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[PMID]:27426246
[Au] Autor:Taus Á
[Ad] Endereço:Servicio de Oncología Médica, Hospital del Mar, IMIM (Instituto Hospital del Mar de Investigaciones Médicas), Barcelona, España. Electronic address: ataus@parcdesalutmar.cat.
[Ti] Título:[Toxicity associated with EGRF inhibition: review and key aspects in the management of afatinib].
[Ti] Título:Toxicidad asociada a la inhibición de EGFR: Revisión y aspectos clave del manejo de afatinib..
[So] Source:Med Clin (Barc);146 Suppl 1:30-5, 2016 Apr.
[Is] ISSN:1578-8989
[Cp] País de publicação:Spain
[La] Idioma:spa
[Ab] Resumo:Afatinib is an irreversible tyrosine kinase inhibitor of the ErbB family, approved for the treatment of patients with non-small cell lung cancer with EGFR-sensitizing mutations. Like other EGFR inhibitors, afatinib can provoke adverse events such as diarrhoea, rash, paronychia or mucositis. The correct management of these adverse events is essential to maintain quality of life in these patients and obtain the maximum benefit from afatinib therapy. This study aimed to review the toxicity of the drug and summarize recommendations for the prevention and treatment of the most significant adverse events associated with afatinib.
[Mh] Termos MeSH primário: Antineoplásicos/efeitos adversos
Biomarcadores Tumorais/antagonistas & inibidores
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Receptores ErbB/antagonistas & inibidores
Neoplasias Pulmonares/tratamento farmacológico
Inibidores de Proteínas Quinases/efeitos adversos
Quinazolinas/efeitos adversos
[Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico
Biomarcadores Tumorais/genética
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Receptores ErbB/genética
Genes erbB
Marcadores Genéticos
Seres Humanos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Mutação
Inibidores de Proteínas Quinases/uso terapêutico
Quinazolinas/uso terapêutico
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Genetic Markers); 0 (Protein Kinase Inhibitors); 0 (Quinazolines); 41UD74L59M (afatinib); EC 2.7.10.1 (ErbB Receptors)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE


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[PMID]:27426244
[Au] Autor:Artal Cortés Á; Gimeno Pelegrín J; Alejandro MÁ
[Ad] Endereço:Servicio de Oncología Médica, Hospital Universitario Miguel Servet, Zaragoza, España. Electronic address: aartalc@salud.aragon.es.
[Ti] Título:[Evidence on afatinib in patients progressing on a first-line treatment].
[Ti] Título:Evidencia de afatinib en pacientes que progresan a un tratamiento de primera línea..
[So] Source:Med Clin (Barc);146 Suppl 1:19-24, 2016 Apr.
[Is] ISSN:1578-8989
[Cp] País de publicação:Spain
[La] Idioma:spa
[Ab] Resumo:After description of the importance of EGFR mutations in non-small cell lung cancer and confirmation that tyrosine-kinase inhibitors are more beneficial than chemotherapy in patients with EGFR+ tumours, treatment with one of these drugs has become the standard recommendation. Despite this advance, patients continue to progress and consequently there is a need to search for alternative treatments. Some studies have analysed afatinib activity after first-generation TKI therapy, as well as its administration in combination with conventional chemotherapy. Afatinib produces significant response rates and progression-free survival times after the development of clinical resistance, which are independent of the presence of the T790M resistance mutation and can be attributed to continued pan-HER inhibition. In addition to the initial clinical trial, LUX-LUNG-1, data are available from the use of afatinib in routine clinical practice, within extended use programs. Overall, response rates of between 7 and 15% can be expected with a duration of approximately 24 months and a median progression-free time of about 4 months. A study combining afatinib with cetuximab has obtained a high response rate. Afatinib toxicity in second-line treatment is similar to that appears when the drug is used as first-line therapy (mainly mucocutaneous and diarrhoea) and can be managed with routine measures. In conclusion, afatinib should be considered as a treatment option in patients with EGFR mutations who show disease progression after a first tyrosine-kinase inhibitor.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Genes erbB
Neoplasias Pulmonares/tratamento farmacológico
Mutação
Inibidores de Proteínas Quinases/uso terapêutico
Quinazolinas/uso terapêutico
[Mh] Termos MeSH secundário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Biomarcadores Tumorais/antagonistas & inibidores
Carcinoma Pulmonar de Células não Pequenas/genética
Cetuximab/uso terapêutico
Esquema de Medicação
Receptores ErbB/antagonistas & inibidores
Marcadores Genéticos
Seres Humanos
Neoplasias Pulmonares/genética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Genetic Markers); 0 (Protein Kinase Inhibitors); 0 (Quinazolines); 41UD74L59M (afatinib); EC 2.7.10.1 (ErbB Receptors); PQX0D8J21J (Cetuximab)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE


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[PMID]:27426245
[Au] Autor:Cobo M; Gutiérrez V; Rodelo L; López O; Ruiz M; Godoy A
[Ad] Endereço:Servicio de Oncología Médica, Hospital Universitario Málaga Regional y Virgen de la Victoria, Málaga, España. Electronic address: manuelcobodols@yahoo.es.
[Ti] Título:[Afatinib in patients with squamous cell carcinoma of the lung: current context and the option of oral treatment].
[Ti] Título:Afatinib en pacientes con carcinoma escamoso de pulmón: contexto actual y opción de un tratamiento oral..
[So] Source:Med Clin (Barc);146 Suppl 1:25-9, 2016 Apr.
[Is] ISSN:1578-8989
[Cp] País de publicação:Spain
[La] Idioma:spa
[Ab] Resumo:Squamous cell carcinoma (SCC) of the lung represents 30% of non-small cell lung cancers (NSCLC). Docetaxel and the EGFR tyrosine kinase inhibitor (TKI), erlotinib, are the only two drugs approved for second-line treatment of advanced SCC. The sensitivity of SCC to TKIs can be explained by EGFR overexpression. Erlotinib demonstrated a significant benefit in terms of overall survival (OS) in successive lines in NSCLC, including squamous histology. The magnitude of this benefit is similar to that of chemotherapy. Afatinib is an irreversible inhibitor of the entire ErbB family (EGFR, HER2-4) that has recently been approved for its current indication, advanced EGFR mutation-positive NSCLC and has well-defined and manageable toxicity, mainly gastrointestinal and cutaneous. The LUX-Lung 8 study was a phase III randomized trial in patients with NSCLC with squamous histology that compared erlotinib versus afatinib as second-line treatment. A total of 795 patients were included and a significant benefit was observed for afatinib in progression-free survival (2.7 vs 1.9 months (HR 0.79 [95%CI 0.68-0.91]; p=0.0012) and in OS (7.9 vs 6.8 months (HR 0.81 [95%CI 0.69-0.95]; p=0.0077), as well as a significant improvement in OS at 12 and 18 months. More diarrhoea and stomatitis was observed with afatinib and more rash with erlotinib, but the overall proportion of toxicity was similar in each group. Afatinib offered better results in quality of life. In summary, afatinib is a second-line treatment option in squamous NSCLC based on its survival advantage over erlotinib.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Carcinoma de Células Escamosas/tratamento farmacológico
Neoplasias Pulmonares/tratamento farmacológico
Inibidores de Proteínas Quinases/uso terapêutico
Quinazolinas/uso terapêutico
[Mh] Termos MeSH secundário: Administração Oral
Biomarcadores Tumorais/antagonistas & inibidores
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma de Células Escamosas/genética
Receptores ErbB/antagonistas & inibidores
Genes erbB
Marcadores Genéticos
Seres Humanos
Neoplasias Pulmonares/genética
Mutação
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Genetic Markers); 0 (Protein Kinase Inhibitors); 0 (Quinazolines); 41UD74L59M (afatinib); EC 2.7.10.1 (ErbB Receptors)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE


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[PMID]:27426243
[Au] Autor:Vidal ÓJ
[Ad] Endereço:Servicio de Oncología Médica, Hospital Universitari i Politècnic La Fe, Valencia, España. Electronic address: juan_osc@gva.es.
[Ti] Título:[Afatinib as first-line therapy in mutation-positive EGFR. Results by type of mutation].
[Ti] Título:Tratamiento con afatinib en primera línea EGFR M+. Resultados según subtipo de mutación..
[So] Source:Med Clin (Barc);146 Suppl 1:12-8, 2016 Apr.
[Is] ISSN:1578-8989
[Cp] País de publicação:Spain
[La] Idioma:spa
[Ab] Resumo:The discovery of endothelial growth factor receptor (EGFR) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma (NSCLC). In phase III trials, the first-generation tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations, achieving progression-free survival of 8-13.5 months. Afatinib, a second-generation irreversible pan-ErbB inhibitor, is the first TKI that has shown a benefit in overall survival (OS) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first-line treatment. Exon 19 deletion (Del19) and the single-point substitution mutation (L858R) in exon 21, called activating mutations due to their ability to confer sensitivity to TKI, represent approximately 90% of the EGFR mutations in NSCLC. Distinct sensitivity to TKI has been observed depending on the type of mutation, with greater progression-free survival in patients with the Del19 mutation. The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation, but no significant increase in that of patients with the L858R mutation. Direct comparison of afatinib and gefitinib as first-line therapy (LUX-Lung 7 trial) showed a statistically-significant increase in progression-free survival (hazard ratio: 0.73; 95% confidence interval, 0.57-0.95; p=0.0165) with afatinib. In the analysis by type of mutation, this benefit was observed for both the Del19 and the L858R mutations.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Genes erbB
Neoplasias Pulmonares/tratamento farmacológico
Mutação
Inibidores de Proteínas Quinases/uso terapêutico
Quinazolinas/uso terapêutico
[Mh] Termos MeSH secundário: Biomarcadores Tumorais/antagonistas & inibidores
Carcinoma Pulmonar de Células não Pequenas/genética
Receptores ErbB/antagonistas & inibidores
Marcadores Genéticos
Seres Humanos
Neoplasias Pulmonares/genética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Genetic Markers); 0 (Protein Kinase Inhibitors); 0 (Quinazolines); 41UD74L59M (afatinib); EC 2.7.10.1 (ErbB Receptors)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE


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[PMID]:26474499
[Au] Autor:Gilbert MA; Lin B; Peterson J; Jang W; Schwob JE
[Ad] Endereço:Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA; Genetics Program, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
[Ti] Título:Neuregulin1 and ErbB expression in the uninjured and regenerating olfactory mucosa.
[So] Source:Gene Expr Patterns;19(1-2):108-19, 2015 Sep-Nov.
[Is] ISSN:1872-7298
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Neuregulin1, a protein involved in signaling through the ErbB receptors, is required for the proper development of multiple organ systems. A complete understanding of the expression profile of Neuregulin1 is complicated by the presence of multiple isoform variants that result from extensive alternative splicing. Remarkably, these numerous protein products display a wide range of divergent functional roles, making the characterization of tissue-specific isoforms critical to understanding signaling. Recent evidence suggests an important role for Neuregulin1 signaling during olfactory epithelium development and regeneration. In order to understand the physiological consequences of this signaling, we sought to identify the isoform-specific and cell type-specific expression pattern of Neuregulin1 in the adult olfactory mucosa using a combination of RT-qPCR, FACS, and immunohistochemistry. To complement this information, we also analyzed the cell-type specific expression patterns of the ErbB receptors using immunohistochemistry. We found that multiple Neuregulin1 isoforms, containing predominantly the Type I and Type III N-termini, are expressed in the uninjured olfactory mucosa. Specifically, we found that Type III Neuregulin1 is highly expressed in mature olfactory sensory neurons and Type I Neuregulin1 is highly expressed in duct gland cells. Surprisingly, the divergent localization of these Neuregulin isoforms and their corresponding ErbB receptors does not support a role for active signaling during normal turnover and maintenance of the olfactory mucosa. Conversely, we found that injury to the olfactory epithelium specifically upregulates the Neuregulin1 Type I isoform bringing the expression pattern adjacent to cells expressing both ErbB2 and ErbB3 which is compatible with active signaling, supporting a functional role for Neuregulin1 specifically during regeneration.
[Mh] Termos MeSH primário: Neuregulina-1/metabolismo
Mucosa Olfatória/metabolismo
Proteínas Oncogênicas v-erbB/metabolismo
Regeneração/fisiologia
[Mh] Termos MeSH secundário: Animais
Éxons
Regulação da Expressão Gênica
Genes erbB
Imuno-Histoquímica
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neuregulina-1/biossíntese
Neuregulina-1/genética
Mucosa Olfatória/lesões
Neurônios Receptores Olfatórios/metabolismo
Proteínas Oncogênicas v-erbB/biossíntese
Proteínas Oncogênicas v-erbB/genética
Isoformas de Proteínas
Regeneração/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Neuregulin-1); 0 (Nrg1 protein, mouse); 0 (Oncogene Proteins v-erbB); 0 (Protein Isoforms)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:161025
[Lr] Data última revisão:
161025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151018
[St] Status:MEDLINE


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[PMID]:26331525
[Au] Autor:Guo L; Eldridge S; Furniss M; Mussio J; Davis M
[Ad] Endereço:Laboratory of Investigative Toxicology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA, 301-846-7495, liang.guo@nih.gov.
[Ti] Título:Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) to Monitor Compound Effects on Cardiac Myocyte Signaling Pathways.
[So] Source:Curr Protoc Chem Biol;7(3):141-185, 2015 Sep 01.
[Is] ISSN:2160-4762
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is a need to develop mechanism-based assays to better inform risk of cardiotoxicity. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are rapidly gaining acceptance as a biologically relevant in vitro model for use in drug discovery and cardiotoxicity screens. Utilization of hiPSC-CMs for mechanistic investigations would benefit from confirmation of the expression and activity of cellular pathways that are known to regulate cardiac myocyte viability and function. This unit describes an approach to demonstrate the presence and function of signaling pathways in hiPSC-CMs and the effects of treatments on these pathways. We present a workflow that employs protocols to demonstrate protein expression and functional integrity of signaling pathway(s) of interest and to characterize biological consequences of signaling modulation. These protocols utilize a unique combination of structural, functional, and biochemical endpoints to interrogate compound effects on cardiomyocytes.
[Mh] Termos MeSH primário: Genes erbB
Células-Tronco Pluripotentes Induzidas/metabolismo
Miócitos Cardíacos/metabolismo
Transdução de Sinais
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Cardiotoxicidade
Linhagem Celular
Sobrevivência Celular
Expressão Gênica
Seres Humanos
Células-Tronco Pluripotentes Induzidas/citologia
Potencial da Membrana Mitocondrial
Miócitos Cardíacos/química
Miócitos Cardíacos/citologia
Fosforilação
Fatores de Transcrição/química
Troponina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Transcription Factors); 0 (Troponin)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150903
[St] Status:MEDLINE
[do] DOI:10.1002/9780470559277.ch150035


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[PMID]:25366420
[Au] Autor:Szmida E; Karpinski P; Leszczynski P; Sedziak T; Kielan W; Ostasiewicz P; Sasiadek MM
[Ad] Endereço:Department of Genetics, Wroclaw Medical University, ul. Marcinkowskiego 1, 50-368, Wroclaw, Poland, e.szmida@gmail.com.
[Ti] Título:Aberrant methylation of ERBB pathway genes in sporadic colorectal cancer.
[So] Source:J Appl Genet;56(2):185-92, 2015 May.
[Is] ISSN:2190-3883
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients. However, in contrast to genetic events, little is known about epigenetic alternations of ErbB-associated genes and their impact on gene expression. Genome-wide methylation in sporadic CRCs (n = 12) paired with adjacent normal tissues have been previously analysed by Illumina Infinium HumanMethylation27 (HM27) at 27,578 CpG sites. For confirmation of our initial genome-wide analysis, we used a published HM27 dataset (GSE25062). Subsequently, CpG island methylation of selected ErbB pathway-associated genes was assessed on 233 CRC samples using methylation-sensitive polymerase chain reaction (MS-PCR) and analysed along with various genetic factors associated with CRC [epigenotype, BRAF and KRAS mutations, microsatellite instability (MSI)]. Methylation and expression integration was performed using published datasets including 25 pairs of CRC and normal colon tissues (GSE25062 and GSE25070), and confirmed with real-time PCR. Our previous microarray-based genome-wide DNA methylation analysis of 12 CRCs revealed that four ErbB-associated genes (PIK3CD, PKCΒ, ERBB4, ) were differentially methylated in CRCs. This was further confirmed by statistical re-analysis of an HM27 dataset (GSE25062). Frequent methylation at these loci in tumours was subsequently confirmed by MS-PCR (63%, 43%, 43% and 92%, respectively). Hypermethylation of PKCΒ associated with KRAS mutation (p = 0.04), whereas hypermethylation of ERBB4 associated with high-methylation epigenotypes (HME), BRAF mutation and MSI (p = 0.001, 0.002 and 0.0002, respectively). One of the four analysed genes (PKCΒ) was significantly downregulated in CRC tissue, as revealed by real-time PCR and re-analysis of the GSE25062 and GSE25070 datasets. After careful re-analysis of published methylation and expression data, we conclude that methylation of ERBB4, PAK7 and PIK3CD has no functional role in CRC carcinogenesis. In contrast, methylation seems to have a potential impact on the biology of colorectal tumours by negatively modulating the expression of PKCΒ. Importantly, the relationship between DNA methylation of PKCΒ and gene expression may warrant further attention in the context of colon cancer chemoprevention and anti-cancer therapy.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
Metilação de DNA
Genes erbB
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Classe I de Fosfatidilinositol 3-Quinases/genética
Ilhas de CpG
Epigênese Genética
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
Meia-Idade
Proteína Quinase C beta/genética
Receptor ErbB-4/genética
Transdução de Sinais
Quinases Ativadas por p21/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.1.11 (PAK7 protein, human); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CD protein, human); EC 2.7.10.1 (ERBB4 protein, human); EC 2.7.10.1 (Receptor, ErbB-4); EC 2.7.11.1 (p21-Activated Kinases); EC 2.7.11.13 (Protein Kinase C beta)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141105
[St] Status:MEDLINE
[do] DOI:10.1007/s13353-014-0253-6


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[PMID]:24858418
[Au] Autor:Yang W; Raufi A; Klempner SJ
[Ad] Endereço:University of California Irvine, Department of Medicine, Orange, CA, USA.
[Ti] Título:Targeted therapy for gastric cancer: molecular pathways and ongoing investigations.
[So] Source:Biochim Biophys Acta;1846(1):232-7, 2014 Aug.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Gastric cancer is currently the second leading cause of worldwide cancer mortality. Ongoing collaborative sequencing efforts have highlighted recurrent somatic genomic aberrations in gastric cancer, however, despite advances in characterizing the genomic landscape, there have been few advances in patient outcomes. Prognosis remains poor with a median overall survival of 12 months for advanced disease. The improved survival with trastuzumab, and more recently ramucirumab, underscore the promise of targeted and biologic therapies and the importance of molecular tumor characterization in gastric cancer. Here we review the most frequent actionable alterations in gastric cancer and highlight ongoing clinical investigations attempting to translate biologic understanding into improved clinical outcomes.
[Mh] Termos MeSH primário: Terapia de Alvo Molecular
Neoplasias Gástricas/terapia
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/uso terapêutico
Animais
Descoberta de Drogas
Genes erbB/fisiologia
Seres Humanos
Terapia de Alvo Molecular/métodos
Terapia de Alvo Molecular/tendências
Proteômica/métodos
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors)
[Em] Mês de entrada:1411
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140527
[St] Status:MEDLINE


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Registro de Ensaios Clínicos
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[PMID]:24099518
[Au] Autor:van Schalkwyk MC; Papa SE; Jeannon JP; Guerrero Urbano T; Spicer JF; Maher J
[Ad] Endereço:1 Department of Research Oncology, King's Health Partners Integrated Cancer Centre , King's College London, London SE1 9RT, United Kingdom .
[Ti] Título:Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer.
[So] Source:Hum Gene Ther Clin Dev;24(3):134-42, 2013 Sep.
[Is] ISSN:2324-8645
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite several advances, 5-year survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unchanged at only 50%. The commonest cause of death is locally advanced/recurrent disease. Consequently, there is an unmet need for new approaches to improve local control in HNSCC. T4 immunotherapy is an autologous cell therapy in which peripheral blood T-cells are genetically engineered using a retroviral vector to coexpress two chimeric receptors: (i) T1E28z is a chimeric antigen receptor that engages multiple ErbB dimers that are commonly upregulated in HNSCC; (ii) 4αß is a chimeric cytokine receptor that converts the weak mitogenic stimulus provided by interleukin (IL)-4 into a strong and selective growth signal, allowing preferential expansion and enrichment of T4(+) T-cells ex vivo. T4 immunotherapy exerts antitumor activity against HNSCC cell lines and tumors in vivo, without significant toxicity. Human T4(+) T-cells also engage mouse ErbB receptors, permitting safety testing in SCID Beige mice. Severe toxicity caused by cytokine release syndrome ensues when human T4(+) T-cells are administered at high doses to mice, particularly with advanced tumor burdens. However, such toxicity is not required for efficacy and is never seen if T-cells are administered by the intratumoral route. To exploit this, we have designed a first-in-man clinical trial in which T4(+) T-cells are administered to patients with locally advanced/recurrent HNSCC. Cells will be administered at a single sitting to multiple sites around the viable tumor circumference. A 3+3 dose escalation design will be used, starting at 10(7) cells (cohort 1), escalating to 10(9) cells (cohort 5). If maximum tolerated dose remains undefined, cohorts 6/7 will receive either low- or high-dose cyclophosphamide before 10(9) T4(+) T-cells. A panel of routine/in-house assays and imaging techniques will be used to monitor safety, efficacy, perturbation of endogenous antitumor immunity, immunogenicity, and T-cell trafficking.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/terapia
Genes erbB
Terapia Genética
Neoplasias de Cabeça e Pescoço/terapia
Imunoterapia
[Mh] Termos MeSH secundário: Adulto
Feminino
Seres Humanos
Masculino
Receptores de Antígenos/genética
Receptores de Antígenos/imunologia
Receptores de Citocinas/genética
Receptores de Citocinas/imunologia
Proteínas Recombinantes/administração & dosagem
Proteínas Recombinantes/efeitos adversos
Proteínas Recombinantes/farmacocinética
Projetos de Pesquisa
Linfócitos T/imunologia
Linfócitos T/transplante
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Antigen); 0 (Receptors, Cytokine); 0 (Recombinant Proteins)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131009
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1089/humc.2013.144


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[PMID]:24004948
[Au] Autor:Malmquist SJ; Abramsson A; McGraw HF; Linbo TH; Raible DW
[Ad] Endereço:Department of Biological Structure, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
[Ti] Título:Modulation of dorsal root ganglion development by ErbB signaling and the scaffold protein Sorbs3.
[So] Source:Development;140(19):3986-96, 2013 Oct.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The multipotent cells of the vertebrate neural crest (NC) arise at the dorsal aspect of the neural tube, then migrate throughout the developing embryo and differentiate into diverse cell types, including the sensory neurons and glia of the dorsal root ganglia (DRG). As multiple cell types are derived from this lineage, it is ideal for examining mechanisms of fate restriction during development. We have isolated a mutant, ouchless, that specifically fails to develop DRG neurons, although other NC derivatives develop normally. This mutation affects the expression of Sorbs3, a scaffold protein known to interact with proteins involved in focal adhesions and several signaling pathways. ouchless mutants share some phenotypic similarities with mutants in ErbB receptors, EGFR homologs that are implicated in diverse developmental processes and associated with several cancers; and ouchless interacts genetically with an allele of erbb3 in DRG neurogenesis. However, the defect in ouchless DRG neurogenesis is distinct from ErbB loss of function in that it is not associated with a loss of glia. Both ouchless and neurogenin1 heterozygous fish are sensitized to the effects of ErbB chemical inhibitors, which block the development of DRG in a dose-dependent manner. Inhibitors of MEK show similar effects on DRG neurogenesis. We propose a model in which Sorbs3 helps to integrate ErbB signals to promote DRG neurogenesis through the activation of MAPK and upregulation of neurogenin1.
[Mh] Termos MeSH primário: Gânglios Espinais/citologia
Gânglios Espinais/metabolismo
Proteínas de Peixe-Zebra/metabolismo
[Mh] Termos MeSH secundário: Animais
Genes erbB/genética
Genes erbB/fisiologia
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Crista Neural/citologia
Crista Neural/metabolismo
Neurogênese/genética
Neurogênese/fisiologia
Transdução de Sinais/genética
Transdução de Sinais/fisiologia
Peixe-Zebra
Proteínas de Peixe-Zebra/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Erbb3b protein, zebrafish); 0 (Intracellular Signaling Peptides and Proteins); 0 (Zebrafish Proteins)
[Em] Mês de entrada:1311
[Cu] Atualização por classe:171112
[Lr] Data última revisão:
171112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130906
[St] Status:MEDLINE
[do] DOI:10.1242/dev.084640



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