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https://www.readbyqxmd.com/read/29776633/molecular-diagnostics-in-colorectal-carcinoma-advances-and-applications-for-2018
#1
REVIEW
Amarpreet Bhalla, Muhammad Zulfiqar, Martin H Bluth
The molecular pathogenesis and classification of colorectal carcinoma are based on the traditional adenomaecarcinoma sequence, serrated polyp pathway, and microsatellite instability (MSI). The genetic basis for hereditary nonpolyposis colorectal cancer is the detection of mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Genetic testing for Lynch syndrome includes MSI testing, methylator phenotype testing, BRAF mutation testing, and molecular testing for germline mutations in MMR genes. Molecular makers with predictive and prognostic implications include quantitative multigene reverse transcriptase polymerase chain reaction assay and KRAS and BRAF mutation analysis...
June 2018: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/29764494/precision-medicine-becomes-reality-tumor-type-agnostic-therapy
#2
REVIEW
Li Yan, Wei Zhang
Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy...
March 31, 2018: Cancer communications
https://www.readbyqxmd.com/read/29763623/molecular-pathological-radiological-and-immune-profiling-of-non-brainstem-pediatric-high-grade-glioma-from-the-herby-phase-ii-randomized-trial
#3
Alan Mackay, Anna Burford, Valeria Molinari, David T W Jones, Elisa Izquierdo, Jurriaan Brouwer-Visser, Felice Giangaspero, Christine Haberler, Torsten Pietsch, Thomas S Jacques, Dominique Figarella-Branger, Daniel Rodriguez, Paul S Morgan, Pichai Raman, Angela J Waanders, Adam C Resnick, Maura Massimino, Maria Luisa Garrè, Helen Smith, David Capper, Stefan M Pfister, Thomas Würdinger, Rachel Tam, Josep Garcia, Meghna Das Thakur, Gilles Vassal, Jacques Grill, Tim Jaspan, Pascale Varlet, Chris Jones
The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV...
May 14, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29762710/base-flipping-dynamics-from-an-intrahelical-to-an-extrahelical-state-exerted-by-thymine-dna-glycosylase-during-dna-repair-process
#4
Lin-Tai Da, Jin Yu
Thymine DNA glycosylase (TDG) is a DNA repair enzyme that excises a variety of mismatched or damaged nucleotides (nts), e.g. dU, dT, 5fC and 5caC. TDG is shown to play essential roles in maintaining genome integrity and correctly programming epigenetic modifications through DNA demethylation. After locating the lesions, TDG employs a base-flipping strategy to recognize the damaged nucleobases, whereby the interrogated nt is extruded from the DNA helical stack and binds into the TDG active site. The dynamic mechanism of the base-flipping process at an atomistic resolution, however, remains elusive...
May 14, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29759559/clinical-importance-of-dna-repair-in-sporadic-colorectal-cancer
#5
REVIEW
Gustavo A Laporte, Natalia M Leguisamo, Antonio N Kalil, Jenifer Saffi
Colorectal cancer (CRC) is the third major cause of cancer-related deaths worldwide. However, despite the scientific efforts to provide a molecular classification to improve CRC clinical practice management, prognosis and therapeutic decision are still strongly dependent on the TNM staging system. Mismatch repair system deficiencies can occur in many organs, but it is mainly a hallmark of CRC influencing clinical outcomes and response to therapy. This review will discuss the effect of the modulation of other DNA repair pathways (direct, excision and double strand break repairs) in the clinical and pathological aspects of colorectal cancer and its potential as prognostic and predictive biomarkers...
June 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29758216/molecular-background-of-colorectal-tumors-from-patients-with-lynch-syndrome-associated-with-germline-variants-in-pms2
#6
S W Ten Broeke, T C van Bavel, A M L Jansen, E Gómez-García, F J Hes, L P van Hest, T G W Letteboer, M J W Olderode-Berends, D Ruano, L Spruijt, M Suerink, C M Tops, R van Eijk, H Morreau, T van Wezel, M Nielsen
BACKGROUND & AIMS: Germline variants in the mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in patients of older ages than colorectal tumors with variants in the other mismatch repair genes...
May 11, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29755653/tumornext-lynch-mmr-a-comprehensive-next-generation-sequencing-assay-for-the-detection-of-germline-and-somatic-mutations-in-genes-associated-with-mismatch-repair-deficiency-and-lynch-syndrome
#7
Phillip N Gray, Pei Tsai, Daniel Chen, Sitao Wu, Jayne Hoo, Wenbo Mu, Bing Li, Huy Vuong, Hsiao-Mei Lu, Navanjot Batth, Sara Willett, Lisa Uyeda, Swati Shah, Chia-Ling Gau, Monalyn Umali, Carin Espenschied, Mike Janicek, Sandra Brown, David Margileth, Lavinia Dobrea, Lawrence Wagman, Huma Rana, Michael J Hall, Theodora Ross, Jonathan Terdiman, Carey Cullinane, Savita Ries, Ellen Totten, Aaron M Elliott
The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29754585/significance-and-implications-of-fda-approval-of-pembrolizumab-for-biomarker-defined-disease
#8
Michael M Boyiadzis, John M Kirkwood, John L Marshall, Colin C Pritchard, Nilofer S Azad, James L Gulley
The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient's tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval...
May 14, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29753908/individual-differences-in-children-s-pronoun-processing-during-reading-detection-of-incongruence-is-associated-with-higher-reading-fluency-and-more-regressions
#9
Sarah Eilers, Simon P Tiffin-Richards, Sascha Schroeder
In two eye tracking experiments, we tested fourth graders' and adults' sensitivity to gender feature mismatches during reading of pronouns and their susceptibility to interference of feature-matching entities in the sentence. In Experiment 1, we showed children and adults two-phrase sentences such as "Leon{m}/Lisa{f} shooed away the sparrow{m}/the seagull{f} and then he{m} ate the tasty sandwich." Eye tracking measures showed no qualitative differences between children's and adults' processing of the pronouns...
May 10, 2018: Journal of Experimental Child Psychology
https://www.readbyqxmd.com/read/29752549/promising-new-agents-for-colorectal-cancer
#10
REVIEW
Satya Das, Kristen K Ciombor, Sigurdis Haraldsdottir, Richard M Goldberg
Choosing the optimal treatment approach for patients with metastatic colorectal cancer (mCRC) demands that oncologists assess both clinical and genomic variables and individualize care based upon the findings. Clinically, choices depend on assessing the side of the colon in which the primary tumor originates, the sites and burden of metastatic disease, the patient's performance status, and their individual comorbidities. Genomic assessment of the tumor to discern the mutational status of genes such as RAS/RAF, HER2, and TRK, as well as assessing whether tumors have defective mismatch repair (dMMR) or high microsatellite instability (MSI-H), all factor in to potential treatment options and can determine clinical trial eligibility...
May 11, 2018: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/29752295/-arid1a-deficiency-may-predict-response-to-immune-checkpoint-blockade
#11
(no author information available yet)
ARID1A deficiency impairs mismatch repair to increase tumor mutation load and promote tumor progression.
May 11, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29748584/the-effects-of-mutational-processes-and-selection-on-driver-mutations-across-cancer-types
#12
Daniel Temko, Ian P M Tomlinson, Simone Severini, Benjamin Schuster-Böckler, Trevor A Graham
Epidemiological evidence has long associated environmental mutagens with increased cancer risk. However, links between specific mutation-causing processes and the acquisition of individual driver mutations have remained obscure. Here we have used public cancer sequencing data from 11,336 cancers of various types to infer the independent effects of mutation and selection on the set of driver mutations in a cancer type. First, we detect associations between a range of mutational processes, including those linked to smoking, ageing, APOBEC and DNA mismatch repair (MMR) and the presence of key driver mutations across cancer types...
May 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29744602/current-clinical-topics-of-lynch-syndrome
#13
REVIEW
Kohji Tanakaya
Lynch syndrome (LS) is one of the most common genetic cancer syndromes, occurring at a rate of 1 per 250-1000 in the general population. This autosomal dominant disease is caused by a germline variant in one of the four mismatch repair genes, MSH2, MLH1, MSH6, PMS2, or the EPCAM gene. LS develops at early ages in colorectal cancer (CRC), endometrial cancer, and various other associated tumors. Accurate diagnosis of LS and utilization of various risk-reduction strategies such as surveillance, prophylactic surgery, and chemoprevention could improve clinical outcomes...
May 9, 2018: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29744038/generating-and-repairing-genetically-programmed-dna-breaks-during-immunoglobulin-class-switch-recombination
#14
REVIEW
Laura Nicolas, Montserrat Cols, Jee Eun Choi, Jayanta Chaudhuri, Bao Vuong
Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR...
2018: F1000Research
https://www.readbyqxmd.com/read/29743854/microsatellite-instability-in-colorectal-cancer
#15
REVIEW
Jafar Nouri Nojadeh, Shahin Behrouz Sharif, Ebrahim Sakhinia
Colorectal cancer (CRC) is a heterogeneous disease that is caused by the interaction of genetic and environmental factors. Although it is one of the most common cancers worldwide, CRC would be one of the most curable cancers if it is detected in the early stages. Molecular changes that occur in colorectal cancer may be categorized into three main groups: 1) Chromosomal Instability (CIN), 2) Microsatellite Instability (MSI), and 3) CpG Island Methylator phenotype (CIMP). Microsatellites, also known as Short Tandem Repeats (STRs) are small (1-6 base pairs) repeating stretches of DNA scattered throughout the entire genome and account for approximately 3 % of the human genome...
2018: EXCLI Journal
https://www.readbyqxmd.com/read/29743009/muver-a-computational-framework-for-accurately-calling-accumulated-mutations
#16
Adam B Burkholder, Scott A Lujan, Christopher A Lavender, Sara A Grimm, Thomas A Kunkel, David C Fargo
BACKGROUND: Identification of mutations from next-generation sequencing data typically requires a balance between sensitivity and accuracy. This is particularly true of DNA insertions and deletions (indels), that can impart significant phenotypic consequences on cells but are harder to call than substitution mutations from whole genome mutation accumulation experiments. To overcome these difficulties, we present muver, a computational framework that integrates established bioinformatics tools with novel analytical methods to generate mutation calls with the extremely low false positive rates and high sensitivity required for accurate mutation rate determination and comparison...
May 9, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29741655/cooperative-recognition-of-t-t-mismatch-by-echinomycin-causes-structural-distortions-in-dna-duplex
#17
Pei-Ching Wu, Shu-Ling Tzeng, Chung-Ke Chang, Ya-Fen Kao, Michael J Waring, Ming-Hon Hou
Small-molecule compounds that target mismatched base pairs in DNA offer a novel prospective for cancer diagnosis and therapy. The potent anticancer antibiotic echinomycin functions by intercalating into DNA at CpG sites. Surprisingly, we found that the drug strongly prefers to bind to consecutive CpG steps separated by a single T:T mismatch. The preference appears to result from enhanced cooperativity associated with the binding of the second echinomycin molecule. Crystallographic studies reveal that this preference originates from the staggered quinoxaline rings of the two neighboring antibiotic molecules that surround the T:T mismatch forming continuous stacking interactions within the duplex...
May 8, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29741625/dna-repair-in-the-archaea-an-emerging-picture
#18
Malcolm F White, Thorsten Allers
There has long been a fascination in the DNA Repair pathways of archaea, for two main reasons. Firstly, many archaea inhabit extreme environments where the rate of physical damage to DNA is accelerated. These archaea might reasonably be expected to have particularly robust or novel DNA repair pathways to cope with this. Secondly, the archaea have long been understood to be a lineage distinct from the bacteria, and to share a close relationship with the eukarya, particularly in their information processing systems...
May 5, 2018: FEMS Microbiology Reviews
https://www.readbyqxmd.com/read/29736026/arid1a-deficiency-promotes-mutability-and-potentiates-therapeutic-antitumor-immunity-unleashed-by-immune-checkpoint-blockade
#19
Jianfeng Shen, Zhenlin Ju, Wei Zhao, Lulu Wang, Yang Peng, Zhongqi Ge, Zachary D Nagel, Jun Zou, Chen Wang, Prabodh Kapoor, Xiangyi Ma, Ding Ma, Jiyong Liang, Shumei Song, Jinsong Liu, Leona D Samson, Jaffer A Ajani, Guo-Min Li, Han Liang, Xuetong Shen, Gordon B Mills, Guang Peng
ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2 . The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression 3 , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2...
May 7, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29734894/-in-situ-vascular-nerve-graft-for-restoration-of-intrinsic-hand-function-an-anatomical-study
#20
Kamran Mozaffarian, Hamid Reza Zemoodeh, Mohammad Zarenezhad, Mohammad Owji
BACKGROUND: In combined high median and ulnar nerve injury, transfer of the posterior interosseous nerve branches to the motor branch of the ulnar nerve (MUN) is previously described in order to restore intrinsic hand function. In this operation a segment of sural nerve graft is required to close the gap between the donor and recipient nerves. However the thenar muscles are not innervated by this nerve transfer. The aim of the present study was to evaluate whether the superficial radial nerve (SRN) can be used as an "in situ vascular nerve graft" to connect the donor nerves to the MUN and the motor branch of median nerve (MMN) at the same time in order to address all denervated intrinsic and thenar muscles...
June 2018: Journal of Hand Surgery Asian-Pacific Volume
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