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https://www.readbyqxmd.com/read/28419182/molecular-classification-of-pulmonary-sarcomatoid-carcinomas-suggests-new-therapeutic-opportunities
#1
N Pécuchet, T Vieira, N Rabbe, M Antoine, H Blons, J Cadranel, P Laurent-Puig, M Wislez
Background: Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3) or APOBEC enzyme deamination (signatures 2&13)...
April 13, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28405512/high-expression-of-pd-1-ligands-is-associated-with-kataegis-mutational-signature-and-apobec3-alterations
#2
Amélie Boichard, Igor F Tsigelny, Razelle Kurzrock
Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related to 8,475 pan-cancer samples available in The Cancer Genome Atlas (TCGA) and conducted a logistic regression analysis based on a large set of variables, such as microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ (POLD1) and polymerase ε (POLE) mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) alterations, lymphocyte markers and mutation burden estimates to determine independent factors that associate with PD-1 ligand overexpression...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28381554/dna-mutagenic-activity-and-capacity-for-hiv-1-restriction-of-the-cytidine-deaminase-apobec3g-depends-on-whether-dna-or-rna-binds-to-tyrosine-315
#3
Bogdan Polevoda, Rebecca Joseph, Alan E Friedman, Ryan P Bennett, Rebecca Greiner, Thareendra De Zoysa, Ryan A Stewart, Harold C Smith
APOBEC3G (A3G) belongs to the AID/APOBEC protein family of cytidine deaminases (CDA) that bind to nucleic acids. A3G mutates the HIV genome by deamination of dC to dU, leading to accumulation of virus-inactivating mutations. Binding to cellular RNAs inhibits A3G binding to substrate single-stranded (ss) DNA and CDA activity. RNA and ssDNA bind to the same three A3G tryptic peptides (amino acids 181-194, 314-320, and 345-374) that form parts of a continuously exposed protein surface extending from the catalytic domain in the C-terminus of A3G to its N-terminus...
April 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28365443/genetic-alterations-as-esophageal-tissues-from-squamous-dysplasia-to-carcinoma
#4
Xi Liu, Min Zhang, Songmin Ying, Chong Zhang, Runhua Lin, Jiaxuan Zheng, Guohong Zhang, Dongping Tian, Yi Guo, Caiwen Du, Yuping Chen, Shaobin Chen, Xue Su, Juan Ji, Wanting Deng, Xiang Li, Shiyue Qiu, Ruijing Yan, Zexin Xu, Yuan Wang, Yuanning Guo, Jiancheng Cui, Shanshan Zhuang, Huan Yu, Qi Zheng, Moshe Marom, Sitong Sheng, Guoqiang Zhang, Songnian Hu, Ruiqiang Li, Min Su
BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is most common subtype of esophageal cancer. Little is known about the genetic changes that occur in esophageal cells during development of ESCC. We performed next-generation sequence analyses of esophageal non-tumor, intraepithelial neoplasia (IEN), and ESCC tissues from the same patients to track genetic changes during tumor development. METHODS: We performed whole-genome, exome, or targeted sequence analyses of 227 esophageal tissue samples from 70 patients with ESCC undergoing resection at Shantou University Medical College in China from 2012 through 2015 (no patients had received chemotherapy or radiation therapy); we analyzed normal tissue, tissue with simple hyperplasia, dysplastic tissue (intraepithelial neoplasia, IEN), and ESCC tissues collected from different regions of the esophagus at the same time...
March 29, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28362825/the-preferred-nucleotide-contexts-of-the-aid-apobec-cytidine-deaminases-have-differential-effects-when-mutating-retrotransposon-and-virus-sequences-compared-to-host-genes
#5
Jeffrey Chen, Thomas MacCarthy
The AID / APOBEC genes are a family of cytidine deaminases that have evolved in vertebrates, and particularly mammals, to mutate RNA and DNA at distinct preferred nucleotide contexts (or "hotspots") on foreign genomes such as viruses and retrotransposons. These enzymes play a pivotal role in intrinsic immunity defense mechanisms, often deleteriously mutating invading retroviruses or retrotransposons and, in the case of AID, changing antibody sequences to drive affinity maturation. We investigate the strength of various hotspots on their known biological targets by evaluating the potential impact of mutations on the DNA coding sequences of these targets, and compare these results to hypothetical hotspots that did not evolve...
March 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28334887/avoidance-of-apobec3b-induced-mutation-by-error-free-lesion-bypass
#6
James I Hoopes, Amber L Hughes, Lauren A Hobson, Luis M Cortez, Alexander J Brown, Steven A Roberts
APOBEC cytidine deaminases mutate cancer genomes by converting cytidines into uridines within ssDNA during replication. Although uracil DNA glycosylases limit APOBEC-induced mutation, it is unknown if subsequent base excision repair (BER) steps function on replication-associated ssDNA. Hence, we measured APOBEC3B-induced CAN1 mutation frequencies in yeast deficient in BER endonucleases or DNA damage tolerance proteins. Strains lacking Apn1, Apn2, Ntg1, Ntg2 or Rev3 displayed wild-type frequencies of APOBEC3B-induced canavanine resistance (CanR)...
March 10, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28266028/triggering-of-tlr-3-4-nod2-and-dc-sign-reduces-viral-replication-and-increases-t-cell-activation-capacity-of-hiv-infected-human-dendritic-cells
#7
Sylvain Cardinaud, Alejandra Urrutia, Angeline Rouers, Pierre-Grégoire Coulon, Jérome Kervevan, Clémence Richetta, Anne Bet, Emmanuel A Maze, Martin Larsen, Maria-Candela Iglesias, Victor Appay, Stéphanie Graff-Dubois, Arnaud Moris
A variety of signals influence the capacity of dendritic cells (DCs) to mount potent antiviral cytotoxic T-cell (CTL) responses. In particular, innate immune sensing by pathogen recognition receptors, such as TLR and C-type lectines, influences DC biology and affects their susceptibility to HIV infection. Yet, whether the combined effects of PPRs triggering and HIV infection influence HIV-specific (HS) CTL responses remain enigmatic. Here, we dissect the impact of innate immune sensing by pathogen recognition receptors on DC maturation, HIV infection, and on the quality of HS CTL activation...
March 7, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28260788/apobec-signature-mutation-generates-an-oncogenic-enhancer-that-drives-lmo1-expression-in-t-all
#8
Z Li, B J Abraham, A Berezovskaya, N Farah, Y Liu, T Leon, A Fielding, S H Tan, T Sanda, A S Weintraub, B Li, S Shen, J Zhang, M R Mansour, R A Young, A T Look
Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells resulting in clonal selection. Although most cancer causing mutations have been detected in the protein-coding regions of the cancer genome, driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention...
March 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28215840/cytidine-deaminase-apobec3a-induction-in-fallopian-epithelium-after-exposure-to-follicular-fluid
#9
Pavla Brachova, Nehemiah S Alvarez, Bradley J Van Voorhis, Lane K Christenson
OBJECTIVE: Ovarian carcinomas that originate from fallopian epithelial cells are suggested to arise due to repeated exposure to ovulatory follicular fluid (FF). Mechanistic explanation(s) for how this occurs are unknown. Here, we sought to understand if FF exposure to fallopian epithelial cells could induce DNA damage and expression of a known family of DNA mutators, apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) cytidine deaminases. METHODS: Follicular fluid and matched patient plasma samples were obtained from donors...
February 16, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28182305/hepatitis-b-virus-covalently-closed-circular-dna-homeostasis-is-independent-of-the-lymphotoxin-pathway-during-chronic-hbv-infection
#10
Marie-Anne Meier, Aleksei Suslov, Sylvia Ketterer, Markus H Heim, Stefan F Wieland
Current treatment options for patients with chronic hepatitis B virus (HBV) infection are not curative as they are not effective in eliminating covalently closed circular DNA (cccDNA). cccDNA is a stable template for HBV transcription in the nucleus of hepatocytes and is thought to be one of the main factors responsible for HBV persistence. Recently, activation of the lymphotoxin beta receptor (LTβR) has been shown to trigger degradation of cccDNA through induction of cytidine deaminases of the APOBEC3 family in HBV cell culture model systems...
February 9, 2017: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/28169999/mechanisms-for-targeted-purposeful-mutation-revealed-in-an-apobec-dna-complex
#11
Emily K Schutsky, Zachary M Hostetler, Rahul M Kohli
No abstract text is available yet for this article.
February 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28131088/long-term-passage-of-vif-null-hiv-1-in-cd4-t-cells-expressing-sub-lethal-levels-of-apobec-proteins-fails-to-develop-apobec-resistance
#12
Eri Miyagi, Sandra Kao, Miyoshi Fumitaka, Alicia Buckler-White, Ron Plishka, Klaus Strebel
APOBEC3G (A3G) is a cytidine deaminase with potent antiviral activity that is antagonized by Vif. A3G is expressed in a cell type-specific manner and some semi-permissive cells, including A3.01, express A3G but fail to block replication of Vif-null HIV-1. Here we explored the semi-permissive nature of A3.01 cells and found it to be defined exclusively by the levels of A3G. Indeed, minor changes in A3G levels rendered A3.01 cells either fully permissive or non-permissive for Vif-null HIV-1. Our data indicate that A3...
April 2017: Virology
https://www.readbyqxmd.com/read/28117753/risks-at-the-dna-replication-fork-effects-upon-carcinogenesis-and-tumor-heterogeneity
#13
REVIEW
Tony M Mertz, Victoria Harcy, Steven A Roberts
The ability of all organisms to copy their genetic information via DNA replication is a prerequisite for cell division and a biological imperative of life. In multicellular organisms, however, mutations arising from DNA replication errors in the germline and somatic cells are the basis of genetic diseases and cancer, respectively. Within human tumors, replication errors additionally contribute to mutator phenotypes and tumor heterogeneity, which are major confounding factors for cancer therapeutics. Successful DNA replication involves the coordination of many large-scale, complex cellular processes...
January 22, 2017: Genes
https://www.readbyqxmd.com/read/28112728/integrated-genomic-and-molecular-characterization-of-cervical-cancer
#14
(no author information available yet)
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib...
March 16, 2017: Nature
https://www.readbyqxmd.com/read/28101245/apobec3b-expression-in-human-leptomeninges-and-meningiomas
#15
Mahlon D Johnson, Jay E Reeder, Mary O'Connell
Nucleic acid-editing enzymes of the apolipoprotein B mRNA-editing enzyme (APOBEC) family have been associated with somatic mutation in cancer. However, the role of APOBEC catalytic subunit 3B (APOBEC3B) editing in the pathogenesis of base substitutions in meningiomas is unknown. In the present study, the expression of APOBEC3B was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in five fetal and one adult human leptomeninges and 38 meningiomas. Genomic DNA was sequenced using the Illumina Tru-Seq Cancer Panel...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28098260/hepatitis-b-virus-x-protein-is-capable-of-down-regulating-protein-level-of-host-antiviral-protein-apobec3g
#16
Ruidong Chen, Xue Zhao, Yongxiang Wang, Youhua Xie, Jing Liu
The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family proteins bind RNA and single-stranded DNA, and create C-to-U base modifications through cytidine deaminase activity. APOBEC3G restricts human immunodeficiency virus 1 (HIV-1) infection by creating hypermutations in proviral DNA, while HIV-1-encoded vif protein antagonizes such restriction by targeting APOBEC3G for degradation. APOBEC3G also inhibits hepatitis B virus (HBV): APOBEC3G co-expression inhibits HBV replication and evidences exist indicating APOBEC3G-mediated HBV hypermutations in patients...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28027479/characterization-of-founder-viruses-in-very-early-siv-rectal-transmission
#17
Zhe Yuan, Fangrui Ma, Andrew J Demers, Dong Wang, Jianqing Xu, Mark G Lewis, Qingsheng Li
A better understanding of HIV-1 transmission is critical for developing preventative strategies. To that end, we analyzed 524 full-length env sequences of SIVmac251 at 6 and 10 days post intrarectal infection of rhesus macaques. There was no tissue compartmentalization of founder viruses across plasma, rectal and distal lymphatic tissues for most animals; however one animal has evidence of virus tissue compartmentalization. Despite identical viral inoculums, founder viruses were animal-specific, primarily derived from rare variants in the inoculum, and have a founder virus signature that can distinguish dominant founder variants from minor founder or untransmitted variants in the inoculum...
February 2017: Virology
https://www.readbyqxmd.com/read/28027327/mutational-profile-of-metastatic-breast-cancers-a-retrospective-analysis
#18
Celine Lefebvre, Thomas Bachelot, Thomas Filleron, Marion Pedrero, Mario Campone, Jean-Charles Soria, Christophe Massard, Christelle Lévy, Monica Arnedos, Magali Lacroix-Triki, Julie Garrabey, Yannick Boursin, Marc Deloger, Yu Fu, Frédéric Commo, Véronique Scott, Ludovic Lacroix, Maria Vittoria Dieci, Maud Kamal, Véronique Diéras, Anthony Gonçalves, Jean-Marc Ferrerro, Gilles Romieu, Laurence Vanlemmens, Marie-Ange Mouret Reynier, Jean-Christophe Théry, Fanny Le Du, Séverine Guiu, Florence Dalenc, Gilles Clapisson, Hervé Bonnefoi, Marta Jimenez, Christophe Le Tourneau, Fabrice André
BACKGROUND: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. METHODS AND FINDINGS: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27991903/structural-basis-for-targeted-dna-cytosine-deamination-and-mutagenesis-by-apobec3a-and-apobec3b
#19
Ke Shi, Michael A Carpenter, Surajit Banerjee, Nadine M Shaban, Kayo Kurahashi, Daniel J Salamango, Jennifer L McCann, Gabriel J Starrett, Justin V Duffy, Özlem Demir, Rommie E Amaro, Daniel A Harki, Reuben S Harris, Hideki Aihara
APOBEC-catalyzed cytosine-to-uracil deamination of single-stranded DNA (ssDNA) has beneficial functions in immunity and detrimental effects in cancer. APOBEC enzymes have intrinsic dinucleotide specificities that impart hallmark mutation signatures. Although numerous structures have been solved, mechanisms for global ssDNA recognition and local target-sequence selection remain unclear. Here we report crystal structures of human APOBEC3A and a chimera of human APOBEC3B and APOBEC3A bound to ssDNA at 3.1-Å and 1...
February 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27924510/global-protein-expression-analysis-of-molecular-markers-of-ds-1-47-a-component-of-implantation-promoting-traditional-chinese-medicine
#20
Yan-Ling Li, Xiao-Yan Zhang, Yu Leng, Yan-Li Wu, Jing Li, Yun-Xia Wu
This study investigated the molecular markers of DS-1-47, a component of an implantation- promoting traditional Chinese medicine consisting of Astragalus mongholicus, Atractylodes macrocephala, Scutellaria baicalensis and Dipsacales, in an attempt to clarify the molecular mechanism and action targets of DS-1-47. Controlled ovarian stimulation (COS) method was used to establish the implantation dysfunction models of mice. Animals were divided into normal pregnant group, COS model group and DS-1-47 group. Laser capture microdissection-double dimensional electrophoresis-mass spectrum (LCM-DE-MS) was used to analyze the uterine protein molecules that were possibly involved in the promotion of implantation...
December 2016: Journal of Huazhong University of Science and Technology. Medical Sciences
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