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[PMID]: 28460470 [Au] Autor: Cheng T; Song Y; Zhang Y; Zhang C; Yin J; Chi Y; Zhou D [Ad] Endereço: Vaccine Research Center, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Science, Shanghai 200031, China. [Ti] Título: A novel oncolytic adenovirus based on simian adenovirus serotype 24. [So] Source: Oncotarget;8(16):26871-26885, 2017 Apr 18. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Among the oncolytic virotherapy, an emerging treatment for tumor, adenoviruses are widely used at present in preclinical and clinical trials. Traditionally, oncolytic adenoviruses were developed based on the human adenovirus serotype 5 (AdHu5). However, AdHu5 has the drawbacks of preexisting anti-AdHu5 immunity in most populations, and extensive sequestration of Adhu5 by the liver through hexon, blood coagulation factor X (FX), and FX receptor interactions. To tackle these problems, we explored a novel oncolytic adenovirus AdC7-SP/E1A-ΔE3 for cancer treatment. AdC7-SP/E1A-ΔE3 was constructed by replacing the E1A promoter with tumor specific promoter survivin promoter and deleting E3 region using direct cloning methods based on simian adenovirus serotype 24 (namely AdC7). We showed that AdC7-SP/E1A-ΔE3 significantly killed tumor cell lines NCI-H508 and Huh7, and inhibited tumor growth in both NCI-H508 and Huh7 xenograft tumor models. Importantly, AdC7-SP/E1A-ΔE3 exhibited the antitumor efficacy via systemic administration. Mechanistically, infected cells were killed by AdC7-SP/E1A-ΔE3 via the p53-independent mitochondrial apoptosis pathway in which phosphorylation of BAD markedly declined and the expresses of Bik significantly went up. Therefore, AdC7-SP/E1A-ΔE3 is a promising candidate for liver and colon tumor treatment. [Mh] Termos MeSH primário: Adenovirus dos Símios/classificação Adenovirus dos Símios/genética Vetores Genéticos/genética Vírus Oncolíticos/genética [Mh] Termos MeSH secundário: Proteínas E1A de Adenovirus/genética Animais Apoptose/genética Linhagem Celular Tumoral Efeito Citopatogênico Viral Modelos Animais de Doenças Deleção de Genes Expressão Gênica Engenharia Genética Terapia Genética Vetores Genéticos/administração & dosagem Vetores Genéticos/efeitos adversos Seres Humanos Proteínas Inibidoras de Apoptose/genética Camundongos Mitocôndrias/genética Terapia Viral Oncolítica Especificidade de Órgãos/genética Regiões Promotoras Genéticas Sorogrupo Transdução de Sinais Carga Tumoral Proteína Supressora de Tumor p53/genética Proteína Supressora de Tumor p53/metabolismo Replicação Viral Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adenovirus E1A Proteins); 0 (BIRC5 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (Tumor Suppressor Protein p53) [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.15845

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[PMID]: 29332262 [Au] Autor: Karpinsky G; Krawczyk MA; Izycka-Swieszewska E; Fatyga A; Budka A; Balwierz W; Sobol G; Zalewska-Szewczyk B; Rychlowska-Pruszynska M; Klepacka T; Dembowska-Baginska B; Kazanowska B; Gabrych A; Bien E [Ad] Endereço: Children's Hospital of Michigan, 3901 Beaubien St, Detroit, MI, USA. [Ti] Título: Tumor expression of survivin, p53, cyclin D1, osteopontin and fibronectin in predicting the response to neo-adjuvant chemotherapy in children with advanced malignant peripheral nerve sheath tumor. [So] Source: J Cancer Res Clin Oncol;144(3):519-529, 2018 Mar. [Is] ISSN: 1432-1335 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: PURPOSE: Selected cell-cycle regulators and extracellular matrix proteins were found to play roles in malignant peripheral nerve sheath tumor (MPNST) biology. We aimed to analyze whether initial tumor tissue expressions of survivin, p53, cyclin D1, osteopontin (OPN) and fibronectin (FN) correlate with the response to neo-adjuvant CHT (naCHT) in children with advanced inoperable MPNST. METHODS: The study included 26 children with MPNST (M/F 14/12, median age 130 months) treated in Polish centers of pediatric oncology between 1992 and 2013. Tissue expression of markers was studied immunohistochemically in the manually performed tissue microarrays and assessed semi-quantitatively as low and high, based on the rate of positive cells and staining intensity. RESULTS: Good response to naCHT was noted in 47.6%, while poor-in 52.4% of patients. The response to naCHT was influenced negatively by the presence of neurofibromatosis NF1 and high initial tumor tissue expression of OPN, survivin, p53 and cyclin D1. Patients with high tumor expression of either OPN, survivin or p53 and those with simultaneous high expression of ≥ 3 of the markers, responded significantly worse to naCHT, than patients, in whom expression of ≤ 2 markers were detected at diagnosis. Nearly, 85% of patients expressing ≥ 3 markers, responded poor to CHT; while 87.5% of children, expressing ≤ 2 markers, were good responders. CONCLUSION: The initial tumor tissue expression of OPN, survivin, p53 and cyclin D1 may serve as markers to predict response to naCHT in pediatric advanced MPNST. Future studies in more numerous group of patients are needed to confirm these preliminary results. [Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico Biomarcadores Tumorais/metabolismo Ciclina D1/metabolismo Citocinas/metabolismo Proteínas Inibidoras de Apoptose/metabolismo Neoplasias da Bainha Neural/diagnóstico Neoplasias da Bainha Neural/tratamento farmacológico Osteopontina/metabolismo [Mh] Termos MeSH secundário: Adolescente Biomarcadores Farmacológicos/metabolismo Criança Pré-Escolar Progressão da Doença Feminino Seres Humanos Lactente Masculino Terapia Neoadjuvante Neoplasias da Bainha Neural/metabolismo Neoplasias da Bainha Neural/patologia Neurilemoma/tratamento farmacológico Neurilemoma/metabolismo Neurilemoma/patologia Prognóstico Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (BIRC5 protein, human); 0 (Biomarkers, Pharmacological); 0 (Biomarkers, Tumor); 0 (CCND1 protein, human); 0 (Cytokines); 0 (Inhibitor of Apoptosis Proteins); 0 (SPP1 protein, human); 0 (migration stimulating factor, human); 106441-73-0 (Osteopontin); 136601-57-5 (Cyclin D1) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180228 [Lr] Data última revisão: 180228 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180115 [St] Status: MEDLINE [do] DOI: 10.1007/s00432-018-2580-1

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[PMID]: 29173363 [Au] Autor: Feng C; Wang T; Zhang Y; Qu K; Tang S [Ad] Endereço: Department of Pediatrics, Chinese PLA General Hospital, Beijing, China. [Ti] Título: Novel Survivin-Targeted Small Interfering RNA Delivered by Nanoparticles. [So] Source: Am J Med Sci;354(5):506-512, 2017 11. [Is] ISSN: 1538-2990 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: The aim of the present study was to investigate the antitumor effect of our novel survivin-targeted small interfering RNA (siRNA) nanoliposomes on xenograft mouse models with human cervical carcinoma HeLa cells, and to evaluate pharmacokinetics. MATERIALS AND METHODS: siRNA nanoliposome was prepared and transfected into xenograft mouse models. Tumor growth in mice was determined and survivin expression was analyzed by using histologic and immunohischemical staining. Furthermore, low, moderate and high doses of survivin siRNA nanoliposomes were injected in 3 groups, and plasma concentrations were detected at various time points by reverse transcription quantitative polymerase chain reaction. Biodistribution of siRNA in tumor and other important organs were also determined. RESULTS: Survivin expression was significantly downregulated by survivin siRNA delivery mediated by nanoliposome, along with significant suppression of cell growth. Peak concentrations were obtained at 15 minutes after injection in each group, with 1,042,538.00, 6,837,099.54 and 14,631,333.15pg/mL, respectively, and the plasma concentration decreased significantly after 24 hours. The half-time life of survivin siRNA nanoliposomes in each group was 3.60, 2.64 and 2.80 hours, respectively. The area under curve values were 952,190.88, 6,800,687.79 and 13,803,680.96h/pg/mL, and the total drug clearance were 1,050.12, 441.13 and 434.67mL/h/kg. A significant accumulation of Cy5-labeled siRNA was found in the tumor, and a nonspecific accumulation was reduced significantly in lung. CONCLUSIONS: Our findings revealed that survivin suppression by siRNA may contribute to tumor inhibition through both proliferation inhibition and apoptosis promotion effect, and the pharmacokinetic characteristics serve as a fundamental role for further studies on its applicability for cancer therapy. [Mh] Termos MeSH primário: Proteínas Inibidoras de Apoptose/farmacologia Lipossomos/farmacologia Nanopartículas/administração & dosagem RNA Interferente Pequeno/farmacologia [Mh] Termos MeSH secundário: Animais Antineoplásicos/farmacologia Proliferação Celular/efeitos dos fármacos Regulação para Baixo/efeitos dos fármacos Células HeLa Seres Humanos Proteínas Inibidoras de Apoptose/farmacocinética Lipossomos/farmacocinética Masculino Camundongos Camundongos Endogâmicos BALB C Camundongos Nus RNA Interferente Pequeno/administração & dosagem RNA Interferente Pequeno/farmacocinética Distribuição Tecidual Ensaios Antitumorais Modelo de Xenoenxerto [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (BIRC5 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (Liposomes); 0 (RNA, Small Interfering) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 171128 [St] Status: MEDLINE

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[PMID]: 28463235 [Au] Autor: Scaini G; Fries GR; Valvassori SS; Zeni CP; Zunta-Soares G; Berk M; Soares JC; Quevedo J [Ad] Endereço: Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. [Ti] Título: Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients. [So] Source: Transl Psychiatry;7(5):e1111, 2017 May 02. [Is] ISSN: 2158-3188 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Bipolar disorder (BD) is a severe psychiatric disorder characterized by phasic changes of mood and can be associated with progressive structural brain change and cognitive decline. The numbers and sizes of glia and neurons are reduced in several brain areas, suggesting the involvement of apoptosis in the pathophysiology of BD. Because the changes in mitochondrial dynamics are closely related with the early process of apoptosis and the specific processes of apoptosis and mitochondrial dynamics in BD have not been fully elucidated, we measured the apoptotic pathway and the expression of mitochondrial fission/fusion proteins from BD patients and healthy controls. We recruited 16 patients with BD type I and sixteen well-matched healthy controls and investigated protein levels of several pro-apoptotic and anti-apoptotic factors, as well as the expression of mitochondrial fission/fusion proteins in peripheral blood mononuclear cells (PBMCs). Our results showed that the levels of the anti-apoptotic proteins Bcl-xL, survivin and Bcl-xL/Bak dimer were significantly decreased, while active caspase-3 protein levels were significantly increased in PBMCs from BD patients. Moreover, we observed the downregulation of the mitochondrial fusion-related proteins Mfn2 and Opa1 and the upregulation of the fission protein Fis1 in PBMCs from BD patients, both in terms of gene expression and protein levels. We also showed a significantly decrease in the citrate synthase activity. Finally, we found a positive correlation between Mfn2 and Opa1 with mitochondrial content markers, as well as a negative correlation between mitochondrial fission/fusion proteins and apoptotic markers. Overall, data reported here are consistent with the working hypothesis that apoptosis may contribute to cellular dysfunction, brain volume loss and progressive cognitive in BD. Moreover, we show an important relationship between mitochondrial dynamics and the cell death pathway activation in BD patients, supporting the link between mitochondrial dysfunction and the pathophysiology of BD. [Mh] Termos MeSH primário: Apoptose/genética Transtorno Bipolar/metabolismo Leucócitos Mononucleares/metabolismo Mitocôndrias/metabolismo [Mh] Termos MeSH secundário: Adulto Proteínas Reguladoras de Apoptose/genética Transtorno Bipolar/sangue Transtorno Bipolar/fisiopatologia Caspase 3/metabolismo Morte Celular Feminino GTP Fosfo-Hidrolases/genética Expressão Gênica/genética Seres Humanos Proteínas Inibidoras de Apoptose/metabolismo Masculino Proteínas de Membrana/genética Dinâmica Mitocondrial/genética Proteínas Mitocondriais/genética Neurônios/metabolismo Regulação para Cima/genética Proteína bcl-X/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Apoptosis Regulatory Proteins); 0 (BIRC5 protein, human); 0 (FIS1 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (Membrane Proteins); 0 (Mitochondrial Proteins); 0 (bcl-X Protein); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (Caspase 3); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.1.- (MFN2 protein, human); EC 3.6.1.- (OPA1 protein, human) [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: 170503 [St] Status: MEDLINE [do] DOI: 10.1038/tp.2017.83

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[PMID]: 28468627 [Au] Autor: Yin Y; Sui C; Meng F; Ma P; Jiang Y [Ad] Endereço: Cancer Institute, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, 110001, China. doustar88@126.com. [Ti] Título: The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species-mediated inactivation of the PI3K /Akt pathway. [So] Source: Lipids Health Dis;16(1):87, 2017 May 03. [Is] ISSN: 1476-511X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Docosahexaenoic acid(DHA) inhibits tumor growth and progression in various cancers, including lung cancer. However, the mechanisms involved remain unclear. The aim of this study was to identify the mechanism of DHA in inhibiting progression of non-small cell lung cancer (NSCLC) in vitro. METHODS: The proliferation of A549 was tested by MTT, and cell apoptosis was analysed using flow cytometer. The migration and invasion were examined respectively by wound healing assay and Transwell invasion assay. The level of ROS (reactive oxygen species, ROS) was checked by DCF (dichlorodihydrofluorescein, DCF) production in cells. The apoptosis associated protein (caspase-3, PARP,Bax,Bcl-2 and survivin) and metastases associated proteins including HEF1, MMP9 and VEGF were detected by Western blot, and the same method was used in the expression of PI3K and Akt. RESULTS: DHA inhibited proliferation and induced apoptosis of A549 cells. Moreover, it suppressed the invasion and metastasis of A549 cells, while downregulating the levels of metastasis-associated proteins, including HEF1, matrix metallopeptidase (MMP9), and vascular endothelial growth factor (VEGF), in a dose -dependent manner. In addition, DHA inactivated Akt phosphorylation. All of these responses were associated with the accumulation of intracellular ROS. DHA downregulated the level of antioxidant enzymes such as catalase, while the antioxidant N-acetyl-cysteine (NAC) reversed the effect of DHA, which further validated our findings. CONCLUSIONS: The present study demonstrates that DHA inhibits the development of non-small lung tumors through an ROS-mediated inactivation of the PI3K/Akt signaling pathway. [Mh] Termos MeSH primário: Antineoplásicos/farmacologia Ácidos Docosa-Hexaenoicos/farmacologia Regulação Neoplásica da Expressão Gênica Fosfatidilinositol 3-Quinases/genética Proteínas Proto-Oncogênicas c-akt/genética Espécies Reativas de Oxigênio/agonistas [Mh] Termos MeSH secundário: Células A549 Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores Proteínas Adaptadoras de Transdução de Sinal/genética Proteínas Adaptadoras de Transdução de Sinal/metabolismo Apoptose/efeitos dos fármacos Caspase 3/genética Caspase 3/metabolismo Catalase/antagonistas & inibidores Catalase/genética Catalase/metabolismo Movimento Celular/efeitos dos fármacos Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Seres Humanos Proteínas Inibidoras de Apoptose/genética Proteínas Inibidoras de Apoptose/metabolismo Metaloproteinase 9 da Matriz/genética Metaloproteinase 9 da Matriz/metabolismo Fosfatidilinositol 3-Quinases/antagonistas & inibidores Fosfatidilinositol 3-Quinases/metabolismo Fosfoproteínas/antagonistas & inibidores Fosfoproteínas/genética Fosfoproteínas/metabolismo Fosforilação/efeitos dos fármacos Poli(ADP-Ribose) Polimerases/genética Poli(ADP-Ribose) Polimerases/metabolismo Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores Proteínas Proto-Oncogênicas c-akt/metabolismo Proteínas Proto-Oncogênicas c-bcl-2/genética Proteínas Proto-Oncogênicas c-bcl-2/metabolismo Espécies Reativas de Oxigênio/metabolismo Transdução de Sinais Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores Fator A de Crescimento do Endotélio Vascular/genética Fator A de Crescimento do Endotélio Vascular/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents); 0 (BCL2 protein, human); 0 (BIRC5 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (NEDD9 protein, human); 0 (Phosphoproteins); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Reactive Oxygen Species); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); 25167-62-8 (Docosahexaenoic Acids); EC 1.11.1.6 (Catalase); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (CASP3 protein, human); EC 3.4.22.- (Caspase 3); EC 3.4.24.35 (MMP9 protein, human); EC 3.4.24.35 (Matrix Metalloproteinase 9) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180219 [Lr] Data última revisão: 180219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170505 [St] Status: MEDLINE [do] DOI: 10.1186/s12944-017-0474-x

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[PMID]: 29253572 [Au] Autor: Kim YS; Jin HO; Hong SE; Song JY; Hwang CS; Park IC [Ad] Endereço: Human Resource Biobank, Cheil General Hospital & Women's Healthcare Center, DanKook University College of Medicine, 17, Seoae-ro 1-gil, Jung-gu, Seoul, 04619, Republic of Korea. [Ti] Título: Silencing of secretory clusterin sensitizes NSCLC cells to V-ATPase inhibitors by downregulating survivin. [So] Source: Biochem Biophys Res Commun;495(2):2004-2009, 2018 01 08. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Secretory clusterin (sCLU) is a stress-associated protein that confers resistance to therapy when overexpressed. In this study, we observed that the V-ATPase inhibitors bafilomycin A1 and concanamycin A significantly stimulated sCLU protein expression. Knockdown of sCLU with siRNA sensitized non-small cell lung cancer (NSCLC) cells to bafilomycin A1, suggesting that sCLU expression renders cells resistant to V-ATPase inhibitors. The dual PI3K/AKT and mTOR inhibitor BEZ235 suppressed sCLU expression and enhanced cell sensitivity induced by bafilomycin A1. Notably, sCLU knockdown further decreased the expression of the survivin protein by bafilomycin A1, and the ectopic expression of survivin alleviated the cell sensitivity by bafilomycin A1 and sCLU depletion, suggesting that increased sensitivity to sCLU depletion in the cells with V-ATPase inhibitors is due, at least in part, to the down-regulation of survivin. Taken together, we demonstrated that the depletion of sCLU expression enhances the sensitivity of NSCLC cells to V-ATPase inhibitors by decreasing survivin expression. Inhibition of the PI3K/AKT/mTOR pathway enhances the sensitivity of NSCLC cells to V-ATPase inhibitors, leading to decreased sCLU and survivin expression. Thus, we suggest that a combination of PI3K/AKT/mTOR inhibitors with V-ATPase inhibitors might be an effective approach for NSCLC treatment. [Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem Carcinoma Pulmonar de Células não Pequenas/terapia Clusterina/genética Terapia Genética/métodos Proteínas Inibidoras de Apoptose/metabolismo Neoplasias Pulmonares/terapia ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores [Mh] Termos MeSH secundário: Células A549 Apoptose/efeitos dos fármacos Carcinoma Pulmonar de Células não Pequenas/genética Carcinoma Pulmonar de Células não Pequenas/patologia Sobrevivência Celular/efeitos dos fármacos Terapia Combinada/métodos Regulação para Baixo/efeitos dos fármacos Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Regulação Neoplásica da Expressão Gênica/genética Inativação Gênica Seres Humanos Neoplasias Pulmonares/genética Neoplasias Pulmonares/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (BIRC5 protein, human); 0 (CLU protein, human); 0 (Clusterin); 0 (Inhibitor of Apoptosis Proteins); EC 3.6.1.- (Vacuolar Proton-Translocating ATPases) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180214 [Lr] Data última revisão: 180214 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171219 [St] Status: MEDLINE

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[PMID]: 29328641 [Au] Autor: Jovic M; Cerovic S; Zolotarevska L; Gacevic M; Stanojevic I; Miller K; Dukic M; Saso L; Jaukovic L; Vojvodic D [Ti] Título: Correlation of local and systemic expression of survivin with histopathological parameters of cutaneous melanoma. [So] Source: Vojnosanit Pregl;73(11):1022-9, 2016 Nov. [Is] ISSN: 0042-8450 [Cp] País de publicação: Serbia [La] Idioma: eng [Ab] Resumo: Background/Aim: Survivin is a multifunctional protein abundantly expressed in tumors of various types, including melanoma. There are still sparse data regarding relationship of melanoma cell survivin expression with accepted histopathological characteristics as well as serum concentration. The aim of this study was to investigate the association of local tumor survivin expression (primary tumor and metastatic lesions) and serum concentration with clinical and histopathological parameters in melanoma patients. Methods: The level of survivin expression was determined immunocytochemically in tumor tissue and with ELISA test in the serum of 84 melanoma patients diagnosed from 2009 to 2013 at the Institute for Pathology and Forensic Medicine and Institute for Medical Research at Military Medical Academy, Belgrade, Serbia. Results: The intensity of survivin expression was significantly higher in the patients whose tumor had ulceration, higher mitotic index, higher Clark and Breslow stage, that made vascular invasion or spread through lymphatic vessels in primary tumor, and was significantly higher in the patients with metastatic disease. Survivin expression and the number of survivin positive cells in metastatic lesions were significantly associated with the duration of disease free interval (DFI). The patients with high expression score had almost double shorter DFI comparing to those with weak local survivin expression and a small number of survivin+cells (9 ± 7 vs 19 ± 13 months, respectively). The degree of tumor infiltrating lymphocytes presence in tumor tissue was significantly associated with serum survivin concentration, with lowest average level detected in samples of patients with the highest degree of infiltration. Serum survivin concentrations were highest in samples of melanoma patients with IA American Joint Commission on Cancer (AJCC) clinical stage, pT1a histological stage, patients whose tumors were still in horizontal growth phase, without signs of lympho-hematological disease spreading, with the highest number of mitoses and the smallest Clark index. Conclusion: Survivin expression in tumor tissue and its serum concetration significantly correlate with clinical and histopathological parameters. Serum levels could be important in initial follow-up as indicators of those patients that would have aggressive local tumor growth and spreading. Survivin determination in tumor tissue is of great significance in estimation of DFI. [Mh] Termos MeSH primário: Biomarcadores Tumorais/análise Proteínas Inibidoras de Apoptose/análise Melanoma/química Neoplasias Cutâneas/química [Mh] Termos MeSH secundário: Adulto Idoso Biomarcadores Tumorais/sangue Intervalo Livre de Doença Feminino Seres Humanos Proteínas Inibidoras de Apoptose/sangue Metástase Linfática Masculino Melanoma/mortalidade Melanoma/secundário Melanoma/terapia Meia-Idade Índice Mitótico Invasividade Neoplásica Estadiamento de Neoplasias Fatores de Risco Neoplasias Cutâneas/mortalidade Neoplasias Cutâneas/patologia Neoplasias Cutâneas/terapia Análise de Sobrevida Fatores de Tempo Carga Tumoral [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (BIRC5 protein, human); 0 (Biomarkers, Tumor); 0 (Inhibitor of Apoptosis Proteins) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180213 [Lr] Data última revisão: 180213 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180113 [St] Status: MEDLINE [do] DOI: 10.2298/VSP150519119J

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[PMID]: 29193199 [Au] Autor: Liu C; Xie Y; Sun B; Geng F; Zhang F; Guo Q; Wu H; Yu B; Wu J; Yu X; Kong W; Zhang H [Ad] Endereço: National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, Changchun, China. [Ti] Título: MUC1- and Survivin-based DNA Vaccine Combining Immunoadjuvants CpG and interleukin-2 in a Bicistronic Expression Plasmid Generates Specific Immune Responses and Antitumour Effects in a Murine Colorectal Carcinoma Model. [So] Source: Scand J Immunol;87(2):63-72, 2018 Feb. [Is] ISSN: 1365-3083 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: DNA vaccination is a promising cancer treatment due to its safety, but poor immunogenicity limits its application. However, immunoadjuvants, heterogeneous prime-boost strategies and combination with conventional treatments can be used to improve the antitumour immune effects. A CpG motif and interleukin-2 (IL-2) cytokine are often used as adjuvants. In this study, a DNA vaccine containing a CpG motif was constructed to evaluate its adjuvant effect. The results show that the cytotoxicity of the DNA vaccine was increased fivefold, and survival lifetime was prolonged twofold by the CpG motif adjuvant. To simplify the industrial production process, a bicistronic plasmid was constructed to carry the fusion genes of survivin/MUC1 (MS) and IL-2 and with a CpG motif in its backbone. The results showed that the antitumour effect of the bicistronic vaccine was the same as that of the two vaccine co-injected regime. Furthermore, the vaccine could suppress metastatic tumour foci by 69.1% in colorectal carcinoma-bearing mice. Moreover, the vaccine induced survivin- and MUC1-specific immune responses in splenocytes and induced the immune promoting factor CCL-19 and GM-CSF upregulated, while metastatic-associated factor MMP-9 and immunosuppressing factor PD-L1 downregulated in tumour tissue. When combining the vaccine with the chemotherapy drug oxaliplatin, the survival was prolonged by about 2.5-fold. In conclusion, the DNA vaccine containing a CpG motif in bicistronic form showed good effects on colorectal cancer by inhibiting both tumour growth and metastasis, and combination with oxaliplatin could improve its antitumour effects. [Mh] Termos MeSH primário: Adjuvantes Imunológicos/genética Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico Vacinas Anticâncer/imunologia Neoplasias Colorretais/imunologia Proteínas Inibidoras de Apoptose/genética Mucina-1/genética Oligodesoxirribonucleotídeos/genética Compostos Organoplatínicos/uso terapêutico Proteínas Repressoras/genética Vacinas de DNA/imunologia [Mh] Termos MeSH secundário: Animais Vacinas Anticâncer/genética Processos de Crescimento Celular Linhagem Celular Tumoral Neoplasias Colorretais/terapia Modelos Animais de Doenças Feminino Genes/genética Seres Humanos Imunidade Interleucina-2/administração & dosagem Interleucina-2/imunologia Camundongos Camundongos Endogâmicos BALB C Metástase Neoplásica Plasmídeos Vacinas de DNA/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adjuvants, Immunologic); 0 (Birc5 protein, mouse); 0 (CPG-oligonucleotide); 0 (Cancer Vaccines); 0 (Inhibitor of Apoptosis Proteins); 0 (Interleukin-2); 0 (Mucin-1); 0 (Oligodeoxyribonucleotides); 0 (Organoplatinum Compounds); 0 (Repressor Proteins); 0 (Vaccines, DNA); 0 (muc1 protein, mouse); 04ZR38536J (oxaliplatin) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180206 [Lr] Data última revisão: 180206 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171202 [St] Status: MEDLINE [do] DOI: 10.1111/sji.12633

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[PMID]: 27770821 [Au] Autor: Zappavigna S; Scuotto M; Cossu AM; Ingrosso D; De Rosa M; Schiraldi C; Filosa R; Caraglia M [Ad] Endereço: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, via L. De Crecchio 7, Naples, 80138, Italy. [Ti] Título: The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells. [So] Source: J Exp Clin Cancer Res;35(1):167, 2016 Oct 22. [Is] ISSN: 1756-9966 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Synthetic structural modification yielded the derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms. METHODS: U87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFκB pathway by western blotting technique. RESULTS: Here, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFκB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFκB pathway. CONCLUSIONS: RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFκB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets. [Mh] Termos MeSH primário: Benzoquinonas/farmacologia Neoplasias Encefálicas/metabolismo Regulação para Baixo Inibidores Enzimáticos/farmacologia Glioblastoma/metabolismo Proteínas Inibidoras de Apoptose/metabolismo [Mh] Termos MeSH secundário: Araquidonato 5-Lipoxigenase/metabolismo Ácido Araquidônico/metabolismo Autofagia Benzoquinonas/síntese química Benzoquinonas/química Neoplasias Encefálicas/tratamento farmacológico Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Ensaios de Seleção de Medicamentos Antitumorais Inibidores Enzimáticos/síntese química Inibidores Enzimáticos/química Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Glioblastoma/tratamento farmacológico Seres Humanos Ácido Linoleico/metabolismo Estresse Oxidativo/efeitos dos fármacos Transdução de Sinais/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Benzoquinones); 0 (Enzyme Inhibitors); 0 (Inhibitor of Apoptosis Proteins); 27YG812J1I (Arachidonic Acid); 9KJL21T0QJ (Linoleic Acid); EC 1.13.11.34 (Arachidonate 5-Lipoxygenase); EC 1.3.11.34 (ALOX5 protein, human); SHC6U8F5ER (embelin) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171219 [Lr] Data última revisão: 171219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE

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[PMID]: 29187434 [Au] Autor: Manouchehri JM; Kalafatis M [Ad] Endereço: Department of Chemistry, Science and Research Center, Cleveland State University, Cleveland, OH, U.S.A. [Ti] Título: Sensitization of rhTRAIL-resistant Triple-negative Breast Carcinoma Through Silibinin Co-Treatment. [So] Source: Anticancer Res;37(12):6593-6599, 2017 12. [Is] ISSN: 1791-7530 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is the most fatal form of breast cancer due to the shortcomings of therapies. However, recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) is a promising anticancer therapeutic that possesses the capability to promote the induction of apoptosis in cancer cells, but some TNBCs are resistant to rhTRAIL's pro-apoptotic effects. Therefore, a combinatorial treatment approach with silibinin and rhTRAIL was considered in order to sensitize rhTRAIL-resistant TNBCs. MATERIALS AND METHODS: The co-treatment of rhTRAIL and silibinin's impact on apoptosis induction in rhTRAIL-resistant TNBC BT-20 and HCC1937 cells was inspected via application of Annexin V/PI assays and western blot analysis. RESULTS: Silibinin possessed the ability to sensitize the examined rhTRAIL-resistant TNBC cells to rhTRAIL-induced apoptosis through the up-regulation of death receptors 4 and 5 and the down-regulation of survivin transcriptionally. CONCLUSION: Silibinin is a good sensitizing agent for rhTRAIL-resistant TNBCs. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos Silimarina/farmacologia Ligante Indutor de Apoptose Relacionado a TNF/farmacologia [Mh] Termos MeSH secundário: Apoptose/genética Western Blotting Linhagem Celular Tumoral Resistência a Medicamentos Antineoplásicos/genética Sinergismo Farmacológico Feminino Citometria de Fluxo Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos Seres Humanos Proteínas Inibidoras de Apoptose/genética Proteínas Inibidoras de Apoptose/metabolismo Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo Proteínas Recombinantes/farmacologia Reação em Cadeia da Polimerase Via Transcriptase Reversa Ligante Indutor de Apoptose Relacionado a TNF/genética Neoplasias de Mama Triplo Negativas/genética Neoplasias de Mama Triplo Negativas/metabolismo Neoplasias de Mama Triplo Negativas/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (BIRC5 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand); 0 (Recombinant Proteins); 0 (Silymarin); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (TNFRSF10B protein, human); 4RKY41TBTF (silybin) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171211 [Lr] Data última revisão: 171211 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171201 [St] Status: MEDLINE

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