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The purpose of this investigation was to assess the diagnostic and prognostic significance of ATP binding cassette subfamily C (ABCC) genes in hepatocellular carcinoma (HCC). The Student t-test was used to compare the expression level of ABCCs between HCC and paraneoplastic tissues. Receiver operating characteristic curve (ROC) analysis was applied for diagnostic efficiency assessment. The Kaplan-Meier method and Cox proportional hazards model were respectively applied for survival analysis. Genes with prognostic significance were subsequently used to construct prognostic models. From the perspective of genome-wide enrichment analysis, the mechanisms of prognosis-related ABCC genes were attempted to be elaborated by gene set enrichment analysis (GSEA). It was observed in the TCGA database that ABCC1, ABCC4, ABCC5, and ABCC10 were significantly upregulated in tumor tissues, while ABCC6 and ABCC7 were downregulated in HCC tissues. Receiver operating characteristic analysis revealed that ABCC7 might be a potential diagnostic biomarker in HCC. ABCC1, ABCC4, ABCC5, and ABCC6 were significantly related to the prognosis of HCC in the TCGA database. The prognostic significance of ABCC1, ABCC4, ABCC5, and ABCC6 was also observed in the Guangxi cohort. In the Guangxi cohort, both polymerase chain reaction and IHC (immunohistochemical) assays demonstrated higher expression of ABCC1, ABCC4, and ABCC5 in HCC compared to liver tissues, while the opposite was true for ABCC6. GSEA analysis indicated that ABCC1 was associated with tumor differentiation, nod-like receptor signal pathway, and so forth. It also revealed that ABCC4 might play a role in HCC by regulating epithelial-mesenchymal transition, cytidine analog pathway, met pathway, and so forth. ABCC5 might be associated with the fatty acid metabolism and KRT19 in HCC. ABCC6 might impact the cell cycle in HCC by regulating E2F1 and myc. The relationship between ABCC genes and immune infiltration was explored, and ABCC1,4,5 were found to be positively associated with infiltration of multiple immune cells, while ABCC6 was found to be the opposite. In conclusion, ABCC1, ABCC4, ABCC5, and ABCC6 might be prognostic biomarkers in HCC. The prognostic models constructed with ABCC1, ABCC4, ABCC5, and ABCC6 had satisfactory efficacy.
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BACKGROUND: Hepatocellular carcinoma (HCC) was frequently considered as a kind of malignant tumor with a poor prognosis. Cyclin-dependent kinases (CDK) 4 was considered to be cell-cycle-related CDK gene. In this study, we explored the clinical significance of CDK4 in HCC patients. METHODS: Data of HCC patients were obtained from The Cancer Genome Atlas database (TCGA) and the Gene Expression Omnibus (GEO) database. Kaplan-Meier analysis and Cox regression model were performed to calculate median survival time (MST) and the hazard ration (HR), respectively. The joint-effect analysis and prognostic risk score model were constructed to demonstrate significance of prognosis-related genes. The differential expression of prognostic genes was further validated using reverse transcription-quantitative PCR (RT-qPCR) of 58 pairs of HCC samples. RESULTS: CDK1 and CDK4 were considered prognostic genes in TCGA and GSE14520 cohort. The result of joint-effect model indicated patients in CDK1 and CDK4 low expression groups had a better prognosis in TCGA (adjusted HR = 0.491; adjusted P = 0.003) and GSE14520 cohort (adjusted HR = 0.431; adjusted P = 0.002). Regarding Kaplan-Meier analysis, high expression of CDK1 and CDK4 was related to poor prognosis in both the TCGA (P < 0.001 and = 0.001 for CDK1 and CDK4, respectively) and the GSE14520 cohort (P = 0.006 and = 0.033 for CDK1 and CDK4, respectively). However, only CDK4 (P = 0.042) was validated in RT-qPCR experiment, while CDK1 (P = 0.075) was not. CONCLUSION: HCC patients with high CDK4 expression have poor prognosis, and CDK4 could be a potential candidate diagnostic biomarker for HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/pathology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Liver Neoplasms/pathology , PrognosisABSTRACT
BACKGROUND: The protein high-mobility group AT-hook 1 (HMGA1) has been demonstrated that modulated cellular proliferation, invasion, and apoptosis with a poor prognosis in miscellaneous carcinomas. However, the mechanism of circumstantial carcinogenesis and association with the immune microenvironment of HMGA1 in hepatocellular carcinoma (HCC) had not been extensively explored. METHODS: The gene expression, clinicopathological correlation, and prognosis analysis were performed in the data obtained from TCGA. The results were further validated by ICGC and GEO database and external validation cohort from Guangxi. The HMGA1 protein expression was further examined in the HPA database. Biological function analyses were conducted by GSEA, STRING database, and Coexpedia online tool. Using TIMER and CIBERSORT method, the relationship between immune infiltrate and HMGA1 was investigated. RESULTS: In HCC, HMGA1 had much higher transcriptional and proteomic expression than in corresponding paraneoplastic tissue. Patients with high HMGA1 expression had a poor prognosis and unpromising clinicopathological features. High HMGA1 expression was closely related to the cell cycle, tumorigenesis, substance metabolism, and immune processes by regulating complex signaling pathways. Notably, HMGA1 may be associated with TP53 mutational carcinogenesis. Moreover, increased HMGA1 expression may lead to an increase in immune infiltration and a decrease in tumor purity in HCC. CIBERSORT analysis elucidated that the amount of B cell naive, B cell memory, T cells gamma delta, macrophages M2, and mast cell resting decreased when HMGA1 expression was high, whereas T cells follicular helper, macrophages M0, and Dendritic cells resting increased. CONCLUSION: In conclusions, HMGA1 is a potent prognostic biomarker and a sign of immune infiltration in HCC, which may be a potential immunotherapy target for HCC.
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BACKGROUND: Cytochrome P450 2C8 (CYP2C8) gene is one of the members of the cytochrome P450 enzymes (CYPs) gene family. The aim of this study was to reveal the function of CYP2C8 in hepatocellular carcinoma (HCC) and its effect on the sorafenib resistance. METHODS: Differential expression analysis in multiple HCC datasets all suggested that CYP2C8 expression was significantly decreased in HCC tissues, compared with para-carcinoma liver tissues. The expression level of CYP2C8 was subsequently compared between HCC tissues and para-carcinoma liver tissues of 70 patients form Guangxi, China, with the result consistent with the above. Survival analysis and ROC analysis indicated that CYP2C8 was equipped with satisfactory diagnostic and prognostic value in HCC. To examine the effect of CYP2C8 on the malignant phenotype of HCC cells, stable transcriptional cell lines with CYP2C8 over-expression were established, and then Cell Counting Kit-8 (CCK8) assay, colony formation assay, cell cycle assay, cell invasion assay and wound healing assay were performed. RESULTS: The results of aforementioned assays suggested that CYP2C8 over-expression restricted the proliferation, clonality, migration, invasion and cell cycle of HCC cells but had no significant effect on cell apoptosis. The enrichment analysis in terms of sequencing data of HCC cell lines with stable CYP2C8 over-expression suggested that CYP2C8 might be related to PI3K/Akt/p27Kip1 axis. The inhibition of CYP2C8 over-expression on PI3K/Akt/p27Kip1 axis was subsequently demonstrated with Western blot assay. In the rescue experiment, it was observed that both P27 inhibitor and PI3K agonist counteracted the repressed malignant phenotype caused by CYP2C8 over-expression, which further demonstrated that CYP2C8 played a role in HCC cells via PI3K/Akt/p27Kip1 axis. DISCUSSION: The results demonstrated that CYP2C8 enhances the anticancer activity of sorafenib in vitro assays and in tumor xenograft model, with Ki-67 down-regulation and PI3K/Akt/p27Kip1 axis inhibition. In conclusion, these findings hinted that CYP2C8 restricted malignant phenotype and sorafenib resistance in HCC via PI3K/Akt/p27kip1 axis.
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OBJECTIVE: To prepare amphiphilic polycaprolactone-poly (arginine polymer) (PCL-R15)/siRNA Nanopexes, and two kinds of nanoparticles with different particle size were prepared by different process. After encapsulated siRNA with electrostatic interaction, both of two nanoplexes (NR60/siRNA and NR160/siRNA) were used to compare the effects in vitro cell levels. METHODS: The particle size and Zeta potential, siRNA loading and protection ability, cytotoxicity, cellular uptake mechanism and gene silencing efficiency of the two nanoplexes were investigated. RESULTS: The results show that the two nanoplexes have similar siRNA protection ability and cytotoxicity, but the difference between the two sizes is about 100 nm and the potential difference is about 20 mV. Moreover, NR160/siRNA complexes have higher cell uptake efficiency, more complex uptake pathways, and show greater gene silencing efficiency. CONCLUSION: These nanoplexes with different particle sizes can cause different transfection efficiency for siRNA delivery in cells.
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Objective:To construct an evaluation indicator system for emergency response capability in health supervision institutions.Methods:It made an initial indicator system by using brain storming,literature method and expert consulting,and constructed an evaluation indicator system by Delphi method.Results:Both the response rates of two round questionnaires survey were 100％.The means of authoritative coefficient for the first-dimension indicators was 0.82.For the second round of expert consulting,the coordination coefficients of the first,second and third-dimension indicators were 0.954,0.820 and 0.565 respectively (P＜0.05).It constructed an evaluation indicator system for emergency response capability among health supervision institutions.There were 4 first-dimension indicators,10 second-dimension indicators and 37 third-dimension indicators in the indicators system.Conclusion:Experts opinions had high reliability.The process of screening indicators was normative.The indicator system was comprehensive,which could be used and examined in practice.
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Objective:To construct an evaluation indicator system for emergency response capability in health supervision institutions.Methods:It made an initial indicator system by using brain storming,literature method and expert consulting,and constructed an evaluation indicator system by Delphi method.Results:Both the response rates of two round questionnaires survey were 100％.The means of authoritative coefficient for the first-dimension indicators was 0.82.For the second round of expert consulting,the coordination coefficients of the first,second and third-dimension indicators were 0.954,0.820 and 0.565 respectively (P＜0.05).It constructed an evaluation indicator system for emergency response capability among health supervision institutions.There were 4 first-dimension indicators,10 second-dimension indicators and 37 third-dimension indicators in the indicators system.Conclusion:Experts opinions had high reliability.The process of screening indicators was normative.The indicator system was comprehensive,which could be used and examined in practice.
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<p><b>OBJECTIVE</b>To investigate the pharmacokinetics and bioavailability of ziprasidone tablets in Chinese healthy volunteers.</p><p><b>METHODS</b>A randomized crossover study was performed in 20 healthy volunteers, who received a single oral dose (40 mg) of the test or reference preparation of ziprasidone. Blood samples were collected from the subjects at different time points following the drug administration, and the plasma concentration of ziprasidone was determined using high-performance liquid chromatography. The pharmacokinetic parameters were analyzed by DAS software and the relative bioavailability was calculated according to the formula F=AUC(t)/AUC(r)x100%.</p><p><b>RESULTS</b>For the test and reference preparation, the pharmacokinetics parameter C(max) was 170.7-/+71.3 and 174.4-/+81.6 ng/ml, t(max) 3.73-/+1.87 and 3.69-/+1.84 h, t((1/2)) 5.57-/+1.62 and 5.61-/+1.73 h, AUC(0-t) 1273-/+252.3 and 1296-/+266.9 ng.h.ml(-1), and AUC(0-infinity)1396-/+276.9 and 1407-/+281.5 ng.h.ml(-1), respectively, with the relative bioavailability of (98.3-/+12.6)%. No significant differences were found in the main parameters of the test and reference preparations as analyzed by ANOVA and two- and one-side t-test.</p><p><b>CONCLUSION</b>The test and reference preparation of ziprasidone are bioequivalent.</p>
Subject(s)
Humans , Young Adult , Administration, Oral , Asian People , Biological Availability , Drug-Related Side Effects and Adverse Reactions , Health , Piperazines , Pharmacokinetics , Tablets , Therapeutic Equivalency , Thiazoles , Pharmacokinetics , Time FactorsABSTRACT
<p><b>OBJECTIVE</b>To study the pharmacokinetics of paroxetine tablet in Chinese healthy volunteers.</p><p><b>METHODS</b>Twenty healthy subjects received a single oral dose of 40 mg paroxetine tablet. The plasma concentrations of paroxetine were determined using high-performance liquid chromatography (HPLC) and the measurements were analyzed with 3P97 program.</p><p><b>RESULTS</b>The plasma concentration curve of paroxetine following a single oral dose administration conformed to the two-compartment open model. The main pharmacokinetics parameters of paroxetine were: C(max)64.74-/+18.43 ng/ml, T(max)5.64-/+1.84 h, t(1/2) 20.03-/+5.33 h, AUC(0-120) 976.47-/+309.49 ng.h/ml, and AUC(0-inf) 1086.75-/+376.54 ng.h/ml.</p><p><b>CONCLUSION</b>The pharmacokinetics of paroxetine in human body conforms to the two-compartment open model.</p>
Subject(s)
Adult , Humans , Young Adult , Administration, Oral , Chromatography, High Pressure Liquid , Paroxetine , Pharmacokinetics , Selective Serotonin Reuptake Inhibitors , Pharmacokinetics , TabletsABSTRACT
<p><b>OBJECTIVE</b>To establish a reversed phase high-performance liquid chromatography (HPLC) system for determining plasma concentration of olanzapine and analyze the pharmacokinetics of olanzapine in healthy Chinese volunteers.</p><p><b>METHODS</b>Ten healthy male subjects received a single oral dose of 20 mg olanzapine tablets. The plasma concentrations of olanzapine were determined by HPLC, and the data were analyzed using 3P97 program.</p><p><b>RESULTS</b>The plasma concentration curve of olanzapine following a single oral dose conformed to the two compartment open model. The main pharmacokinetics parameters of olanzapine were as follow: C(max) was 113.7-/+33.1 microg/L, T(max) 5.07-/+0.65 h, t(1/2) 35.44-/+4.21 h, AUC(0-144) 2,235-/+257 microg.h.L(-1), and AUC(0-inf) 2,516-/+301 microg.h.L(-1).</p><p><b>CONCLUSION</b>The system established in this study allows for highly sensitive, selective and accurate determination of plasma concentration of olanzapine, and provides valuable information for clinical trials.</p>
Subject(s)
Adult , Humans , Male , Antipsychotic Agents , Blood , Pharmacokinetics , Area Under Curve , Benzodiazepines , Blood , Pharmacokinetics , China , Chromatography, High Pressure Liquid , Methods , Reproducibility of ResultsABSTRACT
<p><b>AIM</b>To study the chemical constituents in the mycelia of Hypomyces sp..</p><p><b>METHODS</b>Silica gel column chromatography was employed for the isolation and purification. Chemical and spectral methods were used to determine the structures of the isolated compounds.</p><p><b>RESULTS</b>Two compounds were isolated and identified as: hypomycin C (I) and hypomycin D (II).</p><p><b>CONCLUSION</b>Compounds I and II are new compounds.</p>
