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  1 / 2033 MEDLINE  
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[PMID]:29246084
[Au] Autor:Capetti AF; Cossu MV; Paladini L; Rizzardini G
[Ad] Endereço:a First Division of Infectious Diseases , ASST Fatebenefratelli-Sacco , Milano , Italy.
[Ti] Título:Dolutegravir plus rilpivirine dual therapy in treating HIV-1 infection.
[So] Source:Expert Opin Pharmacother;19(1):65-77, 2018 Jan.
[Is] ISSN:1744-7666
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The HIV-infected population is aging and comorbidities and polypharmacological regimens are increasing. To reduce toxicity and drug burden researchers are evaluating the efficacy, safety and durability of dual therapies as a switch option in subjects who have achieved stable virologic suppression. Initially effective dual combinations relied on protease inhibitors but when dolutegravir, the first integrase inhibitor to display a high genetic barrier, became commercially available, many physicians began to use it in a variety of dual regimens, generating several observational cohorts. Areas covered: This review covers the most recent data from observational cohorts and randomized clinical trials concerning the switch to the dual combination of dolutegravir plus rilpivirine and the reasons that lead to consider this option. Also, viral failures, due to poor adherence or to other factors, and drug resistance are investigated. Articles which are searchable on MEDLINE/PubMed and from the main national/international congresses in the field of HIV therapy are reviewed. Expert opinion: The observation period for this regimen is getting longer and data showing its efficacy in maintaining HIV-1 RNA < 50 copies/mL are now consolidated. Metabolic data suggest some benefit in the lipid profile, improvement in bone mineral density and reduced bone reabsorption.
[Mh] Termos MeSH primário: Infecções por HIV/tratamento farmacológico
Compostos Heterocíclicos com 3 Anéis/administração & dosagem
Rilpivirina/administração & dosagem
[Mh] Termos MeSH secundário: Fármacos Anti-HIV/administração & dosagem
Fármacos Anti-HIV/uso terapêutico
Quimioterapia Combinada
HIV-1/efeitos dos fármacos
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Heterocyclic Compounds, 3-Ring); DKO1W9H7M1 (dolutegravir); FI96A8X663 (Rilpivirine)
[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:171217
[St] Status:MEDLINE
[do] DOI:10.1080/14656566.2017.1417984


  2 / 2033 MEDLINE  
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[PMID]:29317618
[Au] Autor:Kirtane AR; Abouzid O; Minahan D; Bensel T; Hill AL; Selinger C; Bershteyn A; Craig M; Mo SS; Mazdiyasni H; Cleveland C; Rogner J; Lee YL; Booth L; Javid F; Wu SJ; Grant T; Bellinger AM; Nikolic B; Hayward A; Wood L; Eckhoff PA; Nowak MA; Langer R; Traverso G
[Ad] Endereço:Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
[Ti] Título:Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy.
[So] Source:Nat Commun;9(1):2, 2018 01 09.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/administração & dosagem
Sistemas de Liberação de Medicamentos/métodos
Compostos Heterocíclicos com 3 Anéis/administração & dosagem
Piridonas/administração & dosagem
Rilpivirina/administração & dosagem
[Mh] Termos MeSH secundário: Administração Oral
Animais
Fármacos Anti-HIV/farmacocinética
Fármacos Anti-HIV/uso terapêutico
Avaliação Pré-Clínica de Medicamentos
Compostos Heterocíclicos com 3 Anéis/farmacocinética
Compostos Heterocíclicos com 3 Anéis/uso terapêutico
Seres Humanos
Modelos Teóricos
Cooperação do Paciente
Estudo de Prova de Conceito
Piridonas/farmacocinética
Piridonas/uso terapêutico
Rilpivirina/farmacocinética
Rilpivirina/uso terapêutico
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (GSK1265744); 0 (Heterocyclic Compounds, 3-Ring); 0 (Pyridones); DKO1W9H7M1 (dolutegravir); FI96A8X663 (Rilpivirine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02294-6


  3 / 2033 MEDLINE  
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[PMID]:29357370
[Au] Autor:Sathe A; Chalaud G; Oppolzer I; Wong KY; von Busch M; Schmid SC; Tong Z; Retz M; Gschwend JE; Schulz WA; Nawroth R
[Ad] Endereço:Department of Urology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
[Ti] Título:Parallel PI3K, AKT and mTOR inhibition is required to control feedback loops that limit tumor therapy.
[So] Source:PLoS One;13(1):e0190854, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Targeting the PI3K pathway has achieved limited success in cancer therapy. One reason for the disappointing activity of drugs that interfere with molecules that are important player in this pathway is the induction of multiple feedback loops that have been only partially understood. To understand these limitations and develop improved treatment strategies, we comprehensively characterized molecular mechanisms of PI3K pathway signaling in bladder cancer cell lines upon using small molecule inhibitors and RNAi technologies against all key molecules and protein complexes within the pathway and analyzed functional and molecular consequences. When targeting either mTORC1, mTOR, AKT or PI3K, only S6K1 phosphorylation was affected in most cell lines examined. Dephosphorylation of 4E-BP1 required combined inhibition of PI3K and mTORC1, independent from AKT, and resulted in a robust reduction in cell viability. Long-term inhibition of PI3K however resulted in a PDK1-dependent, PIP3 and mTORC2 independent rephosphorylation of AKT. AKT rephosphorylation could also be induced by mTOR or PDK1 inhibition. Combining PI3K/mTOR inhibitors with AKT or PDK1 inhibitors suppressed this rephosphorylation, induced apoptosis, decreased colony formation, cell viability and growth of tumor xenografts. Our findings reveal novel molecular mechanisms that explain the requirement for simultaneous targeting of PI3K, AKT and mTORC1 to achieve effective tumor growth inhibition.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Inibidores Enzimáticos/administração & dosagem
Fosfatidilinositol 3-Quinase/antagonistas & inibidores
Inibidores de Proteínas Quinases/administração & dosagem
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Serina-Treonina Quinases TOR/antagonistas & inibidores
Neoplasias da Bexiga Urinária/tratamento farmacológico
Neoplasias da Bexiga Urinária/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Animais
Protocolos de Quimioterapia Combinada Antineoplásica
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Embrião de Galinha
Retroalimentação Fisiológica/efeitos dos fármacos
Compostos Heterocíclicos com 3 Anéis/administração & dosagem
Seres Humanos
Imidazóis/administração & dosagem
Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores
Fosfoproteínas/metabolismo
Fosforilação/efeitos dos fármacos
Quinolinas/administração & dosagem
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Transdução de Sinais/efeitos dos fármacos
Neoplasias da Bexiga Urinária/patologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents); 0 (EIF4EBP1 protein, human); 0 (Enzyme Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); 0 (Imidazoles); 0 (MK 2206); 0 (Phosphoproteins); 0 (Protein Kinase Inhibitors); 0 (Quinolines); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1); RUJ6Z9Y0DT (dactolisib)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190854


  4 / 2033 MEDLINE  
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[PMID]:28448437
[Au] Autor:Lan K; Zhao Y; Fan Y; Ma B; Yang S; Liu Q; Linghu H; Wang H
[Ad] Endereço:Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. kangyun_lan@126.com.
[Ti] Título:Sulfiredoxin May Promote Cervical Cancer Metastasis via Wnt/ß-Catenin Signaling Pathway.
[So] Source:Int J Mol Sci;18(5), 2017 Apr 27.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:The abnormal elevation of sulfiredoxin (Srx/SRXN1)-an antioxidant enzyme whose main function is to protect against oxidative stress-has been shown to be closely correlated with the progression of several types of cancer, including human cervical cancer. However, the molecular mechanism by which Srx promotes tumor progression, especially cancer metastasis in cervical cancer, has not been elucidated. Here, we show that Srx expression gradually increases during the progression of human cervical cancer and its expression level is closely correlated with lymph node metastasis. Our study also reveals a significant positive correlation between the expression of Srx and ß-catenin in cervical cancer tissues. Loss-of-function studies demonstrate that Srx knockdown using a lentiviral vector-mediated specific shRNA decreases the migration and invasion capacity in HeLa (human papilloma virus 18 type cervical cancer cell line) and SiHa SiHa (cervical squamous cancer cell line). Notably, the exact opposite effects were observed in gain-of-function experiments in C-33A cells. Mechanistically, downregulation or upregulation of Srx leads to an altered expression of proteins associated with the Wnt/ß-catenin signaling pathway. Furthermore, blockage of the Wnt/ß-catenin signaling pathway contributed to attenuated Srx expression and resulted in significant inhibition of cell migration and invasion in cervical cancer cell lines. Combined, Srx might be an oncoprotein in cervical cancer, playing critical roles in activating the Wnt/ß-catenin signaling pathway; it may therefore be a therapeutic target for cervical cancer.
[Mh] Termos MeSH primário: Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo
Neoplasias do Colo do Útero/patologia
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Adulto
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Regulação para Baixo/efeitos dos fármacos
Feminino
Glicogênio Sintase Quinase 3 beta/metabolismo
Células HeLa
Compostos Heterocíclicos com 3 Anéis/farmacologia
Seres Humanos
Imuno-Histoquímica
Metástase Linfática
Meia-Idade
Oxirredutases atuantes sobre Doadores de Grupo Enxofre/antagonistas & inibidores
Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Regulação para Cima/efeitos dos fármacos
Neoplasias do Colo do Útero/metabolismo
Via de Sinalização Wnt/efeitos dos fármacos
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterocyclic Compounds, 3-Ring); 0 (RNA, Small Interfering); 0 (XAV939); 0 (beta Catenin); EC 1.8.- (Oxidoreductases Acting on Sulfur Group Donors); EC 1.8.98.2 (SRXN1 protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE


  5 / 2033 MEDLINE  
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[PMID]:29176314
[Au] Autor:Wang H; Deng X; Zhang J; Ou Z; Mai J; Ding S; Huo S
[Ad] Endereço:Department of Radiation Oncology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
[Ti] Título:Elevated Expression of Zinc Finger Protein 703 Promotes Cell Proliferation and Metastasis through PI3K/AKT/GSK-3ß Signalling in Oral Squamous Cell Carcinoma.
[So] Source:Cell Physiol Biochem;44(3):920-934, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Zinc finger protein 703 (ZNF703), initially identified as a novel oncogene in human breast cancer, is a member of the NET/NlZ family of zinc finger transcription factors. It is recognized that the overexpression of ZNF703 is associated with various types of human cancers, but the role and molecular mechanism of ZNF703 in oral squamous cell carcinoma (OSCC) are unknown. METHODS: ZNF703 expression levels were examined in OSCC tissues and non-cancerous tissues by qRT-PCR and immunohistochemistry (IHC). The molecular mechanisms of ZNF703 and its effects on cell growth and metastasis were explored in vitro and in vivo using the CCK8 assay, colony formation assay, cell cycle analysis, migration and invasion assays, wound-healing assay, western blotting and xenograft experiments in nude mice. RESULTS: In this study, ZNF703 was found to be upregulated in OSCC tissues compared to that in normal tissues at both mRNA and protein levels, and its expression level was closely correlated with the overall survival of patients with OSCC. Silencing of the ZNF703 gene in OSCC cells significantly inhibited cell growth and metastasis in vitro and in vivo. Conversely, the overexpression of ZNF703 in OSCC cells promoted cancer growth and metastasis in vitro. Mechanistically, ZNF703 activated the PI3K/AKT/GSK-3ß signalling pathway and its downstream effectors, thus regulating the cell cycle and epithelial-mesenchymal transition (EMT). Furthermore, the promotive effects of ZNF703 on cellular proliferation and metastasis could be rescued by LY294002 (a PI3K-specific inhibitor) and MK2206 (an Akt-specific inhibitor). CONCLUSION: The results show that ZNF703 promotes cell growth and metastasis through PI3K/Akt/GSK-3ß signalling in OSCC and that it may be a promising target in the treatment of patients with OSCC.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/patologia
Proteínas de Transporte/metabolismo
Glicogênio Sintase Quinase 3 beta/metabolismo
Neoplasias Bucais/patologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
[Mh] Termos MeSH secundário: Animais
Carcinoma de Células Escamosas/metabolismo
Carcinoma de Células Escamosas/mortalidade
Proteínas de Transporte/antagonistas & inibidores
Proteínas de Transporte/genética
Pontos de Checagem do Ciclo Celular
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Cromonas/farmacologia
Transição Epitelial-Mesenquimal
Feminino
Compostos Heterocíclicos com 3 Anéis/farmacologia
Seres Humanos
Imuno-Histoquímica
Estimativa de Kaplan-Meier
Masculino
Camundongos
Camundongos Nus
Microscopia de Fluorescência
Meia-Idade
Morfolinas/farmacologia
Neoplasias Bucais/metabolismo
Neoplasias Bucais/mortalidade
Imagem Óptica
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Transdução de Sinais
Transplante Heterólogo
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Chromones); 0 (Heterocyclic Compounds, 3-Ring); 0 (MK 2206); 0 (Morpholines); 0 (RNA, Small Interfering); 0 (ZNF703 protein, human); 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485360


  6 / 2033 MEDLINE  
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[PMID]:28741965
[Au] Autor:Pialoux G; Marcelin AG; Cawston H; Guilmet C; Finkielsztejn L; Laurisse A; Aubin C
[Ad] Endereço:a Service des Maladies Infectieuses et Tropicales , AP-HP Hôpital Tenon , PARIS , France.
[Ti] Título:Cost-effectiveness of dolutegravir/abacavir/lamivudine in HIV-1 treatment-Naive (TN) patients in France.
[So] Source:Expert Rev Pharmacoecon Outcomes Res;18(1):83-91, 2018 Feb.
[Is] ISSN:1744-8379
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: To evaluate the cost-effectiveness of an integrase inhibitor (INI), dolutegravir (DTG), in combination with abacavir (ABC)/lamivudine (3TC) in France, in treatment-naive (TN) HIV adult patients. METHODS: The ARAMIS microsimulation Markov model, evaluates costs and effects of DTG vs. first-line ARVs options including INIs (raltegravir, elvitegravir/c), protease inhibitors (PIs) (darunavir/r, atazanavir/r, lopinavir/r), non-nucleoside reverse transcriptase inhibitors (efavirenz and rilpivirine). Efficacy and safety data were derived from phase III studies and network meta-analysis. Treatment algorithms were based on French guidelines and experts opinion. Costs included routine HIV and opportunistic infection care, and death. RESULTS: The model showed the fixed-dose combination DTG/ABC/3TC was more effective than all other recommended regimens: patients stayed longer on first-line, and lived longer and healthier. With the exception of EFV, DTG/ABC/3TC was more efficacious and less costly compared to all strategies. The cost per QALY gained (ICER) for DTG compared to EFV was €6,939. DTG/ABC/3TC was more efficacious and less costly compared to INIs and PIs in all deterministic sensitivity analyses. CONCLUSION: DTG/ABC/3TC was cost-effective in the management of HIV TN patients in France. These results are mainly explained by its lower price compared to other INIs and PIs, DTG's superior efficacy and high barrier to resistance.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/administração & dosagem
Didesoxinucleosídeos/administração & dosagem
Infecções por HIV/tratamento farmacológico
Compostos Heterocíclicos com 3 Anéis/administração & dosagem
Lamivudina/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Algoritmos
Fármacos Anti-HIV/efeitos adversos
Fármacos Anti-HIV/economia
Análise Custo-Benefício
Didesoxinucleosídeos/efeitos adversos
Didesoxinucleosídeos/economia
Combinação de Medicamentos
França
Infecções por HIV/economia
Inibidores de Integrase de HIV/administração & dosagem
Inibidores de Integrase de HIV/efeitos adversos
Inibidores de Integrase de HIV/economia
HIV-1
Compostos Heterocíclicos com 3 Anéis/efeitos adversos
Compostos Heterocíclicos com 3 Anéis/economia
Seres Humanos
Lamivudina/efeitos adversos
Lamivudina/economia
Cadeias de Markov
Guias de Prática Clínica como Assunto
Anos de Vida Ajustados por Qualidade de Vida
Resultado do Tratamento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Dideoxynucleosides); 0 (Drug Combinations); 0 (HIV Integrase Inhibitors); 0 (Heterocyclic Compounds, 3-Ring); 0 (abacavir, lamivudine drug combination); 2T8Q726O95 (Lamivudine); DKO1W9H7M1 (dolutegravir)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1080/14737167.2017.1359542


  7 / 2033 MEDLINE  
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[PMID]:28934275
[Au] Autor:Dong J; Zhai B; Sun W; Hu F; Cheng H; Xu J
[Ad] Endereço:Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
[Ti] Título:Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells.
[So] Source:PLoS One;12(9):e0185088, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carcinoma Hepatocelular/enzimologia
Resistência a Medicamentos Antineoplásicos/fisiologia
Neoplasias Hepáticas/enzimologia
Niacinamida/análogos & derivados
Compostos de Fenilureia/farmacologia
[Mh] Termos MeSH secundário: Animais
Carcinoma Hepatocelular/tratamento farmacológico
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Movimento Celular/fisiologia
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/fisiologia
Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Resistência a Múltiplos Medicamentos/fisiologia
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Transição Epitelial-Mesenquimal/fisiologia
Compostos Heterocíclicos com 3 Anéis/farmacologia
Seres Humanos
Neoplasias Hepáticas/tratamento farmacológico
Masculino
Camundongos Endogâmicos BALB C
Camundongos Nus
Invasividade Neoplásica/fisiopatologia
Transplante de Neoplasias
Niacinamida/farmacologia
Fosfatidilinositol 3-Quinases/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Heterocyclic Compounds, 3-Ring); 0 (MK 2206); 0 (Phenylurea Compounds); 0 (Protein Kinase Inhibitors); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185088


  8 / 2033 MEDLINE  
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[PMID]:28923387
[Au] Autor:Park DS; Jo E; Choi J; Lee M; Kim S; Kim HY; Nam J; Ahn S; Hwang JY; Windisch MP
[Ad] Endereço:Medicinal Chemistry Group, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Republic of Korea.
[Ti] Título:Characterization and structure-activity relationship study of iminodipyridinopyrimidines as novel hepatitis C virus inhibitor.
[So] Source:Eur J Med Chem;140:65-73, 2017 Nov 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Upon high-throughput screening of synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified an iminodipyridinopyrimidine (IDPP) scaffold. IDPP did not inhibit HCV replication, but exhibited very potent inhibitory activity on early and late steps of HCV life cycle. Applying an intensive structure-activity relationship (SAR) study, a promising IDPP Lead compound (12c) with excellent potency (EC = 10 nM), high safety margin (SI > 2000), and an acceptable stability in human and rat liver microsomes (t >60 min) was identified. Overall, our results suggest that the IDPP scaffold could be used for the development of novel HCV interventions.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Hepacivirus/efeitos dos fármacos
Compostos Heterocíclicos com 3 Anéis/farmacologia
[Mh] Termos MeSH secundário: Animais
Antivirais/síntese química
Antivirais/química
Células Cultivadas
Relação Dose-Resposta a Droga
Feminino
Compostos Heterocíclicos com 3 Anéis/síntese química
Compostos Heterocíclicos com 3 Anéis/química
Seres Humanos
Masculino
Testes de Sensibilidade Microbiana
Estrutura Molecular
Ratos
Relação Estrutura-Atividade
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(trifluoromethyl)benzyl 2-imino-8-methyl-5-oxo-1-(4-(trifluoromethoxy)benzyl)-1,5-dihydro-2H-dipyrido(1,2-a-2',3'-d)pyrimidine-3-carboxylate); 0 (Antiviral Agents); 0 (Heterocyclic Compounds, 3-Ring)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE


  9 / 2033 MEDLINE  
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[PMID]:28877210
[Au] Autor:Jia J; Qiao Y; Pilo MG; Cigliano A; Liu X; Shao Z; Calvisi DF; Chen X
[Ad] Endereço:Department of Oncology and Hematology, The Second Hospital, Jilin University, Changchun, China.
[Ti] Título:Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade.
[So] Source:PLoS One;12(9):e0184068, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner. Furthermore, we found that Tankyrase inhibitors synergized with MEK and AKT inhibitors to suppress HCC cell proliferation. At the molecular level, Tankyrase inhibitors significantly decreased YAP protein levels, reduced the expression of YAP target genes, and inhibited YAP/TEAD luciferase reporter activity. In addition, Tankyrase inhibitors administration was accompanied by upregulation of Angiomotin-like 1 (AMOTL1) and Angiomotin-like 2 (AMOTL2) proteins, two major negative regulators of YAP. Altogether, the present data indicate that XAV-939 and G007-LK Tankyrase inhibitors could suppress proliferation of hepatocellular carcinoma cells and downregulate YAP/TAZ by stabilizing AMOTL1 and AMOTL2 proteins, thus representing new potential anticancer drugs against hepatocellular carcinoma.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Hepatocelular/tratamento farmacológico
Compostos Heterocíclicos com 3 Anéis/uso terapêutico
Neoplasias Hepáticas/tratamento farmacológico
Sulfonas/uso terapêutico
Tanquirases/antagonistas & inibidores
Triazóis/uso terapêutico
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Apoptose/efeitos dos fármacos
Western Blotting
Proteínas de Transporte/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Proteínas de Membrana/metabolismo
Fosfoproteínas/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AMOTL1 protein, human); 0 (AMOTL2 protein, human); 0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents); 0 (Carrier Proteins); 0 (G007-LK); 0 (Heterocyclic Compounds, 3-Ring); 0 (Membrane Proteins); 0 (Phosphoproteins); 0 (Sulfones); 0 (Triazoles); 0 (XAV939); 0 (YAP1 (Yes-associated) protein, human); EC 2.4.2.30 (Tankyrases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184068


  10 / 2033 MEDLINE  
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[PMID]:28854832
[Au] Autor:Capetti AF; Astuti N; Cattaneo D; Rizzardini G
[Ad] Endereço:a 1st Division of Infectious Diseases , ASST Fatebenefratelli-Sacco , Milano , Italy.
[Ti] Título:Pharmacokinetic drug evaluation of dolutegravir plus rilpivirine for the treatment of HIV.
[So] Source:Expert Opin Drug Metab Toxicol;13(11):1183-1192, 2017 Nov.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The search for simple, potent, metabolic-friendly and nucleoside/nucleotide sparing antiretroviral regimens has led clinical investigators to move steps towards dual therapies. Among these the association of rilpivirine and dolutegravir is emerging as a twin randomized clinical trial (SWORD1&2) and at least three observational cohort describe it as a safe and highly effective regimen for switch from other therapies Areas covered: We review the evidence supporting the use of dolutegravir plus rilpivirine for the treatment of HIV in virologically suppressed patients taking other antiretroviral regimens. The reasons for the switch in clinical practice may range from simplification to tolerability/toxicity issues, to the prevention of future metabolic damage, to predicted drug-drug interactions when treatment of HCV co-infection is planned. Articles searchable on MEDLINE/PubMed and from the main international congresses in the field of HIV therapy were reviewed to provide context for use of dolutegravir plus rilpivirine Expert opinion: This treatment is highly effective in maintaining HIV-1 RNA <50 copies/mL. Although the studies up to date requested patient to switch to drugs they had no experience of, a predictable 'radical change' effect did not impact negatively on the results. Further data from these studies may help elucidate the possible advantage in terms of safety and metabolic effect in the next few months.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/administração & dosagem
Infecções por HIV/tratamento farmacológico
Compostos Heterocíclicos com 3 Anéis/administração & dosagem
Rilpivirina/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Fármacos Anti-HIV/efeitos adversos
Fármacos Anti-HIV/farmacocinética
Interações Medicamentosas
Quimioterapia Combinada
HIV-1/efeitos dos fármacos
Compostos Heterocíclicos com 3 Anéis/efeitos adversos
Compostos Heterocíclicos com 3 Anéis/farmacocinética
Seres Humanos
Ensaios Clínicos Controlados Aleatórios como Assunto
Rilpivirina/efeitos adversos
Rilpivirina/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Heterocyclic Compounds, 3-Ring); DKO1W9H7M1 (dolutegravir); FI96A8X663 (Rilpivirine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2017.1361929



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