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https://www.readbyqxmd.com/read/28808777/phase-ii-study-of-bi-weekly-temozolomide-plus-bevacizumab-for-adult-patients-with-recurrent-glioblastoma
#1
Michael A Badruddoja, Marjorie Pazzi, Abhay Sanan, Kurt Schroeder, Kevin Kuzma, Thomas Norton, Thomas Scully, Daruka Mahadevan, Michael Malek Ahmadi
PURPOSE: Bevacizumab is an active anti-angiogenic agent in the treatment of recurrent glioblastoma. Temozolomide can prolong survival in patients with newly diagnosed glioblastoma. At recurrence, alternate dosing of temozolomide has shown to further deplete methyl-guanine-methyltransferase (MGMT) conferring added activity for patients who have progressed on the standard dosing regimen. In this study, bevacizumab plus biweekly temozolomide was evaluated for efficacy in adult patients with recurrent glioblastoma...
August 14, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28801186/interim-results-from-the-catnon-trial-eortc-study-26053-22054-of-treatment-with-concurrent-and-adjuvant-temozolomide-for-1p-19q-non-co-deleted-anaplastic-glioma-a-phase-3-randomised-open-label-intergroup-study
#2
Martin J van den Bent, Brigitta Baumert, Sara C Erridge, Michael A Vogelbaum, Anna K Nowak, Marc Sanson, Alba Ariela Brandes, Paul M Clement, Jean Francais Baurain, Warren P Mason, Helen Wheeler, Olivier L Chinot, Sanjeev Gill, Matthew Griffin, David G Brachman, Walter Taal, Roberta Rudà, Michael Weller, Catherine McBain, Jaap Reijneveld, Roelien H Enting, Damien C Weber, Thierry Lesimple, Susan Clenton, Anja Gijtenbeek, Sarah Pascoe, Ulrich Herrlinger, Peter Hau, Frederic Dhermain, Irene van Heuvel, Roger Stupp, Ken Aldape, Robert B Jenkins, Hendrikus Jan Dubbink, Winand N M Dinjens, Pieter Wesseling, Sarah Nuyens, Vassilis Golfinopoulos, Thierry Gorlia, Wolfgang Wick, Johan M Kros
BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2...
August 8, 2017: Lancet
https://www.readbyqxmd.com/read/28800752/a-type-i-combi-targeting-approach-for-the-design-of-molecules-with-enhanced-potency-against-brca1-2-mutant-and-o6-methylguanine-dna-methyltransferase-mgmt-expressing-tumour-cells
#3
Zhor Senhaji Mouhri, Elliot Goodfellow, Bertrand Jean-Claude
BACKGROUND: Mutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leads to cell death due to the absence of compensatory DNA repair mechanism. The potency of PARP inhibitors has now been clinically proven. However, disappointingly, acquired resistance mediated by the reactivation of wild type BRCA1/2 has been reported. In order to improve their efficacy, trials are ongoing to explore their combinations with temozolomide (TMZ)...
August 11, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28800313/clinical-validation-of-the-ce-ivd-marked-therascreen-mgmt-kit-in-a-cohort-of-glioblastoma-patients
#4
Véronique Quillien, Audrey Lavenu, François Ducray, David Meyronet, Olivier Chinot, Frédéric Fina, Marc Sanson, Catherine Carpentier, Lucie Karayan-Tapon, Pierre Rivet, Natacha Entz-Werle, Michèle Legrain, Emmanuèle Lechapt Zalcman, Guenaelle Levallet, Fabienne Escande, Carole Ramirez, Dan Chiforeanu, Elodie Vauleon, Dominique Figarella-Branger
BACKGROUND: Pyrosequencing is recognized as a strong technique to analyze the MGMT status of glioblastoma patients. The most commonly used assay, quantifies the methylation levels of CpGs 74 to 78. A more recent CE-marked In Vitro Diagnostic Medical Device (CE-IVD) assay, Therascreen, analyzes CpGs 76-79. METHODS: We performed a comparison of these two assays to evaluate the potential impact of this shift in analyzed CpGs. Therascreen analysis was centrally performed for 102 glioblastoma patients, who were part of a prospective multicenter trial...
July 31, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28798282/feasibility-and-safety-of-extended-adjuvant-temozolomide-beyond-six-cycles-for-patients-with-glioblastoma
#5
S Yp Hsieh, D Tm Chan, M Km Kam, H Hf Loong, W K Tsang, D Mc Poon, S Cp Ng, W S Poon
INTRODUCTION: Temozolomide is the first chemotherapeutic agent proven effective for patients with newly diagnosed glioblastoma. The drug is well tolerated for its low toxicity. The current standard practice is concomitant chemoradiotherapy for 6 weeks followed by 6 cycles of adjuvant temozolomide. Some Caucasian studies have suggested that patients might benefit from extended adjuvant cycles of temozolomide (>6 cycles) to lengthen both progression-free survival and overall survival...
August 11, 2017: Hong Kong Medical Journal, Xianggang Yi Xue za Zhi
https://www.readbyqxmd.com/read/28791452/long-term-daily-temozolomide-with-dose-dependent-efficacy-in-mgmt-promotor-methylation-negative-recurrent-high-grade-astrocytoma
#6
Zhengqiu Zhou, Tracy A Howard, John L Villano
Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day...
August 8, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28775233/genetic-and-immune-features-of-resectable-malignant-brainstem-gliomas
#7
Yang Zhang, Changcun Pan, Junmei Wang, Jingli Cao, Yuhan Liu, Yajie Wang, Liwei Zhang
We surveyed common genetic mutations (IDH1, H3F3A, PPM1D, and TP53) and immune features (PD-L1 expression and CD8+ T cell tumor infiltration) in a series of 62 malignant brainstem gliomas that were resected via microsurgery. IDH1 mutations were mutually exclusive with H3F3A mutations. IDH1 mutations appeared only in adults and occurred more frequently in tumors larger than 10cm3 (8/29 vs 1/32, Fisher's exact test, p=0.010). H3F3A mutations occurred more frequently in children and adolescent patients (19/24 vs 18/38, chi-square test, p=0...
July 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28765916/low-co-expression-of-epidermal-growth-factor-receptor-and-its-chaperone-heat-shock-protein-90-is-associated-with-worse-prognosis-in-primary-glioblastoma-idh-wild-type
#8
Elsa Sartori, Rupert Langer, Erik Vassella, Ekkehard Hewer, Philippe Schucht, Inti Zlobec, Sabina Berezowska
Epidermal growth factor receptor (EGFR) is a major oncogenic driver in glioblastoma (GBM) without mutations in the isocitrate dehydrogenase gene (IDH-wildtype). Heat shock protein 90 (HSP90) is a regulator of the stability of oncogenic proteins including EGFR, thereby acting as a molecular chaperone. We investigated the expression of EGFR and its chaperone HSP90 in GBM, IDH-wildtype. Tissue availability permitted analysis of 237/449 consecutive GBM cases, among them 214 IDH-wildtype (90.3%). The expression of EGFR and HSP90 was analysed by immunohistochemistry on a tissue microarray containing various tumour regions...
August 1, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28759950/chemokine-receptor-cxcr7-is-an-independent-prognostic-biomarker-in-glioblastoma
#9
Lina Deng, Wenxin Zheng, Xueshuang Dong, Jianghua Liu, Chunyu Zhu, Dan Lu, Jin Zhang, Laijun Song, Yuchao Wang, Dan Deng
BACKGROUND: Glioblastoma (GBM) is the most common and most fatal primary brain cancer in adults. Due to the complex nature of GBM, its pathogenesis still remain unclear. Accumulating evidence suggest that chemokine receptor CXCR7 contribute to the development of various types of tumors. OBJECTIVE: We aim to examine the prognostic significance of CXCR7 in GBM. METHODS: CXCR7 were first detected by Immunohistochemistry. The association between CXCR7 and overall survival (OS) were examined...
July 19, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28755323/detection-of-the-alternative-lengthening-of-telomeres-pathway-in-malignant-gliomas-for-improved-molecular-diagnosis
#10
Anne Fogli, Marie-Véronique Demattei, Laetitia Corset, Catherine Vaurs-Barrière, Emmanuel Chautard, Julian Biau, Jean-Louis Kémény, Catherine Godfraind, Bruno Pereira, Toufik Khalil, Nathalie Grandin, Philippe Arnaud, Michel Charbonneau, Pierre Verrelle
Human malignant gliomas exhibit acquisition of either one of two telomere maintenance mechanisms, resulting from either reactivation of telomerase expression or activation of an alternative lengthening of telomeres (ALT) mechanism. In the present study, we analyzed 63 human malignant gliomas for the presence of ALT-specific extrachromosomal circles of telomeric DNA (C-circles) and measured telomerase expression, telomeric DNA content (Telo/Alu method), and telomeric repeat-containing RNAs (TERRA) levels. We also assessed histomolecular markers routinely used in clinical practice...
July 28, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28753842/molecular-and-genomic-profiling-to-identify-actionable-targets-in-chromophobe-renal-cell-cancer
#11
Philip Abbosh, Srinath Sundararajan, Sherri Z Millis, Adam Hauben, Sandeep Reddy, Daniel M Geynisman, Robert Uzzo
Metastatic chromophobe renal cell cancer (chRCC) is a rare subtype of RCC with no standard treatment. We performed molecular profiling of 12 chRCC cases to identify alterations predictive of response to therapy. Tests included immunohistochemistry assays, fluorescence in situ hybridization, and next-generation sequencing. Analysis identified c-KIT overexpression in 6/9 (67%) samples analyzed, and loss of protein expression of RRM1 and MGMT in 11/12 (92%) and of PTEN in 7/12 samples (58%). Mutations of TP53, PTEN, APC, and VHL genes were identified...
January 23, 2017: European Urology Focus
https://www.readbyqxmd.com/read/28753207/the-proline-rich-domain-of-p53-is-dispensable-for-mgmt-dependent-dna-repair-and-cell-survival-following-alkylation-damage
#12
Katherine Baran, Mao Yang, Christopher P Dillon, Leona L Samson, Douglas R Green
In addition to promoting cell death and senescence, p53 also has important cellular survival functions. A mutant p53, lacking a proline-rich domain (p53(ΔP)), that is deficient in controlling both cell death and cell cycle arrest, was employed to determine the biological means by which p53 mediates survival upon DNA damage. While p53(ΔP) and p53(-/-) cells were equally resistant to many DNA damaging agents, p53(ΔP) cells showed an exquisite resistance to high doses of the alkylating agent Diazald (N-Methyl-N-(p-tolylsulfonyl)nitrosamide), as compared to cells completely deficient for p53 function...
July 28, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28752860/enhancing-the-cytotoxicity-of-chemoradiation-with-radiation-guided-delivery-of-anti-mgmt-morpholino-oligonucleotides-in-non-methylated-solid-tumors
#13
P Ambady, Y J Wu, J M Walker, C Kersch, M A Pagel, R L Woltjer, R Fu, L L Muldoon, E A Neuwelt
The DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences...
July 28, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28749454/the-association-of-low-penetrance-variants-in-dna-repair-genes-with-colorectal-cancer-a-systematic-review-and-meta-analysis
#14
Nikhil Aggarwal, Neil D Donald, Salim Malik, Subothini S Selvendran, Mark Jw McPhail, Kevin J Monahan
OBJECTIVES: Approximately 35% of colorectal cancer (CRC) risk is attributable to heritable factors known hereditary syndromes, accounting for 6%. The remainder may be due to lower penetrance polymorphisms particularly of DNA repair genes. DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), direct reversal repair (DRR), and double-strand break repair are complex, evolutionarily conserved, and critical in carcinogenesis. Germline mutations in these genes are associated with high-penetrance CRC syndromes such as Lynch syndrome...
July 27, 2017: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/28748002/high-levels-of-circulating-folate-concentrations-are-associated-with-dna-methylation-of-tumor-suppressor-and-repair-genes-p16-mlh1-and-mgmt-in-elderly-chileans
#15
Hugo Sanchez, Mohammad B Hossain, Lydia Lera, Sandra Hirsch, Cecilia Albala, Ricardo Uauy, Karin Broberg, Ana M Ronco
BACKGROUND: Changes in DNA methylation, one of the most studied epigenetic mechanisms, are considered an initial marker for early cancer detection. We evaluated how availability of dietary factors (folates and vitamin B12) involved in one-carbon metabolism may contribute to DNA methylation changes of cancer-related genes in human subjects. METHODS: We studied, by pyrosequencing, the methylation of tumor suppressor gene p16, DNA repair genes MLH1 and MGMT, and the repetitive element LINE-1 (as a surrogate for global DNA methylation), in blood of elderly individuals (n = 249) who had been exposed to folic acid (FA) through FA-fortified wheat flour during the last 12 years...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28739733/analysis-of-association-between-mgmt-and-p53-gene-single-nucleotide-polymorphisms-and-laryngeal-cancer
#16
Yayun Lv, Chuanliang Jia, Aihua Jiang, Hua Zhang, Yunqiang Wang, Feifei Liu, Linlin Yang, Yan Sun, Runli Lv, Xicheng Song
AIM: To investigate the p53 and O(6)-methylguanine DNA methyltransferase (MGMT)5' upstream sequence gene promoter regions for single nucleotide polymorphisms and explore the p53 gene 5' upstream sequence consisting of two haplotypes to provide a genetic marker for the incidence of laryngeal squamous cell carcinoma. MATERIALS AND METHODS: We included 96 cases of laryngeal squamous cell carcinoma and 102 controls. We used SNaPshot micro-sequencing analysis of the MGMT promoter region for four single nucleotide polymorphisms and p53 gene 5' upstream sequence loci (rs1625649, rs2287499, rs2287498, rs228749) genotypes...
August 2017: Anticancer Research
https://www.readbyqxmd.com/read/28732379/integrative-analysis-of-novel-hypomethylation-and-gene-expression-signatures-in-glioblastomas
#17
Anan Yin, Amandine Etcheverry, Yalong He, Marc Aubry, Jill Barnholtz-Sloan, Luhua Zhang, Xinggang Mao, Weijun Chen, Bolin Liu, Wei Zhang, Jean Mosser, Xiang Zhang
Molecular and clinical heterogeneity critically hinders better treatment outcome for glioblastomas (GBMs); integrative analysis of genomic and epigenomic data may provide useful information for improving personalized medicine. By applying training-validation approach, we identified a novel hypomethylation signature comprising of three CpGs at non-CpG island (CGI) open sea regions for GBMs. The hypomethylation signature consistently predicted poor prognosis of GBMs in a series of discovery and validation datasets...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28728506/microsatellite-instability-and-promoter-hypermethylation-of-dna-repair-genes-in-hematologic-malignancies-a-forthcoming-direction-toward-diagnostics
#18
Priyanjali Bhattacharya, Trupti N Patel
OBJECTIVE: The objective of our review is to highlight the significance of microsatellite hypervariation in diagnostics of hematologic malignancies. METHODS: For the past few decades, extensive experiments in cancer research have explored all the possible pathways and a number of deleterious mutations that either make the tumor suppressor genes (TSGs) dysfunctional or cause the proto-oncogenes to behave abnormally by changing the cellular phenotype hence rendering disease...
July 20, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28726172/combined-treatment-for-non-small-cell-lung-cancer-and-breast-cancer-patients-with-brain-metastases-with-whole-brain-radiotherapy-and-temozolomide-a-systematic-review-and-meta-analysis
#19
REVIEW
Jingru Tian, Yien Luo, Juanjuan Xiang, Jingqun Tang
Brain metastasis is the leading cause of death among advanced non-small cell lung cancer (NSCLC) and breast cancer patients. The standard treatment for brain metastases is radiotherapy. The combination of radiotherapy and chemotherapy has been tested. However, the management of brain metastases has yet to be successful. Here, we aimed to determine the efficacy and safety of whole brain radiotherapy (WBRT) alone or in combination with temozolomide (TMZ) in NSCLC and breast cancer patients with brain metastases...
July 19, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28720507/formation-and-degradation-of-nitrogen-mustard-induced-mgmt-dna-crosslinking-in-16hbe-cells
#20
Jin Cheng, Feng Ye, Guorong Dan, Yuanpeng Zhao, Jiqing Zhao, Zhongmin Zou
N-methyl-2,2-di(chloroethyl)amine (HN2) is a kind of bifunctional alkyltating agent, which can react with nucleophilic groups in DNA and/or protein to form HN2-bridged crosslinking of target molecules, such as DNA-protein crosslinkings (DPC). O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA damage repair enzyme which solely repairs alkyl adduct on DNA directly. However, MGMT was detected to act as a protein cross-linked with DNA via alkylation in presence of HN2, and unexpectedly turned into a DNA damage enhancer in the form of MGMT-DNA cross-link (mDPC)...
July 15, 2017: Toxicology
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