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https://www.readbyqxmd.com/read/29331887/idh1r132h-promotes-malignant-transformation-of-benign-prostatic-epithelium-by-dysregulating-micrornas-involvement-of-igf1r-akt-stat3-signaling-pathway
#1
Lili Zhang, Mei Qi, Tingting Feng, Jing Hu, Lin Wang, Xinjun Li, Wei Gao, Hui Liu, Meng Jiao, Zhen Wu, Xinnuo Bai, Yifan Bie, Long Liu, Bo Han
Risk stratification using molecular features could potentially help distinguish indolent from aggressive prostate cancer (PCa). Mutations in isocitrate dehydrogenase (IDH) acquire an abnormal enzymatic activity, resulting in the production of 2-hydroxyglutarate and alterations in cellular metabolism, histone modification, and DNA methylation. Mutant IDH1 has been identified in various human malignancies, and IDH1R132H constituted the vast majority of mutational events of IDH1. Most recent studies suggested that IDH1 mutations define a methylator subtype in PCa...
January 11, 2018: Neoplasia: An International Journal for Oncology Research
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
#2
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/29278535/the-most-novel-of-the-novel-agents-for-acute-myeloid-leukemia
#3
Alexander E Perl
PURPOSE OF REVIEW: Precious few drugs were successfully developed for acute myeloid leukemia (AML) over the past few decades, despite a dramatic expansion of our understanding of its molecular underpinnings during this time. Then in 2017, a wave of new drugs suddenly became approved. This review serves to introduce the newly available drugs, discuss their impact upon therapy, and highlight additional novel agents that are waiting in the wings. RECENT FINDINGS: Newly approved agents in AML include a tyrosine kinase inhibitor for patients with FMS-like tyrosine kinase 3 mutations, an inhibitor of mutant isocitrate dehydrogenase (IDH)2, and two novel agents using antibody-delivered or liposome-delivered cytotoxics...
December 22, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29278425/genomic-perturbations-reveal-distinct-regulatory-networks-in-intrahepatic-cholangiocarcinoma
#4
Chirag Nepal, Colm J O'Rourke, Douglas Vnp Oliveira, Andrzej Taranta, Steven Shema, Prson Gautam, Julien Calderaro, Andrew Barbour, Chiara Raggi, Krister Wennerberg, Xin W Wang, Anja Lautem, Lewis R Roberts, Jesper B Andersen
Intrahepatic cholangiocarcinoma (iCCA) remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients, and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, 'undetermined'). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, co-mutation profiles and enriched pathways...
December 26, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29274619/circulating-oncometabolite-d-2-hydroxyglutarate-enantiomer-is-a-surrogate-marker-of-isocitrate-dehydrogenase-mutated-intrahepatic-cholangiocarcinomas
#5
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...
December 20, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29261348/mri-features-and-idh-mutational-status-of-grade-ii-diffuse-gliomas-impact-on-diagnosis-and-prognosis
#6
Javier E Villanueva-Meyer, Matthew D Wood, Byung Se Choi, Marc C Mabray, Nicholas A Butowski, Tarik Tihan, Soonmee Cha
OBJECTIVE: Grade II diffuse gliomas (DGs) with isocitrate dehydrogenase (IDH) mutations are associated with better prognosis than their IDH wild-type counterparts. We sought to determine the MRI characteristics associated with IDH mutational status and ascertain whether MRI considered in combination with IDH mutational status can better predict the clinical outcomes of grade II DGs. MATERIALS AND METHODS: Preoperative MRI examinations were retrospectively studied for qualitative tumor characteristics, including location, extent, cortical involvement, margin sharpness, cystic component, mineralization or hemorrhage, and contrast enhancement...
December 20, 2017: AJR. American Journal of Roentgenology
https://www.readbyqxmd.com/read/29258767/immunohistochemical-comparative-analysis-of-gfap-map-2-nogo-a-olig-2-and-wt-1-expression-in-who-2016-classified-neuroepithelial-tumours-and-their-prognostic-value
#7
David Emanuel Schwab, Guilherme Lepski, Christian Borchers, Katrin Trautmann, Frank Paulsen, Jens Schittenhelm
Immunohistochemistry is routinely used in differential diagnosis of tumours of the central nervous system (CNS). The latest 2016 WHO 2016 revision now includes molecular data such as IDH mutation and 1p/19q codeletion thus restructuring glioma classification. Direct comparative information between commonly used immunohistochemical markers for glial tumours GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 concerning quality and quantity of expression and their relation to the new molecular markers are lacking. We therefore compared the immunohistochemical staining results of all five antibodies in 34 oligodendrogliomas, 106 ependymomas and 423 astrocytic tumours...
December 14, 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/29218432/the-2016-revision-of-the-who-classification-of-central-nervous-system-tumours-retrospective-application-to-a-cohort-of-diffuse-gliomas
#8
Te Whiti Rogers, Gurvinder Toor, Katharine Drummond, Craig Love, Kathryn Field, Rebecca Asher, Alpha Tsui, Michael Buckland, Michael Gonzales
The classification of central nervous system tumours has more recently been shaped by a focus on molecular pathology rather than histopathology. We re-classified 82 glial tumours according to the molecular-genetic criteria of the 2016 revision of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System. Initial diagnoses and grading were based on the morphological criteria of the 2007 WHO scheme. Because of the impression of an oligodendroglial component on initial histological assessment, each tumour was tested for co-deletion of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH-1 and 2) genes...
December 7, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29198322/tert-promoter-mutation-and-its-interaction-with-idh-mutations-in-glioma-combined-tert-promoter-and-idh-mutations-stratifies-lower-grade-glioma-into-distinct-survival-subgroups-a-meta-analysis-of-aggregate-data
#9
REVIEW
Huy Gia Vuong, Ahmed M A Altibi, Uyen N P Duong, Hanh T T Ngo, Thong Quang Pham, Aden Ka-Yin Chan, Chul-Kee Park, Kar-Ming Fung, Lewis Hassell
The clinical significance of telomerase reverse transcriptase (TERT) promoter mutation in glioma remains unclear. The aim of our meta-analysis is to investigate the prognostic impact TERT promoter mutation in glioma patients and its interaction with other molecular markers, particularly Isocitrate Dehydrogenase (IDH) mutation from aggregate level data. Relevant articles were searched in four electronic databases including PubMed, Scopus, Web of Science and Virtual Health Library. Pooled HRs were calculated using random effect model weighted by inverse variance method...
December 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29190505/advances-in-sarcoma-gene-mutations-and-therapeutic-targets
#10
REVIEW
Peng Gao, Nicole A Seebacher, Francis Hornicek, Zheng Guo, Zhenfeng Duan
Sarcomas are rare and complex malignancies that have been associated with a poor prognostic outcome. Over the last few decades, traditional treatment with surgery and/or chemotherapy has not significantly improved outcomes for most types of sarcomas. In recent years, there have been significant advances in the understanding of specific gene mutations that are important in driving the pathogenesis and progression of sarcomas. Identification of these new gene mutations, using next-generation sequencing and advanced molecular techniques, has revealed a range of potential therapeutic targets...
November 11, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29180699/mutant-idh1-dependent-chromatin-state-reprogramming-reversibility-and-persistence
#11
Sevin Turcan, Vladimir Makarov, Julian Taranda, Yuxiang Wang, Armida W M Fabius, Wei Wu, Yupeng Zheng, Nour El-Amine, Sara Haddock, Gouri Nanjangud, H Carl LeKaye, Cameron Brennan, Justin Cross, Jason T Huse, Neil L Kelleher, Pavel Osten, Craig B Thompson, Timothy A Chan
Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation...
November 27, 2017: Nature Genetics
https://www.readbyqxmd.com/read/29156679/remote-intracranial-recurrence-of-idh-mutant-gliomas-is-associated-with-tp53-mutations-and-an-8q-gain
#12
Shunsuke Nakae, Takema Kato, Kazuhiro Murayama, Hikaru Sasaki, Masato Abe, Masanobu Kumon, Tadashi Kumai, Kei Yamashiro, Joji Inamasu, Mitsuhiro Hasegawa, Hiroki Kurahashi, Yuichi Hirose
Most IDH mutant gliomas harbor either 1p/19q co-deletions or TP53 mutation; 1p/19q co-deleted tumors have significantly better prognoses than tumors harboring TP53 mutations. To investigate the clinical factors that contribute to differences in tumor progression of IDH mutant gliomas, we classified recurrent tumor patterns based on MRI and correlated these patterns with their genomic characterization. Accordingly, in IDH mutant gliomas (N = 66), 1p/19 co-deleted gliomas only recurred locally, whereas TP53 mutant gliomas recurred both locally and in remote intracranial regions...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156201/which-new-agents-will-be-incorporated-into-frontline-therapy-in-acute-myeloid-leukemia
#13
REVIEW
Richard M Stone
For 4 decades, new agents had not been permanently approved for use in treating acute myeloid leukemia (AML). The long dry spell was broken in 2017, however, with the approval of several agents: midostaurin for addition to chemotherapy in mutant FLT3 patients undergoing intensive chemotherapy, enasidenib in advanced mutant IDH2 patients, CPX-351 in secondary AML patients, and gemtuzumab ozogamicin in conjunction with standard chemotherapy in AML. This review surveys the use of tyrosine kinase inhibitors to treat patients with mutant FLT3 AML, mutant KIT AML, as well as IDH inhibitors and explores some questions regarding their integration into the treatment armamentarium for AML...
December 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29144447/bcat1-restricts-%C3%AE-kg-levels-in-aml-stem-cells-leading-to-idhmut-like-dna-hypermethylation
#14
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/29140606/mr-textural-analysis-on-t2-flair-images-for-the-prediction-of-true-oligodendroglioma-by-the-2016-who-genetic-classification
#15
Wenting Rui, Yan Ren, Yin Wang, Xinyi Gao, Xiao Xu, Zhenwei Yao
BACKGROUND: The genetic status of 1p/19q is important for differentiating oligodendroglioma, isocitrate-dehydrogenase (IDH)-mutant, and 1p/19q-codeleted from diffuse astrocytoma, IDH-mutant according to the 2016 World Health Organization (WHO) criteria. PURPOSE: To assess the value of magnetic resonance textural analysis (MRTA) on T2 fluid-attenuated inversion recovery (FLAIR) images for making a genetically integrated diagnosis of true oligodendroglioma by WHO guidelines...
November 15, 2017: Journal of Magnetic Resonance Imaging: JMRI
https://www.readbyqxmd.com/read/29130549/concomitant-idh-wildtype-glioblastoma-and-idh1-mutant-anaplastic-astrocytoma-in-a-patient-with-constitutional-mismatch-repair-deficiency-syndrome
#16
Francesca Galuppini, Enrico Opocher, Uri Tabori, Isabella Mammi, Melissa Edwards, Britany Campbell, Jacalyn Kelly, Alessandra Viel, Michele Quaia, Francesca Rivieri, Domenico D'Avella, Antonella Arcella, Felice Giangaspero, Matteo Fassan, Marina Paola Gardiman
Constitutional mismatch repair deficiency (CMMRD) is a rare and often under-recognized tumour predisposition syndrome, presenting with both extracranial and malignant brain tumours that occur in children and/or young adults [1]. The genetic defects underlying this disease are biallelic germline mutations in one of the DNA mismatch repair (MMR) genes leading to a constitutional DNA repair defect that causes a cancer predisposition syndrome with early onset [2]. This mechanism is different from Lynch syndrome (LS) where a heterozygous germline loss-of-function mutation is observed and the patients are more prone to develop colon and genitourinary cancers as adults [1]...
November 12, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29122763/prediction-of-idh1-mutation-and-1p-19q-codeletion-status-using-preoperative-mr-imaging-phenotypes-in-lower-grade-gliomas
#17
Y W Park, K Han, S S Ahn, S Bae, Y S Choi, J H Chang, S H Kim, S-G Kang, S-K Lee
BACKGROUND AND PURPOSE: WHO grade II gliomas are divided into three classes: isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant and no 1p/19q codeletion, and IDH-mutant and 1p/19q-codeleted. Different molecular subtypes have been reported to have prognostic differences and different chemosensitivity. Our aim was to evaluate the predictive value of imaging phenotypes assessed with the Visually AcceSAble Rembrandt Images lexicon for molecular classification of lower grade gliomas. MATERIALS AND METHODS: MR imaging scans of 175 patients with lower grade gliomas with known IDH1 mutation and 1p/19q-codeletion status were included (78 grade II and 97 grade III) in the discovery set...
January 2018: AJNR. American Journal of Neuroradiology
https://www.readbyqxmd.com/read/29091765/low-grade-astrocytoma-mutations-in-idh1-p53-and-atrx-cooperate-to-block-differentiation-of-human-neural-stem-cells-via-repression-of-sox2
#18
Aram S Modrek, Danielle Golub, Themasap Khan, Devin Bready, Jod Prado, Christopher Bowman, Jingjing Deng, Guoan Zhang, Pedro P Rocha, Ramya Raviram, Charalampos Lazaris, James M Stafford, Gary LeRoy, Michael Kader, Joravar Dhaliwal, N Sumru Bayin, Joshua D Frenster, Jonathan Serrano, Luis Chiriboga, Rabaa Baitalmal, Gouri Nanjangud, Andrew S Chi, John G Golfinos, Jing Wang, Matthias A Karajannis, Richard A Bonneau, Danny Reinberg, Aristotelis Tsirigos, David Zagzag, Matija Snuderl, Jane A Skok, Thomas A Neubert, Dimitris G Placantonakis
Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer...
October 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/29090344/the-role-of-mutant-idh1-and-idh2-inhibitors-in-the-treatment-of-acute-myeloid-leukemia
#19
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...
December 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
#20
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
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