Kenta Shinozaki

Interaction of the hepatitis B virus X protein with the lysine methyltransferase SET and MYND domain-containing 3 induces activator protein 1 activation

Hepatitis B virus (HBV) is a widespread human pathogen that often causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The detailed mechanisms underlying HBV pathogenesis remain poorly understood. The HBV X protein (HBx) is a multifunctional regulator that modulates viral replication and host cell functions, such as cell cycle progression, apoptosis and protein degradation through interaction with a variety of host factors. Recently, the nonstructural protein 5A (NS5A) of hepatitis C virus has been reported to interact with methyltransferase SET and MYND domain‐containing 3 (SMYD3), which is implicated in chromatin modification and development of cancer. Because HBx shares fundamental regulatory functions concerning viral replication and pathogenesis with NS5A, it was decided to examine whether HBx interacts with SMYD3. In the present study, it was demonstrated by co‐immunoprecipitation analysis that HBx interacts with both ectopically and endogenously expressed SMYD3 in Huh‐7.5 cells. Deletion mutation analysis revealed that the C‐terminal region of HBx (amino acids [aa] 131–154) and an internal region of SMYD3 (aa 269–288) are responsible for their interaction. Immunofluorescence and proximity ligation assays showed that HBx and SMYD3 co‐localize predominantly in the cytoplasm. Luciferase reporter assay demonstrated that the interaction between HBx and SMYD3 activates activator protein 1 (AP‐1) signaling, but not that of nuclear factor‐kappa B (NF‐κB). On the other hand, neither overexpression nor knockdown of SMYD3 altered production of HBV transcripts and HBV surface antigen (HBsAg). In conclusion, a novel HBx‐interacting protein, SMYD3, was identified, leading to proposal of a novel mechanism of AP‐1 activation in HBV‐infected cells.

Preoperative Cholangitis Affects Survival Outcome in Patients with Extrahepatic Bile Duct Cancer

BackgroundIt remains controversial whether preoperative cholangitis affects long-term outcomes after resection in patients with extrahepatic bile duct cancer.MethodsA total of 107 patients with extrahepatic bile duct cancer who underwent resection with curative intent from 2008 to 2014 were retrospectively reviewed. Patients were categorized into two groups according to the presence or absence of preoperative cholangitis. Clinicopathological variables and long-term outcomes were compared in the two groups.ResultsIn the preoperative cholangitis group, the rate of preoperative biliary drainage, the number of tube changes and/or additions, and the rate of lymph node metastasis were higher compared to the no-cholangitis group. Overall survival and disease-free survival were significantly worse in the cholangitis group compared to the no-cholangitis group (p = 0.022, p = 0.007). A poorer prognosis was not observed with an increasing grade of cholangitis in Tokyo Guidelines 2013 (p = 0.09). A multivariate logistic regression analysis revealed that the preoperative cholangitis was an independent prognostic factor for extrahepatic bile duct cancer.ConclusionPreoperative cholangitis is an independent prognostic factor in patients with extrahepatic bile duct cancer regardless of the severity of the cholangitis.

Gallbladder bed pocket score as a preoperative measure for assessing the difficulty of laparoscopic cholecystectomy

Laparoscopic cholecystectomy (Lap‐C) is a standard surgery for symptomatic gallbladder stones and acute or chronic cholecystitis. Resident surgeons often perform this operation early in their training, but they sometimes encounter difficulties for various technical reasons. Although encountering a gallbladder buried deep within the gallbladder bed is a common operative difficulty, literature on the subject scarcely exists.

Clinical significance of bile reflux into the pancreatic duct without pancreaticobiliary maljunction assessed by intraoperative cholangiography

Bile reflux into the pancreatic duct (BRPD) is sometimes demonstrated during intraoperative cholangiography (IOC) even in patients without pancreaticobiliary maljunction. However, the clinical significance of this finding in laparoscopic and open cholecystectomy is unclear.