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[PMID]:29505507
[Au] Autor:Wang CG; Zeng DX; Huang JA; Jiang JH
[Ad] Endereço:Department of Respiratory and Critical Care, First Affiliated Hospital of Soochow University, Suzhou, P.R. China.
[Ti] Título:Effective assessment of low times MET amplification in pleural effusion after epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance: Cases report.
[So] Source:Medicine (Baltimore);97(1):e9021, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: The mechanism of the first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance included T790M mutation, cellular-mesenchymal to epithelial transition factor (MET) or EGFR amplification, PIK3CA mutation, and transformation to small cell lung cancer. MET amplification accounted for only about 5% of the resistance cases. PATIENTS CONCERNS: Few report detected MET amplification in pleural effusion. Here, we reported 2 lung adenocarcinoma cases with MET amplification in pleural effusion rapidly responded to crizotinib after EGFR-TKIs acquired resistance. DIAGNOSES: Biopsy via bronchoscopy, next-generation sequencing (NGS) in pleural effusion. INTERVENTIONS: EGFR-TKIs (Icotinib), MET inhibitor crizotinib. OUTCOMES: After a progression-free survival of 9 months and 23months, respectively, both cases progressed accompanying with pleural effusion. Results of NGS in pleural effusion showed MET amplification (2-3 times) in both cases. The 2 patients were treated with a MET inhibitor crizotinib and rapidly responded. CONCLUSION: MET amplification in pleural effusion could predict a perfect response to crizotinib after EGFR-TKIs acquired resistance, even only a low times gene amplification.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Resistência a Medicamentos Antineoplásicos/genética
Neoplasias Pulmonares/genética
Derrame Pleural Maligno/metabolismo
Proteínas Proto-Oncogênicas c-met/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/tratamento farmacológico
Idoso
Feminino
Amplificação de Genes
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
Masculino
Meia-Idade
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Proto-Oncogênicas c-met/metabolismo
Pirazóis/uso terapêutico
Piridinas/uso terapêutico
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Pyridines); 53AH36668S (crizotinib); EC 2.7.10.1 (MET protein, human); EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180306
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009021


  2 / 47228 MEDLINE  
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[PMID]:29482389
[Au] Autor:Elzahabi HSA; Nossier ES; Khalifa NM; Alasfoury RA; El-Manawaty MA
[Ad] Endereço:a Department of Pharmaceutical Chemistry , Faculty of Pharmacy (Girls), Al-Azhar University , Cairo , Egypt.
[Ti] Título:Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold.
[So] Source:J Enzyme Inhib Med Chem;33(1):546-557, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC : 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC : 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR ß, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Quinase 4 Dependente de Ciclina/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Piridinas/farmacologia
Pirimidinas/farmacologia
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Quinase 4 Dependente de Ciclina/metabolismo
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Piridinas/síntese química
Piridinas/química
Pirimidinas/síntese química
Pirimidinas/química
Receptor do Fator de Crescimento Epidérmico/metabolismo
Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Pyrimidines); 0 (pyrido(3,2-d)pyrimidine); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta); EC 2.7.11.22 (CDK4 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
[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:180228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1437729


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[PMID]:28841528
[Au] Autor:Lavtizar V; Kimura D; Asaoka S; Okamura H
[Ad] Endereço:Laboratory of Maritime Environmental Management, Research Center for Inland Seas, Kobe University, 5-1-1 Fukaeminami, Higashinada-ku, Kobe, Hyogo 658-0022, Japan.
[Ti] Título:The influence of seawater properties on toxicity of copper pyrithione and its degradation product to brine shrimp Artemia salina.
[So] Source:Ecotoxicol Environ Saf;147:132-138, 2018 Jan.
[Is] ISSN:1090-2414
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Copper pyrithione (CuPT) is a biocide, used worldwide to prevent biofouling on submerged surfaces. In aquatic environments it rapidly degrades, however, one of the degradation products (HPT) is known to react with cupric ion back to its parent compound. Not much is known about the behavior and toxicity of CuPT and its degradation product HPT in different water systems. Hence, our aim was to investigate the ecotoxicity of CuPT, HPT as well as Cu to the brine shrimp Artemia salina in natural seawater and organic matter-free artificial seawater. Moreover, in order to elucidate the influence of ionic strength of water on CuPT toxicity, tests were performed in water media with modified salinity. The results showed that CuPT was the most toxic to the exposed crustaceans in a seawater media with the highest salinity and with no organic matter content. HPT in a presence of cupric ion converted to CuPT, but the measured CuPT concentrations and the mortality of A. salina in natural water were lower than in artificial water. The toxicity of CuPT to A. salina was significantly influenced by the organic matter content, salinity, and proportions of constituent salts in water. In a combination with cupric ion, non-hazardous degradation product HPT exhibits increased toxicity due to its rapid transformation to its parent compound.
[Mh] Termos MeSH primário: Artemia/efeitos dos fármacos
Desinfetantes/toxicidade
Compostos Organometálicos/toxicidade
Piridinas/toxicidade
Água do Mar/química
Tionas/toxicidade
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Animais
Desinfetantes/análise
Monitoramento Ambiental/métodos
Substâncias Húmicas/análise
Compostos Organometálicos/análise
Piridinas/análise
Salinidade
Tionas/análise
Poluentes Químicos da Água/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disinfectants); 0 (Humic Substances); 0 (Organometallic Compounds); 0 (Pyridines); 0 (Thiones); 0 (Water Pollutants, Chemical); 0 (copper pyrithione); 6GK82EC25D (pyrithione)
[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:170826
[St] Status:MEDLINE


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[PMID]:28457748
[Au] Autor:Schneider RK; Mullally A; Dugourd A; Peisker F; Hoogenboezem R; Van Strien PMH; Bindels EM; Heckl D; Büsche G; Fleck D; Müller-Newen G; Wongboonsin J; Ventura Ferreira M; Puelles VG; Saez-Rodriguez J; Ebert BL; Humphreys BD; Kramann R
[Ad] Endereço:Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: r.k.schneider@erasmusmc.nl.
[Ti] Título:Gli1 Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target.
[So] Source:Cell Stem Cell;20(6):785-800.e8, 2017 Jun 01.
[Is] ISSN:1875-9777
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1 mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1 cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1 cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Mesenquimais Estromais/metabolismo
Miofibroblastos/metabolismo
Mielofibrose Primária/tratamento farmacológico
Piridinas/farmacologia
Pirimidinas/farmacologia
Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/genética
Seres Humanos
Células Mesenquimais Estromais/patologia
Camundongos
Camundongos Transgênicos
Miofibroblastos/patologia
Mielofibrose Primária/genética
Mielofibrose Primária/metabolismo
Mielofibrose Primária/patologia
Proteína GLI1 em Dedos de Zinco/genética
Proteína GLI1 em Dedos de Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GANT 61); 0 (Gli protein, mouse); 0 (Pyridines); 0 (Pyrimidines); 0 (Zinc Finger Protein GLI1)
[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:170502
[St] Status:MEDLINE


  5 / 47228 MEDLINE  
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[PMID]:29441966
[Au] Autor:Zhao H; Meng W; Li Y; Liu W; Fu B; Yang Y; Zhang Q; Chen G
[Ti] Título:The protective effects of CHIR99021 against oxidative injury in LO2 cells.
[So] Source:Pharmazie;71(11):629-635, 2016 11 02.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Hepatic ischemia-reperfusion injury is one of the most important factors for the prognosis of liver transplantation and hepatic surgery. It was reported that glycogen synthase kinase-3 (GSK-3) regulated injury response during ischemia-reperfusion. In this study, we investigated the protective effects of the GSK-3 inhibitor CHIR99021 against hepatic ischemia-reperfusion injury. A H2O2-induced oxidative injury model using LO2 cells was established. LO2 cells were divided into four groups, including blank control group, CHIR99021 control group treated with CHIR99021 alone, H2O2-injury group treated with H2O2 and protection group treated with H2O2 plus CHIR99021. Cell viability, cell apoptosis or necrosis was determined. Meanwhile, mitochondrial membrane potential, lipid peroxidation, cellular ROS levels, SOD activity, and serum contents of ALS and AST were measured. Protein and mRNA expressions were also detected. The results showed that a cell oxidative injury model was established by treating LO2 cells with 200 µmol/L H2O2 for 6 h. Cells exposed to H2O2 resulted in a significant decrease of cell viability and increase of cell apoptosis, which was accompanied by increasing ROS levels, disruption of mitochondrial membrane potential, excessive lipid peroxidation, reduction of SOD activity, and increased levels of ALT and AST. Treatment with CHIR99021 significantly protected LO2 cells against H2O2-induce oxidative injury by inhibiting the changes of above oxidative injury related indicators. Moreover, CHIR99021 treatment significantly reversed H2O2-induced decrease in p-GSK-3ßSer9 , Bcl-2, Bcl-xl, survivin and ß-catenin expression, whereas it significantly attenuated H2O2-induced increase in caspase-3, cleaved caspase-3 and p-JNK protein expression. In conclusion, CHIR99021 protected LO2 cells against H2O2-induced oxidative injury through reducing GSK-3ß activity and apoptosis, with underlying mechanisms involved in stabilizing mitochondrial membrane potential, attenuating cellular ROS generation, suppressing mitochondria-mediated apoptotic pathway, and activation of GSK-3ß/ß-catenin signaling pathway.
[Mh] Termos MeSH primário: Citoproteção/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Piridinas/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Antioxidantes/metabolismo
Apoptose/efeitos dos fármacos
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
Quinase 3 da Glicogênio Sintase/biossíntese
Quinase 3 da Glicogênio Sintase/genética
Seres Humanos
Peróxido de Hidrogênio/farmacologia
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Necrose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Chir 99021); 0 (Pyridines); 0 (Pyrimidines); BBX060AN9V (Hydrogen Peroxide); EC 2.7.11.26 (Glycogen Synthase Kinase 3)
[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:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6714


  6 / 47228 MEDLINE  
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[PMID]:28453695
[Au] Autor:Suenaga M; Schirripa M; Cao S; Zhang W; Yang D; Murgioni S; Rossini D; Marmorino F; Mennitto A; Ning Y; Okazaki S; Berger MD; Miyamoto Y; Gopez R; Barzi A; Yamaguchi T; Loupakis F; Lenz HJ
[Ad] Endereço:Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
[Ti] Título:Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer.
[So] Source:Ann Oncol;28(5):1015-1022, 2017 05 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102. Patients and methods: We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing. Results: In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance. Conclusion: Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias Colorretais/genética
Enzimas Reparadoras do DNA/genética
Neoplasias Hepáticas/genética
Trifluridina/uso terapêutico
Uracila/análogos & derivados
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Antineoplásicos/farmacologia
Neoplasias Colorretais/tratamento farmacológico
Neoplasias Colorretais/mortalidade
Neoplasias Colorretais/patologia
Intervalo Livre de Doença
Combinação de Medicamentos
Resistência a Medicamentos Antineoplásicos/genética
Feminino
Estudos de Associação Genética
Seres Humanos
Neoplasias Hepáticas/tratamento farmacológico
Neoplasias Hepáticas/mortalidade
Neoplasias Hepáticas/secundário
Masculino
Meia-Idade
Compostos de Fenilureia/farmacologia
Compostos de Fenilureia/uso terapêutico
Modelos de Riscos Proporcionais
Piridinas/farmacologia
Piridinas/uso terapêutico
Estudos Retrospectivos
Resultado do Tratamento
Trifluridina/farmacologia
Uracila/farmacologia
Uracila/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Drug Combinations); 0 (Phenylurea Compounds); 0 (Pyridines); 0 (TAS 102); 24T2A1DOYB (regorafenib); 56HH86ZVCT (Uracil); EC 6.5.1.- (DNA Repair Enzymes); RMW9V5RW38 (Trifluridine)
[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:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx035


  7 / 47228 MEDLINE  
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[PMID]:29489694
[Au] Autor:Amraei R; Parsa A; Babaeian M
[Ad] Endereço:Shahid Behshti University of Medical Sciences, Tehran, Iran.
[Ti] Título:Zolpidem-induced sneezing: A case report of positive rechallenge.
[So] Source:Medicine (Baltimore);97(9):e9918, 2018 Mar.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Zolpidem, as an imidazopyridine, is a widely prescribed drug in clinical practice for short-term treatment of insomnia. Nevertheless, there have been a number of cases associated with the adverse effects of the stated drug recently. Further to the existing reports of adverse reactions to zolpidem, the current script is going to report a case in which zolpidem has induced acute repetitive sneezes. CONCLUSIONS: A high dose of zolpidem may contribute to interruption to the neurons function involved in the sneezing pathway.
[Mh] Termos MeSH primário: Hipnóticos e Sedativos/efeitos adversos
Piridinas/efeitos adversos
Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
Espirro/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adulto
Seres Humanos
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypnotics and Sedatives); 0 (Pyridines); 7K383OQI23 (zolpidem)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180301
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009918


  8 / 47228 MEDLINE  
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[PMID]:28922779
[Au] Autor:Hanley CJ; Mellone M; Ford K; Thirdborough SM; Mellows T; Frampton SJ; Smith DM; Harden E; Szyndralewiez C; Bullock M; Noble F; Moutasim KA; King EV; Vijayanand P; Mirnezami AH; Underwood TJ; Ottensmeier CH; Thomas GJ
[Ad] Endereço:Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK; Genkyotex SA, Plan-les-Ouates, Switzerland; La Jolla Institute for Allergy and Immunology, La Jolla, CA.
[Ti] Título:Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4.
[So] Source:J Natl Cancer Inst;110(1), 2018 Jan 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed. Methods: CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided. Results: Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04). Conclusions: These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types.
[Mh] Termos MeSH primário: Adenocarcinoma/tratamento farmacológico
Fibroblastos Associados a Câncer/patologia
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Carcinoma de Células Escamosas/tratamento farmacológico
Neoplasias Colorretais/química
Neoplasias Esofágicas/tratamento farmacológico
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Bucais/química
Miofibroblastos/patologia
NADPH Oxidases/antagonistas & inibidores
Neoplasias Orofaríngeas/química
[Mh] Termos MeSH secundário: Actinas/análise
Adenocarcinoma/química
Adenocarcinoma/genética
Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Fibroblastos Associados a Câncer/química
Fibroblastos Associados a Câncer/fisiologia
Carcinoma Pulmonar de Células não Pequenas/química
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma de Células Escamosas/química
Carcinoma de Células Escamosas/genética
Contagem de Células
Transdiferenciação Celular/efeitos dos fármacos
Transdiferenciação Celular/genética
Neoplasias Colorretais/patologia
Progressão da Doença
Neoplasias Esofágicas/química
Neoplasias Esofágicas/genética
Feminino
Neoplasias de Cabeça e Pescoço/química
Neoplasias de Cabeça e Pescoço/tratamento farmacológico
Neoplasias de Cabeça e Pescoço/genética
Seres Humanos
Neoplasias Pulmonares/química
Neoplasias Pulmonares/genética
Masculino
Camundongos
Meia-Idade
Neoplasias Bucais/patologia
Miofibroblastos/química
NADPH Oxidase 4
NADPH Oxidases/análise
NADPH Oxidases/genética
Transplante de Neoplasias
Neoplasias Orofaríngeas/patologia
Fenótipo
Pirazóis/uso terapêutico
Piridinas/uso terapêutico
Interferência de RNA
Espécies Reativas de Oxigênio/metabolismo
Taxa de Sobrevida
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ACTA2 protein, human); 0 (Actins); 0 (GKT137831); 0 (Pyrazoles); 0 (Pyridines); 0 (Reactive Oxygen Species); EC 1.6.3.- (NADPH Oxidase 4); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.- (NOX4 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx121


  9 / 47228 MEDLINE  
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[PMID]:28457503
[Au] Autor:Shiraishi Y; Ogawa T; Suzuki T; Iwai M; Kusano M; Zaitsu K; Kondo F; Ishii A; Seno H
[Ad] Endereço:Department of Legal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan; Department of Pharmacy, Fujita Health University Hospital, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
[Ti] Título:Simultaneous quantification of batrachotoxin and epibatidine in plasma by ultra-performance liquid chromatography/tandem mass spectrometry.
[So] Source:Leg Med (Tokyo);25:1-5, 2017 Mar.
[Is] ISSN:1873-4162
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantification of batrachotoxin and epibatidine in plasma. Plasma samples were pretreated by liquid-liquid extraction with acetonitrile and methanol. The toxins were separated on a reversed phase C18-column (2.1mm×50mm, 1.7µm) using a formic acid/acetonitrile gradient elution. Quantification was carried out by mass chromatography with each product ion referenced against midazolam-d as an internal standard (IS). The two toxins and the IS were separated within 2min. The calibration curves for the two toxins spiked into human plasma showed good linearities in the range from 2.5 to 250ng/mL. The detection limits were estimated to be 0.5ng/mL for batrachotoxin and 1ng/mL for epibatidine with a signal-to-noise ratio of 3:1. Overall recoveries ranged from 69.6% to 98.2%, and no significant matrix effects were observed. The intra- and interday accuracies were 94.7-102.3%, and the precisions were 1.0-10.3%. This method was successfully applied for the quantification of batrachotoxin and epibatidine in rat plasma samples taken after intraperitoneal administration of the toxins. This is the first report to use UPLC-MS/MS to simultaneously quantify batrachotoxin and epibatidine in plasma samples.
[Mh] Termos MeSH primário: Analgésicos não Entorpecentes/sangue
Batraquiotoxinas/sangue
Compostos Bicíclicos Heterocíclicos com Pontes/sangue
Cromatografia Líquida de Alta Pressão/métodos
Piridinas/sangue
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Analgésicos não Entorpecentes/química
Animais
Anuros
Batraquiotoxinas/química
Compostos Bicíclicos Heterocíclicos com Pontes/química
Japão
Piridinas/química
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Non-Narcotic); 0 (Batrachotoxins); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Pyridines); M6K314F1XX (epibatidine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29480860
[Au] Autor:Zhu H; Zhao Y; Wang X
[Ad] Endereço:Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
[Ti] Título:The radiosensitive effect of apatinib for hepatocellular carcinoma patient with big paraspinal metastasis: A case report.
[So] Source:Medicine (Baltimore);97(2):e9598, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Hepatocellular carcinoma (HCC) is a highly invasive cancer associated with great mortality rates. The prognosis of advanced HCC is very poor. PATIENT CONCERNS: Here, we report a HCC patient with a big paraspinal metastasis with 10 cm in diameter who failed the treatment of sorafenib. DIAGNOSES: Sorafenib refractory HCC with big paraspinal metastasis. INTERVENTIONS: The concurrent treatment of apatinib with stereotactic body radiotherapy (SBRT). OUTCOMES: The paraspinal metastasis with 10 cm in diameter showed nearly complete response. LESSONS: We think that the apatinib may be a good choice for HCC and it may function as a radiosensitizer of HCC. However, it warrants further investigation in the future prospective clinical studies.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/terapia
Neoplasias Hepáticas/terapia
Piridinas/uso terapêutico
Radiossensibilizantes/uso terapêutico
Neoplasias da Coluna Vertebral/secundário
Neoplasias da Coluna Vertebral/terapia
[Mh] Termos MeSH secundário: Adulto
Antineoplásicos/uso terapêutico
Carcinoma Hepatocelular/diagnóstico por imagem
Carcinoma Hepatocelular/patologia
Evolução Fatal
Seres Humanos
Neoplasias Hepáticas/diagnóstico por imagem
Neoplasias Hepáticas/patologia
Masculino
Neoplasias da Coluna Vertebral/diagnóstico por imagem
Carga Tumoral
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Pyridines); 0 (Radiation-Sensitizing Agents); 5S371K6132 (apatinib)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180227
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009598



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