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https://www.readbyqxmd.com/read/29785153/prevalence-of-deleterious-mutations-among-patients-with-breast-cancer-referred-for-multigene-panel-testing-in-a-romanian-population
#1
Iulian Gabriel Goidescu, Gabriela Caracostea, Dan Tudor Eniu, Florin Vasile Stamatian
Aim: Multigene panel testing for Hereditary Breast and Ovarian Cancer (HBOC) using next generation sequencing is becoming more common in medical care.We report our experience regarding deleterious mutations of high and moderate-risk breast cancer genes (BRCA1/2, TP53, STK11, CDH1, PTEN, PALB2, CHEK2, ATM), as well as more recently identified cancer genes, many of which have increased risk but less well-defined penetrance. Methods: Genetic testing was performed in 130 consecutive cases with breast cancer referred to our clinic for surgical evaluation and who met the 2016 National Comprehensive Cancer Network (NCCN) criteria for genetic testing...
2018: Clujul Medical (1957)
https://www.readbyqxmd.com/read/29774099/camptothecin-induces-g-2-m-phase-arrest-through-the-atm-chk2-cdc25c-axis-as-a-result-of-autophagy-induced-cytoprotection-implications-of-reactive-oxygen-species
#2
Rajapaksha Gedara Prasad Tharanga Jayasooriya, Matharage Gayani Dilshara, Ilandarage Menu Neelaka Molagoda, Cheol Park, Sang Rul Park, Seungheon Lee, Yung Hyun Choi, Gi-Young Kim
In the present study, we report that camptothecin (CPT) caused irreversible cell cycle arrest at the G2 /M phase, and was associated with decreased levels of cell division cycle 25C (Cdc25C) and increased levels of cyclin B1, p21, and phospho-H3. Interestingly, the reactive oxygen species (ROS) inhibitor, glutathione, decreased CPT-induced G2 /M phase arrest and moderately induced S phase arrest, indicating that the ROS is required for the regulation of CPT-induced G2 /M phase arrest. Furthermore, transient knockdown of nuclear factor-erythroid 2-related factor 2 (Nrf2), in the presence of CPT, increased the ROS' level and further shifted the cell cycle from early S phase to the G2 /M phase, indicating that Nrf2 delayed the S phase in response to CPT...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29769598/germline-mutation-in-the-tp53-gene-in-uveal-melanoma
#3
Nikola Hajkova, Jan Hojny, Kristyna Nemejcova, Pavel Dundr, Jan Ulrych, Katerina Jirsova, Johana Glezgova, Ivana Ticha
We performed comprehensive molecular analysis of five cases of metastasizing uveal malignant melanoma (UM) (fresh-frozen samples) with an NGS panel of 73 genes. A likely pathogenic germline TP53 mutation c.760A > G (p.I254V) was found in two tumor samples and matched nontumor tissue. In three cases, pathogenic BAP1 mutation was detected together with germline missense variants of uncertain significance in ATM. All cases carried recurrent activating GNAQ or GNA11 mutation. Moreover, we analyzed samples from another 16 patients with primary UM by direct Sanger sequencing focusing only on TP53 coding region...
May 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29769345/the-major-tegument-protein-of-bovine-herpesvirus-1-vp8-interacts-with-dna-damage-response-proteins-and-induces-apoptosis
#4
Sharmin Afroz, Ravendra Garg, Michel Fodje, Sylvia van Drunen Littel-van den Hurk
VP8, the UL47 gene product in bovine herpes virus-1 (BoHV-1), is a major tegument protein, essential for virus replication in vivo The major DNA damage response protein, ataxia telangiectasia mutated (ATM), phosphorylates Nijmegen breakage syndrome (NBS1) and structural maintenance of chromosome-1 (SMC1) proteins during the DNA damage response. VP8 was found to interact with ATM and NBS1 during transfection and BoHV-1 infection. However, VP8 did not interfere with phosphorylation of ATM in transfected or BoHV-1-infected cells...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29769307/orally-bioavailable-and-blood-brain-barrier-penetrating-atm-inhibitor-az32-radiosensitizes-intracranial-gliomas-in-mice
#5
Jeremy Karlin, Jasmine Allen, Syed F Ahmad, Gareth Hughes, Victoria Sheridan, Rajesh Odedra, Paul Farrington, Elaine B Cadogan, Lucy C Riches, Antonio Garcia-Trinidad, Andrew G Thomason, Bhavika Patel, Jennifer Vincent, Alan Lau, Kurt G Pike, Thomas A Hunt, Amrita Sule, Nicholas C K Valerie, Laura Biddlestone-Thorpe, Jenna Kahn, Jason M Beckta, Nitai Mukhopadhyay, Bernard Barlaam, Sebastien L Degorce, Jason Kettle, Nicola Colclough, Joanne Wilson, Aaron Smith, Ian P Barrett, Li Zheng, Tianwei Zhang, Yingchun Wang, Kan Chen, Martin Pass, Stephen T Durant, Kristoffer Valerie
Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited CNS bioavailability, thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain...
May 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29769262/a-new-molecular-assay-and-genomic-complexity-predict-outcome-in-conventional-and-leukemic-non-nodal-mantle-cell-lymphoma
#6
Guillem Clot, Pedro Jares, Eva Giné, Alba Navarro, Cristina Royo, Magda Pinyol, David Martín-Garcia, Santiago Demajo, Blanca Espinet, Antonio Salar, Ana Ferrer, Ana Muntañola, Marta Aymerich, Hilka Rauert-Wunderlich, Elaine S Jaffe, Joseph M Connors, Randy D Gascoyne, Jan Delabie, Armando López-Guillermo, German Ott, George W Wright, Louis M Staudt, Andreas Rosenwald, David W Scott, Lisa M Rimsza, Sílvia Beà, Elías Campo
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic non-nodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. Herein, we describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples...
May 16, 2018: Blood
https://www.readbyqxmd.com/read/29760836/concomitant-atm-mutations-identified-by-next-generation-sequencing-in-a-patient-with-new-onset-acute-myeloid-leukemia-following-imatinib-treatment-for-chronic-myeloid-leukemia
#7
Matthew K Stein, Melissa Crawley, Eric Vick, Mike G Martin
No abstract text is available yet for this article.
April 2018: World Journal of Oncology
https://www.readbyqxmd.com/read/29759113/distinct-roles-of-atm-and-atr-in-the-regulation-of-arp8-phosphorylation-to-prevent-chromosome-translocations
#8
Jiying Sun, Lin Shi, Aiko Kinomura, Atsuhiko Fukuto, Yasunori Horikoshi, Yukako Oma, Masahiko Harata, Masae Ikura, Tsuyoshi Ikura, Roland Kanaar, Satoshi Tashiro
Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, facilitates DNA repair to prevent chromosome abnormalities. Previously, we showed that ATM deficiency led to the 11q23 chromosome translocation, the most frequent chromosome abnormalities in secondary leukemia. Here, we show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment...
May 8, 2018: ELife
https://www.readbyqxmd.com/read/29756124/functional-promoter-rs189037-variant-of-atm-is-associated-with-decrease-in-lung-diffusing-capacity-after-irradiation-for-non-small-cell-lung-cancer
#9
Jose Luis Lopez Guerra, Yi-Peng Song, Quynh-Nhu Nguyen, Daniel R Gomez, Zhongxing Liao, Ting Xu
Objective: Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasia-mutated gene ATM have been linked with pneumonitis after radiotherapy for lung cancer but have not been evaluated in terms of pulmonary function impairment. Here we investigated potential associations between SNPs in ATM and changes in diffusing capacity of the lung for carbon monoxide (DLCO) in patients with non-small-cell lung cancer (NSCLC) after radiotherapy. Methods: From November 1998 through June 2009, 448 consecutive patients with inoperable primary NSCLC underwent definitive (≥60 Gy) radiotherapy, with or without chemotherapy...
March 2018: Chronic Diseases and Translational Medicine
https://www.readbyqxmd.com/read/29755111/genomic-landscape-and-prognostic-analysis-of-mantle-cell-lymphoma
#10
Ping Yang, Weilong Zhang, Jing Wang, Yuanyuan Liu, Ran An, Hongmei Jing
To gain insight into the molecular pathogenesis of patients with mantle cell lymphoma (MCL), next-generation whole-exome sequencing of 16 MCL patients was performed. We identified recurrent mutations in genes that are well known to be functionally relevant in MCL, including ATM (37.5%), TP53 (31.3%), WHSC1 (31.3%), CCND1 (18.8%), NOTCH2 (6.3%), and CDKN2A (6.3%). We also identified somatic mutations in genes for which a functional role in MCL has not been previously suspected. These genes included CCDC15, APC, CDH1, S1PR1, ATRX, BRCA2, CASP8, and NOTCH3...
May 14, 2018: Cancer Gene Therapy
https://www.readbyqxmd.com/read/29754934/comprehensive-genomic-profiling-of-metastatic-tumors-in-a-phase-2-biomarker-study-of-everolimus-in-advanced-renal-cell-carcinoma
#11
Xin Gao, Opeyemi Jegede, Connor Gray, Paul J Catalano, Jesse Novak, David J Kwiatkowski, Rana R McKay, Daniel J George, Toni K Choueiri, David F McDermott, Sabina Signoretti, Rupal S Bhatt
INTRODUCTION: Genomic events leading to activation of mechanistic target of rapamycin (mTOR) are common in renal cell carcinoma (RCC). Everolimus is an allosteric mTOR inhibitor with efficacy in metastatic RCC. We characterized the genomic profile of RCC tumors from metastatic sites and assessed whether particular alterations correlate with clinical response to everolimus. PATIENTS AND METHODS: An open-label, single-arm phase 2 biomarker study of everolimus 10 mg daily was conducted in metastatic RCC patients...
April 25, 2018: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/29752822/germline-mutations-in-40-cancer-susceptibility-genes-among-chinese-patients-with-high-hereditary-risk-breast-cancer
#12
Junyan Li, Ruilin Jing, Hongyi Wei, Minghao Wang, Xiaowei Qi, Haoxi Liu, Jian Liu, Jianghua Ou, Weihua Jiang, Fuguo Tian, Yuan Sheng, Hengyu Li, Hong Xu, Ruishan Zhang, Aihua Guan, Ke Liu, Hongchuan Jiang, Yu Ren, Jianjun He, Weiwei Huang, Ning Liao, Xiangjun Cai, Jia Ming, Rui Ling, Yan Xu, Chunyan Hu, Jianguo Zhang, Baoliang Guo, Lizhi Ouyang, Ping Shuai, Zhenzhen Liu, Ling Zhong, Zhen Zeng, Ting Zhang, Zhaoling Xuan, Xuanni Tan, Junbin Liang, Qinwen Pan, Li Chen, Fan Zhang, Linjun Fan, Yi Zhang, Xinhua Yang, Jingbo Li, Chongjian Chen, Jun Jiang
Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n=937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations...
May 12, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29748005/genomic-alterations-of-plasma-cell-free-dnas-in-small-cell-lung-cancer-and-their-clinical-relevance
#13
Meijun Du, Jonathan Thompson, Hannah Fisher, Peng Zhang, Chiang-Ching Huang, Liang Wang
OBJECTIVES: To identify genomic variations in cell-free DNA (cfDNA) and evaluate their clinical utility in small cell lung cancer (SCLC). MATERIALS AND METHODS: We performed whole genome sequencing using plasma cfDNAs derived from 24 SCLC patients for copy number variation (CNV) analysis, and targeted sequencing using 17 pairs of plasma cfDNA and their matched gDNA for mutation analysis. We defined somatic mutations by comparing cfDNA to its matched gDNA with 5% variant alleles as the cutoff for mutation calls...
June 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29735551/novel-richter-s-syndrome-xenograft-models-to-study-genetic-architecture-biology-and-therapy-responses
#14
Tiziana Vaisitti, Esteban Braggio, John N Allan, Francesca Arruga, Sara Serra, Alberto Zamò, Wayne Tam, Amy Chadburn, Richard R Furman, Silvia Deaglio
Richter's syndrome (RS) represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemo-immunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft models of RS, RS9737 and RS1316. RS xenografts were genetically, morphologically and phenotypically stable and similar to the corresponding primary tumor...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29731985/association-between-homologous-recombination-repair-gene-mutations-and-response-to-oxaliplatin-in-pancreatic-cancer
#15
Tomohiro Kondo, Masashi Kanai, Tadayuki Kou, Tomohiro Sakuma, Hiroaki Mochizuki, Mayumi Kamada, Masahiko Nakatsui, Norimitsu Uza, Yuzo Kodama, Toshihiko Masui, Kyoichi Takaori, Shigemi Matsumoto, Hidehiko Miyake, Yasushi Okuno, Manabu Muto
Objectives: We aimed to examine the association between homologous recombination repair (HRR)-related gene mutations and efficacy of oxaliplatin-based chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). Results: Non-synonymous mutations in HRR-related genes were found in 13 patients and only one patient had a family history of pancreatic cancer. Eight patients with HRR-related gene mutations (group A) and nine without HRR-related gene mutations (group B) received oxaliplatin-based chemotherapy...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29725502/ciclopirox-activates-atr-chk1-signaling-pathway-leading-to-cdc25a-protein-degradation
#16
Tao Shen, Hongyu Zhou, Chaowei Shang, Yan Luo, Yang Wu, Shile Huang
Ciclopirox olamine (CPX), an off-patent anti-fungal drug, has been found to inhibit the G1 -cyclin dependent kinases partly by increasing the phosphorylation and degradation of Cdc25A. However, little is known about the molecular target(s) of CPX responsible for Cdc25A degradation. Here, we show that CPX induced the degradation of Cdc25A neither by increasing CK1α or decreasing DUB3 expression, nor via activating GSK3β, but through activating Chk1 in rhabdomyosarcoma (Rh30) and breast carcinoma (MDA-MB-231) cells...
January 2018: Genes & Cancer
https://www.readbyqxmd.com/read/29720177/genomic-characterization-of-chronic-lymphocytic-leukemia-cll-in-radiation-exposed-chornobyl-cleanup-workers
#17
Juhi Ojha, Iryna Dyagil, Stuart C Finch, Robert F Reiss, Adam J de Smith, Semira Gonseth, Mi Zhou, Helen M Hansen, Amy L Sherborne, Jean Nakamura, Paige M Bracci, Nataliya Gudzenko, Maureen Hatch, Nataliya Babkina, Mark P Little, Vadim V Chumak, Kyle M Walsh, Dimitry Bazyka, Joseph L Wiemels, Lydia B Zablotska
BACKGROUND: Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. METHODS: A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively)...
May 2, 2018: Environmental Health: a Global Access Science Source
https://www.readbyqxmd.com/read/29719442/ataxia-telangiectasia-gene-atm-mutation-heterozygosity-in-breast-cancer-a-narrative-review
#18
K J Jerzak, T Mancuso, A Eisen
Background: Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. Methods: In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy...
April 2018: Current Oncology
https://www.readbyqxmd.com/read/29710228/immune-profiling-of-premalignant-lesions-in-patients-with-lynch-syndrome
#19
Kyle Chang, Melissa W Taggart, Laura Reyes-Uribe, Ester Borras, Erick Riquelme, Reagan M Barnett, Guido Leoni, F Anthony San Lucas, Maria T Catanese, Federica Mori, Maria G Diodoro, Y Nancy You, Ernest T Hawk, Jason Roszik, Paul Scheet, Scott Kopetz, Alfredo Nicosia, Elisa Scarselli, Patrick M Lynch, Florencia McAllister, Eduardo Vilar
Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS...
April 16, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29702521/dna-damage-pathways-and-b-cell-lymphomagenesis
#20
Gero Knittel, Tim Rehkämper, Pascal Nieper, Anna Schmitt, Ruth Flümann, H Christian Reinhardt
PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity...
April 26, 2018: Current Opinion in Hematology
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