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[PMID]:29385186
[Au] Autor:Eladak S; Moison D; Guerquin MJ; Matilionyte G; Kilcoyne K; N'Tumba-Byn T; Messiaen S; Deceuninck Y; Pozzi-Gaudin S; Benachi A; Livera G; Antignac JP; Mitchell R; Rouiller-Fabre V; Habert R
[Ad] Endereço:Univ. Paris Diderot, Sorbonne Paris Cité, Laboratory of Development of the Gonads, Unit of Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses, France.
[Ti] Título:Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis.
[So] Source:PLoS One;13(1):e0191934, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Using an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 µM BPA decreases basal, but not LH-stimulated, testosterone secreted by the first trimester human fetal testis. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and also to study the effect of BPA on germ cell development using both the hFETA and xenograft models. METHODS: Using the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 µM BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 µM BPA (~ 500 µg/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 µM and 0.038 µM respectively. Mice grafted with second trimester testes received 0.5 and 50 µg/kg/day BPA by oral gavage for 5 weeks. RESULTS: With first trimester human testes, using the hFeTA model, 10 µM BPA increased germ cell apoptosis. In xenografts, germ cell density was also reduced by BPA exposure. Importantly, BPA exposure significantly decreased the percentage of germ cells expressing the pluripotency marker AP-2γ, whilst the percentage of those expressing the pre-spermatogonial marker MAGE-A4 significantly increased. BPA exposure did not affect hCG-stimulated androgen production in first and second trimester xenografts as evaluated by both plasma testosterone level and seminal vesicle weight in host mice. CONCLUSIONS: Exposure to BPA at environmentally relevant concentrations impairs germ cell development in first trimester human fetal testis, whilst gonadotrophin-stimulated testosterone production was unaffected in both first and second trimester testis. Studies using first trimester human fetal testis demonstrate the complementarity of the FeTA and xenograft models for determining the respective short-term and long term effects of environmental exposures.
[Mh] Termos MeSH primário: Compostos Benzidrílicos/toxicidade
Poluentes Ambientais/toxicidade
Células Intersticiais do Testículo/efeitos dos fármacos
Fenóis/toxicidade
Espermatozoides/efeitos dos fármacos
Testículo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Feminino
Xenoenxertos
Seres Humanos
Masculino
Camundongos
Camundongos Nus
Gravidez
Primeiro Trimestre da Gravidez
Segundo Trimestre da Gravidez
Radioimunoensaio
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Testículo/citologia
Testículo/embriologia
Testosterona/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzhydryl Compounds); 0 (Environmental Pollutants); 0 (Phenols); 3XMK78S47O (Testosterone); MLT3645I99 (bisphenol A)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191934


  2 / 58434 MEDLINE  
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[PMID]:29351887
[Au] Autor:Jin R; Chen Q; Yao S; Bai E; Fu W; Wang L; Wang J; Du X; Wei T; Xu H; Jiang C; Qiu P; Wu J; Li W; Liang G
[Ad] Endereço:Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
[Ti] Título:Synthesis and anti-tumor activity of EF24 analogues as IKKß inhibitors.
[So] Source:Eur J Med Chem;144:218-228, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:EF24 is an IKKß inhibitor (IC : 72 µM) containing various anti-tumor activities. In this study, a series of EF24 analogs targeting IKKß were designed and synthesized. Several IKKß inhibitors with better activities than EF24 were screened out and B3 showed best IKKß inhibitory (IC : 6.6 µM). Molecular docking and dynamic simulation experiments further confirmed this inhibitory effect. B3 obviously suppressed the viability of Hela229, A549, SGC-7901 and MGC-803 cells. Then, in SGC-7901 and MGC-803 cells, B3 blocked the NF-κB signal pathway by inhibiting IKKß phosphorylation, and followed arrested the cell cycle at G2/M phase by suppressing the Cyclin B1 and Cdc2 p34 expression, induced the cell apoptosis by down-regulating Bcl-2 protein and up-regulating cleaved-caspase3. Moreover, B3 significantly reduced tumor growth and suppressed the IKKß-NF-κB signal pathway in SGC-7901 xenograft model. In total, this study present a potential IKKß inhibitor as anti-tumor precursor.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Compostos de Benzilideno/química
Compostos de Benzilideno/farmacologia
Quinase I-kappa B/antagonistas & inibidores
Piperidonas/química
Piperidonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/uso terapêutico
Apoptose/efeitos dos fármacos
Compostos de Benzilideno/síntese química
Compostos de Benzilideno/uso terapêutico
Linhagem Celular Tumoral
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos
Seres Humanos
Quinase I-kappa B/metabolismo
Camundongos Nus
Simulação de Acoplamento Molecular
NF-kappa B/metabolismo
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Neoplasias/patologia
Fosforilação/efeitos dos fármacos
Piperidonas/síntese química
Piperidonas/uso terapêutico
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3,5-bis(2-fluorobenzylidene)piperidin-4-one); 0 (Antineoplastic Agents); 0 (Benzylidene Compounds); 0 (NF-kappa B); 0 (Piperidones); EC 2.7.11.10 (I-kappa B Kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE


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[PMID]:28471399
[Au] Autor:Wang CC; Wang YX; Yu NQ; Hu D; Wang XY; Chen XG; Liao YW; Yao J; Wang H; He L; Wu L
[Ad] Endereço:School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. w940984614@hotmail.com.
[Ti] Título:Brazilian Green Propolis Extract Synergizes with Protoporphyrin IX-mediated Photodynamic Therapy via Enhancement of Intracellular Accumulation of Protoporphyrin IX and Attenuation of NF-κB and COX-2.
[So] Source:Molecules;22(5), 2017 May 04.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Brazilian green propolis (BGP) is noted for its impressive antitumor effects and has been used as a folk medicine in various cultures for many years. It has been demonstrated that BGP could enhance the cytotoxic effect of cytostatic drugs on tumor cells. Photodynamic therapy (PDT) is a therapeutic approach used against malignant cells. To assess the synergistic effect of BGP extract on protoporphyrin IX (PpIX)-mediated photocytotoxicity, MTT assays were performed using A431 and HeLa cells. TUNEL assay and Annexin V-FITC/PI staining were performed to confirm the induction of apoptosis. Western blotting analysis was performed to examine the pro-apoptotic proteins, anti-apoptotic proteins and inflammation related proteins in A431 cells. Intracellular accumulation of PpIX was examined by flow cytometry. The synergistic effect of BGP extract in PpIX-PDT was also evaluated with a xenograft model. Our findings reveal that BGP extract increased PpIX-mediated photocytotoxicity in A431 and HeLa cells. PpIX-PDT with BGP extract treatment resulted in a decrease in Bcl-xL and an increase in NOXA, Bax and caspase-3 cleavage. The protein expression levels of p-IKKα/ß, NF-κB and COX-2 were upregulated by PpIX-PDT but significantly attenuated when in combination with BGP extract. BGP extract was also found to significantly enhance the intracellular accumulation of PpIX in A431 cells. BGP extract increased PpIX-mediated photocytotoxicity in a xenograft model as well. Our findings provide evidence for a synergistic effect of BGP extract in PpIX-PDT both in vitro and in vivo.
[Mh] Termos MeSH primário: Ciclo-Oxigenase 2/metabolismo
NF-kappa B/metabolismo
Fotoquimioterapia
Própole
Protoporfirinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Brasil
Linhagem Celular Tumoral
Cromatografia Líquida de Alta Pressão
Sinergismo Farmacológico
Citometria de Fluxo
Xenoenxertos
Seres Humanos
Camundongos Endogâmicos BALB C
Camundongos Nus
Protoporfirinas/farmacocinética
Espectrofotometria Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NF-kappa B); 0 (Protoporphyrins); 9009-62-5 (Propolis); C2K325S808 (protoporphyrin IX); EC 1.14.99.1 (Cyclooxygenase 2)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


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[PMID]:29314203
[Au] Autor:Zhen Q; Gao LN; Wang RF; Chu WW; Zhang YX; Zhao XJ; Lv BL; Liu JB
[Ad] Endereço:Department of Thoracic Surgery, Shijiazhuang No.1 Hospital, Shijiazhuang, Hebei Province, China.
[Ti] Título:LncRNA PCAT-1 promotes tumour growth and chemoresistance of oesophageal cancer to cisplatin.
[So] Source:Cell Biochem Funct;36(1):27-33, 2018 Jan.
[Is] ISSN:1099-0844
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Oesophageal cancer (OC) is one of the most fatal malignancies in the world, and chemoresistance restricts the therapeutic outcome of OC. Long noncoding RNA (lncRNA) was reported to play roles in multiple cancer types. Yet, the function of lncRNA in chemoresistance of OC has not been reported. A lncRNA gene, PCAT-1, showed higher expression in OC tissues, especially higher in secondary OC compared with normal mucosa tissues. Overexpression of PCAT-1 increased the proliferation rate and growth of OC cells. Inhibition of PCAT-1 decreased proliferation and growth of OC cells, and increased cisplatin chemosensitivity. In a mouse OC xenograft model, PCAT-1 inhibition repressed OC growth in vivo. Therefore, PCAT-1 may potentially serve as a therapeutic target for treating OC. PCAT-1 promotes development of OC and represses the chemoresistance of OC to cisplatin, and silencing of PCAT-1 may be a therapeutic strategy for treating OC.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Cisplatino/farmacologia
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Neoplasias Esofágicas/tratamento farmacológico
Neoplasias Esofágicas/patologia
RNA Longo não Codificante/genética
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos/genética
Neoplasias Esofágicas/genética
Seres Humanos
Masculino
Camundongos
Camundongos Nus
RNA Longo não Codificante/metabolismo
Relação Estrutura-Atividade
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (RNA, Long Noncoding); 0 (long non-coding RNA PCAT1, human); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180110
[St] Status:MEDLINE
[do] DOI:10.1002/cbf.3314


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[PMID]:29282749
[Au] Autor:Hou L; Wang J; Wang Y; Hua X; Wu J
[Ad] Endereço:Renji Hospital, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), School of Medicine, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
[Ti] Título:Compared proteomic analysis of 8- and 32-week-old postnatal porcine ovaries.
[So] Source:Cell Biochem Funct;36(1):34-42, 2018 Jan.
[Is] ISSN:1099-0844
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pigs share many anatomical and physiological features with humans, offering a unique and viable model for biomedical research. Tandem mass tag method followed by mass spectrometry analysis was utilized to identify peptides (47,405), proteins (14,701), and protein groups (7634) in ovaries of 8- and 32-week-old postnatal Banna miniature pigs. After annotation and analysis by Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology, the proteins were identified as being involved in hormone metabolic pathways and maintenance, proliferation, and regulation of stem cells. In addition, we found 638 differentially expressed proteins between ovaries of 8- and 32-week-old postnatal Banna miniature pigs. We used Interactive Pathway Explorer to produce an overview of pig ovarian proteomics. Compared with those of the 8-week-old group, the proteins enriched in metabolism of steroid hormones, metabolism of lipids, and energy metabolism pathway were upregulated in the 32-week-old group, indicating physiological characteristics of sexual maturity. These findings have implications in applications of biomedicine. SIGNIFICANCE OF THE STUDY: Pigs share many anatomical and physiological features with humans, offering a unique and viable model for biomedical research. In this study, we used tandem mass tag quantitative proteomics to describe, for the first time, protein expression patterns of postnatal pig ovaries. Proteins involved in hormone metabolic pathways and maintenance, proliferation, and regulation of stem cells were identified. With further analysis by Interactive Pathway Explorer, proteins enriched in metabolism of steroid hormones, metabolism of lipids, and energy metabolism pathway were upregulated in the 32-week-old group, indicating physiological characteristics of sexual maturity. These findings have implications in applications of biomedicine.
[Mh] Termos MeSH primário: Ovário/química
Peptídeos/análise
Proteínas/análise
Proteômica
[Mh] Termos MeSH secundário: Animais
Proliferação Celular
Cromatografia Líquida
Feminino
Espectrometria de Massas
Camundongos
Camundongos Nus
Ovário/metabolismo
Peptídeos/metabolismo
Proteínas/metabolismo
Células-Tronco/citologia
Células-Tronco/metabolismo
Suínos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides); 0 (Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171229
[St] Status:MEDLINE
[do] DOI:10.1002/cbf.3315


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[PMID]:28464467
[Au] Autor:Torigata M; Yamakawa D; Takakura N
[Ad] Endereço:Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
[Ti] Título:Elevated expression of Tie1 is accompanied by acquisition of cancer stemness properties in colorectal cancer.
[So] Source:Cancer Med;6(6):1378-1388, 2017 Jun.
[Is] ISSN:2045-7634
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Tie receptors 1 and 2 (Tie1/2) play crucial roles in embryonic angiogenesis. Recent studies suggest enhanced expression of Tie1 in several types of cancer and negative correlations between Tie1 levels and clinical outcome. These observations suggest important functions of Tie1 not only for vascular formation but also in tumorigenesis. Ligands for Tie2, that is angiopoietins 1-4, have been identified, but not for Tie1. To determine the molecular functions of Tie1, its detailed characterization in tumors would be helpful. Herein, we report that Tie1 is up-regulated in colorectal cancer. Detailed analysis using tumor-bearing models and immunohistochemistry combined with Flow cytometric analysis and cell sorting (FACS) revealed that Tie1 protein was expressed in a small population of malignant tumor cells. Intriguingly, Tie1 expression was observed and could be maintained only in vivo. Further analysis using sphere-formation culture revealed that Tie1-positive cells are enriched within the population of tumor cells with cancer stemness properties. Indeed, Tie1-positive tumor cells derived from a murine model overexpressed Lgr5, a typical stemness marker for colorectal cancer. Our results provide a novel insight into Tie1 function in tumorigenesis and suggest clinical applications to target cancer stem cells.
[Mh] Termos MeSH primário: Neoplasias Colorretais/metabolismo
Receptor de TIE-1/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular
Neoplasias Colorretais/genética
Seres Humanos
Camundongos
Camundongos Nus
Células-Tronco Neoplásicas
RNA Mensageiro/metabolismo
Receptor de TIE-1/genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); EC 2.7.10.1 (Receptor, TIE-1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cam4.1072


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[PMID]:28461099
[Au] Autor:Alaaeldin E; Abu Lila AS; Ando H; Fukushima M; Huang CL; Wada H; Sarhan HA; Khaled KA; Ishida T
[Ad] Endereço:Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
[Ti] Título:Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules.
[So] Source:J Control Release;255:210-217, 2017 Jun 10.
[Is] ISSN:1873-4995
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Many therapeutic strategies have been applied in efforts to conquer the development and/or progression of cancer. The combination of chemotherapy and an RNAi-based approach has proven to be an efficient anticancer therapy. However, the feasibility of such a therapeutic strategy has been substantially restricted either by the failure to achieve the efficient delivery of RNAi molecules to tumor tissue or by the immunostimulatory response triggered by RNAi molecules. In this study, therefore, we intended to investigate the efficacy of using liposomal oxaliplatin (liposomal l-OHP) to guarantee the efficient delivery of RNAi molecules, namely shRNA against thymidylate synthase (TS shRNA) complexed with cationic liposome (TS shRNA-lipoplex), to solid tumors, and to suppress the immunostimulatory effect of RNAi molecules, TS shRNA, following intravenous administration. Herein, we describe how liposomal l-OHP enhanced the intra-tumor accumulation of TS shRNA-lipoplex and significantly reduced the immunostimulatory response triggered by TS shRNA. Consequently, such enhanced accumulation of TS shRNA-lipoplex along with the cytotoxic effect of liposomal l-OHP led to a remarkable tumor growth suppression (compared to mono-therapy) following systemic administration. Our results, therefore, may have important implications for the provision of a safer and more applicable combination therapy of RNAi molecules and anti-cancer agents that can produce a more reliable anti-tumor effect.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Neoplasias/terapia
Compostos Organoplatínicos/administração & dosagem
RNA Interferente Pequeno/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacocinética
Antineoplásicos/uso terapêutico
Linhagem Celular Tumoral
Citocinas/metabolismo
Seres Humanos
Lipossomos
Masculino
Camundongos Endogâmicos BALB C
Camundongos Nus
Neoplasias/genética
Neoplasias/metabolismo
Compostos Organoplatínicos/química
Compostos Organoplatínicos/farmacocinética
Compostos Organoplatínicos/uso terapêutico
Polietilenoglicóis/química
Interferência de RNA
RNA Interferente Pequeno/química
RNA Interferente Pequeno/farmacocinética
RNA Interferente Pequeno/uso terapêutico
Timidilato Sintase/genética
Distribuição Tecidual
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytokines); 0 (Liposomes); 0 (Organoplatinum Compounds); 0 (RNA, Small Interfering); 04ZR38536J (oxaliplatin); 30IQX730WE (Polyethylene Glycols); EC 2.1.1.45 (Thymidylate Synthase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:28903484
[Au] Autor:Yang Y; Gao X; Zhang M; Yan S; Sun C; Xiao F; Huang N; Yang X; Zhao K; Zhou H; Huang S; Xie B; Zhang N
[Ad] Endereço:Department of Neurosurgery, The 1st Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, PR China; Guangdong Provincial Key Laboratory of Pituitary Tumor, Guangzhou, Guangdong Province, PR China; Department of Scientific Research Section, The 1st Affiliated Hospital of Sun Y
[Ti] Título:Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis.
[So] Source:J Natl Cancer Inst;110(3), 2018 Mar 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported. Methods: CircRNA deep sequencing was performed by using 10 pathologically diagnosed glioblastoma samples and their paired adjacent normal brain tissues. Northern blotting, Sanger sequencing, antibody, and liquid chromatograph Tandem Mass Spectrometer were used to confirm the existence of circ-FBXW7 and its encoded protein in in two cell lines. Lentivirus-transfected stable U251 and U373 cells were used to assess the biological functions of the novel protein invitro and invivo (five mice per group). Clinical implications of circ-FBXW7 were assessed in 38 pathologically diagnosed glioblastoma samples and their paired periphery normal brain tissues by using quantitative polymerase chain reaction (two-sided log-rank test). Results: Circ-FBXW7 is abundantly expressed in the normal human brain (reads per kilobase per million mapped reads [RPKM] = 9.31). The spanning junction open reading frame in circ-FBXW7 driven by internal ribosome entry site encodes a novel 21-kDa protein, which we termed FBXW7-185aa. Upregulation of FBXW7-185aa in cancer cells inhibited proliferation and cell cycle acceleration, while knockdown of FBXW7-185aa promoted malignant phenotypes invitro and invivo. FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Moreover, circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues (P < .001). Circ-FBXW7 expression positively associated with glioblastoma patient overall survival (P = .03). Conclusions: Endogenous circRNA encodes a functional protein in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/genética
Proteínas de Ciclo Celular/genética
Transformação Celular Neoplásica/genética
Proteínas F-Box/genética
Glioblastoma/genética
RNA/análise
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Neoplasias Encefálicas/química
Ciclo Celular/genética
Proteínas de Ciclo Celular/análise
Linhagem Celular Tumoral
Proliferação Celular/genética
Proteínas F-Box/análise
Proteína 7 com Repetições F-Box-WD
Feminino
Glioblastoma/química
Meia-Vida
Seres Humanos
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
Transplante de Neoplasias
Fases de Leitura Aberta
Proteínas Proto-Oncogênicas c-myc/metabolismo
Análise de Sequência de RNA
Taxa de Sobrevida
Ubiquitina Tiolesterase/metabolismo
Ubiquitina-Proteína Ligases/análise
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (F-Box Proteins); 0 (F-Box-WD Repeat-Containing Protein 7); 0 (FBXW7 protein, human); 0 (Proto-Oncogene Proteins c-myc); 0 (RNA, circular); 63231-63-0 (RNA); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.1.2.15 (USP28 protein, human); EC 3.4.19.12 (Ubiquitin Thiolesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx166


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[PMID]:27770401
[Au] Autor:Schulte ML; Hight MR; Ayers GD; Liu Q; Shyr Y; Washington MK; Manning HC
[Ad] Endereço:Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
[Ti] Título:Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAF In Vivo.
[So] Source:Mol Imaging Biol;19(3):421-428, 2017 06.
[Is] ISSN:1860-2002
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[ F]fluoroglutamine (4-[ F]F-GLN) positron emission tomography (PET) to predict response to BRAF -targeted therapy in preclinical models of colon cancer. PROCEDURES: Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[ F]F-GLN PET was evaluated in mouse models of human BRAF -expressing and BRAF wild-type CRC. RESULTS: Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [ F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[ F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAF -targeted therapies are ineffective. CONCLUSIONS: 4-[ F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[ F]fluoro-D-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation.
[Mh] Termos MeSH primário: Glutamina/química
Mutação/genética
Tomografia por Emissão de Pósitrons
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
Proteínas Proto-Oncogênicas B-raf/genética
[Mh] Termos MeSH secundário: Sistema ASC de Transporte de Aminoácidos/metabolismo
Animais
Linhagem Celular Tumoral
Neoplasias do Colo/tratamento farmacológico
Neoplasias do Colo/metabolismo
Neoplasias do Colo/patologia
Feminino
Seres Humanos
Neoplasias Hepáticas/secundário
Camundongos Nus
Antígenos de Histocompatibilidade Menor/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Inibidores de Proteínas Quinases/uso terapêutico
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acid Transport System ASC); 0 (Minor Histocompatibility Antigens); 0 (Protein Kinase Inhibitors); 0 (SLC1A5 protein, human); 0RH81L854J (Glutamine); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1007/s11307-016-1008-z


  10 / 58434 MEDLINE  
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[PMID]:29295999
[Au] Autor:Han S; Ren Y; He W; Liu H; Zhi Z; Zhu X; Yang T; Rong Y; Ma B; Purwin TJ; Ouyang Z; Li C; Wang X; Wang X; Yang H; Zheng Y; Aplin AE; Liu J; Shao Y
[Ad] Endereço:Frontier Institute of Science and Technology, and Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
[Ti] Título:ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.
[So] Source:Nat Commun;9(1):28, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.
[Mh] Termos MeSH primário: Regulação Neoplásica da Expressão Gênica/genética
Melanoma/genética
Mutação
Proteínas Proto-Oncogênicas B-raf/genética
Fatores de Transcrição SOXE/genética
Neoplasias Cutâneas/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Inibidores Enzimáticos/farmacologia
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Indóis/farmacologia
Melanoma/tratamento farmacológico
Melanoma/metabolismo
Camundongos Endogâmicos BALB C
Camundongos Nus
Fosforilação
Proteínas Proto-Oncogênicas B-raf/metabolismo
Interferência de RNA
Receptor ErbB-3/genética
Receptor ErbB-3/metabolismo
Fatores de Transcrição SOXE/metabolismo
Neoplasias Cutâneas/tratamento farmacológico
Neoplasias Cutâneas/metabolismo
Sulfonamidas/farmacologia
Sumoilação
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (FOXD3 protein, human); 0 (Forkhead Transcription Factors); 0 (Indoles); 0 (SOX10 protein, human); 0 (SOXE Transcription Factors); 0 (Sulfonamides); 207SMY3FQT (vemurafenib); EC 2.7.10.1 (ERBB3 protein, human); EC 2.7.10.1 (Receptor, ErbB-3); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02354-x



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