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https://www.readbyqxmd.com/read/29773061/development-of-novel-therapeutics-targeting-isocitrate-dehydrogenase-mutations-in-cancer
#1
Horrick Sharma
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (αKG). IDH 1 and IDH2 regulate several cellular processes, including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumor types, including gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and IDH2 mutations involve a gain in neomorphic activity that catalyze αKG conversion to (R)-2-hydroxyglutarate ((R)-2HG)...
May 17, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29770715/enasidenib-for-the-treatment-of-acute-myeloid-leukemia
#2
James Dugan, Daniel Pollyea
In August 2017 the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2. Areas covered: We review the studies leading to enasidenib's approval, as well as common side effects and safety issues experienced during the clinical trials...
May 17, 2018: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/29769567/genomic-alterations-of-ground-glass-nodular-lung-adenocarcinoma
#3
Hyun Lee, Je-Gun Joung, Hyun-Tae Shin, Duk-Hwan Kim, Yujin Kim, Hojoong Kim, O Jung Kwon, Young Mog Shim, Ho Yun Lee, Kyung Soo Lee, Yoon-La Choi, Woong-Yang Park, D Neil Hayes, Sang-Won Um
In-depth molecular pathogenesis of ground-glass nodular lung adenocarcinoma has not been well understood. The objectives of this study were to identify genomic alterations in ground-glass nodular lung adenocarcinomas and to investigate whether viral transcripts were detected in these tumors. Nine patients with pure (n = 4) and part-solid (n = 5) ground-glass nodular adenocarcinomas were included. Six were females with a median age of 58 years. We performed targeted exon sequencing and RNA sequencing...
May 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29769206/targeting-the-idh2-pathway-in-acute-myeloid-leukemia
#4
Maria L Amaya, Daniel A Pollyea
Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. A large percentage of patients succumb to this disease, in spite of aggressive treatments with chemotherapy. Recent advances with mutational analysis led to the discovery of isocitrate dehydrogenase (IDH) mutations in AML. IDH2 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate; its mutated version leads to the accumulation of the oncometabolite (R)-2 hydroxyglutarate, which disrupts several cell processes and leads to a blockage in differentiation...
May 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29742078/enasidenib-for-patients-with-relapsed-acute-myeloid-leukemia-and-the-idh2-mutation
#5
Courtney DiNardo
No abstract text is available yet for this article.
April 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29741404/overexpression-of-fn14-in-gliomas-tumor-progression-and-poor-prognosis
#6
Dan Tan, Feng-Mei Pang, Dan Li, Longbo Zhang, Jun Wu, Zhao-Qian Liu, Xi Li, Han Yan
AIM: To confirm whether the expression level of Fn14 could affect progression or prognosis of glioma patients. METHODS: Glioma cohorts in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas databases were comprehensively analyzed. RESULTS: Low-grade patients had lower expression level of Fn14, while patients with higher expression of Fn14 tended to harbor shorter overall survival and disease-free survival. The expression level of Fn14 was downregulated by IDH1/IDH2 mutations while its gene body methylation was upregulated...
May 9, 2018: Future Oncology
https://www.readbyqxmd.com/read/29730775/dna-methylation-based-reclassification-of-olfactory-neuroblastoma
#7
David Capper, Nils W Engel, Damian Stichel, Matt Lechner, Stefanie Glöss, Simone Schmid, Christian Koelsche, Daniel Schrimpf, Judith Niesen, Annika K Wefers, David T W Jones, Martin Sill, Oliver Weigert, Keith L Ligon, Adriana Olar, Arend Koch, Martin Forster, Sebastian Moran, Oscar M Tirado, Miguel Sáinz-Japeado, Jaume Mora, Manel Esteller, Javier Alonso, Xavier Garcia Del Muro, Werner Paulus, Jörg Felsberg, Guido Reifenberger, Markus Glatzel, Stephan Frank, Camelia M Monoranu, Valerie J Lund, Andreas von Deimling, Stefan Pfister, Rolf Buslei, Julika Ribbat-Idel, Sven Perner, Volker Gudziol, Matthias Meinhardt, Ulrich Schüller
Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB...
May 5, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29728319/current-status-and-trends-in-the-diagnostics-of-aml-and-mds
#8
REVIEW
Evgenii Shumilov, Johanna Flach, Alexander Kohlmann, Yara Banz, Nicolas Bonadies, Martin Fiedler, Thomas Pabst, Ulrike Bacher
Diagnostics of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) have recently been experiencing extensive modifications regarding the incorporation of next-generation sequencing (NGS) strategies into established diagnostic algorithms, classification and risk stratification systems, and minimal residual disease (MRD) detection. Considering the increasing arsenal of targeted therapies (e.g. FLT3 or IDH1/IDH2 inhibitors) for AML, timely and comprehensive molecular mutation screening has arrived in daily practice...
April 27, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29727824/chinese-and-europeans-with-acute-myeloid-leukemia-have-discordant-mutation-topographies
#9
Min Zhang, Jiawei Yin, Qinghua He, Fan Zhang, Hongyu Huang, Biao Wu, Xuedong Wang, Hong Liu, Hongchao Yin, Yan Zeng, Robert Peter Gale, Depei Wu, Bin Yin
Although the topography of mutations in persons of predominately European-descent with acute myeloid leukemia (AML) is well-described this is less so in Asians. We studied AML-related mutations in 289 consecutive Chinese (mostly Han) with newly-diagnosed de novo AML. Full-length coding sequence of NPM1 and CEBPA, IDH1 and IDH2 hotspot mutations and WT1 mutations in exons 7 and 9 were analyzed by PCR as were correlations with clinical and laboratory variables. CEBPA mutations were detected in 20% of subjects (95% confidence interval [CI] 15, 25%), NPM1 mutations in 20% (15, 25%), IDH1 mutations in 4% (1, 6%), IDH2 mutations in 11% (7, 15%) and WT1 mutations in 6% (3, 9%)...
April 22, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29724719/mir142-loss-of-function-mutations-derepress-ash1l-to-increase-hoxa-gene-expression-and-promote-leukemogenesis
#10
Maria C Trissal, Terrence N Wong, Juo-Chin Yao, Rahul Ramaswamy, Iris Kuo, Jack D Baty, Yaping Sun, Gloria Jih, Nishi Parikh, Melissa M Berrien-Elliott, Todd A Fehniger, Timothy J Ley, Ivan Maillard, Pavan Reddy, Daniel C Link
Point mutations in the seed sequence of miR-142-3p are present in a subset of AML and in several subtypes of B cell lymphoma. Here we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased Ash1l protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors...
May 3, 2018: Cancer Research
https://www.readbyqxmd.com/read/29723602/non-small-cell-lung-cancers-with-isocitrate-dehydrogenase-1-or-2-idh1-2-mutations
#11
Laura N Toth, Francine B de Abreu, Laura J Tafe
Isocitrate dehydrogenase 1 and 2 (IDH1/2) are important metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations are associated with the development of multiple malignancies. In this study, we examine the prevalence and features of non-small cell lung cancers (NSCLC) with IDH1/2 mutations. From May 2013 - March 2017, 800 lung cancer samples were successfully sequenced for somatic mutations on the Ion Torrent PGM with the 50 gene AmpliSeq Cancer Hotspot Panel v2 on the Ion Torrent PGM (318 chip)...
April 30, 2018: Human Pathology
https://www.readbyqxmd.com/read/29707521/evaluation-by-flow-cytometry-of-mature-monocyte-subpopulations-for-the-diagnosis-and-follow-up-of-chronic-myelomonocytic-leukemia
#12
Tiphanie Picot, Carmen Mariana Aanei, Pascale Flandrin Gresta, Pauline Noyel, Sylvie Tondeur, Emmanuelle Tavernier Tardy, Denis Guyotat, Lydia Campos Catafal
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis and dysplasia in at least one myeloid cell lineage. This persistent monocytosis should be distinguished from the reactive monocytosis which is sometimes observed in a context of infections or solid tumors. In 2015, Selimoglu-Buet et al. observed an increased percentage of classical monocytes (CD14+ /CD16- >94%) in the peripheral blood (PB) of CMML patients. In this study, using multiparametric flow cytometry (MFC), we assessed the monocytic distribution in PB samples and in bone marrow aspirates from 63 patients with monocytosis or CMML suspicion, and in seven follow-up blood samples from CMML patients treated with hypomethylating agents (HMA)...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29695796/mitochondrial-nadp-dependent-isocitrate-dehydrogenase-deficiency-increases-cisplatin-induced-oxidative-damage-in-the-kidney-tubule-cells
#13
Min Jung Kong, Sang Jun Han, Jee In Kim, Jeen-Woo Park, Kwon Moo Park
Mitochondrial NADP+ -dependent isocitrate dehydrogenase (IDH2) plays an important role in the formation of NADPH, which is critical for the maintenance of mitochondrial redox balance. Cis-diamminedichloroplatinum II (cisplatin), an effective anticancer drug, induces oxidative stress-related nephrotoxicity, limiting its use. Therefore, we investigated whether IDH2, which is a critical enzyme in the NADPH-associated mitochondrial antioxidant system, is involved in cisplatin nephrotoxicity. Idh2 gene-deleted (Idh2-/- ) mice and wild-type (Idh2 +/+ ) littermates were treated with cisplatin, with or without 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (Mito-T), a mitochondria-specific antioxidant...
April 25, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29683816/immunohistochemical-detection-and-molecular-characterization-of-idh-mutant-sinonasal-undifferentiated-carcinomas
#14
Jeffrey K Mito, Justin A Bishop, Peter M Sadow, Edward B Stelow, William C Faquin, Stacey E Mills, Jeffrey F Krane, Christopher A French, Christopher D M Fletcher, Jason L Hornick, Lynette M Sholl, Vickie Y Jo
Recent studies have identified recurrent isocitrate dehydrogenase 2 (IDH2) mutations in a subset of sinonasal undifferentiated carcinomas (SNUCs); however, the true frequency of IDH mutations in SNUC is unknown. We evaluated the utility of mutation-specific IDH1/2 immunohistochemistry (IHC) in a large multi-institutional cohort of SNUC and morphologic mimics. IHC using a multispecific antibody for IDH1/2 (R132/R172) mutant protein was performed on 193 sinonasal tumors including: 53 SNUCs, 8 poorly differentiated carcinomas (PDCARs) and 132 histologic mimics...
April 20, 2018: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29671246/rapid-detection-of-mutation-in-isocitrate-dehydrogenase-1-and-2-genes-using-mass-spectrometry
#15
Masayuki Kanamori, Masamitsu Maekawa, Ichiyo Shibahara, Ryuta Saito, Masashi Chonan, Miki Shimada, Yukihiko Sonoda, Toshihiro Kumabe, Mika Watanabe, Nariyasu Mano, Teiji Tominaga
The 2016 World Health Organization classification of tumors of the central nervous system was recently revised. Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and chromosome 1p/19q codeletion are especially important for both the integrated diagnosis and the determination of surgical strategy. To establish a method for intraoperative molecular diagnosis, a simple, rapid method was developed for the measurement of 2-hydroxyglutarate (2-HG), a specific oncometabolite formed in the presence of IDH gene mutation, using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS)...
April 18, 2018: Brain Tumor Pathology
https://www.readbyqxmd.com/read/29666969/three-case-reports-of-radiation-induced-glioblastoma-after-complete-remission-of-acute-lymphoblastic-leukemia
#16
Takumi Kajitani, Masayuki Kanamori, Ryuta Saito, Yuko Watanabe, Hiroyoshi Suzuki, Mika Watanabe, Shigeo Kure, Teiji Tominaga
Radiation therapy is sometimes performed to control intracranial acute lymphoblastic leukemia (ALL), but may lead to radiation-induced malignant glioma. The clinical, radiological, histological, and molecular findings are described of three cases of radiation-induced glioblastoma after the treatment for ALL. They received radiation therapy at age 6-8 years. The latency from radiation therapy to the onset of radiation-induced glioblastoma was 5-10 years. Magnetic resonance imaging demonstrated diffuse lesions with multiple small enhanced lesions in all cases...
April 17, 2018: Brain Tumor Pathology
https://www.readbyqxmd.com/read/29662659/idh1-mutation-is-associated-with-lower-expression-of-vegf-but-not-microvessel-formation-in-glioblastoma-multiforme
#17
Jiří Polívka, Martin Pešta, Pavel Pitule, Ondřej Hes, Luboš Holubec, Jiří Polívka, Tereza Kubíková, Zbyněk Tonar
Introduction: Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor characterized by pathological vascularization. Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) were observed in GBM. We aimed to assess the intra-tumor hypoxia, angiogenesis and microvessel formation in GBM and to find their associations with IDH1 mutation status and patients prognosis. Methods: 52 patients with a diagnosis of GBM were included into the study...
March 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662631/overlap-at-the-molecular-and-immunohistochemical-levels-between-angioimmunoblastic-t-cell-lymphoma-and-a-subgroup-of-peripheral-t-cell-lymphomas-without-specific-morphological-features
#18
Rebeca Manso, Julia González-Rincón, Manuel Rodríguez-Justo, Giovanna Roncador, Sagrario Gómez, Margarita Sánchez-Beato, Miguel A Piris, Socorro M Rodríguez-Pinilla
The overlap of morphology and immunophenotype between angioimmunoblastic T-cell lymphoma (AITL) and other nodal peripheral T-cell lymphomas (n-PTCLs) is a matter of current interest whose clinical relevance and pathogenic background have not been fully established. We studied a series of 98 n-PTCL samples (comprising 57 AITL and 41 PTCL-NOS) with five TFH antibodies (CD10, BCL-6, PD-1, CXCL13, ICOS), looked for mutations in five of the genes most frequently mutated in AITL ( TET2 , DNMT3A, IDH2, RHOA and PLCG1 ) using the Next-Generation-Sequencing Ion Torrent platform, and measured the correlations of these characteristics with morphology and clinical features...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29661468/successful-treatment-of-cytogenetically-normal-acute-myeloid-leukemia-with-ten-eleven-translocation-2-isocitrate-dehydrogenase-2-and-additional-sex-comb-like-1-nucleophosmin-co-mutations-by-hla-haploidentical-stem-cell-transplantation-a-case-report-and-literature
#19
Y Liu, Y Cao, Y Lin, W-M Dong, R-R Lin, Q Gu, X-B Xie, W-Y Gu
The presence of recurrent gene mutations is increasingly important in acute myeloid leukemia (AML) and sheds new insights into the understanding of leukemogenesis, prognostic evaluation, and clinical therapeutic efficacy. Until now, ten-eleven translocation 2 (TET2) and isocitrate dehydrogenase 2 (IDH2) mutations were reported to be mutually exclusive in AML patients. Similarly, nucleophosmin (NPM1) and additional sex comb-like 1 (ASXL1) mutations were rarely coexisted in AML. A 47-year-old man diagnosed with high-risk AML presented simultaneous mutations of TET2-IDH2 and NPM1-ASXL1 revealed by next-generation sequencing...
April 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29660504/idh2-deficiency-accelerates-skin-pigmentation-in-mice-via-enhancing-melanogenesis
#20
Jung Hyun Park, Hyeong Jun Ku, Jin Hyup Lee, Jeen-Woo Park
Melanogenesis is a complex biosynthetic pathway regulated by multiple agents, which are involved in the production, transport, and release of melanin. Melanin has diverse roles, including determination of visible skin color and photoprotection. Studies indicate that melanin synthesis is tightly linked to the interaction between melanocytes and keratinocytes. α-melanocyte-stimulating hormone (α-MSH) is known as a trigger that enhances melanin biosynthesis in melanocytes through paracrine effects. Accumulated reactive oxygen species (ROS) in skin affects both keratinocytes and melanocytes by causing DNA damage, which eventually leads to the stimulation of α-MSH production...
April 6, 2018: Redox Biology
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