RESUMO
BACKGROUND: Robotic distal pancreatectomy has been accepted to be safe and effective for pancreatic tail lesion. Whether spleen preservation by preserving the splenic vessels with robot assistance is feasible and beneficial remains controversial. Here we would like to compare the operative outcomes of robotic distal pancreatectomy and splenectomy (DPS) with robotic spleen preserving distal pancreatectomy by means of splenic vessel preservation (SVP). METHODS: Between March 2011 and September 2019, 56 consecutive patients undergoing robotic distal pancreatectomy were identified, with 28 patients in each group. Patient demographics, histopathology findings and operative outcomes were prospectively collected and compared between the two groups. A subgroup analysis was made after excluding malignant and pancreatic lesions >6 cm in the DPS group. RESULTS: The two groups had similar conversion rate, blood loss, morbidity and pancreatic fistula rate. There was no operative mortality. The SVP group had shorter median operative time (245 vs 303.5 min, P = 0.019) and shorter median hospital stay (5 vs 6 days, P = 0.019) than the DPS group. However, all malignant lesions occurred in the DPS group and lesion size in DPS group was significantly larger. After matching, there were 28 SVP and 15 DPS. The histopathology findings and lesion size became comparable. The SVP group still had shorter operative time (245 vs 290 min, P = 0.022) and shorter hospital stay (5 vs 7 days, P = 0.014) than the DPS group. CONCLUSION: Apart from avoiding risk of overwhelming postsplenectomy sepsis, robotic SVP had additional advantage of shorter operative time and shorter hospital stay than robotic DPS.
Assuntos
Laparoscopia , Neoplasias Pancreáticas , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Tempo de Internação , Duração da Cirurgia , Pancreatectomia/efeitos adversos , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Baço/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: miR-1226 has been reported to be dysregulated in periodontitis, implying its potential functional role, which needs to be validated. The purpose of this study was to assess the clinical significance of miR-1226 in periodontitis. METHODS: Gingival crevicular fluid samples were collected from 50 healthy volunteers and 72 periodontitis patients. The expression of miR-1226 in collected samples was detected by RT-qPCR. The concentrations of pro-inflammatory cytokines were analyzed by ELISA. The relationship of miR-1226 expression level with patients' characteristics was evaluated by the χ2 test and the Pearson correlation test. RESULTS: It was found that miR-1226 was downregulated in the gingival crevicular fluid of periodontitis patients compared with healthy volunteers. The downregulation of miR-1226 was negatively correlated with the pocket depth, attachment loss, plaque index, bleeding index, and MMP-8 concentration of patients. miR-1226 showed high sensitivity and specificity to discriminate periodontitis patients from healthy volunteers. Additionally, periodontitis patients had a relatively high concentration of pro-inflammatory cytokines, which is correlated with miR-1226 expression negatively. CONCLUSIONS: miR-1226 could be an indicator for the diagnosis of periodontitis and has the potential to predict the development and severity of periodontitis.
Assuntos
Periodontite Crônica , MicroRNAs , Periodontite Crônica/genética , Líquido do Sulco Gengival , Humanos , MicroRNAs/genética , Perda da Inserção Periodontal , Índice PeriodontalRESUMO
Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down-regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.
Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Código das Histonas/genética , Histonas/metabolismo , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/deficiência , Neoplasias Hepáticas/genética , Proteínas Supressoras de Tumor/deficiência , Animais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Feminino , Humanos , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/fisiologia , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Terapia de Alvo Molecular , Prognóstico , Mapeamento de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Neoplásico/genética , Análise de Sequência de RNA , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To investigate how the aquatic bacterial community of a stratified reservoir drives the evolution of water parameters, the microbial community structure and network characteristics of bacteria in a stratified reservoir were investigated using Illumina MiSeq sequencing technology. A total of 42 phyla and 689 distinct genera were identified, which showed significant seasonal variation. Additionally, stratified variations in the bacterial community strongly reflected the vertical gradient and seasonal changes in water temperature, dissolved oxygen, and nutrition concentration. Furthermore, principal coordinate analysis indicated that most microorganisms were likely influenced by changes in water stratification conditions, exhibiting significant differences during the stratification period and mixing period based on Adonis, MRPP, and Anosim. Compared to the stratification period, 123 enhanced operational taxonomic units (OTUs; 29%) and 226 depleted OTUs (52%) were identified during the mixing period. Linear discriminant analysis effect size results showed that 15 major genera were enriched in the mixing period and 10 major genera were enriched in the stratification period. Importantly, network analysis revealed that the keystone species belonged to hgcI_clade, CL500-29, Acidibacter, Paucimonas, Flavobacterium, Prochlorothrix, Xanthomonadales, Chloroflexia, Burkholderiales, OPB56, KI89A_clade, Synechococcus, Caulobacter or were unclassified. Redundancy analysis showed that temperature, dissolved oxygen, pH, chlorophyll-α, total phosphorus, nitrate, and ammonia were important factors influencing the water bacterial community and function composition, which were consistent with the results of the Mantel test analysis. Furthermore, random forest analysis showed that temperature, dissolved oxygen, ammonia, and total dissolved phosphorous were the most important variables predicting water bacterial community and function community α- and ß-diversity (P < 0.05). Overall, these results provide insight into the interactions between the microbial community and water quality evolution mechanism in Zhoucun reservoir.
Assuntos
Água Potável , Microbiota , Bactérias , Microbiologia da Água , Qualidade da ÁguaRESUMO
An increase in the number of smokers, severe air pollution and outbreak of respiratory infectious diseases have caused a sharp increase in patients with respiratory diseases, which seriously threatens the safety of human lives and properties. Garlic, as a medicine-food homology plant, is used as a medicine by its bulbs. It has various pharmacological effects such as anti-inflammation, anti-oxidation, blood lipid lowering, blood pressure lowering, and anti-bacterial effects. Furthermore, the main active substances in garlic are organosulfur compounds. In recent years, many studies have reported the significant protective effects of garlic organosulfur compounds on common respiratory diseases. Based on the literatures from Pubmed and Web of Science in the past 5 years, we reviewed the effects and mechanisms of garlic organosulfur compounds against chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, pulmonary fibrosis and lung cancer in this article. The underlying mechanisms consisted of anti-inflammation, anti-oxidation, anti-apoptosis, reducing mucus secretion, inhibiting extracellular matrix synthesis, inhibiting cancer cell metastasis, and reducing cancer stem cells activity. The article was aimed to provide theoretical and experimental evidences for the further development and cli-nical applications of garlic organosulfur compound products.
Assuntos
Alho , Antioxidantes , Humanos , Oxirredução , Extratos Vegetais , Compostos de EnxofreRESUMO
BACKGROUND: S-Phenyl-L-cysteine is regarded as having potential applicability as an antiretroviral/protease inhibitor for human immunodeficiency virus (HIV). In the present study, optically active S-phenyl-L-cysteine was prepared in a highly efficient manner from inexpensive bromobenzene using tryptophan synthase through a chemoenzymatic method. RESULTS: The chemoenzymatic method used a four-step reaction sequence. The process started with the reaction of magnesium and bromobenzene, followed by a Grignard reaction, and then hydrolysis and enzymatic synthesis using tryptophan synthase. Through this approach, S-phenyl-L-cysteine was chemoenzymatically synthesized using tryptophan synthase from thiophenol and L-serine as the starting material. CONCLUSIONS: High-purity, optically active S-phenyl-L-cysteine was efficiently and inexpensively obtained in a total yield of 81.3% (> 99.9% purity).
Assuntos
Química Orgânica/métodos , Cisteína/análogos & derivados , Compostos Organometálicos/metabolismo , Triptofano Sintase/metabolismo , Bromobenzenos/química , Bromobenzenos/metabolismo , Cisteína/química , Cisteína/metabolismo , Magnésio/química , Magnésio/metabolismo , Modelos Químicos , Estrutura Molecular , Compostos Organometálicos/química , Fenóis/química , Fenóis/metabolismo , Serina/química , Serina/metabolismo , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismo , Triptofano Sintase/químicaRESUMO
PURPOSE: Portal vein (PV) embolization (PVE) is traditionally performed via a PV sheath with selective embolization of PV branches. Here, the efficacy and safety of PVE with the use of only an 18-gauge needle is reported. MATERIALS AND METHODS: Consecutive patients who underwent PVE from 2009 through 2017 were retrospectively reviewed. Forty-five patients (mean age, 60 y ± 7.6; 38 men) underwent 45 PVE procedures. Hepatocellular carcinoma, cholangiocarcinoma, and metastases accounted for 26 (58%), 13 (29%), and 6 (13%) patients, respectively. PVE was performed by puncturing a branch of right PV with an 18-gauge needle under US guidance. Via the same needle, direct portography was performed, followed by PVE with an N-butyl cyanoacrylate/Lipiodol mixture. Percentage increase of future liver remnant (FLR) volume and increase in ratio of FLR to total liver volume were estimated as measures of efficacy. Complications were reported according to Society of Interventional Radiology classification. Fluoroscopy time, procedure time, and dose-area product (DAP) were recorded. RESULTS: Technical success rate was 100%. The median DAP, fluoroscopy time, and procedure time were 74,387 mGy·cm2 (IQR, 90,349 mGy·cm2), 3.5 min (IQR, 2.10 min), and 24 min (IQR, 10.5 min). Among the 23 patients with complete CT volumetry data, mean increase in the ratio of FLR to total liver volume and percentage increase of FLR volume were 12.5% ± 7.7 and 50% ± 33, respectively. There were 3 minor complications (asymptomatic nonocclusive emboli in FLR) and 3 major complications (1 hepatic vein emboli, 1 subphrenic collection, and 1 hepatic infarct). CONCLUSIONS: PVE via a sheathless 18-gauge needle approach is feasible, with satisfactory FLR hypertrophy.
Assuntos
Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/terapia , Colangiocarcinoma/terapia , Embolização Terapêutica/métodos , Embucrilato/administração & dosagem , Óleo Etiodado/administração & dosagem , Neoplasias Hepáticas/terapia , Veia Porta , Idoso , Angiografia Digital , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Neoplasias Colorretais/patologia , Angiografia por Tomografia Computadorizada , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/instrumentação , Embucrilato/efeitos adversos , Desenho de Equipamento , Óleo Etiodado/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Regeneração Hepática , Masculino , Pessoa de Meia-Idade , Agulhas , Portografia/métodos , Punções , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Coronary calcium detection in medicine image processing is a hot research topic. According to the low resolution and complex background in medicine image, an improved coronary calcium detection algorithm based on the Single Shot MultiBox Detector (SSD) in Mimics is proposed in this paper. The algorithm firstly uses the aggregate channel feature model to preprocess the image to obtain the suspected calcium area, which greatly reduces the time of single-frame image detection. The basic network VGG-16 is replaced by Resnet-50, which introduces the identity mapping to solve the problem of reducing the detection accuracy when the number of network layers are increased. Finally, the powerful and flexible two-parameter loss function is used to optimize the training deep network and improve the network model generalization ability. Qualitative and quantitative experiments show that the performance of the proposed detection algorithm exceeds the existing calcium detection algorithms, and the detection efficiency is improved while ensuring the accuracy of calcium detection.
Assuntos
Calcinose/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Redes Neurais de Computação , Algoritmos , Humanos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodosRESUMO
CCCTC-binding factor (CTCF) is a DNA-binding protein that interacts with a large number of highly divergent target sequences throughout the genome. It is implicated in a variety of functions, including chromatin organization and transcriptional control. The functional role of CTCF in tumour pathogenesis remains elusive. We showed that CTCF is frequently upregulated in a subset of primary hepatocellular carcinomas (HCCs) as compared with non-tumoural liver. Overexpression of CTCF was associated with shorter disease-free survival of patients. Short hairpin RNA (shRNA)-mediated suppression of CTCF inhibited cell proliferation, motility and invasiveness in HCC cell lines; these effects were correlated with prominent reductions in the expression of telomerase reverse transcriptase (TERT), the shelterin complex member telomerase repeat-binding factor 1, and forkhead box protein M1 (FOXM1). In contrast, upregulation of CTCF was positively correlated with FOXM1 and TERT expression in clinical HCC biopsies. Depletion of CTCF resulted in reduced motility and invasiveness in HCC cells that could be reversed by ectopic expression of FOXM1, suggesting that FOXM1 is one of the important downstream effectors of CTCF in HCC. Reporter gene analysis suggested that depletion of CTCF is associated with reduced FOXM1 and TERT promoter activity. Chromatin immunoprecipitation (ChIP)-polymerase chain reaction (PCR) analysis further revealed occupancy of the FOXM1 promoter by CTCF in vivo. Importantly, depletion of CTCF by shRNA significantly inhibited tumour progression and metastasis in HCC mouse models. Our work uncovered a novel functional role of CTCF in HCC pathogenesis, which suggests that targeting CTCF could be further explored as a potential therapeutic strategy for HCC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Assuntos
Fator de Ligação a CCCTC/metabolismo , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Proteína Forkhead Box M1/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Sítios de Ligação , Fator de Ligação a CCCTC/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundário , Carcinoma Hepatocelular/terapia , Movimento Celular , Intervalo Livre de Doença , Feminino , Proteína Forkhead Box M1/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Regiões Promotoras Genéticas , Interferência de RNA , Transdução de Sinais , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero , Fatores de Tempo , Transcrição Gênica , Transfecção , Carga TumoralRESUMO
BACKGROUND: Transarterial chemoembolization (TACE) is the most commonly used adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Responses to TACE are variable due to tumor and patient heterogeneity. We had previously demonstrated that expression of Granulin-epithelin precursor (GEP) and ATP-dependent binding cassette (ABC)B5 in liver cancer stem cells was associated with chemoresistance. The present study aimed to evaluate the association between GEP/ABCB5 expression and response to adjuvant TACE after curative resection for HCC. METHODS: Patients received adjuvant TACE after curative resection for HCC and patients received curative resection alone were identified from a prospectively collected database. Clinical samples were retrieved for biomarker analysis. Patients were categorized into 3 risk groups according to their GEP/ABCB5 status for survival analysis: low (GEP-/ABCB5-), intermediate (either GEP+/ABCB5- or GEP-/ABCB5+) and high (GEP+/ABCB5+). Early recurrence (recurrence within 2 years after resection) and disease-free survival were analyzed. RESULTS: Clinical samples from 44 patients who had followed-up for more than 2 years were retrieved for further biomarker analysis. Among them, 18 received adjuvant TACE and 26 received surgery alone. Patients with adjuvant TACE in the intermediate risk group was associated with significantly better overall survival and 2-year disease-free survival than those who had surgery alone (Pâ¯=â¯0.036 and Pâ¯=â¯0.011, respectively). Adjuvant TACE did not offer any significant differences in the early recurrence rate, 2-year disease-free survival and overall survival for patients in low and high risk groups. CONCLUSIONS: Adjuvant TACE can only provide survival benefits for patients in the intermediate risk group (either GEP+/ABCB5- or GEP-/ABCB5+). A larger clinical study is warranted to confirm its role in patient selection for adjuvant TACE.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Hepatectomia , Neoplasias Hepáticas/terapia , Progranulinas/análise , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/mortalidade , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/química , PrognósticoRESUMO
BACKGROUND AND AIM: Liver stiffness measurement using transient elastography appears to be an excellent tool for detection of liver fibrosis and cirrhosis with high accuracy. The aim of this study is to evaluate the efficacy of preoperative liver stiffness measurement in predicting post-hepatectomy liver failure. METHODS: A prospective cohort study of all consecutive patients undergoing hepatectomy for hepatocellular carcinoma from February 2010 to August 2014 was studied. All patients received detailed preoperative assessments including liver stiffness measurement. The primary outcome was post-hepatectomy liver failure according to the International Study Group of Liver Surgery definition. RESULTS: A total of 255 patients were included. Liver stiffness measurement showed significant correlation with grade B or C post-hepatectomy liver failure. (P = 0.003) Using the cutoff at 12 kPa, liver stiffness measurement had a sensitivity of 52.4% and specificity of 73.3% in predication of high-grade (grade B or C) post-hepatectomy liver failure. Liver stiffness measurement > 12 kPa was also an independent prognostic factor for both high-grade post-hepatectomy liver failure and major postoperative complications by multivariate analysis. The diagnostic accuracy was better in patients without right lobe tumor with an area under the receiver operating characteristic of 0.83 compared with an area under the receiver operating characteristic of only 0.62 in patients with right lobe tumor. CONCLUSIONS: Liver stiffness measurement using Fibroscan is good to predict high-grade post-hepatectomy liver failure especially in patients without right lobe tumor.
Assuntos
Técnicas de Imagem por Elasticidade , Hepatectomia , Falência Hepática/diagnóstico por imagem , Fígado/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico por imagem , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Estudos de Coortes , Técnicas de Imagem por Elasticidade/instrumentação , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Curva ROC , Índice de Gravidade de DoençaRESUMO
BACKGROUND & AIMS: Aberrant chromatin modification is a key feature of hepatocellular carcinoma (HCC), which is characterized by strong sexual dimorphism. Both enhancer of zeste homolog 2 (EZH2) and cell cycle-related kinase (CCRK) contribute to hepatocarcinogenesis, yet whether the two oncogenic factors have functional crosstalk is unknown. METHODS: Cellular proliferation and tumorigenicity upon transgenic expression and RNA interference were determined by colony formation and soft agar assays, xenograft, orthotopic and diethylnitrosamine-induced HCC models. Gene regulation was assessed by chromatin immunoprecipitation, site-directed mutagenesis, luciferase reporter, co-immunoprecipitation and expression analyses. Protein levels in clinical specimens were correlated with clinicopathological parameters and patient survival rates. RESULTS: Ectopic CCRK expression in immortalized human liver cells increased EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) to stimulate proliferation and tumor formation. Conversely, knockdown of CCRK reduced EZH2/H3K27me3 levels and decreased HCC cell growth, which could be rescued by EZH2 over-expression. Mechanistically, GSK-3ß phosphorylation by CCRK activated a ß-catenin/TCF/E2F1/EZH2 transcriptional feedback loop to epigenetically enhance androgen receptor (AR) signaling. Simultaneously, the phosphorylation of AKT/EZH2 by CCRK facilitated the co-occupancy of CCRK promoter by EZH2-AR and its subsequent transcriptional activation, thus forming a self-reinforcing circuitry. Lentiviral-mediated knockdown of CCRK, which abrogated the phosphorylation-transcriptional network, prevented diethylnitrosamine-induced tumorigenicity. More importantly, the hyperactivation of the CCRK-EZH2 circuitry in human HCCs correlated with tumor recurrence and poor survival. CONCLUSIONS: These findings uncover an epigenetic vicious cycle in hepatocarcinogenesis that operates through reciprocal regulation of CCRK and EZH2, providing novel therapeutic strategy for HCC.
Assuntos
MicroRNAs/genética , Complexo Repressor Polycomb 2/genética , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/genética , Expressão Ectópica do Gene , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Recidiva Local de Neoplasia/genética , Transdução de Sinais/genética , Taxa de Sobrevida , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
BACKGROUND: Androgen receptor (AR) signalling contributes to male predominance in hepatocellular carcinoma (HCC), which is more pronounced in HBV-endemic areas. Cell cycle-related kinase (CCRK) is essential for AR-induced hepatocarcinogenesis but its molecular function in HBV-associated HCC remains obscure. OBJECTIVE: To determine the molecular function of CCRK in HBV-associated HCC. DESIGN: Transcriptional regulation was assessed by chromatin immunoprecipitation, promoter mutation and luciferase reporter assays. Hepatocellular proliferation and tumourigenesis were examined by colony formation, soft agar assays and using HBV X protein (HBx) transgenic mice with low-dose exposure to diethylnitrosamine. Protein expressions were examined in clinical samples and correlated with patient survival by log-rank Mantel-Cox test. RESULTS: Overexpression of CCRK, but not its kinase-defective mutant, activated ß-catenin/T cell factor signalling through phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) at Ser9, led to upregulation of AR transcriptional activity and, subsequently, expression of HBx. The viral transactivator in turn induced CCRK expression through enhanced AR signalling, thus forming a positive regulatory loop. RNA interference silencing of CCRK, which suppressed the CCRK/GSK-3ß/ß-catenin/AR regulatory loop, significantly suppressed HBx-induced hepatocellular proliferation (p=0.001) and transformation (p<0.001) and remarkably reduced >80% diethylnitrosamine-mediated hepatocarcinogenesis in HBx transgenic mice. Finally, patients with HBV-associated HCC with concordant overexpression of CCRK, GSK-3ß phosphorylation at Ser9, active dephosphorylated ß-catenin and AR phosphorylation at Ser81 had poorer overall (HR=31.26, p<0.0001) and disease-free (HR=3.60, p<0.01) survival rates. CONCLUSIONS: Our findings highlight the critical role of CCRK in a self-reinforcing circuitry that regulates HBV-associated hepatocarcinogenesis. Further characterisation of this intricate viral-host signalling may provide new prognostic biomarkers and therapeutic targets for HCC treatment.
Assuntos
Carcinoma Hepatocelular/metabolismo , Quinases Ciclina-Dependentes/biossíntese , Hepatite B/complicações , Neoplasias Hepáticas/metabolismo , Carcinogênese , Carcinoma Hepatocelular/virologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Interações Hospedeiro-Patógeno , Humanos , Neoplasias Hepáticas/virologia , Prognóstico , Receptores Androgênicos/metabolismo , Fatores de Transcrição TCF/metabolismo , Transativadores/metabolismo , Ativação Transcricional , Regulação para Cima , Proteínas Virais Reguladoras e Acessórias , beta Catenina/metabolismo , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
A simple, new aptamer-photonic crystal encoded suspension array was designed to simultaneously quantify and qualify ochratoxin A(OTA) and fumonisin B1(FB1) in cereal samples. The aptamers of OTA and FB1 were immobilized on the surfaces of photonic crystals by chemical bonding. When the target mycotoxins appear in a sample, the fluorescence-labeled complementary DNA of the aptamer dissociates from their double DNA hybrid and results in an obvious decrease in fluorescence intensity of the microsphere. The difference value of fluorescent intensities for each kind of silica photonic crystal microsphere (SPCM) quantitatively conveys the concentration of mycotoxin, and the structure colors or reflectance peak positions of the SPCMs confirm the kind of mycotoxin detected. The reaction conditions including the immobilization method for aptamers, hybridization, and incubation conditions have been optimized. This developed method displayed a wide linear detection range (0.01-1 ng/mL for OTA and 0.001-1 ng/mL for FB1) and a low limit of detection (0.25 pg/mL for OTA and 0.16 pg/mL for FB1). The recovery rates in the spiked cereal samples ranged from 81.80% to 116.38% for OTA and 76.58%-114.79% for FB1. The positive detection results in the naturally contaminated cereal samples were in agreement with those of classic enzyme-linked immunosorbent assay (ELISA). This simple suspension array scheme displays a great application potential for the high throughput screen assay of mycotoxins.
Assuntos
Aptâmeros de Nucleotídeos/química , Grão Comestível/química , Fumonisinas/análise , Ocratoxinas/análise , Microesferas , Fótons , Dióxido de Silício/químicaRESUMO
UNLABELLED: Sirtuin 1 (SIRT1) has been implicated in telomere maintenance and the growth of hepatocellular carcinoma (HCC). Nevertheless, the role of other sirtuins in the pathogenesis of HCC remains elusive. We found that sirtuin 2 (SIRT2), another member of the sirtuin family, also contributes to cell motility and invasiveness of HCC. SIRT2 is up-regulated in HCC cell lines and in a subset of human HCC tissues (23/45). Up-regulations of SIRT2 in primary HCC tumors were significantly correlated with the presence of microscopic vascular invasion (P = 0.001), a more advanced tumor stage (P = 0.004), and shorter overall survival (P = 0.0499). Functional studies by short hairpin RNA-mediated suppression of SIRT2 expression in HCC cell lines revealed significant inhibition of motility and invasiveness. Depletion of SIRT2 also led to the regression of epithelial-mesenchymal transition (EMT) phenotypes, whereas the ectopic expression of SIRT2 in the immortalized hepatocyte cell line L02 promoted cell motility and invasiveness. Mechanistic studies revealed that SIRT2 regulates the deacetylation and activation of protein kinase B, which subsequently impinges on the glycogen synthase kinase-3ß/ß-catenin signaling pathway to regulate EMT. CONCLUSIONS: Our findings have uncovered a novel role for SIRT2 in HCC metastasis, and provide a rationale to explore the use of sirtuin inhibitors in HCC therapy. (HEPATOLOGY 2013;).
Assuntos
Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , Sirtuína 2/metabolismo , Adulto , Idoso , Apoptose , Movimento Celular , Proliferação de Células , Feminino , Inativação Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células Hep G2 , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , beta Catenina/metabolismoRESUMO
Sustainable development and raising the domestic value-added rate of exports (DVARE) have become essential priorities in the pursuit of high-quality economic growth. An econometric spatial model is developed in this research using data on Chinese enterprises spanning 2008 to 2019. According to a study, exports' domestic value-added rate (DVAR) can be successfully increased using environmental, social, and governance (ESG) practices. Spatial spillover analysis demonstrates that adopting ESG practices boosts export DVAR both within and between regions. According to heterogeneity analysis, the sample's overall increase in DVARE as a result of ESG practices is mostly attributable to the mix and processing trade organizations, the eastern area, and large firms. An examination of the underlying mechanisms shows that businesses that implement advanced technologies are able to reinforce the favorable impact of ESG practices on DVARE. This article gives evidence from real-world studies that show how ESG practices help boost Chinese exports and advance sustainable development. The findings hold significant implications for other developing nations as they make the transition towards a pattern of economic growth.
Assuntos
Comércio , Desenvolvimento Econômico , Desenvolvimento Sustentável , China , Desenvolvimento Sustentável/tendências , Humanos , Tecnologia , Modelos EconométricosRESUMO
BACKGROUND: Liver fibrosis and cirrhosis are well-known risk factors for morbidity after hepatectomy. Liver stiffness measurement (LSM) using transient elastography is a new method for detection of hepatic fibrosis and cirrhosis with high accuracy. Whether LSM can predict posthepatectomy outcomes has not been studied. METHODS: This was a prospective cohort study in which consecutive patients underwent hepatectomy for various indications from February 2010 to July 2011. All patients received detailed preoperative assessments including LSM and indocyanine green (ICG) clearance test. The primary outcome was major postoperative complication. RESULTS: One hundred five patients with a mean age of 59 years were included; 75 (71.4%) had chronic viral hepatitis and 76 (72.4%) had hepatocellular carcinoma. Thirty-four patients (32.4%) received major hepatectomy. The median ICG retention rate at 15 minutes was 4.2 (0.1%-32%) and the median LSM was 9.4 (3.3-75 kPa). For posthepatectomy outcomes, only LSM but not ICG showed significant correlation with major postoperative complications on receiver operating characteristic curves, with area under the curve of 0.79 (P < 0.001). Using the calculated cutoff at 12.0 kPa, LSM had sensitivity of 85.7% and specificity of 71.8% in the prediction of major postoperative complications. It was also an independent prognostic factor for major postoperative complications by multivariate analysis. The operative blood loss and transfusion rate were also significantly higher in patients with LSM >12.0 kPa. CONCLUSIONS: High LSM (>12.0 kPa) predicted worse posthepatectomy outcomes. Preoperative LSM was better than ICG test in the prediction of major postoperative complications. It was a useful preoperative investigation for risk stratification before hepatectomy.
Assuntos
Carcinoma Hepatocelular/cirurgia , Técnicas de Imagem por Elasticidade , Hepatectomia , Hepatite Viral Humana/cirurgia , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Carcinoma Hepatocelular/complicações , Doença Crônica , Feminino , Hepatite Viral Humana/complicações , Humanos , Cirrose Hepática/complicações , Testes de Função Hepática , Neoplasias Hepáticas/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Complicações Pós-Operatórias/diagnóstico , Cuidados Pré-Operatórios , Estudos Prospectivos , Curva ROC , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
BACKGROUND: Radiofrequency ablation (RFA) has been used to treat hepatocellular carcinoma (HCC) and liver metastases for more than 10 years with promising early outcomes. Preliminary results comparing percutaneous and surgical approaches have shown no difference in short-term outcomes. In this study, the longer-term outcomes were presented. METHODS: Patients with liver malignancies treated by RFA were prospectively studied from 2003 to 2011. Post-ablation assessment by computed tomography (CT) scan and serum biochemistry was performed at regular intervals. Recurrence rates and long-term survival were analysed. RESULTS: A total of 233 patients with liver malignancies (75.5% HCC and 24.5% liver metastases) were analysed. Three RFA approaches were used (percutaneous 58.4%, laparoscopic 9.4% and open 32.2%). The median follow-up time was 29 months. Complete ablation was achieved in 83.7%, with no difference between the two approaches. More wound and chest complications were observed in the surgical group. Intra-hepatic recurrences were observed in 69.5%; extra-hepatic recurrences were detected in 22.3%, with no difference between the two groups. There was no statistical difference between the two approaches in overall 1-, 3- and 5-year survival. CONCLUSION: An extended period of follow-up in patients with liver malignancies showed that RFA is an effective treatment. No difference was demonstrated between the percutaneous and surgical approach, in terms of recurrence and survival.
Assuntos
Ablação por Cateter/métodos , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Ablação por Cateter/efeitos adversos , Distribuição de Qui-Quadrado , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Objective: This meta-analysis was designed to investigate the associations between SLCO1B1, APOE and CYP2C9 and the lipid-lowering effects and pharmacokinetics of fluvastatin. Methods: Studies were searched from inception to March 2023, including three SNPs related to fluvastatin, SLCO1B1, CYP2C9 and APOE. Weighted mean differences and corresponding 95% CIs were analyzed to evaluate the associations between SNPs and outcomes. Results: SLCO1B1 521T>C was associated with lower total cholesterol and low-density lipoprotein reduction. Patients carrying 521CC or total cholesterol had a significantly higher area under the curve than those carrying 521TT, but no significant difference existed. Conclusion: CYP2C9 and SLCO1B1 may be associated with the efficacy and pharmacokinetics of fluvastatin.