette M Molinaro, Mitchel S Berger, John Kurhanewicz, Sabrina M Ronen, Susan M Chang, Sarah J Nelson
Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM)...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28324114/novel-25-kb-deletion-of-mertk-causes-retinitis-pigmentosa-with-severe-progression
#19
Daniel R Evans, Jane S Green, Gordon J Johnson, Jeremy Schwartzentruber, Jacek Majewski, Chandree L Beaulieu, Wen Qin, Christian R Marshall, Tara A Paton, Nicole M Roslin, Andrew D Paterson, Somayyeh Fahiminiya, Justin French, Kym M Boycott, Michael O Woods
Purpose: Retinitis pigmentosa (RP) describes a complex group of inherited retinal dystrophies with almost 300 reported genes and loci. We investigated the genetic etiology of autosomal recessive RP (arRP) in a large kindred with 5 affected family members, who reside on the island of Newfoundland, Canada. Methods: Genetic linkage analysis was performed on 12 family members (Infinium HumanOmni2.5-8 BeadChip). Whole exome sequencing analysis (Illumina HiSeq) was performed on one affected individual...
March 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28319049/resisting-fatal-attraction-a-glioma-oncometabolite-prevents-cd8-t-cell-recruitment
#20
Liliana E Lucca, David A Hafler
Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor...
April 3, 2017: Journal of Clinical Investigation
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