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1.
J Cell Mol Med ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33580614

RESUMO

S100 calcium-binding protein A (S100A) family members regulate multiple biological functions related to pancreatic cancer (PC) progression and metastasis. However, the prognostic and oncologic values of S100A family have not been systematically investigated in PC. In the present study, the mRNA expression and potential functions of S100A family were investigated by bioinformatic analysis. Our results demonstrated that overexpression of S100A2, S100A6, S100A10, S100A11, S100A14 and S100A16 was significantly associated with higher T stage, advanced histologic grade and worse prognosis in PC. Besides, one CpG of S100A2, three CpG of S100A6, four CpG of S100A10, four CpG of S100A11, two CpG of S100A14 and five CpG of S100A16 were negatively associated with corresponding S100A family members expression and positively associated with overall survival (OS). The signature based on four CpGs showed good prediction ability of OS. Besides, S100A2 overexpression took part in the regulation of mitotic cell cycle, ECM-receptor interaction and HIF-1α transcription factor network. Overexpression of S100A6, S100A10, S100A11, S100A14 and S100A16 may impair the infiltration and cytolytic activity of CD8+ T cells through focal adhesion-Ras-stimulating signalling pathway in PC. Overall, this study explores the multiple prognostic values and oncologic functions of the S100A family in PC.

2.
Aging (Albany NY) ; 13(2): 2310-2329, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33316775

RESUMO

Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) has been associated with tumor progression in several solid tumors, and inhibits CD8+ T cell-mediated anti-tumor immunity in breast cancer. However, little is known about the potential functions of B3GNT3 in immunosuppression in pancreatic cancer (PC). This study on B3GNT3 aims to provide novel insights into the mechanisms of immune suppression or evasion in PC. To this end, the clinical significance and oncologic roles of B3GNT3 were investigated through bioinformatic analysis and in vitro studies. Potential associations between the expression of B3GNT3 and tumor immunity were mainly analyzed by single-sample gene set enrichment analysis (ssGSEA) and immunofluorescence in tissue microarray (TMA). B3GNT3 overexpression was observed in PC tissue and was associated with larger tumor sizes, higher histologic grades, and poorer overall survival (OS). B3GNT3 overexpression was associated with the mutation status and expression of driver genes, especially for KRAS and SMAD4. B3GNT3 knockdown inhibited the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of PC cells. B3GNT3 overexpression significantly correlated with decreased infiltration of tumor infiltrating lymphocytes (TILs), especially CD8+ T cells. Overall, our results indicate that B3GTN3 plays a novel role in tumor progression and immunosuppression, thus serving as a potential therapeutic target in PC.

3.
ACS Cent Sci ; 6(10): 1657-1670, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33145406

RESUMO

Carbon dioxide (CO2) hydrogenation to liquid fuels including gasoline, jet fuel, diesel, methanol, ethanol, and other higher alcohols via heterogeneous catalysis, using renewable energy, not only effectively alleviates environmental problems caused by massive CO2 emissions, but also reduces our excessive dependence on fossil fuels. In this Outlook, we review the latest development in the design of novel and very promising heterogeneous catalysts for direct CO2 hydrogenation to methanol, liquid hydrocarbons, and higher alcohols. Compared with methanol production, the synthesis of products with two or more carbons (C2+) faces greater challenges. Highly efficient synthesis of C2+ products from CO2 hydrogenation can be achieved by a reaction coupling strategy that first converts CO2 to carbon monoxide or methanol and then conducts a C-C coupling reaction over a bifunctional/multifunctional catalyst. Apart from the catalytic performance, unique catalyst design ideas, and structure-performance relationship, we also discuss current challenges in catalyst development and perspectives for industrial applications.

4.
J Cell Mol Med ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33073486

RESUMO

Integrin ß (ITGB) superfamily members have been reported to play important roles in multiple biological functions in various cancers. However, the prognostic and oncologic values of ITGB superfamily members have not been systematically investigated in pancreatic cancer (PC). In this study, the mRNA expression and biological functions of ITGB superfamily members in PC were evaluated by bioinformatic analysis. Our results demonstrated that ITGB1, ITGB4, ITGB5 and ITGB6 overexpressions were significantly associated with advanced AJCC stage and histologic grade, and worse prognosis in PC. A prognostic signature based on ITGB1, ITGB4, ITGB5 and ITGB6 showed a reliable predictive performance. Furthermore, one CpGs (cg20545410) in promoter region of ITGB1, four (cg18709893, cg15700850, cg20667796 and cg18326022) of ITGB4, two (cg10977398 and cg03518058) of ITGB5 and one (cg23008083) of ITGB6 were negatively associated with their corresponding mRNA expression, and positively associated with prognosis in PC. We also identified TFAP2A as the potential transcription factor for ITGB4, SP1 for ITGB1 and ITGB6, and FHL2 for ITGB5 and ITGB6. ITGB1, ITGB4, ITGB5 and ITGB6 overexpressions were all significantly involved in focal adhesion signalling pathway. ITGB1 and ITGB5 overexpressions also associated with up-regulation of TGF-ß and WNT signalling pathway, whereas ITGB4 and ITGB6 overexpressions associated with up-regulation of Notch signalling pathway. Besides, ITGB1, ITGB5 and ITGB6 overexpressions significantly correlated with immunosuppression in PC. In summary, our study investigated the multilevel prognostic and biological values of ITGB superfamily members in PC.

5.
Cancer Cell Int ; 20: 493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061845

RESUMO

Background: Pancreatic cancer (PC) is one of the most common cancers and the leading cause of cancer-related death worldwide. Exploring novel predictive biomarkers for PC patients' prognosis is in urgent need. Methods: In the present study, we conducted Cox proportional hazards regression to identify critical prognosis-associated lncRNAs (PALncs) in TCGA PC dataset. Based on the results of multivariate analysis, a PALnc-based risk score system was established, and validated in GSE62452 dataset. The validity and reliability of the risk score system for prognosis of PC were evaluated through ROC analysis. And function enrichment analyses for the PALncs were also performed. Result: In the multivariate analysis, four PALncs (LINC00476, C9orf163, LINC00346 and DSCR9) were screened out to develop a risk score system, which showed a high AUC at 3 and 5 years overall survival (0.785 at 3 year OS, 0.863 at 5 year OS) in TCGA datasets. And the ROC analysis of the risk score system for RFS in TCGA dataset revealed that AUC for RFS was 0.799 at 3 years and 0.909 at 5 years. Further, the AUC for OS in the validation cohort was 0.705 at 3 years and 0.959 at 5 years. Furthermore, the functional enrichment analysis revealed that these PALncs may be involved in various pathways related to cancer, including Ras family activation, autophagy in cancer, MAPK signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway, etc. And correlation analysis of these tumor infiltrating immune cells and risk score system revealed that the infiltration level of B cell naïve, plasma cells, and CD8+ T cells are negatively correlated to the risk score system, while macrophages M2 positively correlated to the risk score system. Conclusion: Our study established a four PALncs based risk score system, which reflects immune cell infiltration and predicts patient survival for PC.

6.
Proc Natl Acad Sci U S A ; 117(35): 21391-21402, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817423

RESUMO

Syntaxin17, a key autophagosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, can associate with ATG8 family proteins SNAP29 and VAMP8 to facilitate the membrane fusion process between the double-membraned autophagosome and single-membraned lysosome in mammalian macroautophagy. However, the inherent properties of Syntaxin17 and the mechanistic basis underlying the interactions of Syntaxin17 with its binding proteins remain largely unknown. Here, using biochemical, NMR, and structural approaches, we systemically characterized Syntaxin17 as well as its interactions with ATG8 family proteins, SNAP29 and VAMP8. We discovered that Syntaxin17 alone adopts an autoinhibited conformation mediated by a direct interaction between its Habc domain and the Qa-SNARE motif. In addition, we revealed that the Qa-SNARE region of Syntaxin17 contains one LC3-interacting region (LIR) motif, which preferentially binds to GABARAP subfamily members. Importantly, the GABARAP binding of Syntaxin17 can release its autoinhibited state. The determined crystal structure of the Syntaxin17 LIR-GABARAP complex not only provides mechanistic insights into the interaction between Syntaxin17 and GABARAP but also reveals an unconventional LIR motif with a C-terminally extended 310 helix for selectively binding to ATG8 family proteins. Finally, we also elucidated structural arrangements of the autophagic Syntaxin17-SNAP29-VAMP8 SNARE core complex, and uncovered its conserved biochemical and structural characteristics common to all other SNAREs. In all, our findings reveal three distinct states of Syntaxin17, and provide mechanistic insights into the Syntaxin17-mediated autophagosome-lysosome fusion process.


Assuntos
Autofagossomos/fisiologia , Lisossomos/fisiologia , Proteínas Qa-SNARE/metabolismo , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Proteínas R-SNARE/metabolismo , Motivos de Aminoácidos , Proteínas Reguladoras de Apoptose/metabolismo , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Escherichia coli , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo
7.
World J Gastroenterol ; 26(19): 2305-2322, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32476795

RESUMO

Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion. With regard to diagnosis, remarkable advances have been made: Chromogranin A is recommended as a general marker for pNETs. But other new biomarker modalities, like circulating tumor cells, multiple transcript analysis, microRNA profile, and cytokines, should be clarified in future investigations before clinical application. Therefore, the currently available serum biomarkers are insufficient for diagnosis, but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs. Surgical resection is still the only curative therapeutic option for localized pNETs. However, a debulking operation has also been proven to be effective for controlling the disease. As for drug therapy, steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor, while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs. Great progress has been achieved in the combination of systematic therapy with local control treatments. The optimal timing of local control intervention, planning of sequential therapies, and implementation of multidisciplinary care remain pending.

8.
J Control Release ; 326: 120-130, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32585230

RESUMO

Adjuvants that contain pathogen-associated molecular patterns (PAMPs) can enhance vaccination efficacy by binding to pattern recognition receptors (PRRs), thereby stimulating immune responses. Particularly effective may be the combination of multiple PAMPs that activate different PRRs, which occurs with natural pathogens. Here we hypothesized the enhanced effects would occur in two adjuvants that stimulate different PRRs: CpG oligodeoxynucleotide (CpG-ODN), which is Toll-like receptor 9 agonist; and 5'-triphosphate, short, double-stranded RNA (3pRNA), which activates retinoic acid-inducible gene I (RIG-I). The model antigen ovalbumin (OVA) was loaded and adjuvants were surface-adsorbed to aluminum hydroxide nanoparticles (hereafter NP-3pRNA-CpG) by electrostatic interaction with an average size of 120 nm and a negative surface charge for targeting lymph nodes. These nanoparticles were efficiently internalized by antigen-presenting cells (APCs) in the lymph nodes, and the resulting APC activation and antigen cross-presentation generated strong humoral immunity and cytotoxic T lymphocyte responses and IFN-γ secretion. NP-3pRNA-CpG significantly suppressed B16-OVA tumor growth and prolonged survival of tumor-bearing mice in therapeutic and prophylactic models, illustrating the enhanced effects of CpG-ODN and 3pRNA. Our study highlights the potential of combining multiple adjuvants for effective vaccine design.

9.
Oncogene ; 39(23): 4507-4518, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32366907

RESUMO

N6-methyladenosine (m6A) RNA methylation contributes to the cancer stem cell (CSC) phenotype through regulating gene expression. YTHDF2, an m6A reader, was shown to be associated with hepatocellular carcinoma (HCC) patient prognosis. However, the effect of YTHDF2 on liver CSC and cancer metastasis and the molecular mechanism of this effect have not been documented. Here, we show that YTHDF2 expression is negatively correlated with HCC patient survival in both data from the Cancer Genome Atlas (TCGA) database and clinical data from our center. By detecting CD133+ cells and carrying out sphere culture assays, we found that knockdown of YTHDF2 led to impaired stemness in Hep3B and Huh7 cells. In contrast, overexpression of YTHDF2 increased the CSC phenotype. Mechanistically, the knockdown and overexpression of YTHDF2 in liver cancer cells resulted in decreased and increased m6A levels in the 5'-untranslated region (UTR) of OCT4 mRNA, respectively, leading to decreased and increased OCT4 protein expression, respectively. A luciferase activity assay showed that mutation of the corresponding m6A methylation sequence in the 5'-UTR of OCT4 mRNA caused significantly decreased gene expression, suggesting a role for YTHDF2-dependent m6A methylation in protein translation. Polysome profiling results also indicated the knockdown and overexpression of YTHDF2 could decrease and increase OCT4 translation, respectively. In particular, overexpression of OCT4 rescued the impaired stemness caused by YTHDF2 depletion, which confirmed the effect of YTHDF2 on CSC phenotype is dependent on OCT4. In vivo, the loss of YTHDF2 reduced tumor burden and inhibited lung metastasis following orthotopic transplantation in nude mice. Last, we demonstrated that YTHDF2 expression is positively correlated with OCT4 expression and m6A levels in the 5'-UTR of OCT4 mRNA in clinical HCC specimens. In conclusion, YTHDF2 promotes the CSC liver phenotype and cancer metastasis by modulating the m6A methylation of OCT4 mRNA.


Assuntos
Adenosina/análogos & derivados , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas de Ligação a RNA/genética , Adenosina/metabolismo , Animais , Carcinoma Hepatocelular/mortalidade , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Masculino , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica/patologia , Transplante de Neoplasias , Prognóstico , RNA Mensageiro/metabolismo , Esferoides Celulares , Transplante Heterólogo , Células Tumorais Cultivadas
10.
Pancreas ; 49(5): 655-662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433403

RESUMO

OBJECTIVE: This study developed a prognosis-associated miRNA (PAM)-based risk score system to predict overall survival for pancreatic cancer. METHODS: We screened potential PAMs using bioinformatics technology. A risk score system integrating the PAMs was established, and the predictive value was evaluated. The targets of these PAMs were identified and functional enrichment analysis was performed. RESULTS: Seven PAMs (hsa-mir-188, hsa-mir-1301, hsa-mir-424, hsa-mir-5010, hsa-mir-584, hsa-mir-5091, and hsa-mir-3613) were identified. We also developed a risk score system, which showed a high Harrell concordance index (C-index, 0.723) for overall survival in the Cancer Genome Atlas data sets. The areas under the curve of the receiver operating characteristic curve at the 1-, 2-, and 3-year survival points were 0.718, 0.832, and 0.903, respectively. In addition, both the C-index and the areas under the curve for recurrence-free survival showed a good outcome, indicating that the system had a satisfactory predictive power. Furthermore, 49 target genes of PAMs were identified. Functional enrichment analysis revealed that these targets may be involved in various biological pathways, including the transforming growth factor ß signaling pathway, Notch signaling, and downregulation of SMAD2/3. CONCLUSIONS: The findings of this study suggest that the 7-miRNA-based risk score system is a promising prognostic model for pancreatic cancer.

11.
Aging (Albany NY) ; 12(3): 3025-3041, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32045367

RESUMO

BACKGROUND: Obg-like ATPase 1 (OLA1) has been found to have a dual role in cancers. However, the relationship between OLA1 and hepatocellular carcinoma (HCC) remains unclear. RESULTS: High expression of OLA1 in HCC was detected in public datasets and clinical samples, and correlated with poor prognosis. Downregulation of OLA1 significantly inhibited the proliferation, migration, invasion and tumorigenicity of HCC cells. Mechanistically, GSEA showed that OLA1 might promote tumor progression by regulating the cell cycle and apoptosis. In addition, OLA1 knockdown resulted in G0/G1 phase arrest and high levels of apoptosis. OLA1 could bind with P21 and upregulate CDK2 expression to promote HCC progression. CONCLUSIONS: Overall, these findings uncover a role for OLA1 in regulating the proliferation and apoptosis of HCC cells. MATERIALS AND METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were analyzed to identify gene expression. Immunohistochemistry staining, western blot and real-time polymerase chain reaction were performed to evaluate OLA1 expression in samples. Cell count Kit-8, wound-healing, transwell and flow cytometry assays were used to analyze HCC cell progression. Subcutaneous xenotransplantation models were used to investigate the role of OLA1 in vivo. Coimmunoprecipitation was used to analyze protein interactions.

12.
Nutr. hosp ; 36(6): 1430-1437, nov.-dic. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-191165

RESUMO

Aim: this study was performed to investigate the association between selenium concentrations, dietary intake, and the risk of hepatocellular carcinoma (HCC). Methods: we identified eligible studies in PubMed and EMBASE databases, in addition to the reference lists of original studies and review articles on this topic, up to 1 Feb 2019. A summary of standardized mean differences (SMD) with 95% confidence intervals (CI) was calculated using a random-effects model. Heterogeneity between studies was assessed using Cochran Q and I2 statistics. Results: finally, a meta-analysis showed that dietary intake of selenium and tissue selenium concentration were not associated with HCC risk (dietary SMD = -0.11, 95% CI: -0.26 to 0.03; tissue SMD = -0.12, 95% CI: -0.56 to 0.33). However, samples from toenail, whole blood, and serum all showed an inverse association with HCC risk (toenail SMD = -0.53, 95% CI: -0.72 to -0.35; whole blood SMD = -2.21, 95% CI: -2.67 to -1.76; tissue SMD = -1.26, 95% CI: -1.71 to -0.81). Dose-response data from few studies showed that an extra increase in serum selenium was dramatically related with a lower risk of HCC (adjusted p-trend < 0.05). This study showed that selenium concentration in toenail, whole blood and serum was inversely associated with HCC risk. Conclusion: increased concentration in serum selenium was related to a lower risk of HCC. However, these results based on dietary intake and tissue samples, which included few studies, did not reach statistical significance


Objetivo: este estudio se realizó para investigar la asociación entre las concentraciones de selenio, la ingesta dietética y el riesgo de carcinoma hepatocelular (CHC). Métodos: identificamos estudios elegibles en las bases de datos PubMed y EMBASE, además de las listas de referencias de los estudios originales y artículos de revisión sobre este tema hasta el 1 de febrero de 2019. Se realizó un resumen de las diferencias medias estandarizadas (SMD) con intervalos de confianza (CI) del 95% utilizando un modelo de efectos aleatorios. La heterogeneidad entre estudios se evaluó utilizando las estadísticas de Cochran Q e I2. Resultados: por último, el metaanálisis mostró que la concentración de selenio en la ingesta dietética y de selenio tisular no estaban asociadas al riesgo de HCC (SMD dietética -0,11, IC 95%: -0,26 a 0,03; SMD tisular -0,12, IC 95%: -0,56 a 0,33). Sin embargo, las muestras de uña del pie, sangre entera y suero mostraron todas ellas una asociación inversa con el riesgo de CHC (SMD ungueal -0.53, IC 95%: -0.72 a -0.35; SMD de sangre entera -2.21, IC 95%: -2.67 a -1.76; SMD tisular -1.26, IC 95%: -1.71 a -0.81). Los datos de dosis-respuesta de pocos estudios mostraron que los incrementos del selenio sérico se relacionaban fuertemente con un menor riesgo de CHC (tendencia de p ajustada < 0.05). Este estudio demostró que la concentración de selenio en las uñas del pie, en sangre entera y en suero se asocian inversamente al riesgo de CHC. Conclusión: el aumento de la concentración de selenio sérico se relacionó con menor riesgo de CHC. Sin embargo, los resultados de la ingesta dietética y los tejidos, que incluían pocos estudios, no alcanzaron la significación estadística


Assuntos
Humanos , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/epidemiologia , Dieta , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/epidemiologia , Selênio/sangue , Medição de Risco
13.
BMC Gastroenterol ; 19(1): 177, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699035

RESUMO

BACKGROUND: Choledocholithiasis is an endemic condition in the world. Although rare, foreign body migration with biliary complications needs to be considered in the differential diagnosis for patients presenting with typical symptoms even many years after cholecystectomy, EPCP, war-wound, foreign body ingestion or any other particular history before. It is of great clinical value as the present review may offer some help when dealing with choledocholithiasis caused by foreign bodies. CASE PRESENTATION: We reported a case of choledocholithiasis caused by fishbone from choledochoduodenal anastomosis regurgitation. Moreover, we showed up all the instances of choledocholithiasis caused by foreign bodies published until June 2018 and wrote the world's first literature review of foreign bodies in the bile duct of 144 cases. The findings from this case suggest that the migration of fishbone can cause various consequences, one of these, as we reported here, is as a core of gallstone and a cause of choledocholithiasis. CONCLUSION: The literature review declared the choledocholithiasis caused by foreign bodies prefer the wrinkly and mainly comes from three parts: postoperative complications, foreign body ingestion, and post-war complications such as bullet injury and shrapnel wound. The Jonckheere-Terpstra test indicated the ERCP was currently the treatment of choice. It is a very singular case of choledocholithiasis caused by fishbone, and the present review is the first one concerning choledocholithiasis caused by foreign bodies all over the world.


Assuntos
Coledocolitíase , Ducto Colédoco , Corpos Estranhos , Migração de Corpo Estranho , Laparoscopia/métodos , Idoso , Coledocolitíase/sangue , Coledocolitíase/diagnóstico , Coledocolitíase/etiologia , Coledocolitíase/cirurgia , Coledocostomia/efeitos adversos , Coledocostomia/métodos , Ducto Colédoco/diagnóstico por imagem , Ducto Colédoco/cirurgia , Feminino , Corpos Estranhos/diagnóstico por imagem , Corpos Estranhos/etiologia , Migração de Corpo Estranho/complicações , Migração de Corpo Estranho/cirurgia , Gastrectomia/efeitos adversos , Gastrectomia/métodos , Humanos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Ultrassonografia/métodos
14.
Nutr Hosp ; 36(6): 1430-1437, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31718210

RESUMO

Introduction: Aim: this study was performed to investigate the association between selenium concentrations, dietary intake, and the risk of hepatocellular carcinoma (HCC). Methods: we identified eligible studies in PubMed and EMBASE databases, in addition to the reference lists of original studies and review articles on this topic, up to 1 Feb 2019. A summary of standardized mean differences (SMD) with 95% confidence intervals (CI) was calculated using a random-effects model. Heterogeneity between studies was assessed using Cochran Q and I2 statistics. Results: finally, a meta-analysis showed that dietary intake of selenium and tissue selenium concentration were not associated with HCC risk (dietary SMD = -0.11, 95% CI: -0.26 to 0.03; tissue SMD = -0.12, 95% CI: -0.56 to 0.33). However, samples from toenail, whole blood, and serum all showed an inverse association with HCC risk (toenail SMD = -0.53, 95% CI: -0.72 to -0.35; whole blood SMD = -2.21, 95% CI: -2.67 to -1.76; tissue SMD = -1.26, 95% CI: -1.71 to -0.81). Dose-response data from few studies showed that an extra increase in serum selenium was dramatically related with a lower risk of HCC (adjusted p-trend < 0.05). This study showed that selenium concentration in toenail, whole blood and serum was inversely associated with HCC risk. Conclusion: increased concentration in serum selenium was related to a lower risk of HCC. However, these results based on dietary intake and tissue samples, which included few studies, did not reach statistical significance.


Assuntos
Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/epidemiologia , Dieta , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/epidemiologia , Selênio/sangue , Humanos , Medição de Risco
15.
Nat Commun ; 10(1): 3459, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371777

RESUMO

Myosin VI plays crucial roles in diverse cellular processes. In autophagy, Myosin VI can facilitate the maturation of autophagosomes through interactions with Tom1 and the autophagy receptors, Optineurin, NDP52 and TAX1BP1. Here, we report the high-resolution crystal structure of the C-terminal cargo-binding domain (CBD) of Myosin VI in complex with Tom1, which elucidates the mechanistic basis underpinning the specific interaction between Myosin VI and Tom1, and uncovers that the C-terminal CBD of Myosin VI adopts a unique cargo recognition mode to interact with Tom1 for tethering. Furthermore, we show that Myosin VI can serve as a bridging adaptor to simultaneously interact with Tom1 and autophagy receptors through two distinct interfaces. In all, our findings provide mechanistic insights into the interactions of Myosin VI with Tom1 and relevant autophagy receptors, and are valuable for further understanding the functions of these proteins in autophagy and the cargo recognition modes of Myosin VI.


Assuntos
Citoesqueleto de Actina/metabolismo , Cadeias Pesadas de Miosina/química , Domínios e Motivos de Interação entre Proteínas , Proteínas/química , Autofagossomos/metabolismo , Autofagia/fisiologia , Proteínas de Ciclo Celular , Cristalografia por Raios X , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana Transportadoras , Modelos Moleculares , Proteínas de Neoplasias , Proteínas Nucleares , Ligação Proteica , Fator de Transcrição TFIIIA
16.
ISA Trans ; 80: 360-370, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30033234

RESUMO

This paper introduces a new combined technique for wind turbine islanding detection using the trajectory of state variables and wavelet transform in microgrid system. The proposed relay is utilized of energy variation state of time-frequency transform coefficients of local signals in two-dimensional space. In order to improve of the proposed relay performance, a signal selection method based on the correlation concept between islanding and non-islanding signals. From of all patterns, the best of them with high correlation in islanding status is selected for the proposed relay learning. A neuro-fuzzy machine is used as learning of selected patterns to avoid threshold selection. The proposed technique is utilized to wind turbine islanding detection in a microgrid system contains various types of distributed generation including wind turbine, Combined Heat and Power (CHP) and photovoltaic system. Many islanding and non-islanding situation including motor starting, various load and capacitor switching in various operation conditions in the studied microgrid are simulated. Millstone characteristics of the proposed technique are included passive-based technique, negligible None Detection Zone (NDZ), suitable for microgrid application, performance increment in detection and fast detection time. Operation results of the proposed relay in various conditions confirm the performance of the proposed detection relay.

17.
J Neurophysiol ; 120(2): 839-847, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29742030

RESUMO

Successful negotiation of obstacles during walking relies on the integration of visual information about the environment with ongoing locomotor commands. When information about the body and the environment is removed through occlusion of the lower visual field, individuals increase downward head pitch angle, reduce foot placement precision, and increase safety margins during crossing. However, whether these effects are mediated by loss of visual information about the lower extremities, the obstacle, or both remains to be seen. Here we used a fully immersive, virtual obstacle negotiation task to investigate how visual information about the lower extremities is integrated with information about the environment to facilitate skillful obstacle negotiation. Participants stepped over virtual obstacles while walking on a treadmill with one of three types of visual feedback about the lower extremities: no feedback, end-point feedback, and a link-segment model. We found that absence of visual information about the lower extremities led to an increase in the variability of leading foot placement after crossing. The presence of a visual representation of the lower extremities promoted greater downward head pitch angle during the approach to and subsequent crossing of an obstacle. In addition, having greater downward head pitch was associated with closer placement of the trailing foot to the obstacle, further placement of the leading foot after the obstacle, and higher trailing foot clearance. These results demonstrate that the fidelity of visual information about the lower extremities influences both feedforward and feedback aspects of visuomotor coordination during obstacle negotiation. NEW & NOTEWORTHY Here we demonstrate that visual information about the lower extremities is utilized for precise foot placement and control of safety margins during obstacle negotiation. We also found that when a visual representation of the lower extremities is present, this information is used in the online control of foot trajectory. Together, our results highlight how visual information about the body and the environment is integrated with motor commands for planning and online control of obstacle negotiation.


Assuntos
Retroalimentação Sensorial , Locomoção , Extremidade Inferior , Desempenho Psicomotor , Adulto , Fenômenos Biomecânicos , Feminino , Cabeça , Humanos , Masculino , Realidade Virtual , Adulto Jovem
18.
J Control Release ; 280: 39-50, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29730153

RESUMO

Salmonella VNP20009 inhibits tumor growth in preclinical models but its efficacy in humans is limited, potentially because cells mount an autophagy response that destroys the therapeutic bacteria. To neutralize this protective response, we combined VNP20009 with long-circulating liposomes containing the autophagy arrest agent hydroxychloroquine. This combination was associated with significantly larger numbers of intracellular Salmonella, accumulated autophagic vacuoles and much greater cell death in vitro. The combination was also associated with greater tumor-targeting ability, slower tumor growth and longer survival than free hydroxychloroquine in a murine model of melanoma. Our results suggest that combining tumor-targeting Salmonella with autophagy arrest may be effective for treating highly aggressive melanoma.


Assuntos
Antineoplásicos/química , Vacinas Bacterianas/química , Hidroxicloroquina/química , Melanoma Experimental/tratamento farmacológico , Salmonella/metabolismo , Animais , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Vacinas Bacterianas/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/sangue , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Quimioterapia Combinada/métodos , Humanos , Hidroxicloroquina/uso terapêutico , Lipossomos/química , Camundongos , Tamanho da Partícula , Propriedades de Superfície , Distribuição Tecidual/efeitos dos fármacos
19.
Cell Chem Biol ; 25(6): 718-727.e3, 2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29657086

RESUMO

Here, we provide structural insights into PyrE3, a flavin-dependent [4 + 2] cyclase that catalyzes trans-decalin formation in the biosynthesis of pyrroindomycins. PyrE3 shares an architecture/domain organization head-to-tail similarity with the members of the family of para-hydroxybenzoate hydroxylase (pHBH)-fold monooxygenases, and possesses a flavin adenine dinucleotide (FAD)-binding domain, a middle domain, and a C-terminal thioredoxin-like domain. The FAD-binding domain forms a central hub of the protein structure, and binds with FAD in a "closed" conformation of pHBH-fold family monooxygenases known for their highly dynamic catalytic processes. FAD plays an essential structural role in PyrE3, where it is amenable to redox change; however, redox change has little effect on [4 + 2] cyclization activity. PyrE3 appears to selectively accommodate a tetramate-containing, linear polyene intermediate in a highly positively charged pocket, which is located at the interface between the FAD-binding domain and the middle domain, and can accelerate trans-decalin formation likely through an endo-selective [4 + 2] transition state.


Assuntos
Dinitrocresóis/metabolismo , Macrolídeos/metabolismo , Oxigenases de Função Mista/metabolismo , Naftalenos/metabolismo , Biocatálise , Cristalografia por Raios X , Dinitrocresóis/química , Macrolídeos/química , Oxigenases de Função Mista/química , Modelos Moleculares , Estrutura Molecular , Naftalenos/química
20.
Autophagy ; 14(1): 66-79, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29394115

RESUMO

OPTN (optineurin), a ubiquitin-binding scaffold protein, functions as an important macroautophagy/autophagy receptor in selective autophagy processes. Mutations in OPTN have been linked with human neurodegenerative diseases including ALS and glaucoma. However, the mechanistic basis underlying the recognition of ubiquitin by OPTN and its regulation by TBK1-mediated phosphorylation are still elusive. Here, we demonstrate that the UBAN domain of OPTN preferentially recognizes linear ubiquitin chain and forms an asymmetric 2:1 stoichiometry complex with the linear diubiquitin. In addition, our results provide new mechanistic insights into how phosphorylation of UBAN would regulate the ubiquitin-binding ability of OPTN and how disease-associated mutations in the OPTN UBAN domain disrupt its interaction with ubiquitin. Finally, we show that defects in ubiquitin-binding may affect the recruitment of OPTN to linear ubiquitin-decorated mutant Huntington protein aggregates. Taken together, our findings clarify the interaction mode between UBAN and linear ubiquitin chain in general, and expand our knowledge of the molecular mechanism of ubiquitin-decorated substrates recognition by OPTN as well as the pathogenesis of neurodegenerative diseases caused by OPTN mutations.


Assuntos
Autofagia , Doenças Neurodegenerativas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição TFIIIA/metabolismo , Ubiquitina/metabolismo , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Proteínas de Ciclo Celular , Glaucoma/genética , Glaucoma/metabolismo , Células HeLa , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Proteínas de Membrana Transportadoras , Mutação , Doenças Neurodegenerativas/genética , Fosforilação , Agregados Proteicos , Ligação Proteica , Fator de Transcrição TFIIIA/genética
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