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Mismatch repair

Kaname Miyashita, Kei Fujii, Kenichi Taguchi, Mototsugu Shimokawa, Mitsuaki A Yoshida, Yasunobu Abe, Jun Okamura, Shinya Oda, Naokuni Uike
PURPOSE: Microsatellite instability (MSI) has been a long-standing biomarker candidate for drug resistance in tumour cells. Despite numerous clinical studies, the data in the literature are not conclusive. The complexity of the MSI phenomenon in some malignancies may, at least partly, account for the discrepancy. In addition, methodological problems are also pointed out in the assay techniques. We previously established a unique fluorescent technique in which the major methodological problems in conventional assays are overcome...
October 25, 2016: Journal of Cancer Research and Clinical Oncology
Katharina Wimmer, Thorsten Rosenbaum, Ludwine Messiaen
Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have a high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but any of the diagnostic features of NF1 may be present in a CMMRD patient...
October 25, 2016: Clinical Genetics
Fernando Grigera, Robert Wuerffel, Amy L Kenter
Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme, methyl CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when the Mbd4 exons 6-8 are deleted in a switching B cell line DSB formation is severely reduced and CSR frequency is impaired...
October 24, 2016: Molecular and Cellular Biology
Romain Capoulade, Xin Zeng, Jessica R Overbey, Gorav Ailawadi, John H Alexander, Deborah Ascheim, Michael Bowdish, Annetine C Gelijns, Paul Grayburn, Irving L Kron, Robert A Levine, Michael J Mack, Serguei Melnitchouk, Robert E Michler, John C Mullen, Patrick O'Gara, Michael K Parides, Peter Smith, Pierre Voisine, Judy Hung
BACKGROUND: In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty...
October 25, 2016: Circulation
Setsu Nakae, Atsushi Hijikata, Toshiyuki Tsuji, Kouki Yonezawa, Ken-Ichi Kouyama, Kouta Mayanagi, Sonoko Ishino, Yoshizumi Ishino, Tsuyoshi Shirai
Archaeal NucS nuclease was thought to degrade the single-stranded region of branched DNA, which contains flapped and splayed DNA. However, recent findings indicated that EndoMS, the orthologous enzyme of NucS, specifically cleaves double-stranded DNA (dsDNA) containing mismatched bases. In this study, we determined the structure of the EndoMS-DNA complex. The complex structure of the EndoMS dimer with dsDNA unexpectedly revealed that the mismatched bases were flipped out into binding sites, and the overall architecture most resembled that of restriction enzymes...
October 17, 2016: Structure
C Velter, F Bourlond, C Wettle, B Lioure, D Lipsker, C Maugard, B Cribier
BACKGROUND: Muir-Torre syndrome (MTS), a cutaneous variant of Lynch syndrome, consists of hereditary predisposition to cutaneous tumours and gastrointestinal and gynaecological neoplasms, with autosomal dominant transmission. It is associated with mutations in genes coding for proteins in the DNA mismatch repair system. PATIENTS AND METHODS: Herein, we report a case of a male patient presenting Waldenstrom's macroglobulinemia since the age of 50 and which, after the age of 65 years, developed into sebaceous tumours (5 sebaceous adenomas, 1 sebaceoma, 1 sebaceous carcinoma) and colonic lesions (4 adenomas)...
October 19, 2016: Annales de Dermatologie et de Vénéréologie
Beibei Wang, Joshua Francis, Monika Sharma, Sean M Law, Alexander V Predeus, Michael Feig
Allostery is conformation regulation by propagating a signal from one site to another distal site. This study focuses on the long-range communication in DNA mismatch repair proteins MutS and its homologs where intramolecular signaling has to travel over 70 Å to couple lesion detection to ATPase activity and eventual downstream repair. Using dynamic network analysis based on extensive molecular dynamics simulations, multiple preserved communication pathways were identified that would allow such long-range signaling...
October 2016: PLoS Computational Biology
Ashton A Connor, Robert E Denroche, Gun Ho Jang, Lee Timms, Sangeetha N Kalimuthu, Iris Selander, Treasa McPherson, Gavin W Wilson, Michelle A Chan-Seng-Yue, Ivan Borozan, Vincent Ferretti, Robert C Grant, Ilinca M Lungu, Eithne Costello, William Greenhalf, Daniel Palmer, Paula Ghaneh, John P Neoptolemos, Markus Buchler, Gloria Petersen, Sarah Thayer, Michael A Hollingsworth, Alana Sherker, Daniel Durocher, Neesha Dhani, David Hedley, Stefano Serra, Aaron Pollett, Michael H A Roehrl, Prashant Bavi, John M S Bartlett, Sean Cleary, Julie M Wilson, Ludmil B Alexandrov, Malcolm Moore, Bradly G Wouters, John D McPherson, Faiyaz Notta, Lincoln D Stein, Steven Gallinger
Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium...
October 20, 2016: JAMA Oncology
James W Behan, Adam Sutton, Ashley Wysong
Skin cancer is the most common of human cancers and outnumbers all other types of cancer combined in the USA by over threefold. The majority of non-melanoma skin cancers are easily treated with surgery or locally destructive techniques performed under local anesthesia in the cost-effective outpatient setting. However, there is a subset of "high-risk" cases that prove challenging in terms of morbidity, mortality, adjuvant treatment required, as well as overall cost to the health care system. In our opinion, the term "high risk" when applied to skin cancer can mean one of three things: a high-risk tumor with aggressive histologic and/or clinical features with an elevated risk for local recurrence or regional/distant metastasis, a high-risk patient with the ongoing development of multiple skin cancers, and a high-risk patient based on immunosuppression...
December 2016: Current Treatment Options in Oncology
Noriyasu Chika, Minoru Fukuchi, Okihide Suzuki, Tetsuya Ito, Azusa Yamamoto, Toru Ishiguro, Youichi Kumagai, Keiichiro Ishibashi, Erito Mochiki, Hideyuki Ishida
The loss of mismatch repair(MMR)function as a result of MLH1 promoter methylation is closely correlated with high frequency microsatellite instability, and tumors with such characteristics are resistant to anticancer drugs such as 5-FU. We examined the incidence and characteristics of deficient MMR(dMMR)in elderly gastric cancer patients by performing a comprehensive immunohistochemical screening. The study was conducted in 199 patients diagnosed with gastric cancer, aged 75 years or older, who underwent a gastrectomy between April 2005 and January 2014...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Friederike Finsterbusch, Ramya Ravindranathan, Ihsan Dereli, Marcello Stanzione, Daniel Tränkner, Attila Tóth
Orderly chromosome segregation during the first meiotic division requires meiotic recombination to form crossovers between homologous chromosomes (homologues). Members of the minichromosome maintenance (MCM) helicase family have been implicated in meiotic recombination. In addition, they have roles in initiation of DNA replication, DNA mismatch repair and mitotic DNA double-strand break repair. Here, we addressed the function of MCMDC2, an atypical yet conserved MCM protein, whose function in vertebrates has not been reported...
October 2016: PLoS Genetics
Narges Shayesteh Moghaddam, Ahmadreza Jahadakbar, Amirhesam Amerinatanzi, Mohammad Elahinia, Michael Miller, David Dean
: The aim of this study is to investigate the behavior of the healthy mandible under maximum molar bite force to demonstrate the problems associated with the current standard of care procedures for mandibular segmental defect reconstruction (ie, use of Ti-6Al-4V hardware and either a single- or double-barrel fibular graft). With current Ti-6Al-4V mandibular reconstruction hardware, there is a significant stiffness mismatch among the hardware, graft, and the remaining host anatomy. How the distribution of mechanical forces through the mandible is altered after a segmental bone loss and reconstruction is incompletely understood...
September 2016: Plastic and Reconstructive Surgery. Global Open
Michael T Schweizer, Heather H Cheng, Maria S Tretiakova, Funda Vakar-Lopez, Nola Klemfuss, Eric Q Konnick, Elahe A Mostaghel, Peter S Nelson, Evan Y Yu, R Bruce Montgomery, Lawrence D True, Colin C Pritchard
Precision oncology entails making treatment decisions based on a tumor's molecular characteristics. For prostate cancer, identifying clinically relevant molecular subgroups is challenging, as molecular profiling is not routine outside of academic centers. Since histologic variants of other cancers correlates with specific genomic alterations, we sought to determine if ductal adenocarcinoma of the prostate (dPC) - a rare and aggressive histopathologic variant - was associated with any recurrent actionable mutations...
October 15, 2016: Oncotarget
Takashi Takeda, Kouji Banno, Megumi Yanokura, Masataka Adachi, Moito Iijima, Haruko Kunitomi, Kanako Nakamura, Miho Iida, Yuya Nogami, Kiyoko Umene, Kenta Masuda, Yusuke Kobayashi, Wataru Yamagami, Akira Hirasawa, Eiichiro Tominaga, Nobuyuki Susumu, Daisuke Aoki
Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP)...
October 14, 2016: Genes
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Siavash Rahimi, Iolia Akaev, Costa Repanos, Peter A Brennan, Jean Daniel Dubois
Primary lingual intestinal-type adenocarcinomas are extremely rare with only a few cases described. A case with immunohistochemical expression of Androgen Receptor (AR) which was treated solely by chemo-radiotherapy is reported herein. A 54-year-old male was referred with symptoms of fullness in his tongue. Clinical examination showed an asymmetry of the tongue with a hard mass palpable within the middle of the tongue. Biopsy showed intestinal-type adenocarcinoma. The tumour showed positive staining with cytokeratin 7, cytokeratin 20, CDX2, AR, β-catenin and was mismatch repair proteins (MMR) proficient...
October 17, 2016: Head and Neck Pathology
Sahishnu Patel, Anthony P Gualtieri, Helen H Lu, William N Levine
Rotator cuff tear is a very common shoulder injury that often necessitates surgical intervention for repair. Despite advances in surgical techniques for rotator cuff repair, there is a high incidence of failure after surgery because of poor healing capacity attributed to many factors. The complexity of tendon-to-bone integration inherently presents a challenge for repair because of a large biomechanical mismatch between the tendon and bone and insufficient regeneration of native tissue, leading to the formation of fibrovascular scar tissue...
October 17, 2016: Annals of the New York Academy of Sciences
Zhaohui Jin, Harry H Yoon
Preliminary clinical studies of anti-programmed cell death-1 (anti-PD-1) therapy in gastro-esophageal cancers have suggested promising single-agent activity. In patients who received prior treatment for advanced disease, pembrolizumab has been associated with a response rate of 20% in programmed cell death-1 ligand 1 (PD-L1)-positive tumors, and nivolumab with a response rate of 12% in unselected tumors. Both agents yielded a median duration of response lasting ~6-7 months. PD-L1 expression and microsatellite instability (MSI) have emerged as potential predictive markers for PD-1/PD-L1 blockade...
October 2016: Journal of Gastrointestinal Oncology
Manojkumar Bupathi, Christina Wu
Colorectal cancer (CRC) is a heterogeneous disease for which the treatment backbone has primarily been cytotoxic chemotherapy. With better understanding of the involved molecular mechanisms, it is now known that there are a number of epigenetic and genetic events, which are involved in CRC pathogenesis. Specific biomarkers have been identified which can be used to determine the clinical outcome of patients beyond tumor staging and predict for treatment efficacy. Molecular testing is now routinely performed to select for patients that will benefit the most from targeted agents and immunotherapy...
October 2016: Journal of Gastrointestinal Oncology
Kelsey M Boyle, Jacqueline K Barton
DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells...
October 1, 2016: Inorganica Chimica Acta
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