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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


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[PMID]:29396713
[Au] Autor:Kiladjian JJ; Guglielmelli P; Griesshammer M; Saydam G; Masszi T; Durrant S; Passamonti F; Jones M; Zhen H; Li J; Gadbaw B; Perez Ronco J; Khan M; Verstovsek S
[Ad] Endereço:Centre d'Investigations Cliniques (CIC1427), Hôpital Saint-Louis, AP-HP, INSERM, CLIP2 "Saint-Louis - Paris Nord," Early Phase Research Center, Université Paris Diderot, 1, Avenue Claude Vellefaux, 75010, Paris, France. jean-jacques.kiladjian@aphp.fr.
[Ti] Título:Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies.
[So] Source:Ann Hematol;97(4):617-627, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov .
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Interferons/uso terapêutico
Janus Quinases/antagonistas & inibidores
Policitemia Vera/tratamento farmacológico
Inibidores de Proteínas Quinases/uso terapêutico
Pirazóis/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Antineoplásicos/efeitos adversos
Sangria/efeitos adversos
Terapia Combinada/efeitos adversos
Estudos Cross-Over
Monitoramento de Medicamentos
Resistência a Múltiplos Medicamentos
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Hidroxiureia/efeitos adversos
Hidroxiureia/uso terapêutico
Interferons/efeitos adversos
Janus Quinases/metabolismo
Masculino
Meia-Idade
Policitemia Vera/metabolismo
Policitemia Vera/fisiopatologia
Policitemia Vera/terapia
Padrões de Prática Médica
Inibidores de Proteínas Quinases/efeitos adversos
Pirazóis/efeitos adversos
Reprodutibilidade dos Testes
Esplenomegalia/etiologia
Esplenomegalia/prevenção & controle
[Pt] Tipo de publicação:CLINICAL TRIAL; CLINICAL TRIAL, PHASE III; COMPARATIVE STUDY; EQUIVALENCE TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (INCB018424); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 9008-11-1 (Interferons); EC 2.7.10.2 (Janus Kinases); X6Q56QN5QC (Hydroxyurea)
[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:180204
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3225-1


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[PMID]:29268127
[Au] Autor:Khan I; Garikapati KR; Shaik AB; Makani VKK; Rahim A; Shareef MA; Reddy VG; Pal-Bhadra M; Kamal A; Kumar CG
[Ad] Endereço:Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India; Academy of Scientific and Innovative Research, New Delhi 110 025, India.
[Ti] Título:Design, synthesis and biological evaluation of 1, 4-dihydro indeno[1,2-c] pyrazole linked oxindole analogues as potential anticancer agents targeting tubulin and inducing p53 dependent apoptosis.
[So] Source:Eur J Med Chem;144:104-115, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A series of 1, 4-dihydroindeno-[1,2-c] pyrazole linked oxindole conjugates have been synthesized by using Knoevenagel condensation method and further evaluated for their antiproliferative activity against HeLa, A549 and MDA-MB-231 human cancer cell lines along with HEK-293 (normal human embryonic kidney cells). Among the derivatives, compounds 12a, 12b, and 12d showed excellent cytotoxicity with IC values ranging between 1.33 to 4.33 µM. Furthermore, detailed biological assays showed that there was accumulation of mitotic cells in G2/M phase, disruption of microtubule network and increase in the G2/M checkpoint proteins (Cyclin B1 and CDK1). Moreover, compound 12d with IC value of 1.33 µM showed significant upregulation of tumor suppressor proteins like p53, p21 and pro-apoptotic Bax. The molecular docking analysis demonstrated that these congeners occupy the colchicine binding pocket of the tubulin.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Pirazóis/química
Pirazóis/farmacologia
Moduladores de Tubulina/química
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Desenho de Drogas
Ensaios de Seleção de Medicamentos Antitumorais
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos
Células HEK293
Células HeLa
Seres Humanos
Indóis/química
Indóis/farmacologia
Simulação de Acoplamento Molecular
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Tubulina (Proteína)/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Indoles); 0 (Pyrazoles); 0 (Tubulin); 0 (Tubulin Modulators); 0 (Tumor Suppressor Protein p53); 0S9338U62H (2-oxindole)
[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:171222
[St] Status: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


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[PMID]:28453705
[Au] Autor:Mato AR; Hill BT; Lamanna N; Barr PM; Ujjani CS; Brander DM; Howlett C; Skarbnik AP; Cheson BD; Zent CS; Pu JJ; Kiselev P; Foon K; Lenhart J; Henick Bachow S; Winter AM; Cruz AL; Claxton DF; Goy A; Daniel C; Isaac K; Kennard KH; Timlin C; Fanning M; Gashonia L; Yacur M; Svoboda J; Schuster SJ; Nabhan C
[Ad] Endereço:Center for CLL, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.
[Ti] Título:Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.
[So] Source:Ann Oncol;28(5):1050-1056, 2017 05 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem
Intervalo Livre de Doença
Esquema de Medicação
Seres Humanos
Estimativa de Kaplan-Meier
Leucemia Linfocítica Crônica de Células B/mortalidade
Meia-Idade
Modelos de Riscos Proporcionais
Purinas/administração & dosagem
Pirazóis/administração & dosagem
Pirimidinas/administração & dosagem
Quinazolinonas/administração & dosagem
Estudos Retrospectivos
Sulfonamidas/administração & dosagem
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (PCI 32765); 0 (Purines); 0 (Pyrazoles); 0 (Pyrimidines); 0 (Quinazolinones); 0 (Sulfonamides); N54AIC43PW (venetoclax); YG57I8T5M0 (idelalisib)
[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:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx031


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Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Texto completo
[PMID]:29466156
[Au] Autor:Drilon A; Laetsch TW; Kummar S; DuBois SG; Lassen UN; Demetri GD; Nathenson M; Doebele RC; Farago AF; Pappo AS; Turpin B; Dowlati A; Brose MS; Mascarenhas L; Federman N; Berlin J; El-Deiry WS; Baik C; Deeken J; Boni V; Nagasubramanian R; Taylor M; Rudzinski ER; Meric-Bernstam F; Sohal DPS; Ma PC; Raez LE; Hechtman JF; Benayed R; Ladanyi M; Tuch BB; Ebata K; Cruickshank S; Ku NC; Cox MC; Hawkins DS; Hong DS; Hyman DM
[Ad] Endereço:From Memorial Sloan Kettering Cancer Center (A. Drilon, J.F.H., R.B., M.L., D.M.H.) and Weill Cornell Medical College (A. Drilon, D.M.H.), New York; University of Texas Southwestern Medical Center-Children's Health, Dallas (T.W.L.); Stanford Cancer Center, Stanford University, Palo Alto (S.K.), Chil
[Ti] Título:Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.
[So] Source:N Engl J Med;378(8):731-739, 2018 02 22.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS: A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS: Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias/tratamento farmacológico
Pirazóis/uso terapêutico
Pirimidinas/uso terapêutico
Receptores Proteína Tirosina Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Criança
Pré-Escolar
Intervalo Livre de Doença
Feminino
Seres Humanos
Lactente
Estimativa de Kaplan-Meier
Masculino
Meia-Idade
Neoplasias/química
Proteínas de Fusão Oncogênicas/análise
Proteínas Quinases/análise
Proteínas Quinases/genética
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ARRY-470); 0 (Antineoplastic Agents); 0 (Oncogene Proteins, Fusion); 0 (Pyrazoles); 0 (Pyrimidines); EC 2.7.- (Protein Kinases); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.11.28 (tropomyosin kinase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180222
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1714448


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[PMID]:29318288
[Au] Autor:Beyzaei H; Motraghi Z; Aryan R; Zahedi MM; Samzadeh-Kermani A
[Ti] Título:Green One-pot Synthesis of Novel Polysubstituted Pyrazole Derivatives as Potential Antimicrobial Agents.
[So] Source:Acta Chim Slov;64(4):911-918, 2017 Dec.
[Is] ISSN:1318-0207
[Cp] País de publicação:Slovenia
[La] Idioma:eng
[Ab] Resumo:Various biological properties of natural and synthetic pyrazole derivatives such as anti-inflammatory, antimicrobial, neuroprotective, anticonvulsant, antidepressant and anticancer activities encouraged us to propose a new, fast, green and eco-friendly procedure for the preparation of some novel 5-amino-3-(aryl substituted)-1-(2,4-dinitrophenyl)-1H-pyrazole-4-carbonitriles. They were efficiently synthesized via one-pot two-step process reaction of malononitrile, 2,4-dinitrophenylhydrazine and different benzaldehydes in deep eutectic solvent (DES) glycerol/potassium carbonate. The products yield and reaction times were considerably improved in the presence of applied DES. Antibacterial effects of all newly synthesized pyrazoles in comparison with several common antibiotics were evaluated against a variety of Gram-positive and Gram-negative pathogenic bacteria. In addition to, their inhibitory activities on three fungi were compared to some current antifungal agents. The moderate to good antimicrobial potentials particularly against fungi were observed in the major heterocyclic compounds according to the IZD, MIC, MBC and MFC results.
[Mh] Termos MeSH primário: Anti-Infecciosos/síntese química
Pirazóis/síntese química
[Mh] Termos MeSH secundário: Anti-Infecciosos/farmacologia
Pirazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Pyrazoles)
[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:180111
[St] Status:MEDLINE


  8 / 23421 MEDLINE  
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[PMID]:29231667
[Au] Autor:Myrstad M; Vandvik I; Engebretsen EH; Tveit A
[Ti] Título:Hjerneslag etter seponering av nye antikoagulasjonsmidler før kirurgi..
[So] Source:Tidsskr Nor Laegeforen;137(23-24), 2017 12 12.
[Is] ISSN:0807-7096
[Cp] País de publicação:Norway
[La] Idioma:nor
[Mh] Termos MeSH primário: Anticoagulantes/administração & dosagem
Antitrombinas/administração & dosagem
Dabigatrana/administração & dosagem
Inibidores do Fator Xa/administração & dosagem
Cuidados Pré-Operatórios/efeitos adversos
Pirazóis/administração & dosagem
Piridonas/administração & dosagem
Acidente Vascular Cerebral/etiologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Fibrilação Atrial/tratamento farmacológico
Seres Humanos
Masculino
Meia-Idade
Medição de Risco
Fatores de Risco
Acidente Vascular Cerebral/diagnóstico por imagem
Procedimentos Cirúrgicos Operatórios
Fatores de Tempo
Tomografia Computadorizada por Raios X
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Antithrombins); 0 (Factor Xa Inhibitors); 0 (Pyrazoles); 0 (Pyridones); 3Z9Y7UWC1J (apixaban); I0VM4M70GC (Dabigatran)
[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:171213
[St] Status:MEDLINE
[do] DOI:10.4045/tidsskr.17.0532


  9 / 23421 MEDLINE  
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[PMID]:28460431
[Au] Autor:Du J; Wu X; Tong X; Wang X; Wei J; Yang Y; Chang Z; Mao Y; Shao YW; Liu B
[Ad] Endereço:The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, 210008, China.
[Ti] Título:Circulating tumor DNA profiling by next generation sequencing reveals heterogeneity of crizotinib resistance mechanisms in a gastric cancer patient with MET amplification.
[So] Source:Oncotarget;8(16):26281-26287, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Crizotinib has been used to counter MET gene amplification in a number of different human malignancies. Transient response to crizotinib in MET-amplified gastric cancer has been reported, but the mechanisms of resistance are not well studied. Here, we reported a stage IV gastric cancer patient with high levels of MET amplification. The implementation of crizotinib treatment led to significant symptomatic improvement in the first 2 months, but was followed by rapid disease progression. Periodic mutation profiling of patient's circulating tumor DNA (ctDNA) by next generation sequencing (NGS) revealed a number of genetic alterations including re-occurrence of MET amplification, multiple secondary MET mutations, a dramatic increase of FGFR2 gene relative copy number as well as mutations in other downstream and bypassing elements, which may collectively related to the patient's cancer progression. Our results illustrate the complex and heterogeneous molecular mechanisms for crizotinib resistance in this patient, and demonstrate the great potential of ctDNA profiling for treatment decision-making and prognosis in clinical practice.
[Mh] Termos MeSH primário: DNA Tumoral Circulante
Resistência a Medicamentos Antineoplásicos/genética
Amplificação de Genes
Proteínas Proto-Oncogênicas c-met/genética
Pirazóis/farmacologia
Piridinas/farmacologia
Neoplasias Gástricas/genética
[Mh] Termos MeSH secundário: Adulto
Linhagem Celular Tumoral
Feminino
Perfilação da Expressão Gênica
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Modelos Biológicos
Modelos Moleculares
Mutação
Estadiamento de Neoplasias
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Conformação Proteica
Inibidores de Proteínas Quinases/farmacologia
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Proto-Oncogênicas c-met/química
Pirazóis/uso terapêutico
Piridinas/uso terapêutico
Neoplasias Gástricas/diagnóstico
Neoplasias Gástricas/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Circulating Tumor DNA); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Pyridines); 53AH36668S (crizotinib); EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
[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:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15457


  10 / 23421 MEDLINE  
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[PMID]:29339254
[Au] Autor:ElBordiny HS; El-Miligy MM; Kassab SE; Daabees H; Mohamed Ali WA; Abdelhamid Mohamed El-Hawash S
[Ad] Endereço:Pharmaceutical Chemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, El-Buhaira, 22516, Egypt.
[Ti] Título:Design, synthesis, biological evaluation and docking studies of new 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives as potent antioxidants and 15-lipoxygenase inhibitors.
[So] Source:Eur J Med Chem;145:594-605, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:New candidates of 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives (4-7) were designed combining the pyrazoline/isoxazoline heterocycles and 2-phenylindole to explore its potential as 15-lipoxygenase (15-LOX) inhibitors. The design of the new derivatives was based on utilizing the antioxidant properties of pyrazoline, 2-phenylindole and the good 15-LOX inhibition properties of indolylpyrazoline. The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields. The resulting indolylpyrazolines/isoxazolines were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide dismutase (SOD); indolylpyrazoline (4b) was the most potent antioxidant against SOD assay (IC = 1.78 µM) to be superior to ascorbic by 2 folds. Consistently, (4b) was the most potent inhibitor when tested against Soybean 15-LOX (IC = 3.84 µM) excelling quercetin as standard inhibitor by 1.8 folds. Some of the new derivatives were docked into the active binding site of human 15-LOX (PDB entry 4NRE) emphasizing the most potent derivative (4b) and the least potent one (4c). Docking solutions of compounds (4b), (4c), (5b) and (6c) revealed that (4b) was the only compound that got stabilized into the catalytic pocket of enzyme by π-cation interaction with the catalytic Fe and formation of one hydrogen bond with Ile 676 amino acid. Other derivatives including the least potent one variably got stabilized into the active binding pocket by π-cation interaction with the catalytic Fe but failed to form hydrogen bond with Ile 676. For the future optimization of the generated inhibitors, (i) antioxidant activity against SOD, (ii) the inhibitor stabilization by π-cation interaction with the catalytic Fe and (iii) formation of hydrogen bond with Ile 676 should be regarded.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Araquidonato 15-Lipoxigenase/metabolismo
Desenho de Drogas
Indóis/farmacologia
Inibidores de Lipoxigenase/farmacologia
[Mh] Termos MeSH secundário: Androstenóis/síntese química
Androstenóis/química
Androstenóis/farmacologia
Antioxidantes/síntese química
Antioxidantes/química
Relação Dose-Resposta a Droga
Seres Humanos
Indóis/síntese química
Indóis/química
Inibidores de Lipoxigenase/síntese química
Inibidores de Lipoxigenase/química
Simulação de Acoplamento Molecular
Estrutura Molecular
Pirazóis/síntese química
Pirazóis/química
Pirazóis/farmacologia
Feijão de Soja/enzimologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Androstenols); 0 (Antioxidants); 0 (Indoles); 0 (Lipoxygenase Inhibitors); 0 (Pyrazoles); 1XA84ITL1H (azastene); 3QD5KJZ7ZJ (pyrazole); EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE



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