BackgroundAngiotensinogen is the precursor of angiotensin II, which is associated with ischemia-reperfusion injury. Angiotensin II reduces liver regeneration after hepatectomy and causes dysfunction and failure of reduced-size liver transplants. However, the regulation of angiotensinogen during liver regeneration is still unclear.AimsTo investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.MethodsA mouse in vitro partial hepatectomy animal model was used to evaluate the expression of interleukin-6 (IL-6) and angiotensinogen during liver regeneration. Serum IL-6 and angiotensinogen were detected by enzyme immunoassay (EIA). Angiotensinogen mRNA was detected by RT-PCR. Tissue levels of angiotensinogen protein were detected by Western blot analysis. Primary cultures of mouse hepatocytes were used to investigate IL-6-induced angiotensinogen. Chemical inhibitors were used to perturb signal transduction pathways. Synthetic double-stranded oligodeoxynucleotides (ODNs) were used as ‘decoy’ cis-elements to investigate transcription. Ki 67 staining and quantification were used to verify liver regeneration.ResultsIn the in vivo model, the levels of serum IL-6 and angiotensinogen correlated. In the in vitro model, IL-6 transcriptionally regulated angiotensinogen expression. Additionally, IL-6 mediated angiotensinogen expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and JAK/p38 signaling. Decoy ODN analyses revealed that STAT3 and nuclear factor-kB (NF-kB) also played critical roles in the transcriptional regulation of angiotensinogen by IL-6. IL-6-mediated signaling, JAK2, STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice.ConclusionDuring liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the JAK/STAT3 and JAK/p38/NF-kB signaling pathways. Interruption of the molecular mechanisms of angiotensinogen regulation may be applied as the basis of therapeutic strategies for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.

Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) benefit advanced lung adenocarcinoma (ADC) patients harboring activating EGFR mutations. We aimed to identify biomarkers to monitor and predict the progression of patients receiving EGFR-TKIs via a comprehensive omic analysis. Methods:We applied quantitative proteomics to generate the TKI resistance-associated pleural effusion (PE) proteome from ADC patients with or without EGFR-TKI resistance. Candidates were selected from integrated genomic and proteomic datasets. The PE (n=33) and serum (n=329) levels of potential biomarkers were validated with enzyme-linked immunosorbent assays (ELISAs). Western blotting was applied to detect protein expression in tissues, PEs and a cell line. Gene knockdown, TKI treatment and proliferation assays were used to determine EGFR-TKI sensitivity. Progression-free survival (PFS) and overall survival (OS) were assessed to evaluate the prognostic values of the potential biomarkers.Results: Fifteen proteins were identified as potential biomarkers of EGFR-TKI resistance. Cadherin-3 (CDH3) was overexpressed in ADC tissues compared to Research.

Choledochal cysts are common in Asian children. Primary sclerosing cholangitis (PSC), which is characterized by inflammation and fibrosis and may lead to bile duct stricture over the intrahepatic or extrahepatic bile duct, is rare in children. Here we report a case of a 10-year-old boy who presented with a choledochal cyst originating from PSC. He had suffered from repeated abdominal pain and cholangitis for 3 years. A type IV choledochal cyst was suspected from the ultrasound and computed tomography image showing a distended gallbladder and dilatation of the bilateral intrahepatic duct at the hepatic hilar area and common bile duct (CBD). During laparotomy, a markedly distended gallbladder was noted and was shown to have no communication with the CBD by intraoperative cholangiogram. Choledochal cysts with extrahepatic and intrahepatic duct dilatation at the hilar area and marked stenosis with nearly total obstruction of the distal CBD were noted. Hepaticojejunostomy was performed. The histopathologic findings demonstrated a typical PSC picture. The patient's postoperative course was uneventful for 8 months after surgery, and he received no medication during a regular follow-up.

Epidermal growth factor receptor (EGFR) mutation is a predictor of the initial treatment efficacy of tyrosine kinase inhibitors (TKIs) in advanced lung adenocarcinoma (ADC). Unfortunately, neither EGFR mutations nor molecular markers can accurately monitor cancer progression or predict patient survival. EGFR‐TKI susceptibility‐associated biomarkers to benefit lung ADC patients are in high demand. Plural effusion (PE) has been recognized as a promising source for biomarker discovery. By integrating PE proteomic and tissue genomic analyses, we herein identified fifteen proteins as potential biomarkers of EGFR‐TKI resistance. Among these candidates, cadherin‐3 (CDH3) attracted our attention, as we observed that the CDH3 protein expression level was indeed positively correlated with malignancy as well as EGFR‐TKI resistance in our verified cancerous tissues, PEs and cell lines. Importantly, altered soluble CDH3 (sCDH3) levels in the serum could be used to monitor the efficacy of EGFR‐TKIs at one month after treatment. Furthermore, the baseline serum sCDH3 level was associated with progression‐free survival in ADC patients with mutant but not wild‐type EGFR. Finally, we observed that the baseline serum sCDH3 level was positively associated with tumor stage and overall survival in advanced non‐small cell lung cancer patients. Our results collectively establish a biomarker dataset for EGFR‐TKI resistance and sCDH3 is identified as a survival predictor and real‐time indicator of treatment efficacy in ADC patients received EGFR‐TKI therapy. Support or Funding Information Ministry of Science and Technology, Taiwan, R.O.C. (108‐2320‐B‐182‐007‐MY3) and Chang Gung Medical Research Fund (CORPD1J0091, CMRPD1H0081‐3, CMRPD1H0641‐2, CMRPD1H0082 and BMRP894).