Base de dados : MEDLINE Pesquisa : D08.811.277.151.486.250.500.500 [Categoria DeCS] Referências encontradas : 300 [refinar] Mostrando: 1 .. 10   no formato [Detalhado]

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[PMID]: 28639893 [Au] Autor: Yan X; Li Q; Ni D; Xie Y; He Q; Wan Q; Liu Y; Lyu Z; Mao Z; Zhou Q [Ad] Endereço: 1 The College of Laboratory Medicine, Chongqing Medical University, Chongqing, China. [Ti] Título: Apobec-1 complementation factor regulates cell migration and apoptosis through Dickkopf1 by acting on its 3' untranslated region in MCF7 cells. [So] Source: Tumour Biol;39(6):1010428317706218, 2017 Jun. [Is] ISSN: 1423-0380 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A1CF (apobec-1 complementation factor) acts as a component of the apolipoprotein-B messenger RNA editing complex. Previous researches mainly focused on its post-transcriptional cytidine to uridine RNA editing. However, few study reported its role in progression of breast carcinoma cells. Wound healing assay and flow cytometry were applied to detect the migration and apoptosis; western blot, real-time polymerase chain reaction, and dual-luciferase assays were applied to investigate the potential regulation mechanism of A1CF-mediated cell migration and apoptosis. Knockdown of A1CF decreased cell migration and enhanced cell apoptosis in MCF7 cells in vitro. Western blot analysis showed that knockdown of A1CF decreased Dickkopf1 but increased c-Myc and ß-catenin expression, and overexpression of A1CF can get opposite results. Knockdown of Dickkopf1 in A1CF-overexpressed cells decreased cell migration and enhanced cell apoptosis compared with A1CF-overexpressed cells. Luciferase-fused 3' untranslated region of human Dickkopf1 activity was highly upregulated in A1CF-overexpressed MCF7 cells, but this upregulation can be inhibited by mutating conserved binding motifs of Dickkopf1 3' untranslated region. A1CF played a crucial role in cell migration and survival through affecting 3' untranslated region of Dickkopf1 to upregulate its expression in MCF7 cells. [Mh] Termos MeSH primário: Desaminase APOBEC-1/genética Neoplasias da Mama/genética Peptídeos e Proteínas de Sinalização Intercelular/genética Proteínas de Ligação a RNA/genética [Mh] Termos MeSH secundário: Regiões 3' não Traduzidas Apoptose/genética Neoplasias da Mama/patologia Movimento Celular/genética Feminino Regulação Neoplásica da Expressão Gênica Técnicas de Silenciamento de Genes Seres Humanos Peptídeos e Proteínas de Sinalização Intercelular/biossíntese Células MCF-7 Ligação Proteica Edição de RNA/genética beta Catenina/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (3' Untranslated Regions); 0 (DKK1 protein, human); 0 (Intercellular Signaling Peptides and Proteins); 0 (RNA-Binding Proteins); 0 (beta Catenin); EC 3.5.4.36 (APOBEC-1 Deaminase); EC 3.5.4.36 (APOBEC1 protein, human) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170713 [Lr] Data última revisão: 170713 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170623 [St] Status: MEDLINE [do] DOI: 10.1177/1010428317706218

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[PMID]: 28585179 [Au] Autor: Liang P; Sun H; Sun Y; Zhang X; Xie X; Zhang J; Zhang Z; Chen Y; Ding C; Xiong Y; Ma W; Liu D; Huang J; Songyang Z [Ad] Endereço: Key Laboratory of Gene Engineering of the Ministry of Education, Guangzhou Key Laboratory of Healthy Aging Research and State Key Laboratory of Biocontrol, SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China. liangpp5@mail.sysu.edu.cn. [Ti] Título: Effective gene editing by high-fidelity base editor 2 in mouse zygotes. [So] Source: Protein Cell;8(8):601-611, 2017 Aug. [Is] ISSN: 1674-8018 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Targeted point mutagenesis through homologous recombination has been widely used in genetic studies and holds considerable promise for repairing disease-causing mutations in patients. However, problems such as mosaicism and low mutagenesis efficiency continue to pose challenges to clinical application of such approaches. Recently, a base editor (BE) system built on cytidine (C) deaminase and CRISPR/Cas9 technology was developed as an alternative method for targeted point mutagenesis in plant, yeast, and human cells. Base editors convert C in the deamination window to thymidine (T) efficiently, however, it remains unclear whether targeted base editing in mouse embryos is feasible. In this report, we generated a modified high-fidelity version of base editor 2 (HF2-BE2), and investigated its base editing efficacy in mouse embryos. We found that HF2-BE2 could convert C to T efficiently, with up to 100% biallelic mutation efficiency in mouse embryos. Unlike BE3, HF2-BE2 could convert C to T on both the target and non-target strand, expanding the editing scope of base editors. Surprisingly, we found HF2-BE2 could also deaminate C that was proximal to the gRNA-binding region. Taken together, our work demonstrates the feasibility of generating point mutations in mouse by base editing, and underscores the need to carefully optimize base editing systems in order to eliminate proximal-site deamination. [Mh] Termos MeSH primário: Desaminase APOBEC-1/genética Proteínas de Bactérias/genética Sistemas CRISPR-Cas Transferência Embrionária Endonucleases/genética Edição de Genes/métodos Zigoto/metabolismo [Mh] Termos MeSH secundário: Desaminase APOBEC-1/metabolismo Animais Proteínas de Bactérias/metabolismo Sequência de Bases Citidina/genética Citidina/metabolismo Embrião de Mamíferos Endonucleases/metabolismo Células HEK293 Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Camundongos Camundongos Endogâmicos C57BL Microinjeções Plasmídeos/química Plasmídeos/metabolismo Mutação Puntual RNA Guia/genética RNA Guia/metabolismo Timidina/genética Timidina/metabolismo Zigoto/crescimento & desenvolvimento Zigoto/transplante [Pt] Tipo de publicação: LETTER [Nm] Nome de substância: 0 (Bacterial Proteins); 0 (RNA, Guide); 5CSZ8459RP (Cytidine); EC 3.1.- (Cas9 endonuclease Streptococcus pyogenes); EC 3.1.- (Endonucleases); EC 3.5.4.36 (APOBEC-1 Deaminase); VC2W18DGKR (Thymidine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170824 [Lr] Data última revisão: 170824 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170607 [St] Status: MEDLINE [do] DOI: 10.1007/s13238-017-0418-2

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[PMID]: 28319449 [Au] Autor: Greig JA; Limberis MP; Bell P; Chen SJ; Calcedo R; Rader DJ; Wilson JM [Ad] Endereço: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania. [Ti] Título: Non-Clinical Study Examining AAV8.TBG.hLDLR Vector-Associated Toxicity in Chow-Fed Wild-Type and LDLR Rhesus Macaques. [So] Source: Hum Gene Ther Clin Dev;28(1):39-50, 2017 Mar. [Is] ISSN: 2324-8645 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Vectors based on adeno-associated virus serotype 8 (AAV8) have been evaluated in several clinical trials of gene therapy for hemophilia B with encouraging results. In preparation for a Phase 1 clinical trial of AAV8 gene therapy for the treatment of homozygous familial hypercholesterolemia (HoFH), the safety of the clinical candidate vector, AAV8.TBG.hLDLR, was evaluated in wild-type rhesus macaques and macaques heterozygous for a nonsense mutation in the low-density lipoprotein receptor (LDLR) gene (LDLR ). Intravenous infusion of 1.25 × 10 GC/kg of AAV8.TBG.hLDLR expressing the human version of LDLR was well tolerated and associated with only mild histopathology that was restricted to the liver and sporadic, low-level, and transient elevations in transaminases. Some animals developed T cells to both capsid and the hLDLR transgene, although these adaptive immune responses were most evident at the early time points from peripheral blood and in mononuclear cells derived from the liver. This toxicology study supports the safety of AAV8.TBG.hLDLR for evaluation in HoFH patients, and provides some context for evaluating previously conducted clinical trials of AAV8 in patients with hemophilia. [Mh] Termos MeSH primário: Desaminase APOBEC-1/genética Dependovirus/genética Terapia Genética Vetores Genéticos/administração & dosagem Hiperlipoproteinemia Tipo II/terapia Fígado/patologia Receptores de LDL/genética [Mh] Termos MeSH secundário: Desaminase APOBEC-1/deficiência Animais Colesterol/sangue Modelos Animais de Doenças Feminino Vetores Genéticos/toxicidade Seres Humanos Hiperlipoproteinemia Tipo II/genética Fígado/metabolismo Macaca mulatta Masculino Mutação/genética Receptores de LDL/deficiência [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptors, LDL); 97C5T2UQ7J (Cholesterol); EC 3.5.4.36 (APOBEC-1 Deaminase) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170726 [Lr] Data última revisão: 170726 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170321 [St] Status: MEDLINE [do] DOI: 10.1089/humc.2017.014

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[PMID]: 28319445 [Au] Autor: Greig JA; Limberis MP; Bell P; Chen SJ; Calcedo R; Rader DJ; Wilson JM [Ad] Endereço: 1 Gene Therapy Program, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania. [Ti] Título: Nonclinical Pharmacology/Toxicology Study of AAV8.TBG.mLDLR and AAV8.TBG.hLDLR in a Mouse Model of Homozygous Familial Hypercholesterolemia. [So] Source: Hum Gene Ther Clin Dev;28(1):28-38, 2017 Mar. [Is] ISSN: 2324-8645 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The homozygous form of familial hypercholesterolemia (HoFH) is an excellent model for developing in vivo gene therapy in humans. The success of orthotropic liver transplantation in correcting the metabolic abnormalities in HoFH suggests that the correction of low-density lipoprotein receptor (LDLR) expression in hepatocytes via gene therapy should be sufficient for therapeutic efficacy. Vectors based on adeno-associated virus serotype 8 (AAV8) have been previously developed for liver-targeted gene therapy of a number of genetic diseases, including HoFH. In preparation for initiating a Phase 1 clinical trial of AAV8-mediated LDLR gene therapy for HoFH, a combined pharmacology/toxicology study was conducted in a mouse model of HoFH. No dose-limiting toxicities were found at or below 6.0 × 10 GC/kg. Therefore, the maximally tolerated dose is greater than the highest dose that was tested. Mild and transient liver pathology was noted at the highest dose. Therefore, the no effect dose was greater than or equal to the middle dose of 7.5 × 10 GC/kg. The minimally effective dose was determined to be ≤7.5 × 10 GC/kg, based on stable reductions in cholesterol that were considered to be clinically significant. This translates to a therapeutic window of ≥80-fold for the treatment of HoFH. [Mh] Termos MeSH primário: Desaminase APOBEC-1/genética Dependovirus/genética Terapia Genética Vetores Genéticos/administração & dosagem Hiperlipoproteinemia Tipo II/terapia Fígado/patologia Receptores de LDL/genética [Mh] Termos MeSH secundário: Desaminase APOBEC-1/deficiência Animais Colesterol/sangue Modelos Animais de Doenças Feminino Vetores Genéticos/toxicidade Homozigoto Seres Humanos Hiperlipoproteinemia Tipo II/genética Fígado/metabolismo Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Receptores de LDL/deficiência [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Receptors, LDL); 97C5T2UQ7J (Cholesterol); EC 3.5.4.36 (APOBEC-1 Deaminase) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170726 [Lr] Data última revisão: 170726 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170321 [St] Status: MEDLINE [do] DOI: 10.1089/humc.2017.007

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[PMID]: 28150227 [Au] Autor: Xiao J; Li X; Chen L; Han X; Zhao W; Li L; Chen JG [Ad] Endereço: School of Ophthalmology and Optometry and Eye Hospital, China State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, National Ministry of Health of China, and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, 325000 [Ti] Título: Apobec1 Promotes Neurotoxicity-Induced Dedifferentiation of Müller Glial Cells. [So] Source: Neurochem Res;42(4):1151-1164, 2017 Apr. [Is] ISSN: 1573-6903 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Retinal Müller glial cells in mammals acquire stem and progenitor cell properties after neurotoxic treatment. However, the molecular mechanisms underlying proliferation and dedifferentiation of adult Müller cells in the mammalian retina were unclear. In this study, treatments with N-methyl-D-aspartate (NMDA) plus epidermal growth factor (EGF) led to the proliferation of Müller cells and expression of stem cell markers including Nanog and Nestin in the retina. The increased mRNA for Nanog and Nestin were coincident with reduced methylation of a Nanog promoter and a Nestin enhancer specific in the neural stem cells, respectively. We found that Apolipoprotein B mRNA editing catalytic subunit 1 (Apobec1) was upregulated early in the retina treated with NMDA and EGF. Moreover, overexpression of Apobec1 in primary Müller cells increased expression of Nestin and reduced methylation of the Nestin enhancer. The data suggest that neurotoxicity-induced Apobec1 may promote expression of Nestin and help cell cycle reentry of retinal Müller cells via DNA demethylation. This study provides novel insights into the molecular mechanisms underlying dedifferentiation and proliferation of Müller cells in the mammalian retina. [Mh] Termos MeSH primário: Desaminase APOBEC-1/biossíntese Desdiferenciação Celular/fisiologia Células Ependimogliais/metabolismo Fator de Crescimento Epidérmico/toxicidade N-Metilaspartato/toxicidade [Mh] Termos MeSH secundário: Animais Desdiferenciação Celular/efeitos dos fármacos Células Cultivadas Células Ependimogliais/efeitos dos fármacos Camundongos Camundongos Endogâmicos C57BL [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 62229-50-9 (Epidermal Growth Factor); 6384-92-5 (N-Methylaspartate); EC 3.5.4.36 (APOBEC-1 Deaminase); EC 3.5.4.36 (Apobec1 protein, mouse) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170203 [St] Status: MEDLINE [do] DOI: 10.1007/s11064-016-2151-2

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[PMID]: 28112728 [Au] Autor: Cancer Genome Atlas Research Network; Albert Einstein College of Medicine; Analytical Biological Services; Barretos Cancer Hospital; Baylor College of Medicine; Beckman Research Institute of City of Hope; Buck Institute for Research on Aging; Canada's Michael Smith Genome Sciences Centre; Harvard Medical School; Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services; HudsonAlpha Institute for Biotechnology; ILSbio, LLC; Indiana University School of Medicine; Institute of Human Virology; Institute for Systems Biology; International Genomics Consortium; Leidos Biomedical; Massachusetts General Hospital; McDonnell Genome Institute at Washington University; Medical College of Wisconsin; Medical University of South Carolina; Memorial Sloan Kettering Cancer Center; Montefiore Medical Center; NantOmics; National Cancer Institute; National Hospital, Abuja, Nigeria; National Human Genome Research Institute; National Institute of Environmental Health Sciences; National Institute on Deafness &Other Communication Disorders; Ontario Tumour Bank, London Health Sciences Centre; Ontario Tumour Bank, Ontario Institute for Cancer Research; Ontario Tumour Bank, The Ottawa Hospital; Oregon Health &Science University; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center; SRA International; St Joseph's Candler Health System; Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University; Research Institute at Nationwide Children's Hospital; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University; University of Bergen; University of Texas MD Anderson Cancer Center; University of Abuja Teaching Hospital; University of Alabama at Birmingham; University of California, Irvine; University of California Santa Cruz; University of Kansas Medical Center; University of Lausanne; University of New Mexico Health Sciences Center; University of North Carolina at Chapel Hill; University of Oklahoma Health Sciences Center; University of Pittsburgh; University of São Paulo, Ribeir ão Preto Medical School; University of Southern California; University of Washington; University of Wisconsin School of Medicine &Public Health; Van Andel Research Institute; Washington University in St Louis [Ti] Título: Integrated genomic and molecular characterization of cervical cancer. [So] Source: Nature;543(7645):378-384, 2017 03 16. [Is] ISSN: 1476-4687 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: 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. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers. [Mh] Termos MeSH primário: Neoplasias do Colo do Útero/genética [Mh] Termos MeSH secundário: Desaminase APOBEC-1/genética Adenocarcinoma/genética Antígeno B7-H1/genética Carcinoma de Células Escamosas/genética Caspase 8/genética Feminino Genômica Antígenos HLA-A/genética Papillomavirus Humano 16/genética Papillomavirus Humano 16/isolamento & purificação Seres Humanos Queratinas/genética Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo Terapia de Alvo Molecular Mutação Proteínas Nucleares/genética PTEN Fosfo-Hidrolase/genética Fosfatidilinositol 3-Quinases/metabolismo Proteína 2 Ligante de Morte Celular Programada 1/genética Proteínas Serina-Treonina Quinases/genética Proteínas Serina-Treonina Quinases/metabolismo Proteômica Proteínas Proto-Oncogênicas p21(ras)/genética RNA Longo não Codificante/genética Receptor ErbB-3/genética Receptores de Fatores de Crescimento Transformadores beta/genética Receptores de Fatores de Crescimento Transformadores beta/metabolismo Transdução de Sinais Fatores de Transcrição/genética Neoplasias do Colo do Útero/classificação Neoplasias do Colo do Útero/tratamento farmacológico Integração Viral [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (ARID1A protein, human); 0 (B7-H1 Antigen); 0 (BCAR4 non-coding RNA, human); 0 (CD274 protein, human); 0 (HLA-A Antigens); 0 (KRAS protein, human); 0 (Nuclear Proteins); 0 (PDCD1LG2 protein, human); 0 (Programmed Cell Death 1 Ligand 2 Protein); 0 (RNA, Long Noncoding); 0 (Receptors, Transforming Growth Factor beta); 0 (Transcription Factors); 68238-35-7 (Keratins); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (ERBB3 protein, human); EC 2.7.10.1 (Receptor, ErbB-3); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.30 (transforming growth factor-beta type II receptor); EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (PTEN protein, human); EC 3.4.22.- (CASP8 protein, human); EC 3.4.22.- (Caspase 8); EC 3.5.4.36 (APOBEC-1 Deaminase); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171123 [Lr] Data última revisão: 171123 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170124 [St] Status: MEDLINE [do] DOI: 10.1038/nature21386

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[PMID]: 28069890 [Au] Autor: Snyder EM; McCarty C; Mehalow A; Svenson KL; Murray SA; Korstanje R; Braun RE [Ad] Endereço: The Jackson Laboratory, Bar Harbor, Maine 04609, USA. [Ti] Título: APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo. [So] Source: RNA;23(4):457-465, 2017 Apr. [Is] ISSN: 1469-9001 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Editing of the human and murine mRNA by APOBEC1, the catalytic enzyme of the protein complex that catalyzes C-to-U RNA editing, creates an internal stop codon within the APOB coding sequence, generating two protein isoforms. It has been long held that APOBEC1-mediated editing activity is dependent on the RNA binding protein A1CF. The function of A1CF in adult tissues has not been reported because a previously reported null allele displays embryonic lethality. This work aimed to address the function of A1CF in adult mouse tissues using a conditional allele. Unexpectedly, -null mice were viable and fertile with modest defects in hematopoietic, immune, and metabolic parameters. C-to-U RNA editing was quantified for multiple targets, including , in the small intestine and liver. In all cases, no changes in RNA editing efficiency were observed. Blood plasma analysis demonstrated a male-specific increase in solute concentration and increased cellularity in the glomeruli of male -null mice. Urine analysis showed a reduction in solute concentration, suggesting abnormal water homeostasis and possible kidney abnormalities exclusive to the male. Computational identification of kidney C-to-U editing sites from polyadenylated RNA-sequencing identified a number of editing sites exclusive to the kidney. However, molecular analysis of kidney C-to-U editing showed no changes in editing efficiency with A1CF loss. Taken together, these observations demonstrate that A1CF does not act as the APOBEC1 complementation factor in vivo under normal physiological conditions and suggests new roles for A1CF, specifically within the male adult kidney. [Mh] Termos MeSH primário: Desaminase APOBEC-1/genética Apolipoproteínas B/genética Ribonucleoproteínas Nucleares Heterogêneas/genética Glomérulos Renais/metabolismo Edição de RNA RNA Mensageiro/genética [Mh] Termos MeSH secundário: Desaminase APOBEC-1/metabolismo Animais Apolipoproteínas B/metabolismo Sequência de Bases Feminino Ribonucleoproteínas Nucleares Heterogêneas/deficiência Intestino Delgado/metabolismo Glomérulos Renais/patologia Fígado/metabolismo Masculino Camundongos Camundongos Knockout Especificidade de Órgãos Isoformas de Proteínas/genética Isoformas de Proteínas/metabolismo RNA Mensageiro/metabolismo Fatores Sexuais Desequilíbrio Hidroeletrolítico [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Apolipoproteins B); 0 (Heterogeneous-Nuclear Ribonucleoproteins); 0 (Protein Isoforms); 0 (RNA, Messenger); 0 (apobec-1 complementation factor, mouse); EC 3.5.4.36 (APOBEC-1 Deaminase); EC 3.5.4.36 (Apobec1 protein, mouse) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170906 [Lr] Data última revisão: 170906 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170111 [St] Status: MEDLINE [do] DOI: 10.1261/rna.058818.116

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[PMID]: 27749842 [Au] Autor: Faltas BM; Prandi D; Tagawa ST; Molina AM; Nanus DM; Sternberg C; Rosenberg J; Mosquera JM; Robinson B; Elemento O; Sboner A; Beltran H; Demichelis F; Rubin MA [Ad] Endereço: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York, USA. [Ti] Título: Clonal evolution of chemotherapy-resistant urothelial carcinoma. [So] Source: Nat Genet;48(12):1490-1499, 2016 Dec. [Is] ISSN: 1546-1718 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime. [Mh] Termos MeSH primário: Desaminase APOBEC-1/genética Carcinoma de Células de Transição/genética Evolução Clonal/genética Resistência a Medicamentos Antineoplásicos/genética Mutagênese/genética Mutação/genética Molécula L1 de Adesão de Célula Nervosa/genética Neoplasias da Bexiga Urinária/genética [Mh] Termos MeSH secundário: Antineoplásicos/farmacologia Carcinoma de Células de Transição/tratamento farmacológico Carcinoma de Células de Transição/secundário Células Clonais/metabolismo Células Clonais/patologia Exoma Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Estudos Prospectivos Neoplasias da Bexiga Urinária/tratamento farmacológico Neoplasias da Bexiga Urinária/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Neural Cell Adhesion Molecule L1); EC 3.5.4.36 (APOBEC-1 Deaminase) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161108 [St] Status: MEDLINE [do] DOI: 10.1038/ng.3692

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[PMID]: 27096365 [Au] Autor: Komor AC; Kim YB; Packer MS; Zuris JA; Liu DR [Ad] Endereço: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. [Ti] Título: Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. [So] Source: Nature;533(7603):420-4, 2016 05 19. [Is] ISSN: 1476-4687 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Current genome-editing technologies introduce double-stranded (ds) DNA breaks at a target locus as the first step to gene correction. Although most genetic diseases arise from point mutations, current approaches to point mutation correction are inefficient and typically induce an abundance of random insertions and deletions (indels) at the target locus resulting from the cellular response to dsDNA breaks. Here we report the development of 'base editing', a new approach to genome editing that enables the direct, irreversible conversion of one target DNA base into another in a programmable manner, without requiring dsDNA backbone cleavage or a donor template. We engineered fusions of CRISPR/Cas9 and a cytidine deaminase enzyme that retain the ability to be programmed with a guide RNA, do not induce dsDNA breaks, and mediate the direct conversion of cytidine to uridine, thereby effecting a C→T (or G→A) substitution. The resulting 'base editors' convert cytidines within a window of approximately five nucleotides, and can efficiently correct a variety of point mutations relevant to human disease. In four transformed human and murine cell lines, second- and third-generation base editors that fuse uracil glycosylase inhibitor, and that use a Cas9 nickase targeting the non-edited strand, manipulate the cellular DNA repair response to favour desired base-editing outcomes, resulting in permanent correction of ~15-75% of total cellular DNA with minimal (typically ≤1%) indel formation. Base editing expands the scope and efficiency of genome editing of point mutations. [Mh] Termos MeSH primário: Sistemas CRISPR-Cas Citidina Desaminase/metabolismo Citidina/genética Engenharia Genética/métodos Genoma/genética Mutação Puntual/genética Uridina/genética [Mh] Termos MeSH secundário: Desaminase APOBEC-1 Animais Apolipoproteína E4/genética Sequência de Bases Proteínas Associadas a CRISPR/metabolismo Linhagem Celular Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética DNA/genética DNA/metabolismo Clivagem do DNA Reparo do DNA Desoxirribonuclease I/metabolismo Genes p53/genética Seres Humanos Mutação INDEL/genética Camundongos RNA Guia/genética Moldes Genéticos Uracila-DNA Glicosidase/antagonistas & inibidores [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S. [Nm] Nome de substância: 0 (Apolipoprotein E4); 0 (CRISPR-Associated Proteins); 0 (RNA, Guide); 5CSZ8459RP (Cytidine); 9007-49-2 (DNA); EC 3.1.21.1 (Deoxyribonuclease I); EC 3.2.2.- (Uracil-DNA Glycosidase); EC 3.5.4.36 (APOBEC-1 Deaminase); EC 3.5.4.36 (APOBEC1 protein, human); EC 3.5.4.36 (Apobec1 protein, mouse); EC 3.5.4.5 (Cytidine Deaminase); WHI7HQ7H85 (Uridine) [Em] Mês de entrada: 1606 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160421 [St] Status: MEDLINE [do] DOI: 10.1038/nature17946

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[PMID]: 26738439 [Au] Autor: Ikeda T; Ong EB; Watanabe N; Sakaguchi N; Maeda K; Koito A [Ad] Endereço: Department of Retrovirology and Self-Defense, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. [Ti] Título: Creation of chimeric human/rabbit APOBEC1 with HIV-1 restriction and DNA mutation activities. [So] Source: Sci Rep;6:19035, 2016 Jan 07. [Is] ISSN: 2045-2322 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: APOBEC1 (A1) proteins from lagomorphs and rodents have deaminase-dependent restriction activity against HIV-1, whereas human A1 exerts a negligible effect. To investigate these differences in the restriction of HIV-1 by A1 proteins, a series of chimeric proteins combining rabbit and human A1s was constructed. Homology models of the A1s indicated that their activities derive from functional domains that likely act in tandem through a dimeric interface. The C-terminal region containing the leucine-rich motif and the dimerization domains of rabbit A1 is important for its anti-HIV-1 activity. The A1 chimeras with strong anti-HIV-1 activity were incorporated into virions more efficiently than those without anti-HIV-1 activity, and exhibited potent DNA-mutator activity. Therefore, the C-terminal region of rabbit A1 is involved in both its packaging into the HIV-1 virion and its deamination activity against both viral cDNA and genomic RNA. This study identifies the novel molecular mechanism underlying the target specificity of A1. [Mh] Termos MeSH primário: Desaminase APOBEC-1/farmacologia Fármacos Anti-HIV/farmacologia HIV-1/fisiologia Proteínas Recombinantes de Fusão/farmacologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Avaliação Pré-Clínica de Medicamentos Escherichia coli/genética Genoma Bacteriano Genoma Viral Células HEK293 HIV-1/efeitos dos fármacos Seres Humanos Mutagênicos/farmacologia Mutação Multimerização Proteica Coelhos Homologia de Sequência de Aminoácidos Vírion/efeitos dos fármacos Vírion/fisiologia Montagem de Vírus [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anti-HIV Agents); 0 (Mutagens); 0 (Recombinant Fusion Proteins); EC 3.5.4.36 (APOBEC-1 Deaminase) [Em] Mês de entrada: 1612 [Cu] Atualização por classe: 161230 [Lr] Data última revisão: 161230 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160108 [St] Status: MEDLINE [do] DOI: 10.1038/srep19035

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