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[PMID]:29206995
[Au] Autor:Wyatt AW; Annala M; Aggarwal R; Beja K; Feng F; Youngren J; Foye A; Lloyd P; Nykter M; Beer TM; Alumkal JJ; Thomas GV; Reiter RE; Rettig MB; Evans CP; Gao AC; Chi KN; Small EJ; Gleave ME
[Ad] Endereço:Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland; Department of Medicine and Department of Radiation Oncology, UCSF Helen Diller Family Comprehensive
[Ti] Título:Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.
[So] Source:J Natl Cancer Inst;109(12), 2017 Dec 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. Methods: We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Results: Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Conclusions: Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.
[Mh] Termos MeSH primário: DNA Tumoral Circulante/sangue
Neoplasias de Próstata Resistentes à Castração/genética
Neoplasias de Próstata Resistentes à Castração/patologia
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/genética
Proteína BRCA2/genética
Biomarcadores Tumorais/sangue
Biomarcadores Tumorais/genética
Inibidor de Quinase Dependente de Ciclina p27/genética
Variações do Número de Cópias de DNA
Seres Humanos
Biópsia Líquida
Masculino
Mutação
Metástase Neoplásica
Proteínas Nucleares/genética
PTEN Fosfo-Hidrolase/genética
Fosfatidilinositol 3-Quinases/genética
Receptores Androgênicos/genética
Proteínas Repressoras/genética
Proteínas de Ligação a Retinoblastoma/genética
Proteína Supressora de Tumor p53/genética
Ubiquitina-Proteína Ligases/genética
Via de Sinalização Wnt/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APC protein, human); 0 (Adenomatous Polyposis Coli Protein); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Biomarkers, Tumor); 0 (CDKN1B protein, human); 0 (Circulating Tumor DNA); 0 (Nuclear Proteins); 0 (RB1 protein, human); 0 (Receptors, Androgen); 0 (Repressor Proteins); 0 (Retinoblastoma Binding Proteins); 0 (SPOP protein, human); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.1.- (PIK3R1 protein, human); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (PTEN protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx118


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[PMID]:28792655
[Au] Autor:Bendelsmith CR; Skrypek MM; Patel SR; Pond DA; Linabery AM; Bendel AE
[Ad] Endereço:Department of Hematology-Oncology, Children's Minnesota, Minneapolis, Minnesota.
[Ti] Título:Multiple pilomatrixomas in a survivor of WNT-activated medulloblastoma leading to the discovery of a germline APC mutation and the diagnosis of familial adenomatous polyposis.
[So] Source:Pediatr Blood Cancer;65(1), 2018 Jan.
[Is] ISSN:1545-5017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Because children diagnosed with WNT-activated medulloblastoma have a 10-year overall survival rate of 95%, active long-term follow-up is critically important in reducing mortality from other causes. Here, we describe an 11-year-old adopted female who developed multiple pilomatrixomas 3 years after diagnosis of WNT-activated medulloblastoma, an unusual finding that prompted deeper clinical investigation. A heterozygous germline APC gene mutation was discovered, consistent with familial adenomatous polyposis. Screening endoscopy revealed numerous precancerous polyps that were excised. This case highlights the importance of long-term follow-up of pediatric cancer survivors, including attention to unexpected symptoms, which might unveil an underlying cancer predisposition syndrome.
[Mh] Termos MeSH primário: Proteína da Polipose Adenomatosa do Colo
Polipose Adenomatosa do Colo
Sobreviventes de Câncer
Neoplasias Cerebelares
Mutação em Linhagem Germinativa
Doenças do Cabelo
Meduloblastoma
Segunda Neoplasia Primária
Pilomatrixoma
Neoplasias Cutâneas
Proteínas Wnt
[Mh] Termos MeSH secundário: Polipose Adenomatosa do Colo/diagnóstico
Polipose Adenomatosa do Colo/genética
Polipose Adenomatosa do Colo/metabolismo
Polipose Adenomatosa do Colo/patologia
Proteína da Polipose Adenomatosa do Colo/genética
Proteína da Polipose Adenomatosa do Colo/metabolismo
Neoplasias Cerebelares/diagnóstico
Neoplasias Cerebelares/genética
Neoplasias Cerebelares/metabolismo
Neoplasias Cerebelares/patologia
Criança
Feminino
Doenças do Cabelo/diagnóstico
Doenças do Cabelo/genética
Doenças do Cabelo/metabolismo
Doenças do Cabelo/patologia
Seres Humanos
Meduloblastoma/diagnóstico
Meduloblastoma/genética
Meduloblastoma/metabolismo
Meduloblastoma/patologia
Segunda Neoplasia Primária/diagnóstico
Segunda Neoplasia Primária/genética
Segunda Neoplasia Primária/metabolismo
Segunda Neoplasia Primária/patologia
Pilomatrixoma/diagnóstico
Pilomatrixoma/genética
Pilomatrixoma/metabolismo
Pilomatrixoma/patologia
Neoplasias Cutâneas/diagnóstico
Neoplasias Cutâneas/genética
Neoplasias Cutâneas/metabolismo
Neoplasias Cutâneas/patologia
Proteínas Wnt/genética
Proteínas Wnt/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APC protein, human); 0 (Adenomatous Polyposis Coli Protein); 0 (Wnt Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171129
[Lr] Data última revisão:
171129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.1002/pbc.26756


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[PMID]:28916710
[Au] Autor:Nakagawa N; Li J; Yabuno-Nakagawa K; Eom TY; Cowles M; Mapp T; Taylor R; Anton ES
[Ad] Endereço:University of North Carolina Neuroscience Center, Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
[Ti] Título:APC sets the Wnt tone necessary for cerebral cortical progenitor development.
[So] Source:Genes Dev;31(16):1679-1692, 2017 Aug 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenomatous polyposis coli (APC) regulates the activity of ß-catenin, an integral component of Wnt signaling. However, the selective role of the APC-ß-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated ß-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC-ß-catenin pathway indicates that the maintenance of appropriate ß-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex. APC deletion deregulates ß-catenin, leads to high Wnt tone, and disrupts Notch1 signaling and primary cilium maintenance necessary for radial progenitor functions. ß-Catenin deregulation directly disrupts cilium maintenance and signaling via Tulp3, essential for intraflagellar transport of ciliary signaling receptors. Surprisingly, deletion of ß-catenin or inhibition of ß-catenin activity in APC-null progenitors rescues the APC-null phenotype. These results reveal that APC-regulated ß-catenin activity in cortical progenitors sets the appropriate Wnt tone necessary for normal cerebral cortical development.
[Mh] Termos MeSH primário: Proteína da Polipose Adenomatosa do Colo/fisiologia
Córtex Cerebral/embriologia
Células-Tronco Neurais/metabolismo
Neurogênese
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/genética
Animais
Proliferação Celular
Córtex Cerebral/citologia
Córtex Cerebral/metabolismo
Cílios/metabolismo
Proteínas Hedgehog/metabolismo
Camundongos
Camundongos Knockout
Células-Tronco Neurais/citologia
Receptor Notch1/metabolismo
beta Catenina/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenomatous Polyposis Coli Protein); 0 (CTNNB1 protein, mouse); 0 (Hedgehog Proteins); 0 (Notch1 protein, mouse); 0 (Receptor, Notch1); 0 (Shh protein, mouse); 0 (adenomatous polyposis coli protein, mouse); 0 (beta Catenin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171029
[Lr] Data última revisão:
171029
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.1101/gad.302679.117


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[PMID]:28856770
[Au] Autor:Graupner A; Eide DM; Brede DA; Ellender M; Lindbo Hansen E; Oughton DH; Bouffler SD; Brunborg G; Olsen AK
[Ad] Endereço:Department of Molecular Biology, Norwegian Institute of Public Health, Oslo, 0403, Norway.
[Ti] Título:Genotoxic effects of high dose rate X-ray and low dose rate gamma radiation in Apc mice.
[So] Source:Environ Mol Mutagen;58(8):560-569, 2017 Oct.
[Is] ISSN:1098-2280
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Risk estimates for radiation-induced cancer in humans are based on epidemiological data largely drawn from the Japanese atomic bomb survivor studies, which received an acute high dose rate (HDR) ionising radiation. Limited knowledge exists about the effects of chronic low dose rate (LDR) exposure, particularly with respect to the application of the dose and dose rate effectiveness factor. As part of a study to investigate the development of colon cancer following chronic LDR vs. acute HDR radiation, this study presents the results of genotoxic effects in blood of exposed mice. CBAB6 F1 Apc (wild type) and Apc mice were chronically exposed to estimated whole body absorbed doses of 1.7 or 3.2 Gy Co-γ-rays at a LDR (2.2 mGy h ) or acutely exposed to 2.6 Gy HDR X-rays (1.3 Gy min ). Genotoxic endpoints assessed in blood included chromosomal damage (flow cytometry based micronuclei (MN) assay), mutation analyses (Pig-a gene mutation assay), and levels of DNA lesions (Comet assay, single-strand breaks (ssb), alkali labile sites (als), oxidized DNA bases). Ionising radiation (ca. 3 Gy) induced genotoxic effects dependent on the dose rate. Chromosomal aberrations (MN assay) increased 3- and 10-fold after chronic LDR and acute HDR, respectively. Phenotypic mutation frequencies as well as DNA lesions (ssb/als) were modulated after acute HDR but not after chronic LDR. The Apc genotype did not influence the outcome in any of the investigated endpoints. The results herein will add to the scant data available on genotoxic effects following chronic LDR of ionising radiation. Environ. Mol. Mutagen. 58:560-569, 2017. © 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
[Mh] Termos MeSH primário: Sobrevivência Celular/efeitos da radiação
Aberrações Cromossômicas/efeitos da radiação
Dano ao DNA/efeitos da radiação
Neoplasias Induzidas por Radiação/genética
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/genética
Animais
Relação Dose-Resposta à Radiação
Raios gama
Seres Humanos
Camundongos
Testes para Micronúcleos
Mutação
Neoplasias Induzidas por Radiação/patologia
Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenomatous Polyposis Coli Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1002/em.22121


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[PMID]:28791728
[Au] Autor:Barrow TM; Klett H; Toth R; Böhm J; Gigic B; Habermann N; Scherer D; Schrotz-King P; Skender S; Abbenhardt-Martin C; Zielske L; Schneider M; Ulrich A; Schirmacher P; Herpel E; Brenner H; Busch H; Boerries M; Ulrich CM; Michels KB
[Ad] Endereço:German Cancer Consortium (DKTK), Heidelberg, Germany.
[Ti] Título:Smoking is associated with hypermethylation of the APC 1A promoter in colorectal cancer: the ColoCare Study.
[So] Source:J Pathol;243(3):366-375, 2017 Nov.
[Is] ISSN:1096-9896
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Smoking tobacco is a known risk factor for the development of colorectal cancer and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never-smokers, 47 former smokers, and 13 active smokers, and in adjacent mucosa from 49 never-smokers, 64 former smokers, and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS < 1 × 10 ) in the tumours of active smokers. The APC 1A promoter was hypermethylated in 7 of 36 tumours from never-smokers (19%), 12 of 47 tumours from former smokers (26%), and 8 of 13 tumours from active smokers (62%). Promoter hypermethylation was positively associated with duration of smoking (Spearman rank correlation, ρ = 0.26, p = 0.03) and was confined to tumours, with hypermethylation never being observed in adjacent mucosa. Further analysis of adjacent mucosa revealed significant hypomethylation of four loci associated with the TNXB gene in tissue from active smokers. Our findings provide exploratory evidence for hypermethylation of the key tumour suppressor gene APC being implicated in smoking-associated colorectal carcinogenesis. Further work is required to establish the validity of our observations in independent cohorts. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Proteína da Polipose Adenomatosa do Colo/genética
Neoplasias Colorretais/genética
Metilação de DNA/genética
Regiões Promotoras Genéticas/genética
Fumar/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Idoso
Epigênese Genética/genética
Feminino
Seres Humanos
Neoplasias Pulmonares/genética
Masculino
Meia-Idade
Fumar/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APC protein, human); 0 (Adenomatous Polyposis Coli Protein)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.1002/path.4955


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[PMID]:28759012
[Au] Autor:Li D; Zhang Y; Liu K; Zhao Y; Xu B; Xu L; Tan L; Tian Y; Li C; Zhang W; Cao H; Zhan YY; Hu T
[Ad] Endereço:Cancer Research Center, Xiamen University Medical College, Xiamen, China.
[Ti] Título:Berberine inhibits colitis-associated tumorigenesis via suppressing inflammatory responses and the consequent EGFR signaling-involved tumor cell growth.
[So] Source:Lab Invest;97(11):1343-1353, 2017 Nov.
[Is] ISSN:1530-0307
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The anti-inflammatory and anti-tumor effects of berberine, a traditional Chinese medicine, were separately discovered in pathological intestinal tissues. However, whether the anti-inflammatory effect of berberine contributes to its anti-tumor effect on colitis-associated colorectal cancer (CACRC) remains unknown. In the present study, we found that berberine effectively inhibited colitis-associated tumorigenesis and colonic epithelium hyperproliferation in dextran sulfate sodium (DSS)-treated Apc mice. A mechanistic study identified that these inhibitory effects of berberine occurred through blocking interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in colonic macrophages. An in vitro study on cell lines identified that berberine treatment of Raw 264.7 macrophages resulted in conditioned media with fewer proliferative effects on a cell line with a heterozygous Apc mutation (Immorto-Min colonic epithelium, IMCE). EGFR-ERK signaling act downstream of berberine/pro-inflammatory cytokines axis to regulate CACRC cell proliferation. Furthermore, in vivo administration of IL-6 to DSS-treated Apc mice effectively weakened the inhibitory effects of berberine on tumorigenesis and EGFR-ERK signaling in colon tissues. Altogether, the results of our studies have revealed that berberine inhibits the development of CACRC by interfering with inflammatory response-driven EGFR signaling in tumor cell growth. The findings of this study support the possibility that berberine and other anti-inflammatory drugs may be beneficial in the treatment of CACRC.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/uso terapêutico
Anticarcinógenos/uso terapêutico
Berberina/uso terapêutico
Carcinogênese/efeitos dos fármacos
Colite/tratamento farmacológico
Neoplasias Colorretais/prevenção & controle
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/genética
Proteína da Polipose Adenomatosa do Colo/metabolismo
Animais
Anti-Inflamatórios não Esteroides/farmacologia
Anticarcinógenos/farmacologia
Berberina/farmacologia
Linhagem Celular
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Colite/imunologia
Colite/metabolismo
Colite/fisiopatologia
Colo/efeitos dos fármacos
Colo/imunologia
Colo/metabolismo
Colo/patologia
Neoplasias Colorretais/etiologia
Mucosa Intestinal/efeitos dos fármacos
Mucosa Intestinal/imunologia
Mucosa Intestinal/metabolismo
Mucosa Intestinal/patologia
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Macrófagos/metabolismo
Macrófagos/patologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Mutação
Células RAW 264.7
Distribuição Aleatória
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Receptor do Fator de Crescimento Epidérmico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenomatous Polyposis Coli Protein); 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Anticarcinogenic Agents); 0 (adenomatous polyposis coli protein, mouse); 0I8Y3P32UF (Berberine); EC 2.7.10.1 (EGFR protein, mouse); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1038/labinvest.2017.71


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[PMID]:28698030
[Au] Autor:Hunt M; Lu P; Tuszynski MH
[Ad] Endereço:Dept. of Neurosciences, University of California - San Diego, La Jolla, CA, USA.
[Ti] Título:Myelination of axons emerging from neural progenitor grafts after spinal cord injury.
[So] Source:Exp Neurol;296:69-73, 2017 Oct.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neural progenitor cells (NPCs) grafted to sites of spinal cord injury (SCI) extend numerous axons over long distances and form new synaptic connections with host neurons. In the present study we examined the myelination of axons emerging from NPC grafts. Rat embryonic day 14 (E14) multipotent NPCs constitutively expressing GFP were grafted into adult C5 spinal cord hemisection lesions; 3months later we examined graft-derived axonal diameter and myelination using transmission electron microscopy. 104 graft-derived axons were characterized. Axon diameter ranged from 0.15 to 1.70µm, and 24% of graft-derived axons were myelinated by host oligodendrocytes caudal to the lesion. The average diameter of myelinated axons (0.72±0.3µm) was significantly larger than that of non-myelinated axons (0.61±0.2µm, p<0.05). Notably, the G-ratio of myelinated graft-derived axons (0.77±0.01) was virtually identical to that of the normal, intact spinal cord described in published reports. These findings indicate that axons emerging from early stage neural grafts into the injured spinal cord recapitulate both the small/medium size range and myelin thickness of intact spinal cord axons.
[Mh] Termos MeSH primário: Axônios/patologia
Bainha de Mielina/patologia
Células-Tronco Neurais/transplante
Traumatismos da Medula Espinal/cirurgia
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/metabolismo
Animais
Axônios/fisiologia
Axônios/ultraestrutura
Células Cultivadas
Embrião de Mamíferos
Feminino
Proteína Glial Fibrilar Ácida/metabolismo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Peptídeos e Proteínas de Sinalização Intercelular/farmacologia
Microscopia Eletrônica de Transmissão e Varredura
Proteína Básica da Mielina/metabolismo
Bainha de Mielina/metabolismo
Bainha de Mielina/ultraestrutura
Células-Tronco Neurais/efeitos dos fármacos
Células-Tronco Neurais/ultraestrutura
Ratos
Ratos Endogâmicos F344
Ratos Transgênicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenomatous Polyposis Coli Protein); 0 (Glial Fibrillary Acidic Protein); 0 (Intercellular Signaling Peptides and Proteins); 0 (Myelin Basic Protein); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE


  8 / 1753 MEDLINE  
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[PMID]:28663347
[Au] Autor:Juanes MA; Bouguenina H; Eskin JA; Jaiswal R; Badache A; Goode BL
[Ad] Endereço:Department of Biology, Brandeis University, Waltham, MA juanes@brandeis.edu.
[Ti] Título:Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover.
[So] Source:J Cell Biol;216(9):2859-2875, 2017 Sep 04.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell motility depends on tight coordination between the microtubule (MT) and actin cytoskeletons, but the mechanisms underlying this MT-actin cross talk have remained poorly understood. Here, we show that the tumor suppressor protein adenomatous polyposis coli (APC), which is a known MT-associated protein, directly nucleates actin assembly to promote directed cell migration. By changing only two residues in APC, we generated a separation-of-function mutant, APC (m4), that abolishes actin nucleation activity without affecting MT interactions. Expression of full-length APC carrying the m4 mutation (APC (m4)) rescued cellular defects in MT organization, MT dynamics, and mitochondrial distribution caused by depletion of endogenous APC but failed to restore cell migration. Wild-type APC and APC (m4) localized to focal adhesions (FAs), and APC (m4) was defective in promoting actin assembly at FAs to facilitate MT-induced FA turnover. These results provide the first direct evidence for APC-mediated actin assembly in vivo and establish a role for APC in coordinating MTs and actin at FAs to direct cell migration.
[Mh] Termos MeSH primário: Citoesqueleto de Actina/metabolismo
Actinas/metabolismo
Proteína da Polipose Adenomatosa do Colo/metabolismo
Movimento Celular
Adesões Focais/metabolismo
Microtúbulos/metabolismo
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/genética
Actinas/genética
Proteína da Polipose Adenomatosa do Colo/genética
Linhagem Celular Tumoral
Adesões Focais/genética
Seres Humanos
Microscopia de Fluorescência
Microscopia de Vídeo
Microtúbulos/genética
Mutagênese Sítio-Dirigida
Mutação
Interferência de RNA
Transdução de Sinais
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (APC protein, human); 0 (Actins); 0 (Adenomatous Polyposis Coli Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201702007


  9 / 1753 MEDLINE  
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[PMID]:28650985
[Au] Autor:Hayes KS; Cliffe LJ; Bancroft AJ; Forman SP; Thompson S; Booth C; Grencis RK
[Ad] Endereço:School of Biological Sciences, FBMH, MAHSC, University of Manchester, Manchester, United Kingdom.
[Ti] Título:Chronic Trichuris muris infection causes neoplastic change in the intestine and exacerbates tumour formation in APC min/+ mice.
[So] Source:PLoS Negl Trop Dis;11(6):e0005708, 2017 Jun.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Incidences of infection-related cancers are on the rise in developing countries where the prevalence of intestinal nematode worm infections are also high. Trichuris muris (T. muris) is a murine gut-dwelling nematode that is the direct model for human T. trichiura, one of the major soil-transmitted helminth infections of humans. In order to assess whether chronic infection with T. muris does indeed influence the development of cancer hallmarks, both wild type mice and colon cancer model (APC min/+) mice were infected with this parasite. Parasite infection in wild type mice led to the development of neoplastic change similar to that seen in mice that had been treated with the carcinogen azoxymethane. Additionally, both chronic and acute infection in the APCmin/+ mice led to an enhanced tumour development that was distinct to the site of infection suggesting systemic control. By blocking the parasite induced T regulatory response in these mice, the increase in the number of tumours following infection was abrogated. Thus T. muris infection alone causes an increase in gut pathologies that are known to be markers of cancer but also increases the incidence of tumour formation in a colon cancer model. The influence of parasitic worm infection on the development of cancer may therefore be significant.
[Mh] Termos MeSH primário: Proteína da Polipose Adenomatosa do Colo/deficiência
Proteína da Polipose Adenomatosa do Colo/metabolismo
Carcinogênese
Neoplasias do Colo/epidemiologia
Tricuríase/complicações
Trichuris/patogenicidade
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/genética
Animais
Doença Crônica
Neoplasias do Colo/etiologia
Modelos Animais de Doenças
Incidência
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenomatous Polyposis Coli Protein); 0 (adenomatous polyposis coli protein, mouse)
[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:170627
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005708


  10 / 1753 MEDLINE  
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[PMID]:28628120
[Au] Autor:Nakayama M; Sakai E; Echizen K; Yamada Y; Oshima H; Han TS; Ohki R; Fujii S; Ochiai A; Robine S; Voon DC; Tanaka T; Taketo MM; Oshima M
[Ad] Endereço:Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
[Ti] Título:Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation.
[So] Source:Oncogene;36(42):5885-5896, 2017 Oct 19.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated Apc Trp53 villin-CreER compound mice, in which mutant p53 was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids. Mutant Trp53 , but not Trp53-null mutation accelerated submucosal invasion with generation of desmoplastic microenvironment. The nuclear accumulation of p53 was evident in Apc Trp53 homozygous tumors like human CRC. Although p53 was distributed to the cytoplasm in Apc Trp53 heterozygous tumors, it accumulated in the nuclei at the invasion front, suggesting a regulation mechanism for p53 localization by the microenvironment. Importantly, mutant p53 induced drastic morphological changes in the tumor organoids to complex glandular structures, which was associated with the acquisition of invasiveness. Consistently, the branching scores of human CRC that carry TP53 mutations at codon 273 significantly increased in comparison with those of TP53 wild-type tumors. Moreover, allografted Apc Trp53 organoid tumors showed a malignant histology with an increased number of myofibroblasts in the stroma. These results indicate that nuclear-accumulated mutant p53 induces malignant progression of intestinal tumors through complex tumor gland formation and acquisition of invasiveness. Furthermore, RNA sequencing analyses revealed global gene upregulation by mutant p53 , which was associated with the activation of inflammatory and innate immune pathways. Accordingly, it is possible that mutant p53 induces CRC progression, not only by a cell intrinsic mechanism, but also by the generation or activation of the microenvironment, which may synergistically contribute to the acceleration of submucosal invasion. Therefore, the present study indicates that nuclear-accumulated mutant p53 is a potential therapeutic target for the treatment of advanced CRCs.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica
Neoplasias Intestinais/patologia
Neoplasias Hepáticas/secundário
Mutação
Proteína Supressora de Tumor p53/genética
[Mh] Termos MeSH secundário: Proteína da Polipose Adenomatosa do Colo/metabolismo
Animais
Progressão da Doença
Perfilação da Expressão Gênica
Seres Humanos
Neoplasias Intestinais/genética
Neoplasias Intestinais/metabolismo
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos NOD
Camundongos Knockout
Camundongos SCID
Invasividade Neoplásica
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
Microambiente Tumoral
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenomatous Polyposis Coli Protein); 0 (Tumor Suppressor Protein p53); 0 (adenomatous polyposis coli protein, mouse); EC 3.6.5.2 (Kras2 protein, mouse); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2017.194



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