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[PMID]:28742247
[Au] Autor:Zhiwei W; Yuan J; Yihui Y; Xin H; Jingtao C; Lei S; Yongjian D
[Ti] Título:Ventana immunohistochemistry assay for anaplastic lymphoma kinase gene rearrangement detection in patients with non-small cell lung cancer: A meta-analysis.
[So] Source:Thorac Cancer;8(5):471-476, 2017 Sep.
[Is] ISSN:1759-7714
[Cp] País de publicação:Singapore
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The aim of this study was to evaluate the diagnostic value of Ventana immunohistochemistry (IHC) assay for anaplastic lymphoma kinase (ALK) gene rearrangement screening in patients with non-small cell lung cancer (NSCLC). METHODS: Open published studies that reported the diagnostic performance of Ventana IHC assay for ALK gene rearrangement detection in NSCLC patients were extracted from PubMed, Embase, Google scholar, Wanfang, and China National Knowledge Infrastructure. The general information and number of true positive (tp), false positive (fp), false negative (fn), and true negative (tn) cases identified by Ventana IHC assay were extracted. The diagnostic sensitivity, specificity, positive likelihood ratio (+lr), negative likelihood ratio (-lr), diagnostic odds ratio (dor) and the summary receiver operating characteristic (ROC) curve were calculated using Stata 11.0 software. RESULTS: Ten studies, including 240 ALK positive and 1973 ALK negative NSCLC patients were included in this meta-analysis. The pooled diagnostic sensitivity, specificity, +lr, -lr, and dor were 0.94 (95% confidence interval [CI] 0.85-0.98), 1.00 (95% CI 0.99-1.00), 859.61 (95% CI 60.81-1200.00), 0.06 (95% CI 0.03-0.16), and 1400.00 (95% CI 813.29-23 000.00), respectively. The area under the ROC curve was 0.996 for Ventana IHC assay in detecting ALK gene rearrangement in NSCLC patients. CONCLUSION: The sensitivity and specificity of Ventana IHC assay for the detection of ALK gene rearrangement were high, thus Ventana IHC could substitute fluorescence in situ hybridization for the screening of ALK+ NSCLC patients.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
Rearranjo Gênico
Neoplasias Pulmonares/metabolismo
Receptores Proteína Tirosina Quinases/metabolismo
[Mh] Termos MeSH secundário: Carcinoma Pulmonar de Células não Pequenas/genética
Seres Humanos
Imuno-Histoquímica/métodos
Neoplasias Pulmonares/genética
Proteínas de Fusão Oncogênicas/metabolismo
Curva ROC
Receptores Proteína Tirosina Quinases/genética
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (Oncogene Proteins, Fusion); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (anaplastic lymphoma kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1111/1759-7714.12468


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Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
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[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]:29225170
[Au] Autor:He MH; Zhang Q; Shu G; Lin JC; Zhao L; Liang XX; Yin L; Shi F; Fu HL; Yuan ZX
[Ad] Endereço:Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China.
[Ti] Título:Dihydromyricetin sensitizes human acute myeloid leukemia cells to retinoic acid-induced myeloid differentiation by activating STAT1.
[So] Source:Biochem Biophys Res Commun;495(2):1702-1707, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply a new combination therapy based on ATRA. Therefore, research strategies to further sensitize cells to retinoids are urgently needed. In this study, we showed that Dihydromyricetin (DMY), a 2,3-dihydroflavonol compound, exhibited a strong synergy with ATRA to promote APL NB4 cell differentiation. We observed that DMY sensitized the NB4 cells to ATRA-induced cell growth inhibition, CD11b expression, NBT reduction and myeloid regulator expression. PML-RARα might not be essential for DMY-enhanced differentiation when combined with ATRA, while the enhanced differentiation was dependent on the activation of p38-STAT1 signaling pathway. Taken together, our study is the first to evaluate the synergy of DMY and ATRA in NB4 cell differentiation and to assess new opportunities for the combination of DMY and ATRA as a promising approach for future differentiation therapy.
[Mh] Termos MeSH primário: Flavonóis/administração & dosagem
Leucemia Promielocítica Aguda/tratamento farmacológico
Fator de Transcrição STAT1/metabolismo
Tretinoína/administração & dosagem
[Mh] Termos MeSH secundário: Antineoplásicos/administração & dosagem
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Sinergismo Farmacológico
Seres Humanos
Leucemia Mieloide Aguda/tratamento farmacológico
Leucemia Mieloide Aguda/metabolismo
Leucemia Mieloide Aguda/patologia
Leucemia Promielocítica Aguda/metabolismo
Leucemia Promielocítica Aguda/patologia
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Proteínas de Fusão Oncogênicas/metabolismo
Proteólise/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Flavonols); 0 (Oncogene Proteins, Fusion); 0 (STAT1 Transcription Factor); 0 (STAT1 protein, human); 0 (promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein); 5688UTC01R (Tretinoin); KD8QND6427 (dihydromyricetin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:29273914
[Au] Autor:Shao H; Cen J; Chen S; Qiu H; Pan J
[Ad] Endereço:Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, People's Republic of China.
[Ti] Título:Myeloid neoplasms with t(12;22)(p13;q12)/MN1-EVT6: a systematic review of 12 cases.
[So] Source:Ann Hematol;97(3):417-424, 2018 Mar.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality involving the ETS transcription factor ETV6 and meningioma 1 (MN1) genes. In this study, we analyzed the clinical, cytogenetic, and molecular features of five new patients with the t(12;22)/MN1-EVT6 who presented with acute myeloid leukemia or chronic myelomonocytic leukemia. We subsequently reviewed the literature and identified seven additional cases reported with t(12;22)/MN1-EVT6. Our data suggest that neoplasms carrying the t(12;22)/MN1-ETV6, although rare, can commonly present as myeloid neoplasms at the initial diagnosis, including acute myeloid leukemia (n = 8), myelodysplastic syndrome (n = 2), and myelodysplastic/myeloproliferative neoplasms (n = 2). There were five men and seven women with a median age of 43 years (range, 15-63 years) at initial diagnosis. Cytogenetics revealed t(12;22) as the sole abnormality in five patients, with the remaining seven patients harboring additional chromosomal aberrations. Of the five patients who received known therapy regimens, all of them had poor response to the idarubicin/mitoxantrone + cytarabine regimen. Of the seven patients with follow-up information, six patients died with a median overall survival time of only 5 months (range, 1-12 months) after the emergence of t(12;22). In summary, patients with t(12;22) are frequently associated with myeloid neoplasms, poor response to chemotherapy, and inferior outcome.
[Mh] Termos MeSH primário: Neoplasias da Medula Óssea/genética
Proteínas de Fusão Oncogênicas/genética
Proteínas Proto-Oncogênicas c-ets/genética
Proteínas Repressoras/genética
Translocação Genética
Proteínas Supressoras de Tumor/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Neoplasias da Medula Óssea/patologia
Cromossomos Humanos Par 12
Cromossomos Humanos Par 13
Feminino
Seres Humanos
Masculino
Meia-Idade
Estudos Retrospectivos
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (ETS translocation variant 6 protein); 0 (MN1 protein, human); 0 (Oncogene Proteins, Fusion); 0 (Proto-Oncogene Proteins c-ets); 0 (Repressor Proteins); 0 (Tumor Suppressor Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171224
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3208-2


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[PMID]:28743306
[Au] Autor:Lyu X; Wang X; Zhang L; Chen Z; Zhao Y; Hu J; Fan R; Song Y
[Ad] Endereço:School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450000, China.
[Ti] Título:Detection of 22 common leukemic fusion genes using a single-step multiplex qRT-PCR-based assay.
[So] Source:Diagn Pathol;12(1):55, 2017 Jul 25.
[Is] ISSN:1746-1596
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Fusion genes generated from chromosomal translocation play an important role in hematological malignancies. Detection of fusion genes currently employ use of either conventional RT-PCR methods or fluorescent in situ hybridization (FISH), where both methods involve tedious methodologies and require prior characterization of chromosomal translocation events as determined by cytogenetic analysis. In this study, we describe a real-time quantitative reverse transcription PCR (qRT-PCR)-based multi-fusion gene screening method with the capacity to detect 22 fusion genes commonly found in leukemia. This method does not require pre-characterization of gene translocation events, thereby facilitating immediate diagnosis and therapeutic management. METHODS: We performed fluorescent qRT-PCR (F-qRT-PCR) using a commercially-available multi-fusion gene detection kit on a patient cohort of 345 individuals comprising 108 cases diagnosed with acute myeloid leukemia (AML) for initial evaluation; remaining patients within the cohort were assayed for confirmatory diagnosis. Results obtained by F-qRT-PCR were compared alongside patient analysis by cytogenetic characterization. RESULTS: Gene translocations detected by F-qRT-PCR in AML cases were diagnosed in 69.4% of the patient cohort, which was comparatively similar to 68.5% as diagnosed by cytogenetic analysis, thereby demonstrating 99.1% concordance. Overall gene fusion was detected in 53.7% of the overall patient population by F-qRT-PCR, 52.9% by cytogenetic prediction in leukemia, and 9.1% in non-leukemia patients by both methods. The overall concordance rate was calculated to be 99.0%. Fusion genes were detected by F-qRT-PCR in 97.3% of patients with CML, followed by 69.4% with AML, 33.3% with acute lymphoblastic leukemia (ALL), 9.1% with myelodysplastic syndromes (MDS), and 0% with chronic lymphocytic leukemia (CLL). CONCLUSIONS: We describe the use of a F-qRT-PCR-based multi-fusion gene screening method as an efficient one-step diagnostic procedure as an effective alternative to lengthy conventional diagnostic procedures requiring both cytogenetic analysis followed by targeted quantitative reverse transcription (qRT-PCR) methods, thus allowing timely patient management.
[Mh] Termos MeSH primário: Leucemia Mieloide Aguda/genética
Reação em Cadeia da Polimerase Multiplex/métodos
Fusão Oncogênica/genética
Reação em Cadeia da Polimerase em Tempo Real/métodos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Criança
Pré-Escolar
Feminino
Seres Humanos
Lactente
Recém-Nascido
Leucemia/genética
Masculino
Meia-Idade
Proteínas de Fusão Oncogênicas/genética
Translocação Genética/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oncogene Proteins, Fusion)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1186/s13000-017-0634-3


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[PMID]:29284709
[Au] Autor:Sump B; Brickner JH
[Ad] Endereço:Department of Molecular Biosciences, Northwestern University, Evanston, Illinois 60208, USA.
[Ti] Título:Nup98 regulation of histone methylation promotes normal gene expression and may drive leukemogenesis.
[So] Source:Genes Dev;31(22):2201-2203, 2017 11 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nuclear pore proteins (Nups) interact with chromosomes to regulate gene expression and chromatin structure. A new study by Franks and colleagues (pp. 2222-2234) provides new mechanistic insight into the molecular basis by which Nup98 promotes gene activation in normal hematopoietic cells and how that process is altered by translocations to cause excess expression of developmental genes in leukemia.
[Mh] Termos MeSH primário: Histonas/genética
Proteínas de Fusão Oncogênicas/genética
[Mh] Termos MeSH secundário: Proteínas de Homeodomínio/genética
Leucemia/genética
Metilação
Complexo de Proteínas Formadoras de Poros Nucleares/genética
Translocação Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; REVIEW; COMMENT
[Nm] Nome de substância:
0 (Histones); 0 (Homeodomain Proteins); 0 (Nuclear Pore Complex Proteins); 0 (Oncogene Proteins, Fusion)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE
[do] DOI:10.1101/gad.310359.117


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[PMID]:29277318
[Au] Autor:Eryilmaz IE; Kordan Y; Vuruskan BA; Kaygisiz O; Tunca B; Cecener G
[Ad] Endereço:Uludag University, Faculty of Medicine, Medical Biology Department, Gorukle, Bursa, Turkey.
[Ti] Título:T2E (TMPRSS2-ERG) fusion transcripts are associated with higher levels of AMACR mRNA and a subsequent prostate cancer diagnosis in patients with atypical small acinar proliferation.
[So] Source:Gene;645:69-75, 2018 Mar 01.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Genetic rearrangements involving androgen-regulated transmembrane protease serine 2 (TMPRSS2) and genes from the ETS transcription factor family, most commonly ERG and ETV1, result in alteration that responsible for oncogenic activity in prostate cancer (PC). The aims of the present study were to: 1) investigate the frequency of these fusion transcripts in prostate tissue samples obtained from patients diagnosed with atypical small acinar proliferation (ASAP), 2) determine any clinical significance of T2E expression at the RNA level in predicting PC detection in subsequent biopsies, and 3) evaluate expression of the PC marker, alpha-methylacyl-CoA racemase (AMACR), according to T2E status by real-time quantitative reverse transcription PCR (RT-qPCR). T2E transcripts were detected in 31.7% (n=20) of the patients examined, and this was significantly associated with subsequent detection of PC in ASAP patients with a prostate specific antigen (PSA) level of 4-10ng/ml (p=0.045). AMACR expression was also significantly higher in the patients who were diagnosed with PC in subsequent biopsies than in the patients who were not diagnosed with PC (p=0.034) and in T2E-positive ASAP patients (p=0.002) compared to T2E-negative ASAP patients. Although these results need to be further clinically validated, we suggest that the presence of T2E transcript, in association with higher AMACR expression, is an indicator of PC risk from a T2E-positive focus or an unsampled malignant gland adjacent to a T2E-positive site in ASAP lesions.
[Mh] Termos MeSH primário: Células Acinares/patologia
Proteínas de Fusão Oncogênicas/genética
Neoplasias da Próstata/diagnóstico
Racemases e Epimerases/genética
[Mh] Termos MeSH secundário: Idoso
Biópsia
Detecção Precoce de Câncer
Predisposição Genética para Doença
Seres Humanos
Masculino
Meia-Idade
Neoplasias da Próstata/genética
Estudos Retrospectivos
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oncogene Proteins, Fusion); 0 (TMPRSS2-ERG fusion protein, human); EC 5.1.- (Racemases and Epimerases); EC 5.1.99.4 (alpha-methylacyl-CoA racemase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


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[PMID]:28465216
[Au] Autor:Roskoski R
[Ad] Endereço:Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States. Electronic address: rrj@brimr.org.
[Ti] Título:ROS1 protein-tyrosine kinase inhibitors in the treatment of ROS1 fusion protein-driven non-small cell lung cancers.
[So] Source:Pharmacol Res;121:202-212, 2017 Jul.
[Is] ISSN:1096-1186
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:ROS1 protein-tyrosine kinase fusion proteins are expressed in 1-2% of non-small cell lung cancers. The ROS1 fusion partners include CD74, CCDC6, EZR, FIG, KDELR2, LRIG3, MSN, SDC4, SLC34A2, TMEM106B, TMP3, and TPD52L1. Physiological ROS1 is closely related to the ALK, LTK, and insulin receptor protein-tyrosine kinases. ROS1 is a so-called orphan receptor because the identity of its activating ligand, if any, is unknown. The receptor is expressed during development, but little is expressed in adults and its physiological function is unknown. The human ROS1 gene encodes 2347 amino acid residues and ROS1 is the largest protein-tyrosine kinase receptor protein. Unlike the ALK fusion proteins that are activated by the dimerization induced by their amino-terminal portions, the amino-terminal domains of several of its fusion proteins including CD74 apparently lack the ability to induce dimerization so that the mechanism of constitutive protein kinase activation is unknown. Downstream signaling from the ROS1 fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module, the phosphatidyl inositol 3-kinase cell survival pathway, and the Vav3 cell migration pathway. Moreover, several of the ROS1 fusion proteins are implicated in the pathogenesis of a very small proportion of other cancers including glioblastoma, angiosarcoma, and cholangiocarcinoma as well as ovarian, gastric, and colorectal carcinomas. The occurrence of oncogenic ROS1 fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ROS1 inhibitors. Although the percentage of lung cancers driven by ROS1 fusion proteins is low, owing to the large number of new cases of non-small cell lung cancer per year, the number of new cases of ROS1-positive lung cancers is significant and ranges from 2000 to 4000 per year in the United States and 10,000-15,000 worldwide. Crizotinib was the first inhibitor approved by the US Food and Drug Administration for the treatment of ROS1-positive non-small cell lung cancer in 2016. Other drugs that are in clinical trials for the treatment of these lung cancers include ceritinib, cabozantinib, entrectinib, and lorlatinib. Crizotinib forms a complex within the front cleft between the small and large lobes of an active ROS1 protein-kinase domain and it is classified as type I inhibitor.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Neoplasias Pulmonares/tratamento farmacológico
Pulmão/efeitos dos fármacos
Proteínas de Fusão Oncogênicas/antagonistas & inibidores
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Tirosina Quinases/antagonistas & inibidores
Proteínas Proto-Oncogênicas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Carcinoma Pulmonar de Células não Pequenas/patologia
Ensaios Clínicos como Assunto
Seres Humanos
Pulmão/metabolismo
Pulmão/patologia
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/patologia
Modelos Moleculares
Proteínas de Fusão Oncogênicas/análise
Proteínas de Fusão Oncogênicas/metabolismo
Proteínas Tirosina Quinases/análise
Proteínas Tirosina Quinases/metabolismo
Proteínas Proto-Oncogênicas/análise
Proteínas Proto-Oncogênicas/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Oncogene Proteins, Fusion); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.10.1 (ROS1 protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  9 / 7526 MEDLINE  
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[PMID]:28743050
[Au] Autor:Zhu B; Wang JY; Zhou JJ; Zhou F; Cheng W; Liu YT; Wang J; Chen X; Chen DH; Luo L; Hua ZC
[Ad] Endereço:The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China.
[Ti] Título:PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells.
[So] Source:J Inorg Biochem;175:92-100, 2017 Oct.
[Is] ISSN:1873-3344
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acute promyelocytic leukemia (APL) is characterized and driven by the promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) fusion gene. Previous studies have highlighted the importance of PML-RARα degradation in the treatment against APL. Considering the presence of two zinc fingers in the PML-RARα fusion protein, we explored the function of zinc homeostasis in maintaining PML-RARα stability. We demonstrated for the first time that zinc depletion by its chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) triggered PML-RARα degradation in NB4 APL cells via the proteasome pathway rather than the autophagy-lysosomal pathway. In contrast, autophagy protected TPEN-mediated PML-RARα degradation in NB4 APL cells. We further demonstrated that crosstalk between zinc homeostasis and nitric oxide pathway played a key role in maintaining PML-RARα stability in NB4 APL cells. These results demonstrate that zinc homeostasis is vital for maintaining PML-RARα stability, and zinc depletion by TPEN may be useful as a potential strategy to trigger PML-RARα degradation in APL cells. We also found that TPEN triggered apoptosis of NB4 APL cells in a time-dependent manner. The relationship between PML-RARα degradation and apoptosis triggered by TPEN deserves further study.
[Mh] Termos MeSH primário: Leucemia Promielocítica Aguda/metabolismo
Proteínas de Fusão Oncogênicas/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Proteólise
Zinco/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
Leucemia Promielocítica Aguda/genética
Leucemia Promielocítica Aguda/patologia
Proteínas de Fusão Oncogênicas/genética
Complexo de Endopeptidases do Proteassoma/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oncogene Proteins, Fusion); 0 (promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein); EC 3.4.25.1 (Proteasome Endopeptidase Complex); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


  10 / 7526 MEDLINE  
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[PMID]:28748614
[Au] Autor:Zarnegar S; Durham BH; Khattar P; Shukla NN; Benayed R; Lacouture ME; Lavi E; Lyden DC; Diamond EL; Dunkel IJ; Abdel-Wahab O
[Ad] Endereço:Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
[Ti] Título:Novel activating BRAF fusion identifies a recurrent alternative mechanism for ERK activation in pediatric Langerhans cell histiocytosis.
[So] Source:Pediatr Blood Cancer;65(1), 2018 Jan.
[Is] ISSN:1545-5017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism. Genomic evaluation for activating kinase fusions should be strongly considered in pediatric LCH patients lacking more common mutations.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética
MAP Quinases Reguladas por Sinal Extracelular
Histiocitose de Células de Langerhans/genética
Proteínas de Fusão Oncogênicas/genética
Proteínas Proto-Oncogênicas B-raf/genética
[Mh] Termos MeSH secundário: Criança
Ativação Enzimática/genética
Seres Humanos
Masculino
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Oncogene Proteins, Fusion); 0 (PACSIN2 protein, human); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171201
[Lr] Data última revisão:
171201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1002/pbc.26699



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