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https://www.readbyqxmd.com/read/29346525/frailty-syndrome-and-genomic-instability-in-older-adults-suitability-of-the-cytome-micronucleus-assay-as-a-diagnostic-tool
#1
María Sánchez-Flores, Diego Marcos-Pérez, Laura Lorenzo-López, Ana Maseda, José C Millán-Calenti, Stefano Bonassi, Eduardo Pásaro, Blanca Laffon, Vanessa Valdiglesias
Frailty, a condition involving increased risk of disability and mortality in older adults, has emerged as a reliable way to predict the effect of aging. Genomic instability may help to anticipate recognition of frail individuals and improving frailty outcomes. Our objective was to evaluate the potential of the micronucleus (MN) frequency, evaluated in lymphocytes and buccal cells, to anticipate frailty identification and improve diagnosis reliability. Our results, from a group of older adults over 65, showed that frail individuals had significantly higher frequencies of MN in lymphocytes (19...
January 13, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/29344903/nuclear-genes-involved-in-mitochondrial-diseases-caused-by-instability-of-mitochondrial-dna
#2
REVIEW
Joanna Rusecka, Magdalena Kaliszewska, Ewa Bartnik, Katarzyna Tońska
Mitochondrial diseases are defined by a respiratory chain dysfunction and in most of the cases manifest as multisystem disorders with predominant expression in muscles and nerves and may be caused by mutations in mitochondrial (mtDNA) or nuclear (nDNA) genomes. Most of the proteins involved in respiratory chain function are nuclear encoded, although 13 subunits of respiratory chain complexes (together with 2 rRNAs and 22 tRNAs necessary for their translation) encoded by mtDNA are essential for cell function...
January 17, 2018: Journal of Applied Genetics
https://www.readbyqxmd.com/read/29342134/chromosomal-instability-drives-metastasis-through-a-cytosolic-dna-response
#3
Samuel F Bakhoum, Bryan Ngo, Ashley M Laughney, Julie-Ann Cavallo, Charles J Murphy, Peter Ly, Pragya Shah, Roshan K Sriram, Thomas B K Watkins, Neil K Taunk, Mercedes Duran, Chantal Pauli, Christine Shaw, Kalyani Chadalavada, Vinagolu K Rajasekhar, Giulio Genovese, Subramanian Venkatesan, Nicolai J Birkbak, Nicholas McGranahan, Mark Lundquist, Quincey LaPlant, John H Healey, Olivier Elemento, Christine H Chung, Nancy Y Lee, Marcin Imielenski, Gouri Nanjangud, Dana Pe'er, Don W Cleveland, Simon N Powell, Jan Lammerding, Charles Swanton, Lewis C Cantley
Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29340115/hypermutation-and-microsatellite-instability-in-gastrointestinal-cancers
#4
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/29338484/the-association-between-micronucleus-nucleoplasmic-bridges-and-nuclear-buds-frequency-and-the-degree-of-uterine-cervical-lesions
#5
Goneta Gashi, Vesna Mahovlić, Suzana Manxhuka-Kerliu, Arjeta Podrimaj-Bytyqi, Luljeta Gashi, Isa R Elezaj
BACKGROUND AND AIM: The loss of genomic stability play an important role in carcinogenesis. Therefore, it is imperative to use certain biomarkers of DNA damage due to genomic instability in order to predict cancer risk. The aim of this study was the evaluation of genomic instability in patients with cervical lesions. MATERIALS AND METHODS: We investigated the genetic damages in 80 subjects: (40) patients with high grade squamous intraepithelial lesions (HSIL), (20) patients with invasive squamous cervical cancer (SCC) and (20) healthy women with a biomarker in two different tissues; the micronucleus (MN) test in peripheral blood lymphocytes (PBL), and in buccal exfoliated cells (BEC)...
January 17, 2018: Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals
https://www.readbyqxmd.com/read/29338072/targeting-her2-in-colorectal-cancer-the-landscape-of-amplification-and-short-variant-mutations-in-erbb2-and-erbb3
#6
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/29337161/cellular-redox-cancer-and-human-papillomavirus
#7
REVIEW
Alfredo Cruz-Gregorio, Joaquín Manzo-Merino, Marcela Lizano
High-risk Human Papillomavirus (HR-HPV) is the causative agent of different human cancers. A persistent HR-HPV infection alters several cellular processes involved in cell proliferation, apoptosis, immune evasion, genomic instability and transformation. Cumulative evidence from past studies indicates that HR-HPV proteins are associated with oxidative stress (OS) and has been proposed as a risk factor for cancer development. Reactive oxygen and nitrogen species (RONS) regulate a plethora of processes inducing cellular proliferation, differentiation and death...
January 11, 2018: Virus Research
https://www.readbyqxmd.com/read/29336607/alu-sirna-to-increase-alu-element-methylation-and-prevent-dna-damage
#8
Maturada Patchsung, Sirapat Settayanon, Monnat Pongpanich, Dharm Mutirangura, Pornrutsami Jintarith, Apiwat Mutirangura
Global DNA hypomethylation promoting genomic instability leads to cancer and deterioration of human health with age. AIM: To invent a biotechnology that can reprogram this process. METHODS: We used Alu siRNA to direct Alu interspersed repetitive sequences methylation in human cells. We evaluated the correlation between DNA damage and Alu methylation levels. RESULTS: We observed an inverse correlation between Alu element methylation and endogenous DNA damage in white blood cells...
January 16, 2018: Epigenomics
https://www.readbyqxmd.com/read/29336210/semi-supervised-identification-of-cancer-subgroups-using-survival-outcomes-and-overlapping-grouping-information
#9
Wei Wei, Zequn Sun, Willian A da Silveira, Zhenning Yu, Andrew Lawson, Gary Hardiman, Linda E Kelemen, Dongjun Chung
Identification of cancer patient subgroups using high throughput genomic data is of critical importance to clinicians and scientists because it can offer opportunities for more personalized treatment and overlapping treatments of cancers. In spite of tremendous efforts, this problem still remains challenging because of low reproducibility and instability of identified cancer subgroups and molecular features. In order to address this challenge, we developed Integrative Genomics Robust iDentification of cancer subgroups (InGRiD), a statistical approach that integrates information from biological pathway databases with high-throughput genomic data to improve the robustness for identification and interpretation of molecularly-defined subgroups of cancer patients...
January 1, 2018: Statistical Methods in Medical Research
https://www.readbyqxmd.com/read/29335541/modulation-of-uvb-induced-carcinogenesis-by-activation-of-alternative-dna-repair-pathways
#10
Yan Sha, Vladimir Vartanian, Nichole Owen, Stephanie J Mengden Koon, Marcus J Calkins, Courtney S Thompson, Zahra Mirafzali, Sara Mir, Lisa E Goldsmith, Huaping He, Chun Luo, Scott M Brown, Paul W Doetsch, Andy Kaempf, Jeong Y Lim, Amanda K McCullough, R Stephen Lloyd
The molecular basis for ultraviolet (UV) light-induced nonmelanoma and melanoma skin cancers centers on cumulative genomic instability caused by inefficient DNA repair of dipyrimidine photoproducts. Inefficient DNA repair and subsequent translesion replication past these DNA lesions generate distinct molecular signatures of tandem CC to TT and C to T transitions at dipyrimidine sites. Since previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited, we have engineered the N-terminally truncated form (Δ228) UV endonuclease (UVDE) from Schizosaccharomyces pombe to include a TAT cell-penetrating peptide sequence with or without a nuclear localization signal (NLS): UVDE-TAT and UVDE-NLS-TAT...
January 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29335443/elucidating-the-genomic-architecture-of-asian-egfr-mutant-lung-adenocarcinoma-through-multi-region-exome-sequencing
#11
Rahul Nahar, Weiwei Zhai, Tong Zhang, Angela Takano, Alexis J Khng, Yin Yeng Lee, Xingliang Liu, Chong Hee Lim, Tina P T Koh, Zaw Win Aung, Tony Kiat Hon Lim, Lavanya Veeravalli, Ju Yuan, Audrey S M Teo, Cheryl X Chan, Huay Mei Poh, Ivan M L Chua, Audrey Ann Liew, Dawn Ping Xi Lau, Xue Lin Kwang, Chee Keong Toh, Wan-Teck Lim, Bing Lim, Wai Leong Tam, Eng-Huat Tan, Axel M Hillmer, Daniel S W Tan
EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29334356/p53-suppresses-mutagenic-rad52-and-pol%C3%AE-pathways-by-orchestrating-dna-replication-restart-homeostasis
#12
Sunetra Roy, Karl-Heinz Tomaszowski, Jessica W Luzwick, Soyoung Park, Jun Li, Maureen Murphy, Katharina Schlacher
Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks driving genomic instability genetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease...
January 15, 2018: ELife
https://www.readbyqxmd.com/read/29332159/transposable-elements-genome-innovation-chromosome-diversity-and-centromere-conflict
#13
REVIEW
Savannah J Klein, Rachel J O'Neill
Although it was nearly 70 years ago when transposable elements (TEs) were first discovered "jumping" from one genomic location to another, TEs are now recognized as contributors to genomic innovations as well as genome instability across a wide variety of species. In this review, we illustrate the ways in which active TEs, specifically retroelements, can create novel chromosome rearrangements and impact gene expression, leading to disease in some cases and species-specific diversity in others. We explore the ways in which eukaryotic genomes have evolved defense mechanisms to temper TE activity and the ways in which TEs continue to influence genome structure despite being rendered transpositionally inactive...
January 13, 2018: Chromosome Research
https://www.readbyqxmd.com/read/29330809/analysis-of-hypoxia-and-the-hypoxic-response-in-tumor-xenografts
#14
Nuray Böğürcü, Sascha Seidel, Boyan K Garvalov, Till Acker
Solid tumors are often characterized by insufficient oxygen supply (hypoxia), as a result of inadequate vascularization, which cannot keep up with the rapid growth rate of the tumor. Tumor hypoxia is a negative prognostic and predictive factor and is associated with a more aggressive phenotype in various tumor entities. Activation of the hypoxic response in tumors, which is centered around the hypoxia-inducible transcription factors (HIFs), has been causally linked to neovascularization, increased radio- and chemoresistance, altered cell metabolism, genomic instability, increased metastatic potential, and tumor stem cell characteristics...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29329208/advances-in-molecular-profiling-and-categorisation-of-pancreatic-adenocarcinoma-and-the-implications-for-therapy
#15
REVIEW
Rille Pihlak, Jamie M J Weaver, Juan W Valle, Mairéad G McNamara
Pancreatic ductal adenocarcinoma (PDAC) continues to be a disease with poor outcomes and short-lived treatment responses. New information is emerging from genome sequencing identifying potential subgroups based on somatic and germline mutations. A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of PDAC is KRAS, with other recorded alterations being SMAD4 and CDKN2A. Mutations in the deoxyribonucleic acid (DNA) damage repair pathway have also been investigated in PDAC and multiple clinical trials are ongoing with DNA-damaging agents...
January 12, 2018: Cancers
https://www.readbyqxmd.com/read/29327083/r-loops-targets-for-nuclease-cleavage-and-repeat-instability
#16
REVIEW
Catherine H Freudenreich
R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias...
January 11, 2018: Current Genetics
https://www.readbyqxmd.com/read/29326161/sumo2-3-modification-of-activating-transcription-factor-5-atf5-controls-its-dynamic-translocation-at-the-centrosome
#17
Yunsheng Yuan, Kari Gaither, Eugene Kim, Edward Liu, Ming Hu, Kathy Lengel, Dongmeng Qian, Yidi Xu, Bin Wang, Henning Knipprath, David Liu
Activating transcription factor 5 (ATF5) is a member of the ATF/CREB family of transcription factors. ATF5 regulates stress responses and cell survival, proliferation, and differentiation and also plays a role in viral infections, cancer, diabetes, schizophrenia, and the olfactory system. Moreover, it was found to also have a critical, cell cycle-dependent structural function at the centrosome. However, the mechanism that controls ATF5's localization at the centrosome is unclear. Here, we report that ATF5 is SUMO2/3- modified at a conserved SUMO-targeting consensus site in various types of mammalian cells...
January 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29325523/fanconi-anemia-with-sun-sensitivity-caused-by-a-xeroderma-pigmentosum-associated-missense-mutation-in-xpf
#18
Isabell Popp, Maqsood Punekar, Nick Telford, Stavros Stivaros, Kate Chandler, Meenakshi Minnis, Anna Castleton, Claire Higham, Louise Hopewell, D Gareth Evans, Anja Raams, Arjan F Theil, Stefan Meyer, Detlev Schindler
BACKGROUND: Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks. CASE PRESENTATION: A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy...
January 11, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29324392/abnormal-rna-splicing-and-genomic-instability-after-induction-of-dnmt3a-mutations-by-crispr-cas9-gene-editing
#19
Lauren G Banaszak, Valentina Giudice, Xin Zhao, Zhijie Wu, Shouguo Gao, Kohei Hosokawa, Keyvan Keyvanfar, Danielle M Townsley, Fernanda Gutierrez-Rodrigues, Maria Del Pilar Fernandez Ibanez, Sachiko Kajigaya, Neal S Young
DNA methyltransferase 3A (DNMT3A) mediates de novo DNA methylation. Mutations in DNMT3A are associated with hematological malignancies, most frequently acute myeloid leukemia. DNMT3A mutations are hypothesized to establish a pre-leukemic state, rendering cells vulnerable to secondary oncogenic mutations and malignant transformation. However, the mechanisms by which DNMT3A mutations contribute to leukemogenesis are not well-defined. Here, we successfully created four DNMT3A-mutated K562 cell lines with frameshift mutations resulting in truncated DNMT3A proteins...
January 4, 2018: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/29323295/alcohol-and-endogenous-aldehydes-damage-chromosomes-and-mutate-stem-cells
#20
Juan I Garaycoechea, Gerry P Crossan, Frédéric Langevin, Lee Mulderrig, Sandra Louzada, Fentang Yang, Guillaume Guilbaud, Naomi Park, Sophie Roerink, Serena Nik-Zainal, Michael R Stratton, Ketan J Patel
Haematopoietic stem cells renew blood. Accumulation of DNA damage in these cells promotes their decline, while misrepair of this damage initiates malignancies. Here we describe the features and mutational landscape of DNA damage caused by acetaldehyde, an endogenous and alcohol-derived metabolite. This damage results in DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements. We combined transplantation of single haematopoietic stem cells with whole-genome sequencing to show that this damage occurs in stem cells, leading to deletions and rearrangements that are indicative of microhomology-mediated end-joining repair...
January 11, 2018: Nature
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