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https://www.readbyqxmd.com/read/28202508/chemosensitivity-of-idh1-mutant-gliomas-due-to-an-impairment-in-parp1-mediated-dna-repair
#1
Yanxin Lu, Jakub Kwintkiewicz, Yang Liu, Katherine Tech, Lauren N Frady, Yu-Ting Su, Wendy Bautista, Seog In Moon, Jeffrey MacDonald, Matthew G Edwend, Mark R Gilbert, Chunzhang Yang, Jing Wu
Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28193778/ag-221-a-first-in-class-therapy-targeting-acute-myeloid-leukemia-harboring-oncogenic-idh2-mutations
#2
Katharine Yen, Jeremy Travins, Fang Wang, Muriel D David, Erin Artin, Kim Straley, Anil Padyana, Stefan Gross, Byron DeLaBarre, Erica Tobin, Yue Chen, Raj Nagaraja, Sung Choe, Lei Jin, Zenon Konteatis, Giovanni Cianchetta, Jeffrey O Saunders, Francesco G Salituro, Cyril Quivoron, Paule Opolon, Olivia Bawa, Véronique Saada, Angelo Paci, Sophie Broutin, Olivier A Bernard, Stéphane de Botton, Benoît S Marteyn, Monika Pilichowska, YingXia Xu, Cheng Fang, Fan Jiang, Wentao Wei, Shengfang Jin, Lee Silverman, Wei Liu, Hua Yang, Lenny Dang, Marion Dorsch, Virginie Penard-Lacronique, Scott A Biller, Shin-San Michael Su
Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite, (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the Tet family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach...
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28161760/incidence-survival-pathology-and-genetics-of-adult-latino-americans-with-glioblastoma
#3
Maryam Shabihkhani, Donatello Telesca, Masoud Movassaghi, Yalda B Naeini, Kourosh M Naeini, Seyed Amin Hojat, Diviya Gupta, Gregory M Lucey, Michael Ontiveros, Michael W Wang, Lauren S Hanna, Desiree E Sanchez, Sergey Mareninov, Negar Khanlou, Harry V Vinters, Marvin Bergsneider, Phioanh Leia Nghiemphu, Albert Lai, Linda M Liau, Timothy F Cloughesy, William H Yong
: Latino Americans are a rapidly growing ethnic group in the United States but studies of glioblastoma in this population are limited. We have evaluated characteristics of 21,184 glioblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. This SEER data from 2001 to 2011 draws from 28% of the U.S. POPULATION: Latinos have a lower incidence of GBM and present slightly younger than non-Latino Whites. Cubans present at an older age than other Latino sub-populations...
February 4, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28148839/2-hydroxyglutarate-produced-by-neomorphic-idh-mutations-suppresses-homologous-recombination-and-induces-parp-inhibitor-sensitivity
#4
Parker L Sulkowski, Christopher D Corso, Nathaniel D Robinson, Susan E Scanlon, Karin R Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini K Sundaram, Denise C Hegan, Nathan R Fons, Gregory A Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk M De Feyter, Robin A de Graaf, Yulia V Surovtseva, Maureen Kachman, Stephanie Halene, Murat Günel, Peter M Glazer, Ranjit S Bindra
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28133974/novel-therapeutic-approaches-in-chondrosarcoma
#5
Genovefa Polychronidou, Vasilios Karavasilis, Seth M Pollack, Paul H Huang, Alex Lee, Robin L Jones
Chondrosarcoma is a malignant tumor of bones, characterized by the production of cartilage matrix. Due to lack of effective treatment for advanced disease, the clinical management of chondrosarcomas is exceptionally challenging. Current research focuses on elucidating the molecular events underlying the pathogenesis of this rare bone malignancy, with the goal of developing new molecularly targeted therapies. Signaling pathways suggested to have a role in chondrosarcoma include Hedgehog, Src, PI3k-Akt-mTOR and angiogenesis...
January 30, 2017: Future Oncology
https://www.readbyqxmd.com/read/28126746/genetically-defined-oligodendroglioma-is-characterized-by-indistinct-tumor-borders-at-mri
#6
D R Johnson, F E Diehn, C Giannini, R B Jenkins, S M Jenkins, I F Parney, T J Kaufmann
BACKGROUND AND PURPOSE: In 2016, the World Health Organization revised the brain tumor classification, making IDH mutation and 1p/19q codeletion the defining features of oligodendroglioma. To determine whether imaging characteristics previously associated with oligodendroglial tumors are still applicable, we evaluated the MR imaging features of genetically defined oligodendrogliomas. MATERIALS AND METHODS: One hundred forty-eight adult patients with untreated World Health Organization grade II and III infiltrating gliomas with histologic oligodendroglial morphology, known 1p/19q status, and at least 1 preoperative MR imaging were retrospectively identified...
January 26, 2017: AJNR. American Journal of Neuroradiology
https://www.readbyqxmd.com/read/28124097/pan-mutant-idh1-inhibitor-bay-1436032-for-effective-treatment-of-idh1-mutant-astrocytoma-in-vivo
#7
Stefan Pusch, Sonja Krausert, Viktoria Fischer, Jörg Balss, Martina Ott, Daniel Schrimpf, David Capper, Felix Sahm, Jessica Eisel, Ann-Christin Beck, Manfred Jugold, Viktoria Eichwald, Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp, Markus Bauser, Wolfgang Wick, Andreas Unterberg, Christel Herold-Mende, Michael Platten, Andreas von Deimling
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations...
January 25, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28122345/epigenetic-silencing-of-xaf1-in-high-grade-gliomas-is-associated-with-idh1-status-and-improved-clinical-outcome
#8
Thomas R Reich, Olivier J Switzeny, Mirjam Renovanz, Clemens Sommer, Bernd Kaina, Markus Christmann, Maja T Tomicic
XAF1 (X-linked inhibitor of apoptosis (XIAP)-associated factor 1) is a tumor suppressor that counteracts the anti-apoptotic effects of XIAP and can sensitize cells to cell death triggering events. XAF1 knockdown abrogated the temozolomide (TMZ)-induced G2-arrest and prevented TMZ-induced apoptosis in the glioblastoma (GB) cell line LN229. Promoter methylation of XAF1 was found to be inversely correlated with mRNA expression in GB cells. We analyzed XAF1 methylation in a panel of 16 GB cell lines and 80 patients with first-diagnosed WHO grade III/IV high-grade gliomas using methylation-sensitive high-resolution melt (MS-HRM) analysis...
January 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28116838/insular-primary-glioblastomas-with-idh-mutations-clinical-and-biological-specificities
#9
Nobuhiro Hata 秦暢宏, Ryusuke Hatae, Koji Yoshimoto, Hideki Murata, Daisuke Kuga, Yojiro Akagi, Yuhei Sangatsuda, Satoshi O Suzuki, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara
Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations...
January 24, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28110298/idh1-mutation-in-diffuse-gliomas-in-persons-age-55-years-and-over
#10
Chase Robinson, B K Kleinschmidt-DeMasters
Diffuse astrocytoma (DA), anaplastic astrocytoma (AA), and glioblastoma (GBM) are defined by the World Health Organization (WHO) based on IDH-mutational status. The vast majority of IDH-mutated gliomas (90% of which involve a mutation in IDH1 R132H, which can be assessed by IDH1 immunohistochemistry [IHC]) occur in persons younger than 55 years of age. This raises the question as to the prevalence of IDH-mutant tumors in older persons and whether the gliomas in older patients should be routinely tested. Since January 1, 2014, we have employed a standard screening panel for all gliomas regardless of patient age...
January 21, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28091987/expression-and-prognostic-value-of-micrornas-in-lower-grade-glioma-depends-on-idh1-2-status
#11
Wen Cheng, Xiufang Ren, Chuanbao Zhang, Sheng Han, Anhua Wu
Histological and genomic characteristics are widely used in glioma management and research. This study investigated their relationship to the expression and prognostic value of microRNAs (miRNAs) in lower-grade glioma (LGG). A total of 447 LGG samples with available clinical and genomic information from The Cancer Genome Atlas database were reviewed. Samples with isocitrate dehydrogenase (IDH) 1/2 mutations (n = 366) were randomly divided into training and validation sets to establish and confirm a four-miRNA-based risk classifier...
January 16, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28079713/interrogating-idh-mutation-in-brain-tumor-magnetic-resonance-and-hyperpolarization
#12
Jingzhe Hu, Travis C Salzillo, Napapon Sailasuta, Frederick F Lang, Pratip Bhattacharya
Magnetic resonance spectroscopy (MRS) offers the possibility to noninvasively quantify 2HG concentration in the brain in the clinic, thereby serving as a valuable tool for patient-stratification as well as targeted treatment monitoring. Recently, hyperpolarized magnetic resonance techniques have opened up new opportunities for metabolic imaging not possible with conventional MRS in the brain. With over 10,000-fold increase in signal-to-noise ratio (SNR), dynamic metabolic processes can be interrogated in vivo with very high specificity by hyperpolarized MRI...
February 2017: Topics in Magnetic Resonance Imaging: TMRI
https://www.readbyqxmd.com/read/28078132/impressive-response-to-dual-braf-and-mek-inhibition-in-patients-with-braf-mutant-intrahepatic-cholangiocarcinoma-2-case-reports-and-a-brief-review
#13
Viraj Lavingia, Marwan Fakih
Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control...
December 2016: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28074068/a-cpg-island-methylator-phenotype-in-acute-myeloid-leukemia-independent-of-idh-mutations-and-associated-with-a-favorable-outcome
#14
A D Kelly, H Kroeger, J Yamazaki, R Taby, F Neumann, S Yu, J T Lee, B Patel, Y Li, R He, S Liang, Y Lu, M Cesaroni, S A Pierce, S M Kornblau, C E Bueso-Ramos, F Ravandi, H M Kantarjian, J Jelinek, J-Pj Issa
Genetic changes are infrequent in acute myeloid leukemia (AML) compared to other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation (DREAM) data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CIMP (A-CIMP(+))...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28058510/homozygous-mutation-p-pro304his-in-idh3a-encoding-isocitrate-dehydrogenase-subunit-is-associated-with-severe-encephalopathy-in-infancy
#15
Aviva Fattal-Valevski, Hila Eliyahu, NItai D Fraenkel, Ganit Elmaliach, Moran Hausman-Kedem, Avraham Shaag, Dror Mandel, Ophry Pines, Orly Elpeleg
Mitochondrial encephalopathies are a heterogeneous group of disorders which generally carries a grave prognosis. Using exome sequencing, we identified a homozygous mutation, Pro-304-His in the IDH3A gene, in a patient suffering from infantile encephalopathy with peripheral and autonomic nervous system involvement. Mammalian isocitrate dehydrogenase (IDH) 3 is a heterotetramer of 2alfa, 1beta, and 1gamma subunits, and IDH3A encodes the alfa subunit of the mitochondrial NAD(+)-dependent IDH. Here we show that in contrast to wild-type human IDH3A, the human IDH3A which harbor the p...
January 2017: Neurogenetics
https://www.readbyqxmd.com/read/28058097/genetics-and-epigenetics-of-myelodysplastic-syndromes-and-response-to-drug-therapy-new-insights
#16
REVIEW
Saeid Shahrabi, Abbas Khosravi, Mohammad Shahjahani, Fakher Rahim, Najmaldin Saki
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied...
October 10, 2016: Oncology Reviews
https://www.readbyqxmd.com/read/28056258/-advance-of-molecular-subtyping-and-precise-treatment-for-gliomas
#17
W Hua, Y Mao
With the advance of genomics research, there have been a new breakthrough in the molecular classification of gliomas. Glioblastoma (WHO grade Ⅳ) could be subtyped to proneural, neural, classical, and mesochymal according to the mRNA expression. Lower grade gliomas (WHO grade Ⅱ and Ⅲ) could be divided into 5 types using 1p/19q co-deletion, isocitrate dehydrogenase(IDH) mutation, and TERTp (promotor region) mutation. In 2016, a new classification of tumors of the central nervous system was proposed, and some new markers such as IDH1 mutation were introduced into the diagnosis of gliomas...
1, 2017: Zhonghua Wai Ke za Zhi [Chinese Journal of Surgery]
https://www.readbyqxmd.com/read/28052098/idh1-r132h-mutation-enhances-cell-migration-by-activating-akt-mtor-signaling-pathway-but-sensitizes-cells-to-5-fu-treatment-as-nadph-and-gsh-are-reduced
#18
Huixia Zhu, Ye Zhang, Jianfeng Chen, Jiangdong Qiu, Keting Huang, Mindan Wu, Chunlin Xia
AIM OF STUDY: Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. MATERIALS AND METHODS: Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively...
2017: PloS One
https://www.readbyqxmd.com/read/27999734/molecular-and-clinical-characterization-of-pd-l1-expression-at-transcriptional-level-via-976-samples-of-brain-glioma
#19
Zheng Wang, Chuanbao Zhang, Xing Liu, Zhiliang Wang, Lihua Sun, Guanzhang Li, Jingshan Liang, Huimin Hu, Yanwei Liu, Wei Zhang, Tao Jiang
Background: PD-L1 has been widely reported as immune check points in a range of malignancies as well as some immune-originated diseases. In glioma, the role of PD-L1 remains unclear. We aimed at investigating its role at transcriptome level and relationship with clinical practice. Method and patients: In total, 976 glioma samples with transcriptome data, including 301 microarray data from Chinese Glioma Genome Atlas (CGGA project) and 675 RNAseq data from TCGA project, were enrolled into our study. Clinical and IDH mutation data were also available...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27994066/phase-iii-randomized-study-of-radiation-and-temozolomide-versus-radiation-and-nitrosourea-therapy-for-anaplastic-astrocytoma-results-of-nrg-oncology-rtog-9813
#20
Susan Chang, Peixin Zhang, J Gregory Cairncross, Mark R Gilbert, Jean-Paul Bahary, Carol A Dolinskas, Arnab Chakravarti, Kenneth D Aldape, Erica H Bell, David Schiff, Kurt Jaeckle, Paul D Brown, Geoffrey R Barger, Maria Werner-Wasik, Helen Shih, David Brachman, Marta Penas-Prado, H Ian Robins, Karl Belanger, Christopher Schultz, Grant Hunter, Minesh Mehta
BACKGROUND: The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. METHODS: Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99)...
December 18, 2016: Neuro-oncology
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