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https://www.readbyqxmd.com/read/29355075/durable-clinical-benefit-with-nivolumab-plus-ipilimumab-in-dna-mismatch-repair-deficient-microsatellite-instability-high-metastatic-colorectal-cancer
#1
Michael J Overman, Sara Lonardi, Ka Yeung Mark Wong, Heinz-Josef Lenz, Fabio Gelsomino, Massimo Aglietta, Michael A Morse, Eric Van Cutsem, Ray McDermott, Andrew Hill, Michael B Sawyer, Alain Hendlisz, Bart Neyns, Magali Svrcek, Rebecca A Moss, Jean-Marie Ledeine, Z Alexander Cao, Shital Kamble, Scott Kopetz, Thierry André
Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported...
January 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29352574/mismatch-repair-status-as-a-beneficial-predictor-of-fluorouracil-based-adjuvant-chemotherapy-for-pancreatic-cancer
#2
Dingkong Liang, Si Shi, Chen Liang, Qingcai Meng, Bo Zhang, Quanxing Ni, Jin Xu, Xianjun Yu
BACKGROUND: Prior studies have indicated that patients with colorectal cancer with deficient mismatch repair have particular clinicopathologic features that distinguish them from patients with tumors with proficient mismatch repair. However, the effect of the mismatch repair status on outcomes after adjuvant chemotherapy for pancreatic cancer is still unknown. METHODS: Pancreatic cancer patients who underwent R0 resection between January 2013 and December 2015 at Fudan University Shanghai Cancer Center were included in this study...
January 15, 2018: Surgery
https://www.readbyqxmd.com/read/29352080/functional-analysis-of-cancer-associated-dna-polymerase-%C3%AE%C2%B5-variants-in-saccharomyces-cerevisiae
#3
Stephanie R Barbari, Daniel P Kane, Elizabeth A Moore, Polina V Shcherbakova
DNA replication fidelity relies on base selectivity of the replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). Ultramutated human cancers without MMR defects carry alterations in the exonuclease domain of DNA polymerase ε (Polε). They have been hypothesized to result from defective proofreading. However, modeling in yeast of the most common variant, Polε-P286R, produced an unexpectedly strong mutator effect that exceeded the effect of proofreading deficiency by two orders of magnitude and indicated the involvement of other infidelity factors...
January 19, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29351939/retroperitoneal-bile-leak-after-laparoscopic-cholecystectomy
#4
Dee Zhen Lim, Enoch Wong, Sayed Hassen, Yahya Al-Habbal
Bile duct injury (BDI) is a well-recognised complication of laparoscopic cholecystectomy (LC). Following a BDI, bile usually leaks into the peritoneal space and causes biliary peritonitis. This manifests as non-specific abdominal pain and fever occurring several days after the surgery. It can be managed by laparoscopic washout with or without bile duct repair. We present a rare case of retroperitoneal bile leak post-LC. The mechanism of injury here was likely partial avulsion from excessive traction of the cystic duct during intraoperative cholangiogram...
January 18, 2018: BMJ Case Reports
https://www.readbyqxmd.com/read/29351848/a-distinct-class-of-genome-rearrangements-driven-by-heterologous-recombination
#5
Ana María León-Ortiz, Stephanie Panier, Grzegorz Sarek, Jean-Baptiste Vannier, Harshil Patel, Peter J Campbell, Simon J Boulton
Erroneous DNA repair by heterologous recombination (Ht-REC) is a potential threat to genome stability, but evidence supporting its prevalence is lacking. Here we demonstrate that recombination is possible between heterologous sequences and that it is a source of chromosomal alterations in mitotic and meiotic cells. Mechanistically, we find that the RTEL1 and HIM-6/BLM helicases and the BRCA1 homolog BRC-1 counteract Ht-REC in Caenorhabditis elegans, whereas mismatch repair does not. Instead, MSH-2/6 drives Ht-REC events in rtel-1 and brc-1 mutants and excessive crossovers in rtel-1 mutant meioses...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29350327/hypermutated-tumors-and-immune-checkpoint-inhibition
#6
Kristen K Ciombor, Richard M Goldberg
Microsatellite instability-high/DNA mismatch repair deficient tumors are found across the cancer spectrum and often harbor markedly increased numbers of mutations when compared to microsatellite stable/DNA mismatch repair proficient tumors. As a result of this high mutational load, tumor-infiltrating lymphocyte density is increased and more immunogenic neoepitopes are expressed, leading to upregulation of immune checkpoints in these tumors. Checkpoint inhibitors such as pembrolizumab and nivolumab, both immunoglobulin G4 (IgG4) monoclonal antibodies that block interactions between the programmed cell death receptor-1 and its ligands, have significant activity in this tumor class...
January 19, 2018: Drugs
https://www.readbyqxmd.com/read/29348907/microsatellite-stability-and-mismatch-repair-proficiency-in-nasopharyngeal-carcinoma-may-not-predict-programmed-death-1-blockade-resistance
#7
Xiyi Liao, Liang Zhao, Sangang Wu, Hua Zheng, Haojun Chen, Huan Zhang, ZiJing Wang, Qin Lin
The US FDA granted accelerated approval to pembrolizumab for microsatellite instability-high and mismatch repair deficient cancers. The response of programmed death-1 blockade in mismatch repair proficiency (pMMR) colorectal cancer is very poor, however, whether such treatment is effective in pMMR nasopharyngeal carcinoma (NPC) remains unknown. We report a case of a 51-year-old man with NPC. PET-CT scan revealed a space-occupying lesion in the left lung, and the pathologic result confirmed the occupying lesion originated from NPC...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348823/prevalence-of-pathogenic-germline-variants-detected-by-multigene-sequencing-in-unselected-japanese-patients-with-ovarian-cancer
#8
Akira Hirasawa, Issei Imoto, Takuya Naruto, Tomoko Akahane, Wataru Yamagami, Hiroyuki Nomura, Kiyoshi Masuda, Nobuyuki Susumu, Hitoshi Tsuda, Daisuke Aoki
Pathogenic germline BRCA1, BRCA2 (BRCA1/2), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1), 8 (3...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348162/mutation-burden-predicts-anti-pd-1-response
#9
(no author information available yet)
A new study finds that objective response rates to anti-PD-1 therapies correlate with tumor mutation burden for most of the 27 cancer types studied. Objective response rates were higher than expected for Merkel cell carcinoma and renal cell carcinoma, which may be particularly immunogenic. The objective response rate was unexpectedly low for colorectal cancer with mismatch repair proficiency.
January 18, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29346513/pancancer-analysis-identifies-prognostic-high-apobec1-expression-level-implicated-in-cancer-in-frame-insertions-and-deletions
#10
Ahmadreza Niavarani, Asieh Shahrabi Farahani, Maryam Sharafkhah, Minoo Rassoulzadegan
Genome insertions and deletions (indels) show tremendous functional impacts despite they are much less common than single nucleotide variants, which are at the center of studies assessing cancer mutational signatures. We studied 8,891 tumor samples of 32 types from The Cancer Genome Atlas in order to explore those genes which are potentially implicated in cancer indels. Survival analysis identified in-frame indels as the most important variants predicting adverse outcome. Transcriptome-wide association study identified 16 genes overexpressed in both tumor samples and tumor types with high number of in-frame indels, of whom four (APOBEC1, BCL2L15, FOXL1, and PDX1) were identified with gene products distributed within the nucleus...
January 13, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29345160/inherited-forms-of-bladder-cancer-a-review-of-lynch-syndrome-and-other-inherited-conditions
#11
Aaron Phelan, Antonio Lopez-Beltran, Rodolfo Montironi, Shaobo Zhang, Maria R Raspollini, Monica Cheng, Hristos Z Kaimakliotis, Michael O Koch, Liang Cheng
Environmental factors that play a role in the urothelial carcinogenesis have been well characterized. Current research is continuously exploring potential heritable forms of bladder cancer. Lynch syndrome is a well-known inheritable disease that increases the risk for a variety of cancers, including urothelial carcinomas. Screening of patients with known Lynch syndrome is important to evaluate for development of new primary tumors. Further study may provide more information on what level of follow-up each patient needs...
January 18, 2018: Future Oncology
https://www.readbyqxmd.com/read/29342268/reduced-expression-of-mismatch-repair-genes-msh6-msh2-directly-promotes-pituitary-tumor-growth-via-the-atr-chk1-pathway
#12
Shinsuke Uraki, Hiroyuki Ariyasu, Asako Doi, Shintaro Kawai, Ken Takeshima, Shuhei Morita, Junya Fukai, Koji Fujita, Hiroto Furuta, Masahiro Nishi, Kokichi Sugano, Naoko Inoshita, Naoyuki Nakao, Shozo Yamada, Takashi Akamizu
Context: The mechanisms of pituitary adenoma (PA) pathogenesis and proliferation remain largely unknown. Objectives: To evaluate the direct association between PA proliferation and expression of mismatch repair (MMR) genes and proteins, and to clarify the role of MMR genes in the molecular mechanism of PA proliferation. Experimental Design: We performed quantitative analyses by real-time PCR and immunohistochemistry to detect MMR gene and protein expression in human PAs (n = 47)...
January 12, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29341452/contribution-of-mlh1-constitutional-methylation-for-lynch-syndrome-diagnosis-in-patients-with-tumor-mlh1-downregulation
#13
Diana Pinto, Carla Pinto, Joana Guerra, Manuela Pinheiro, Rui Santos, Hege Marie Vedeld, Zeremariam Yohannes, Ana Peixoto, Catarina Santos, Pedro Pinto, Paula Lopes, Ragnhild Lothe, Guro Elisabeth Lind, Rui Henrique, Manuel R Teixeira
Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p...
January 17, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29340115/hypermutation-and-microsatellite-instability-in-gastrointestinal-cancers
#14
REVIEW
Kizuki Yuza, Masayuki Nagahashi, Satoshi Watanabe, Kazuaki Takabe, Toshifumi Wakai
Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339372/correction-mismatch-repair-proteins-initiate-epigenetic-alterations-during-inflammation-driven-tumorigenesis
#15
(no author information available yet)
No abstract text is available yet for this article.
January 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29338072/targeting-her2-in-colorectal-cancer-the-landscape-of-amplification-and-short-variant-mutations-in-erbb2-and-erbb3
#16
Jeffrey S Ross, Marwan Fakih, Siraj M Ali, Julia A Elvin, Alexa B Schrock, James Suh, Jo-Anne Vergilio, Shakti Ramkissoon, Eric Severson, Sugganth Daniel, David Fabrizio, Garrett Frampton, James Sun, Vincent A Miller, Philip J Stephens, Laurie M Gay
BACKGROUND: In contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2-targeted therapies. METHODS: In this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer-related genes, tumor mutational burden, and microsatellite instability...
January 16, 2018: Cancer
https://www.readbyqxmd.com/read/29337394/3d-printing-of-materials-with-tunable-failure-via-bioinspired-mechanical-gradients
#17
Dimitri Kokkinis, Florian Bouville, André R Studart
Mechanical gradients are useful to reduce strain mismatches in heterogeneous materials and thus prevent premature failure of devices in a wide range of applications. While complex graded designs are a hallmark of biological materials, gradients in manmade materials are often limited to 1D profiles due to the lack of adequate fabrication tools. Here, a multimaterial 3D-printing platform is developed to fabricate elastomer gradients spanning three orders of magnitude in elastic modulus and used to investigate the role of various bioinspired gradient designs on the local and global mechanical behavior of synthetic materials...
January 16, 2018: Advanced Materials
https://www.readbyqxmd.com/read/29336605/colorectal-carcinomas-with-isolated-loss-of-pms2-staining-by-immunohistochemistry
#18
Lindsay Alpert, Reetesh K Pai, Amitabh Srivastava, Wendy McKinnon, Rebecca Wilcox, Rhonda K Yantiss, Ramir Arcega, Hanlin L Wang, Marie E Robert, Xiuli Liu, Rish K Pai, Lei Zhao, Maria Westerhoff, Heather Hampel, Sonia Kupfer, Namrata Setia, Shu-Yuan Xiao, John Hart, Wendy L Frankel
CONTEXT: - Isolated loss of PMS2 staining is an uncommon immunophenotype in colorectal carcinomas, accounting for approximately 4% of tumors with microsatellite instability. Limited information regarding these tumors is available in the literature. OBJECTIVE: - To compare the clinicopathologic features of colorectal carcinomas with isolated PMS2 loss by immunohistochemistry to those with other forms of mismatch repair deficiency. DESIGN: - Ninety-three colorectal carcinomas with isolated PMS2 loss by immunohistochemistry and 193 with other forms of mismatch repair deficiency were identified...
January 16, 2018: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/29333623/evaluation-of-universal-immunohistochemical-screening-of-sebaceous-neoplasms-in-a-service-setting
#19
K Schon, E Rytina, J Drummond, J Simmonds, S Abbs, R Sandford, M Tischkowitz
BACKGROUND: Muir-Torre syndrome (MTS) is a subtype of Lynch syndrome, which encompasses the combination of sebaceous skin tumours or keratoacanthomas and internal malignancy, due to mutations in DNA mismatch repair genes. Sebaceous neoplasms (SNs) may occur before other malignancies, and may lead to the diagnosis, which allows testing of other family members, cancer surveillance, risk-reducing surgery or prevention therapies. AIM: To evaluate the efficacy of universal immunohistochemistry (IHC) screening of SNs in a service setting...
January 14, 2018: Clinical and Experimental Dermatology
https://www.readbyqxmd.com/read/29331023/temozolomide-analog-pmx-465-downregulates-mgmt-expression-in-hct116-colorectal-carcinoma-cells
#20
Zhikuan Yang, Danping Wei, Feifei Liu, Jing Liu, Xiaoming Wu, Malcolm F G Stevens, Tracey D Bradshaw, Ying Luo, Jihong Zhang
The efficacy of temozolomide (TMZ) treatment for cancers is currently limited by inherent or the development of resistance, particularly, but not exclusively, due to the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) in a significant proportion of tumors. We have found that TMZ analog C8-methyl imidazole tetrazine (PMX 465) displayed good anticancer activity against the colorectal carcinoma HCT116 cells which are MGMT-overexpressing and mismatch repair (MMR)-deficient. In this study, we found that PMX 465 could downregulate the expression of MGMT in HCT116 cells at the protein and mRNA levels...
January 13, 2018: Journal of Cellular Biochemistry
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