Development of targeted therapy for hepatocellular carcinoma (HCC) remains a major challenge. We have recently identified an elevated expression of the fifth subunit of COP9 signalosome (CSN5) in early HCC as compared to dysplastic stage. In the present study, we explored the possibility of CSN5 being a potential therapeutic target for HCC. Our results show that CSN5 knockdown by small interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell cycle progression in HCC cells in vitro. The downregulation of CSN5 was sufficient to interfere with CSN function as evidenced by the accumulation of neddylated Cullin1 and changes in the protein levels of CSN controlled substrates SKP2, p53, p27 and NF-kB, albeit to a different degree depending on the HCC cell line, which could account for the CSN5 knockdown phenotype. The transcriptomic analysis of CSN5 knockdown signature showed that the anti-proliferative effect was driven by a common subset of molecular alterations including downregulation of CDK6 and ITGB1, which were functionally interconnected with key oncogenic regulators MYC and TGFβ1 involved in the control of proliferation, apoptotic cell death and HCC progression. Consistent with microarray analysis, western blotting revealed that CSN5 depletion increased phosphorylation of Smad 2/3, key mediators of TGFβ1 signaling, decreased the protein levels of ITGB1, CDK6, and cyclin D1 and caused reduced expression of anti-apoptotic Bcl-2 while elevating the levels of pro-apoptotic Bak. A chemically modified variant of CSN5 siRNA was then selected for in vivo application based on the growth inhibitory effect and minimal induction of unwanted immune response. Systemic delivery of the CSN5 3/8 variant by stable-nucleic-acid-lipid-particles (SNALP) significantly suppressed the tumor growth in Huh7-luc+ orthotopic xenograft model. Taken together, these results indicate that CSN5 plays a pivotal role in HCC pathogenesis and maybe an attractive molecular target for systemic HCC therapy.

Summary:Liver dysfunction is a common problem in BMT recipients and it is important to determine the etiology in order to institute appropriate therapy. The purpose of this study was to evaluate the possible causes of liver dysfunction during the first post-transplant year in BMT recipients and to identify a possible relationship between pre-existing liver dysfunction and viral hepatitis with prognosis after BMT. We reviewed liver status before and after BMT in 130 consecutive patients at the Catholic Hematopoietic Stem Cell Transplantation Center. Liver dysfunction during the first post-transplant year occurred in 85 out of 101 (84.2%) allogeneic BMT recipients and 13 out of 29 (44.8%) autologous BMT recipients. In allogeneic BMT, GVHD and drug hepatotoxicity were major causes. In autologous BMT, drug hepatotoxicity was the most common cause. Eighteen out of 130 patients (13.8%) had abnormal liver function tests before BMT. These patients did not have an increased risk of post-transplant liver dysfunction, GVHD, and death compared to patients who had normal liver function tests prior to BMT. Nine patients were hepatitis B antigen positive and three patients were anti-HCV positive prior to BMT. There was no significant increase in the incidence of post-transplant liver dysfunction, GVHD, and death in these patients. Bone Marrow Transplantation (2000) 26, 193-197.

TNSC-EGD without sedation was found to be feasible, safe, and accurate for evaluating esophageal varices, gastric varices, and red color signs in patients with cirrhosis - even in those with marked bleeding diathesis. Furthermore, it was significantly better tolerated by patients, without altering endoscopist satisfaction. Our findings indicate that TNSC-EGD without sedation might be viewed as a potential alternative to POC-EGD for evaluation of varices.

The objective of this study was to use a nationwide epidemiological survey to investigate the factors that affect within-visit blood pressure (BP) variability. We analyzed the Korean National Health and Nutrition Examination Survey (KNHNES) data for 2005 (n=5488). We examined three within-visit BP variability parameters that include the following: the alarm reaction (AR), defined as the first BP reading minus the third BP reading; the BP discrepancy, defined as the maximal BP reading minus the minimal BP reading (ΔBPmax); and the s.d. (BPSD). Age, fasting glucose, eGFR, total cholesterol, LDL cholesterol, and the metabolic syndrome (MetS) score were the relevant factors that affected the systolic AR, ΔSBPmax and SBPSD. Multiple linear regression models revealed that age (P<0.0001), the office systolic BP (SBP) level (P<0.0001), the MetS score (P<0.0001), the female gender (P=0.007) and the eGFR (P=0.049) were independently associated with the systolic AR, whereas age (P<0.0001), the office SBP level (P<0.0001), and the female gender (P=0.024 and 0.022) were independently associated with ΔSBPmax and SBPSD, respectively. Within-visit BP variability, especially the variability associated with the SBP, was significantly associated with increased age, female gender and cardiovascular risk factors, such as hypertension, low eGFR and adverse glucose and lipid profiles. In addition, increased age, female gender, the eGFR and the MetS score were independently relevant factors that affected the systolic AR. Systolic within-visit BP variability and systolic AR are associated with cardiovascular risk factors.