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Mismatch repair

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https://www.readbyqxmd.com/read/28634291/rhodium-metalloinsertor-binding-generates-a-lesion-with-selective-cytotoxicity-for-mismatch-repair-deficient-cells
#1
Julie M Bailis, Alyson G Weidmann, Natalie F Mariano, Jacqueline K Barton
The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)](2+) (Rh-PPO)...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28626031/mismatch-repair-deficiency-confers-sensitivity-to-checkpoint-blockade
#2
(no author information available yet)
PD-1 blockade with pembrolizumab achieves responses in 53% of patients with MMR-deficient tumors.
June 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28625978/the-alkylating-chemotherapeutic-temozolomide-induces-metabolic-stress-in-idh1-mutant-cancers-and-potentiates-nad-depletion-mediated-cytotoxicity
#3
Kensuke Tateishi, Fumi Higuchi, Julie Miller, Mara V A Koerner, Nina Lelic, Ganesh M Shankar, Shota Tanaka, David E Fisher, Tracy Batchelor, A John Iafrate, Hiroaki Wakimoto, Andrew S Chi, Daniel P Cahill
IDH1-mutant gliomas are dependent upon the canonical coenzyme nicotinamide adenine dinucleotide (NAD+) for survival. It is known that Poly(ADP-ribose) polymerase (PARP) activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide (TMZ) could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of TMZ on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to TMZ, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis...
June 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28625833/colorectal-cancer-cell-line-proteomes-are-representative-of-primary-tumors-and-predict-drug-sensitivity
#4
Jing Wang, Dmitri Mouradov, Xiaojing Wang, Robert N Jorissen, Matthew C Chambers, Lisa J Zimmerman, Suhas Vasaikar, Christopher G Love, Shan Li, Kym Lowes, Karl-Johan Leuchowius, Helene Jousset, Janet Weinstock, Christopher Yau, John Mariadason, Zhiao Shi, Yuguan Ban, Xi Chen, Robert J C Coffey, Robbert J C Slebos, Antony W Burgess, Daniel C Liebler, Bing Zhang, Oliver M Sieber
BACKGROUND AND AIMS: Proteomics holds promise for individualizing cancer treatment. We analyzed to what extent the proteomic landscape of human colorectal cancer (CRC) is maintained in established CRC cell lines and the utility of proteomics for predicting therapeutic responses. METHODS: Proteomic and transcriptomic analyses were performed on 44 CRC cell lines, compared against primary CRCs (n=95) and normal tissues (n=60), and integrated with genomic and drug sensitivity data...
June 15, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28624221/mir-1290-is-a-biomarker-in-dna-mismatch-repair-deficient-colon-cancer-and-promotes-resistance-to-5-fluorouracil-by-directly-targeting-hmsh2
#5
Ling Ye, Tao Jiang, Huanzhang Shao, Lin Zhong, Zhaowen Wang, Yuan Liu, Huamei Tang, Bingyu Qin, Xiaoqing Zhang, Junwei Fan
5-Fluorouracil (5FU)-based adjuvant therapy is the first-line therapy for treating stage II and III colon cancer after surgery. However, its therapeutic efficacy is limited because of chemoresistance, especially in deficient mismatch repair (dMMR) colon cancer. Here, we first used laser capture microdissection to obtain purified cells from four dMMR and four proficient mismatch repair (pMMR) colon cancer tissues. Second, microRNA (miRNA) microarray chips were used to identify miRNAs that are differentially expressed between these two classes of tumors...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28623884/mitochondrial-rna-processing-in-absence-of-trna-punctuations-in-octocorals
#6
Gaurav G Shimpi, Sergio Vargas, Angelo Poliseno, Gert Wörheide
BACKGROUND: Mitogenome diversity is staggering among early branching animals with respect to size, gene density, content and order, and number of tRNA genes, especially in cnidarians. This last point is of special interest as tRNA cleavage drives the maturation of mitochondrial mRNAs and is a primary mechanism for mt-RNA processing in animals. Mitochondrial RNA processing in non-bilaterian metazoans, some of which possess a single tRNA gene in their mitogenomes, is essentially unstudied despite its importance in understanding the evolution of mitochondrial transcription in animals...
June 17, 2017: BMC Molecular Biology
https://www.readbyqxmd.com/read/28619747/successful-immune-checkpoint-blockade-in-a-patient-with-advanced-stage-microsatellite-unstable-biliary-tract-cancer
#7
Elena Czink, Matthias Kloor, Benjamin Goeppert, Stefan Froehling, Sebastian Uhrig, Tim F Weber, Joern Meinel, Christian Sutter, Karl Heinz Weiss, Peter Schirmacher, Magnus von Knebel Doeberitz, Dirk Jaeger, Christoph Springfeld
Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy...
June 15, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28616688/somatic-mutations-of-the-coding-microsatellites-within-the-beta-2-microglobulin-gene-in-mismatch-repair-deficient-colorectal-cancers-and-adenomas
#8
Mark Clendenning, Alvin Huang, Harindra Jayasekara, Marie Lorans, Susan Preston, Neil O'Callaghan, Bernard J Pope, Finlay A Macrae, Ingrid M Winship, Roger L Milne, Graham G Giles, Dallas R English, John L Hopper, Aung K Win, Mark A Jenkins, Melissa C Southey, Christophe Rosty, Daniel D Buchanan
In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M...
June 14, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28614837/renal-oxygenation-and-hemodynamics-in-kidney-injury
#9
Alexander Bullen, Zhi Zhao Liu, Mark Hepokoski, Ying Li, Prabhleen Singh
Acute kidney injury (AKI) continues to be a major therapeutic challenge. Despite significant advances made in cellular and molecular pathophysiology of AKI, major gaps in knowledge exist regarding the changes in renal hemodynamics and oxygenation in the early stages and through the continuum of AKI. Particular features of renal hemodynamics and oxygenation increase the susceptibility of the kidney to sustain injury due to oxygen demand-supply mismatch and also play an important role in the recovery and repair from AKI as well as the transition of AKI to chronic kidney disease...
June 15, 2017: Nephron
https://www.readbyqxmd.com/read/28611049/comprehensive-evaluation-of-protein-coding-mononucleotide-microsatellites-in-microsatellite-unstable-colorectal-cancer
#10
Johanna Kondelin, Alexandra E Gylfe, Sofie Lundgren, Tomas Tanskanen, Jiri Hamberg, Mervi Aavikko, Kimmo Palin, Heikki Ristolainen, Riku Katainen, Eevi Kaasinen, Minna Taipale, Jussi Taipale, Laura Renkonen-Sinisalo, Heikki Järvinen, Jan Böhm, Jukka-Pekka Mecklin, Pia Vahteristo, Sari Tuupanen, Lauri A Aaltonen, Esa Pitkänen
<span style="background-color: white;">Approximately 15% of colorectal cancers (CRC) exhibit microsatellite instability (MSI), which leads to accumulation of a large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite...
June 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28608265/constitutional-mismatch-repair-deficiency-and-lynch-syndrome-among-consecutive-arab-bedouins-with-colorectal-cancer-in-israel
#11
Naim Abu Freha, Yaara Leibovici Weissman, Alexander Fich, Inbal Barnes Kedar, Marisa Halpern, Ignacio Sztarkier, Doron M Behar, Orly Arbib Sneh, Alex Vilkin, Hagit N Baris, Rachel Gingold, Flavio Lejbkowicz, Yaron Niv, Yael Goldberg, Zohar Levi
We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing...
June 12, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28607805/simplified-microsatellite-instability-detection-protocol-provides-equivalent-sensitivity-to-robust-detection-strategies-in-lynch-syndrome-patients
#12
Hadi Babaei, Mehrdad Zeinalian, Mohammad Hassan Emami, Mortaza Hashemzadeh, Najmeh Farahani, Rasoul Salehi
OBJECTIVE: : Germline mutations in mismatch repair (MMR) genes cause Lynch syndrome (LS). LS is an inherited disease, and an important consequence of MMR deficiency is microsatellite instability (MSI) phenotype. MSI phenotype influences the efficacy of 5 fluorouracil (5-FU) chemotherapy. Reproducible, cost effective, and easy to perform laboratory tests are required to include MSI detection in routine laboratory practice. Evaluation of CAT25 as monomorphic short tandem repeat sequence enables CAT25 to be an efficient screening tool among hereditary nonpolyposis colorectal cancer (HNPCC) patients compared with other methods used currently...
May 2017: Cancer Biology & Medicine
https://www.readbyqxmd.com/read/28606195/a-mismatch-between-supply-and-demand-of-social-support-in-dementia-care-a-qualitative-study-on-the-perspectives-of-spousal-caregivers-and-their-social-network-members
#13
Alieske E H Dam, Lizzy M M Boots, Martin P J van Boxtel, Frans R J Verhey, Marjolein E de Vugt
BACKGROUND: Access to social support contributes to feelings of independence and better social health. This qualitative study aims to investigate multi-informant perspectives on informal social support in dementia care networks. METHODS: Ten spousal caregivers of people with dementia (PwD) completed an ecogram, a social network card and a semi-structured interview. The ecogram aimed to trigger subjective experiences regarding social support. Subsequently, 17 network members were interviewed...
June 13, 2017: International Psychogeriatrics
https://www.readbyqxmd.com/read/28602968/delayed-onset-biallelic-mismatch-repair-deficiency-syndrome
#14
Derek W Ebner, Badr Al-Bawardy, Seth Sweetser
No abstract text is available yet for this article.
June 7, 2017: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28596308/mismatch-repair-deficiency-predicts-response-of-solid-tumors-to-pd-1-blockade
#15
Dung T Le, Jennifer N Durham, Kellie N Smith, Hao Wang, Bjarne R Bartlett, Laveet K Aulakh, Steve Lu, Holly Kemberling, Cara Wilt, Brandon S Luber, Fay Wong, Nilofer S Azad, Agnieszka A Rucki, Dan Laheru, Ross Donehower, Atif Zaheer, George A Fisher, Todd S Crocenzi, James J Lee, Tim F Greten, Austin G Duffy, Kristen K Ciombor, Aleksandra D Eyring, Bao H Lam, Andrew Joe, S Peter Kang, Matthias Holdhoff, Ludmila Danilova, Leslie Cope, Christian Meyer, Shibin Zhou, Richard M Goldberg, Deborah K Armstrong, Katherine M Bever, Amanda N Fader, Janis Taube, Franck Housseau, David Spetzler, Nianqing Xiao, Drew M Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, James R Eshleman, Bert Vogelstein, Robert A Anders, Luis A Diaz
The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients...
June 8, 2017: Science
https://www.readbyqxmd.com/read/28596016/multi-disciplinary-summit-on-genetics-services-for-women-with-gynecologic-cancers-a-society-of-gynecologic-oncology-white-paper
#16
Leslie M Randall, Bhavana Pothuri, Elizabeth M Swisher, John P Diaz, Adam Buchanan, Catherine T Witkop, C Bethan Powell, Ellen Blair Smith, Mark E Robson, Jeff Boyd, Robert L Coleman, Karen Lu
OBJECTIVE: To assess current practice, advise minimum standards, and identify educational gaps relevant to genetic screening, counseling, and testing of women affected by gynecologic cancers. METHODS: The Society of Gynecologic Oncology (SGO) organized a multidisciplinary summit that included representatives from the American College of Obstetricians and Gynecologists (ACOG), the American Society Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), and patient advocacy groups, BrightPink and Facing our Risk of Cancer Empowered (FORCE)...
June 7, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28591715/brca2-egfr-and-ntrk-mutations-in-mismatch-repair-deficient-colorectal-cancers-with-msh2-or-mlh1-mutations
#17
Safoora Deihimi, Avital Lev, Michael Slifker, Elena Shagisultanova, Qifang Xu, Kyungsuk Jung, Namrata Vijayvergia, Eric A Ross, Joanne Xiu, Jeffrey Swensen, Zoran Gatalica, Mark Andrake, Roland L Dunbrack, Wafik S El-Deiry
Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28589142/specific-locus-amplified-fragment-sequencing-reveals-spontaneous-single-nucleotide-mutations-in-rice-osmsh6-mutants
#18
Hairui Cui, Qiongyu Wu, Bin Zhu
Genomic stability depends in part on an efficient DNA lesion recognition and correction by the DNA mismatch repair (MMR) system. We investigated mutations arising spontaneously in rice OsMsh6 mutants by specific-locus amplified fragment sequencing. Totally 994 single-nucleotide mutations were identified in three mutants and on average the mutation density is about 1/136.72 Kb per mutant line. These mutations were relatively randomly distributed in genome and might be accumulated in generation-dependent manner...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28585546/a-molecular-portrait-of-microsatellite-instability-across-multiple-cancers
#19
Isidro Cortes-Ciriano, Sejoon Lee, Woong-Yang Park, Tae-Min Kim, Peter J Park
Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types...
June 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28585041/clinical-impact-of-mismatch-repair-protein-testing-on-outcome-of-early-staged-colorectal-carcinomas
#20
Jatin Sundersham Gandhi, Malini Goswami, Anila Sharma, Parul Tanwar, Gurudutt Gupta, Nikhil Gupta, Sunil Pasricha, Anurag Mehta, Shivender Singh, Mohit Agarwal, Nitin Gupta
INTRODUCTION: Colorectal cancer is the third most common cancer in men and second most common in women globally. In the present study, we aimed to analyse the proportion of patients with loss of immunostaining for mismatch repair (MMR) proteins in all newly diagnosed stage II cases of colorectal cancer for the purpose of prognostication, for determination of further chemotherapeutic strategy and for familial screening. METHOD: From January 2014 to December 2015, 62 consecutive newly diagnosed cases of stage II colorectal cancer were included in the study...
June 5, 2017: Journal of Gastrointestinal Cancer
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