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Yu Zhang,1,2,* Xiao Xi Zhang,3,* Rui Yan Yuan,1,4,* Tai Ren,1,4 Zi Yu Shao,1,4 Hong Fei Wang,1,4 Wei Long Cai,5 Li Tian Chen,1,4 Xu An Wang,4 Ping Wang2 1Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, People’s Republic of China; 2Department of General Surgery, Hangzhou First People’s Hospital, Hangzhou 310006, People’s Republic of China; 3Shanghai Health Development Research Center, Shanghai 200040, People’s Republic of China; 4Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, People’s Republic of China; 5Department of General Surgery, Huzhou Central Hospital, Zhejiang 313000, People’s Republic of China *These authors contributed equally to this work Background: Cordycepin, the main active ingredient of a traditional Chinese herbal remedy – extracted from Cordyceps sinensis – has been demonstrated as a very effective anti-inflammatory and antitumor drug. The present study investigated its antitumor effect on pancreatic cancer, a highly aggressive cancer with extremely poor prognosis due to malignancy, and clarified its underlying mechanism both in vitro and in vivo. Methods: The antitumor viability of cordycepin on human pancreatic cancer MIAPaCa-2 and Capan-1 cells was determined by colony formation assays. Annexin V/PI double staining and flow cytometry assay were used to investigate whether cordycepin induced apoptosis and cell cycle arrest. The mitochondrial membrane potential (ΔΨm) was analyzed by Rhodamine 123 staining, and expression of related proteins evaluated by Western blot and immunohistochemistry, both on pancreatic cancer cells and tumor xenografts to reveal the potential mechanism for the effect of cordycepin. Furthermore, the in vivo efficacy was examined on nude mice bearing MIAPaCa-2 cell tumors treated by intraperitoneal injection of cordycepin (0, 15, and 50 mg/kg/d) for 28 days. Results: Cordycepin inhibited cell viability, proliferation and colony formation ability and induced cell cycle arrest and early apoptosis of human pancreatic cancer cells (MIAPaCa-2 and Capan-1) in a dose- and time-dependent manner. The same effect was also observed in vivo. Decrease of ΔΨm and upregulation of Bax, cleaved caspase-3, cleaved caspase-9, and cleaved PARP as well as downregulation of Bcl-2 both in vitro and in vivo indicated that the mitochondria-mediated intrinsic pathway was involved in cordycepin’s antitumor effect. Conclusion: Our data showed that cordycepin inhibited the activity of pancreatic cancer both in vitro and in vivo by regulating apoptosis-related protein expression through the mitochondrial pathway and suggest that cordycepin may be a promising therapeutic option for pancreatic cancer. Keywords: cordycepin, pancreatic cancer, proliferation, apoptosis, mitochondrial pathway

A seroepidemiological study of hepatitis E virus (HEV) infection was conducted in Japan, where HEV infection is not considered endemic. Methods. IgG and IgM class antibodies to HEV were measured with a newly developed enzyme-linked immunosorbent assay in which recombinant virus-like particles were used as an antigen. A total of 1253 individuals (401 males and 852 females; age range, 6–89 years) were enrolled from two different areas: area 1 (n = 478), in which hepatitis C was endemic; and area 2 (n = 775), in which it was not endemic. Results. The HEV antibody (IgG class) positive rate was 6.7% in area 1 and 4.6% in area 2. Similarly, the HAV antibody (IgG class) positive rates were 65.3% and 72.3%. The age- and sex-specific prevalence of both HAV and HEV antibodies was quite similar in the two areas, and the HAV antibody positive rate clearly increased with age in both males and females. On the other hand, the HEV antibody positive rate showed a slight tendency to increase with age in males, but not in females. None of the 32 individuals with the HEV antibody who were interviewed had a history of visiting countries in which hepatitis E was endemic. In both areas, the mean age, percentage of males, and HAV antibody positive rate were significantly higher in the group of individuals with the HEV antibody than in the group of those without it, according to conventional statistical analyses. Of the three factors age, male sex, presence of HAV antibody, and the area factor, only male sex was statistically significant (P < 0.001) on multivariate logistic regression analysis. Two (0.2%) of the total of 1253 individuals were positive for the IgM class antibody to HEV. Conclusions. Our results suggest the possibility that HEV infection is circulating in Japan at a low level. HEV infection was associated with male sex, but not with HAV infection.

Objective: The study aim was to explore the role of DEK in tumor progression and prognostic of hepatocellular carcinoma (HCC). Methodology: DEK protein in 178 samples of HCC was evaluated by immunohistochemical method. Additionally, the correlation between DEK expression and the clinicopathological features was evaluated by x 2 test or Fisher’s exact test, the survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also by the Cox analysis. Results: DEK protein expression was noted in 86 cases of HCC, and 61 cases of normal liver tissues. DEK positive rate were closely correlated with the tumor size, grade, AJCC stage and survival rate (P < 0.05, respectively). HCC with large tumor, lower grade, and late-stage, concomitant with DEK expression, had the lowest 5-years survival rate than HCC with above factors but without DEK expression (P < 0.01, respectively). DEK expression emerged as significant independent hazard factors for survival in HCC (P < 0.01). Conclusions: DEK could promote aggressiveness of cancer behavior, and hence poor prognosis of the HCC. It might be an independent poor prognostic factor and can serve as a useful new therapeutic biomarker.

Ezrin is involved in maintaining cell structure and cell motility. Expression levels of the ezrin gene correlate with numerous human malignancies. The aim of this study was to explore the role of ezrin in tumor progression and the prognostic evaluation of colorectal adenocarcinoma (CRA). The levels of ezrin protein in 186 CRA samples were evaluated using immunohistochemistry. Furthermore, the correlation between the expression of ezrin and the clinicopathological features of CRA was evaluated with the χ2 and Fisher's exact tests, survival rates were calculated using the Kaplan-Meier method, and the correlation between prognostic factors and patient survival was calculated by Cox analysis. Ezrin protein expression demonstrated an immunohistochemical cytoplasmic staining pattern in CRA. The difference between the positive rate of ezrin expression in CRA (38.7%, 72/186) and the adjacent normal mucosal tissues was deemed to be statistically significant (91.9%, 171/186; P=0.000). The positive rate of ezrin expression in cases with a large tumor, serosal invasion, lymph node (LN) metastasis, high LN ratio (LNR) and at a late tumor stage was significantly lower than in cases without these factors (P=0.044, P=0.032, P=0.002, P=0.011 and P=0.000, respectively). The 5-year survival rate of CRA without ezrin expression was lower than CRA with expression (P=0.000). Furthermore, analysis by Kaplan-Meier demonstrated that CRA cases with poor differentiation, serosal invasion and at a late tumor stage combined with no ezrin expression had a lower survival rate than cases that had these factors plus ezrin expression (P=0.000, respectively). Additionally, the non-expression of ezrin emerged as a significant independent prognostic factor in CRA prognosis (HR, 0.562; 95% CI, 0.404-0.783; P=0.001), in addition to the LNR (HR, 0.589; 95% CI, 0.369-0.939; P=0.026) and tumor stage (HR, 0.655; 95% CI, 0.487-0.880; P=0.005). This study demonstrated that ezrin may be useful to identify at-risk patients who may benefit from a more aggressive adjuvant therapy following tumor resection. Ezrin may serve as a useful therapeutic biomarker.

The study aims to explore the expression of IMP3 in HCC and the correlation between its expression and prognosis.We collected several clinical and pathological files including 92 cases of HCC and 58 cases of adjacent liver tissues. Expression of IMP3 in these tissues was detected by immunohistochemistry, while compared with clinicopathological characteristics and expression of Ki-67. A χ2 test was used to analyze the relationship between expression of IMP3 and clinicοpathologic factors. The Kaplan-Meier survival curve was used to calculate survival rate. A Cox analysis was used to evaluate the relationship between index and patients’ lifetime.The positive rate of IMP3 in HCC tissues was significantly higher than that in adjacent tissues. The expression of IMP3 was related to the histological differentiation of HCC, metastasis, the stage of ACJJ, the expression of Ki-67 and survival. The ACJJ stage, metastases and the expression of IMP3 were independent factors for the HCC patients’ survival.IMP3, which is associated with tumor formation, invasion, tumor cell proliferation and so on, may become the target for inhabiting cell proliferation and the biomarker for predicting prognosis.