NALP3 INFLAMMASOME; ENDOTHELIAL FUNCTION; OXIDATIVE STRESS; AMYLOID-BETA; ATHEROSCLEROSIS; EXPRESSION; MICROPARTICLES; RECOGNITION; INHIBITION; MECHANISMS

Objectives. The purpose of this study is to evaluate whether Berberine can suppress the inflammatory response in atherosclerosis lesions and its potential associated signaling pathways and mechanism of action. Methods. We isolated human peripheral blood mononuclear cells. After co-culturing them with ox-LDL stimulated cells, ROS was measured by its fluorescence intensity and NADPH oxidase activity was detected by the OD value from the spectrophotometer. Human peripheral blood mononuclear cells were then pretreated with different concentrations of berberine after treatment with NLRP3 activator ATP. Western blot was used to measure the releas of IL-1 beta. We also used confocal microscopy to detect the nuclear import of NF-kB in macrophages. Results. In this study we observed that berberine suppressed IL-1 beta secretion that was induced by the activation of the NLRP3 inflammasome in macrophages. In addition, we demonstrated that berberine may possibly reduce reactive oxygen species (ROS)-dependent NLRP3 inflammasome activation. Moreover, Berberine inhibited the expression of pro-IL-1 beta through inhibition of the nuclear factor kappa b (NF-kappa B) pathway, which prevented the priming IL-1 beta secretion. Conclusion. Our results suggest that berberine alleviates NLRP3 inflammation activation by reducing IL-1 beta secretion from macrophages, which could be an important therapeutic target in atherosclerosis.

TERM-FOLLOW-UP; CAVERNOUS HEMANGIOMA; MICROWAVE ABLATION; RADIATION-THERAPY; LIVER; EXPERIENCE; ULTRASONOGRAPHY; MANAGEMENT; COMPLICATIONS; EMBOLIZATION

Recent studies have shown that radiofrequency (RF) ablation therapy is a safe, feasible, and effective procedure for hepatic hemangiomas, even huge hepatic hemangiomas. RF ablation has the following advantages in the treatment of hepatic hemangiomas: minimal invasiveness, definite efficacy, high safety, fast recovery, relatively simple operation, and wide applicability. It is necessary to formulate a widely accepted consensus among the experts in China who have extensive expertise and experience in the treatment of hepatic hemangiomas using RF ablation, which is important to standardize the application of RF ablation for the management of hepatic hemangiomas, regarding the selection of patients with suitable indications to receive RF ablation treatment, the technical details of the techniques, therapeutic effect evaluations, management of complications, etc. A final consensus by a Chinese panel of experts who have the expertise of using RF ablation to treat hepatic hemangiomas was reached by means of literature review, comprehensive discussion, and draft approval.

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ALGORITHM

Nurse rostering is a complex and hard discrete optimization problem as well as a very common personnel scheduling task which occurs in each hospital ward. To solve the highly constrained nurse rostering problem, various approaches have been developed including some effective variable neighbourhood search methods. In this paper, a randomized variable neighbourhood search algorithm, which is much simpler than existing methods of the similar type, is proposed. The algorithm uses random combined group operators to iteratively search better solutions and a cycle shift operator to diversify the search space when stagnating in local optima. Computational experiments are carried out with fifty-five instances from the First International Nurse Rostering Competition. Under the time limit of the competition, results achieved show that the proposed algorithm is very competitive with the state-of-the-art methods. Comparison of results with respect to the average performance with other algorithms indicates that our approach is more stable. Analysis and discussion based on extensive experiments are also presented to investigate critical features of our algorithm. (C) 2017 Elsevier Ltd. All rights reserved.

ANTIDIABETIC DRUG METFORMIN; HEPATOCELLULAR-CARCINOMA CELLS; INTRAHEPATIC CHOLANGIOCARCINOMA; GASTRIC-CANCER; BREAST-CANCER; STEM-CELLS; OLD DRUG; THERAPY; PATHWAY; PROLIFERATION

Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways. Metformin upregulated the expression of p21(waf1) and p27(kip1), and downregulated the expression of cyclin D1, a key protein required for cell cycle progression. The combination of gemcitabine and cisplatin inhibited the proliferation and induced the apoptosis of human cholangiocarcinoma cells by inducing the phosphorylation of AMPK, downregulating cyclin D1, and activating caspase-3. Administration of metformin enhanced the efficacy of gemcitabine and cisplatin to suppress the growth of cholangiocarcinoma tumors established in experimental models by inhibiting cell proliferation and inducing cell apoptosis through their effects on AMPK, cyclin D1 and caspase-3. Given that metformin has been used to treat type 2 diabetes patients for over half a century due to its superior safety profile, the results presented here indicate that metformin may be a potent agent for enhancing the efficacy of gemcitabine and cisplatin in the treatment of cholangiocarcinoma.

CANCER CELLS; TRANSITION; APOPTOSIS

microRNA (miRNA) plays critical role in HCC initiation and development, many miRNAs have been reported to regulate HCC progression. In this study, we studied the role of miR-1299 in cell proliferation of HCC. We found miR-1299 was significantly downregulated in HCC cells and tissues. miR-1299 overexpression inhibited cell proliferation and arrested cell cycle in G0/G1 phase analyzed by MTT assay, soft agar assay, BrdU cell proliferation assay and cell cycle assay, while miR-1299 knockdown promoted cell proliferation and accelerated G1/S transition. Further analysis suggested the key regulator of G1/S transition, cyclin-dependent kinase 6 (CDK6) was the target of miR-1299, miR-1299 inhibited CDK6 expression and bound to the 3'UTR of CDK6. When double knockdown of miR-1299 and CDK6 promoted cell proliferation copied the phenotype caused by miR-1299 overexpression, suggesting miR-1299 inhibits cell proliferation by targeting CDK6. In summary, our data revealed miR-1299 inhibits cell proliferation, and might be a target for HCC therapy. (C) 2016 Published by Elsevier Masson SAS.

TOLL-LIKE RECEPTOR-4; FACTOR MIF; CELLS; PATHWAY; LUNG; ATHEROSCLEROSIS; ADENOCARCINOMA; MODULATION; EXPRESSION; RESISTANCE

Macrophage migration inhibitory factor (MIF) is up-regulated in diverse solid tumors and acts as the critical link between immune response and tumorigenesis. In this study, we demonstrated that MIF overexpression promoted migration of breast cancer cells by elevating TLR4 expression. Further investigation evidenced that MIF induced ROS generation. MIF-induced ROS led to ERK phosphorylation, which facilitated HMGB1 release from the nucleus to the cytoplasm. MIF overexpression also induced caveolin-1 phosphorylation. Caveolin-1 phosphorylation contributed to HMGB1 secretion from the cytoplasm to the extracellular matrix. The extracellular HMGB1 activated TLR4 signaling including NF-kappa B phosphorylation, which was responsible for the transcription of Snail and Twist as well as MMP2 activation. Furthermore, MIF-induced caveolin-1-dependent HMGB1 secretion might control the recruitment of CD11b+ immune cells. Our data suggested that MIF affected the intrinsic properties of tumors and the host immune response in tumor microenvironment by regulating the TLR4/HMGB1 axis, leading to metastasis of breast cancer. (C) 2016 Published by Elsevier Ireland Ltd.

HUMAN HEPATOCELLULAR-CARCINOMA; TRANSCRIPTION FACTOR NETWORK; CANCER-CELLS; LIVER DEVELOPMENT; GASTRIC-CANCER; EXPRESSION; MICRORNA-122; RESISTANCE; DIAGNOSIS; PATHWAY

Hepatocyte nuclear factor 6 (HNF6) is a liver-enriched transcription factor and highly expressed in mature bile duct epithelial cells. This study sought to investigate the role of HNF6, particularly the molecular mechanisms for how HNF6 is involved in the growth and metastasis of cholangiocarcinoma (CCA) cells.;-;The expression of HNF6, miR-122 and key molecules was examined by Western blot analysis and real-time RT-PCR. Stable transfectants, HCCC-HNFlow and RBE-HNFhigh, were generated from human CCA HCCC-9810 and RBE cells, respectively. The regulatory effect of HNF6 on miR-122 was evaluated by luciferase reporter assay. Cell proliferation, cycle distribution, migration and invasion were analyzed. The xenograft model was used to assess the effects of HNF6 overexpression on tumorigenesis, growth, metastasis and therapeutic potentials.;-;Human CCA tissues and cells expressed lower levels of HNF6, which positively correlated with miR-122. HNF6 regulated the expression of miR-122 by stimulating its promoter. HNF6 overexpression inhibited cell proliferation by inducing cell cycle arrest at G1 phase through regulating miR-122, cyclin G1 and insulin-like growth factor-1 receptor. HNF6 inhibited the migration and invasion of CCA cells by regulating matrix metalloproteinase-2 and metalloproteinase-9, reversion-inducing-cysteine-rich protein with kazal motifs, E-cadherin and N-cadherin. Co-transfection of anti-miR-122 abrogated the effects of HNF6. HNF6 overexpression inhibited the ability of cells to form tumors and to metastasize to the lungs of mice, and the growth of established tumors.;-;The results indicate that HNF6 may serve as a tumor suppressor by regulating miR-122, and its overexpression may represent a mechanism-based therapy for CCA.

NF-KAPPA-B; TUMOR-SUPPRESSOR; LIVER-CANCER; ACTIVATION; ANGIOGENESIS; METASTASIS; APOPTOSIS

MicroRNAs (miRNAs) are short, non-coding RNAs with post-transcriptional regulatory function, playing crucial roles in cancer development and progression of hepatocellular carcinoma (HCC). Previous studies have indicated that miR-1180 was implicated in diverse biological processes. However, the underlying mechanism of miR-1180 in HCC has not been intensively investigated. In this study, we aimed to investigate the role of miR-1180 and its target genes in HCC. We found that miR-1180 expression was significantly increased in HCC cells and clinical tissues compared with their corresponding controls. Overexpression of miR-1180 promoted cell proliferation in HCC cell line HepG2. TNFAIP3 interacting protein 2 (TNIP2), a potential target gene of miR-1180, and were validated by a luciferase assay. Further studies revealed that miR-1180 regulated cell proliferation of HCC by directly suppressing TNIP2 expression and the knockdown of TNIP2 expression reversed the effect of miR-1180-in on HCC cell proliferation. In summary, our data indicated that miR-1180 might act as a tumor promoter by targeting TNIP2 during development of HCC. (C) 2016 Elsevier Masson SAS. All rights reserved.

CLASS-I; NKG2D LIGANDS; T-CELLS; GENE; RISK; SUSCEPTIBILITY; EXPRESSION; INDUCTION; DISEASES; IL-6

Background: We explored the relationship of interferon-gamma (IFN-gamma) and MHC class-I chain related gene A (MICA) genes polymorphisms with hepatocellular carcinoma (HCC) risk, and tried to determine whether the interaction existed between these two genes polymorphisms on the basis of HCC.;-;Material/Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect the genotypes of the 3 single-nucleotide polymorphisms (SNPs) and to analyze the correlation of each SNP with HCC susceptibility in 120 HCC patients and 124 healthy people. The association strength between the 3 SNPs and HCC is represented with odds ratio (OR) and 95% confidence interval (95% CI). Hardy-Weinberg equilibrium (HWE) was tested by x2 test in the control group.;-;Results: GG genotype of IFN-gamma rs2069727 polymorphism had apparently different distributions in case and control groups (P<0.05), and might confer increased risk of HCC (OR=3.40, 95% CI=1.23-9.38). Analysis of MICA rs2596542 polymorphism also yielded the same result (OR=2.90, 95% CI=1.10-7.67), as did their risk alleles. Specifically, the interaction between rs2596542 and rs2069705 polymorphisms increased the HCC risk by 1.41 times and between rs2596542 and rs2069727 polymorphisms the increased risk of HCC by 5.56 times.;-;Conclusions: IFN-gamma rs2069727 and MICA rs2596542 polymorphisms may be related to the incidence of HCC. Interaction exists between the polymorphisms of IFN-gamma and MICA, which may increase risk of HCC.