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1.
Biomed Res Int ; 2021: 8849415, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337056

RESUMO

Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system, and its early asymptomatic characteristic increases the difficulty of diagnosis and treatment. This study is aimed at obtaining some novel biomarkers with diagnostic and prognostic meaning and may find out potential therapeutic targets for HCC. We screen differentially expressed genes (DEGs) from the HCC gene expression profile GSE14520 using GEO2R. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted by using the clusterProfiler software while a protein-protein interaction (PPI) network was performed based on the STRING database. Then, prognosis analysis of hub genes was conducted using The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to further verify the expression of hub genes and explore the correlation between gene expression and clinicopathological parameters. A total of 1053 DEGs were captured, containing 497 upregulated genes and 556 downregulated genes. GO and KEGG analysis indicated that the downregulated DEGs were mainly enriched in the fatty acid catabolic process while upregulated DEGs were primarily enriched in the cell cycle. Simultaneously, ten hub genes (CYP3A4, UGT1A6, AOX1, UGT1A4, UGT2B15, CDK1, CCNB1, MAD2L1, CCNB2, and CDC20) were identified by the PPI network. Five prognosis-related hub genes (CYP3A4, CDK1, CCNB1, MAD2L1, and CDC20) were uncovered by the survival analysis based on TCGA database. The ten hub genes were further validated by qRT-PCR using samples obtained from our hospital. The prognosis-related hub genes such as CYP3A4, CDK1, CCNB1, MAD2L1, and CDC20 could be considered potential diagnosis biomarkers and prognosis targets for HCC. We also use Oncomine for further verification, and we found CCNB1, CCNB2, CDK1, and CYP3A4 which were highly expressed in HCC. Meanwhile, CCNB1, CCNB2, and CDK1 are highly expressed in almost all cancer types, which may play an important role in cancer. Still, further functional study should be conducted to explore the underlying mechanism and biological effect in the near future.


Assuntos
Carcinoma Hepatocelular/genética , Biologia Computacional , Redes Reguladoras de Genes , Neoplasias Hepáticas/genética , Transdução de Sinais/genética , Adulto , Idoso , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Análise de Sobrevida , Transcriptoma , Regulação para Cima/genética
2.
Br J Cancer ; 122(11): 1580-1589, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32291392

RESUMO

Isocitrate dehydrogenase (IDH) enzymes catalyse the oxidative decarboxylation of isocitrate and therefore play key roles in the Krebs cycle and cellular homoeostasis. Major advances in cancer genetics over the past decade have revealed that the genes encoding IDHs are frequently mutated in a variety of human malignancies, including gliomas, acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and thyroid carcinoma. A series of seminal studies further elucidated the biological impact of the IDH mutation and uncovered the potential role of IDH mutants in oncogenesis. Notably, the neomorphic activity of the IDH mutants establishes distinctive patterns in cancer metabolism, epigenetic shift and therapy resistance. Novel molecular targeting approaches have been developed to improve the efficacy of therapeutics against IDH-mutated cancers. Here we provide an overview of the latest findings in IDH-mutated human malignancies, with a focus on glioma, discussing unique biological signatures and proceedings in translational research.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Animais , Transformação Celular Neoplásica/genética , Humanos , Mutação
4.
Cancers (Basel) ; 12(2)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979226

RESUMO

Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster I pheochromocytomas and paragangliomas (PCPGs). SDHB-mutated PCPGs are characterized by alterations in the electron transport chain, metabolic reprogramming of the tricarboxylic cycle, and elevated levels of reactive oxygen species (ROS). We discovered that SDHB-deficient PCPG cells exhibit increased oxidative stress burden, which leads to elevated demands for glutathione metabolism. Mechanistically, nuclear factor erythroid 2-related factor 2 (NRF2)-guided glutathione de novo synthesis plays a key role in supporting cellular survival and the proliferation of SDHB-knockdown (SDHBKD) cells. NRF2 blockade not only disrupted ROS homeostasis in SDHB-deficient cells but also caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, a potent NRF2 inhibitor, showed a promising effect in suppressing SDHBKD metastatic lesions in vivo, with prolonged overall survival in mice bearing PCPG allografts. Our findings highlight a novel therapeutic strategy of targeting the NRF2-driven glutathione metabolic pathway against SDHB-mutated PCPG.

5.
Surg Endosc ; 34(7): 2926-2938, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31463723

RESUMO

BACKGROUND: Laparoscopic approach for gallbladder cancer (GBC) has long been contraindicated, but few recent studies have demonstrated the oncologic outcomes of this treatment. The purpose of this study was to compare the perioperative outcomes and long-term survival for laparoscopic surgery versus traditional open surgery of GBC. METHOD: Between January 2014 and December 2018, 63 GBC patients who received radical resection were enrolled in this study, with 32 patients in laparoscopic group and 31 cases in laparotomy group. Perioperative data and postoperative survival were retrospectively evaluated. RESULTS: Laparoscopic approach was associated with less intraoperative bleeding (267.20 ± 47.07 vs. 502.60 ± 69.70, P = 0.007), fewer postoperative days of oral diet recovery (2.34 ± 0.31 vs. 3.32 ± 0.35, P = 0.041), and hospital stay (11.03 ± 0.99 vs. 14.35 ± 1.11, P = 0.028). There were no significant differences between two groups regarding other perioperative outcomes. Patients in laparoscopic group showed better 1-year overall survival than those in laparotomy group (72.91% vs. 47.82%, P = 0.086). Subgroup analysis for GBC patients in T3 stages revealed that laparoscopic approach was associated with less intraoperative bleeding (268.00 ± 57.19 vs. 541.50 ± 101.30, P = 0.009), fewer postoperative days of hospital stay (9.87 ± 1.10 vs. 14.90 ± 1.53, P = 0.017), and improved 1-year overall survival (P = 0.023). Subgroup analysis for GBCs in TNM III and TNM IV stages showed comparable intraoperative parameters and postoperative survival between two groups. CONCLUSION: Laparoscopic surgery for GBCs may offer the comparable perioperative outcomes as conventional laparotomy procedure, and tend to be associated with less intraoperative bleeding, faster oral diet recovery, shorter hospital stay, and improved 1-year overall survival.


Assuntos
Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/cirurgia , Laparoscopia/métodos , Laparotomia/métodos , Adulto , Idoso , Colecistectomia Laparoscópica/métodos , Feminino , Neoplasias da Vesícula Biliar/patologia , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do Tratamento
6.
J Gastrointest Surg ; 24(10): 2244-2250, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31621026

RESUMO

OBJECTIVES: The role of laparoscopic hepatectomy (LH) for intrahepatic cholangiocarcinoma (ICC) remains indefinite, though the utilization of this minimally invasive approach has been increasing for ICC. We herein performed a meta-analysis to investigate this issue. METHODS: Six retrospective studies including 384 patients who had undergone LH and 2147 patients who had undergone open hepatectomy (OH) for ICC were included. The fixed-effects or random-effects models were utilized for data analysis. RESULTS: Compared with patients who had undergone OH for ICC, patients who had undergone LH for ICC experienced more R0 resections (81.6 versus 73.8%, risk ratio (RR) = 1.08, 95% confidence interval (CI) 1.02-1.14; P = 0.008) but less major hepatectomies (37.7 versus 54.2%, RR = 0.69, 95% CI 0.60-0.79; P < 0.0001), less lymph node dissections (38.0 versus 61.5%, RR = 0.62, 95% CI 0.54-0.70; P < 0.0001), and smaller tumor size resected (4.14 versus 4.94 cm, weighted mean difference = - 0.80 cm, 95% CI - 1.38 to - 0.22 cm; P = 0.007). No significant difference was observed in other perioperative results (all P > 0.05) or overall survival (hazard ratio (HR) = 1.38, 95% CI 0.63-3.02; P = 0.43). CONCLUSIONS: LH has comparable safety, feasibility, and oncological efficacy to that of OH for ICC and has superiority in R0 resection over OH. It may be time to consider LH for ICC only if a more thorough effort on lymph node dissection is undertaken in selective patients at experienced centers.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Laparoscopia , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Hepatectomia , Humanos , Estudos Retrospectivos
7.
Biosci Trends ; 13(6): 488-501, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31875583

RESUMO

The development of Minimally invasive pancreaticoduodenectomy (MIPD) in Chinese mainland has been extremely quick. However, the safety and oncologic outcomes remain controversial. This review evaluates the current status of MIPD in Chinese mainland. A systematic literature search was performed using: Pubmed, Web of Sci, CNKI, Wanfang Data and Sinomed databases to filter all studies published up to and including June 2019 using key words "pancreaticoduodenectomy," or "Whipple operation" combined with "laparoscopy," or "laparoscopic," or "robotic," or "da Vinci," or "minimally invasive," or "hand-assisted". This systematic review included 39 articles that documented 2,653 MIPDs in Chinese mainland. The weighted average operative time was 370.6 min, and the weighted average blood loss was 278.0 mL. The overall morbidity was 31.9%, which Clavien-Dindo ≥ 3 complications accounted for 13.4%. Pancreatic fistula, delayed gastric emptying, bile leak and postoperative hemorrhage were reported in 20.9%, 5.5%, 3.5% and 6.0% of patients respectively. The average lengh of hospital stay was 16.1 days. The overall surgical mortality was 1.7%. The mean number of harvested lymph nodes was 13.5, and the rate of positive margin was 5.3%. Based on Chinese national condition, the operative volume of MIPD in Chinese mainland is the leading position in the world, and compared with some large international meta-analysis, no inferior perioperative and short-term oncological outcomes were observed in MIPD of Chinese mainland. However, research on survival analysis and phased learning curve outcomes is needed urgently before the innovative techniques are widely accepted.


Assuntos
Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Pancreaticoduodenectomia/métodos , China , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Pancreaticoduodenectomia/efeitos adversos
8.
J Cell Physiol ; 235(5): 4279-4290, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31612516

RESUMO

Signaling pathways transmit extracellular cues into cells and regulate transcriptome and epigenome to maintain or change the cell identity. Protein kinases and phosphatases are critical for signaling transduction and regulation. Here, we report that CDK11, a member of the CDK family, is required for the maintenance of human embryonic stem cell (hESC) self-renewal. Our results show that, among the three main isoforms of CDK11, CDK11p46 is the main isoform safeguarding the hESC identity. Mechanistically, CDK11 constrains two important mitogen-activated protein kinase (MAPK) signaling pathways (JNK and p38 signaling) through modulating the activity of protein phosphatase 1. Furthermore, CDK11 knockdown activates transforming growth factor ß (TGF-ß)/SMAD2/3 signaling and upregulates certain nonneural differentiation-associated genes. Taken together, this study uncovers a kinase required for hESC self-renewal through fine-tuning MAPK and TGF-ß signaling at appropriate levels. The kinase-phosphatase axis reported here may shed new light on the molecular mechanism sustaining the identity of hESCs.


Assuntos
Quinases Ciclina-Dependentes/metabolismo , Células-Tronco Embrionárias/fisiologia , Transdução de Sinais/fisiologia , Proliferação de Células , Quinases Ciclina-Dependentes/genética , Regulação para Baixo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Isoformas de Proteínas , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Drug Des Devel Ther ; 13: 1271-1280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114163

RESUMO

Background: Ovarian cancer is a leading cause of death in gynecologic malignancies. The high mortality is mainly caused by advanced stage at presentation in most patients. Even after the combination of cytoreductive surgery and systemic platinum and taxane treatment, most patients relapse and eventually succumb to the disease. Therefore, there is an urgent need for new treatments. Purpose: A novel folate (FA)-targeted co-delivery of docetaxel (DTX) and gemcitabine (GEM) nanoparticles (NPs) was developed to overcome ovarian cancer. Materials and methods: Physicochemical characteristics of NPs such as size, morphology, and release profiles were explored. In vitro and in vivo studies were carried out to assess the efficacy of their antitumor activity in target cells. Results: FA modified DTX and GEM co-loaded NPs were prepared using the solvent evaporation method. The NPs with a particle size of ~120nm were stable in the observation period. The hemolysis results indicated that FA-PEG2000-PLGA was potentially feasible for targeted antitumor drug delivery through blood circulation. In vitro release study suggested that in comparison with the free drug, PLGA-DTX/GEM NPs and FA-PEG2000-PLGA-DTX/GEM NPs had sustained-release properties. However, there was no obvious difference between the two NPs with the same drug in the release profile. Ovarian cancer cells in vitro efficiently took up the non-targeted and FA-targeted NPs; improved cytotoxicity was observed in the FA-targeted NPs, showing a 3.59- fold drop in the IC50 in SKOV-3 cells as compared to DTX/GEM alone. Cellular uptake showed that through surface modification, more drugs entered the cell successfully. Pharmacodynamics results showed a statistically significant effect on the rate of reduction of tumor volume for FA-PEG2000-PLGA-DTX/GEM NPs than other groups and no toxicity of organs. Conclusion: The present study indicates that the FA-PEG2000-PLGA-DTX/GEM NPs provides a promising platform for the treatment of ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Poliglactina 910/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Docetaxel/química , Docetaxel/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de Superfície
10.
Cell Stem Cell ; 20(2): 274-289.e7, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-27939217

RESUMO

The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self-renewal. PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hESCs. Of particular note, PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and, thus, production of α-ketoglutarate, a key metabolite in the regulation of ESC fate. Our study shows that PHB has an unexpected nuclear role in hESCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Epigênese Genética , Chaperonas de Histonas/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Autorrenovação Celular/genética , Cromatina/metabolismo , Imunoprecipitação da Cromatina , Genes Controladores do Desenvolvimento , Genoma Humano , Células HEK293 , Histonas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Humanos , Isocitrato Desidrogenase/metabolismo , Ácidos Cetoglutáricos/metabolismo , Masculino , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica/genética , RNA Interferente Pequeno/metabolismo
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