Liver fibrosis is the common outcome of almost all cases of chronic liver disease. The hallmark of liver fibrosis is the activation of hepatic stellate cells (HSCs). microRNA‑34a (miR‑34a), which regulates a plethora of target proteins involved in the cell cycle, apoptosis, differentiation and cellular development, is found to be upregulated in both activated HSCs and liver fibrosis, while it is consistently downregulated in numerous cancer types. In the present study, the possible mechanisms underlying the role of miR‑34a and miR‑34c in the activation of the HSCs was investigated. Through bioinformatics analysis and a luciferase reporter assay, five genes were identified to be the target genes of miR‑34a and miR‑34c. Of these, peroxisome proliferator‑activated receptor γ (PPARγ) was selected for further investigation. Mutation luciferase reporter assay confirmed the direct interaction of PPARγ and miR‑34a and miR‑34c. Western blot analysis and quantitative polymerase chain reaction demonstrated that the expression of PPARγ was negatively correlated with the expression of miR‑34a and miR‑34c during the activation of HSCs. In activated human HSCs, inhibitors of miR‑34a and miR‑34c upregulated the expression of PPARγ and downregulated the expression of α‑smooth muscle actin. These data suggested that the miR‑34 family may be involved the process of liver fibrosis by targeting PPARγ.

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Objectives: Lysophosphatidic acid (LPA) is a bioactive lipid mediator involved in tumour progression, cell invasion and metastasis. The mechanism of action of LPA in the invasive and metastatic capacity of human hepatocellular carcinoma (HCC) is not fully understood. This study investigated the effects of LPA on HCC cell invasion and induction of matrix metalloproteinase (MMP) À2 and À9. Methods: LPA receptor levels in HCC cell lines were detected by Western blot analysis; HCC cell invasion was analysed by the Transwell Õ system. The LPA receptor blocker Ki16425 was used to determine whether HCC cell invasion was LPA dependent. Expression of the MMP2 and MMP9 genes in HCC cells was determined by real-time quantitative reverse transcription-polymerase chain reaction (qPCR). Results: LPA increased HCC cell invasion, which was LPA-receptor dependent. Real-time RT-qPCR showed that LPA increased MMP9, but not MMP2, expression in HCC cells. Pharmacological inhibition of LPA receptors with Ki16452 significantly attenuated LPA-induced HCC cell invasion. Conclusions: HCC invasiveness is facilitated by LPA and may be relevant to tumour progression. Thus, LPA receptors may be a potential therapeutic target for HCC. KeywordsLysophosphatidic acid (LPA), hepatocellular carcinoma (HCC), invasion, matrix metalloproteinase (MMP) Date

How can we plan efficiently in a large and complex environment when the time budget is limited? Given the original simulator of the environment, which may be computationally very demanding, we propose to learn online an approximate but much faster simulator that improves over time. To plan reliably and efficiently while the approximate simulator is learning, we develop a method that adaptively decides which simulator to use for every simulation, based on a statistic that measures the accuracy of the approximate simulator. This allows us to use the approximate simulator to replace the original simulator for faster simulations when it is accurate enough under the current context, thus trading off simulation speed and accuracy. Experimental results in two large domains show that when integrated with POMCP, our approach allows to plan with improving efficiency over time.