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Baoxiong Zhuang,1,* Zhihua Li,1,* Jiadong Pang,2,* Wenbin Li,1 Pinbo Huang,1 Jie Wang,1 Yu Zhou,1 Qing Lin,1 Quanbo Zhou,1 Xiao Ye,1 Huilin Ye,1 Yimin Liu,1 Li-Ming Zhang,2 Rufu Chen1 1Department of Hepato-Pancreato-Billiary Surgery, Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2DSAPM Lab and PCFM Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, People’s Republic of China *Authors share co-first authorship Abstract: As a topical hemostatic agent, thrombin has wide application for many surgical treatments. However, native thrombin always suffers from its physical and chemical instabilities. In this work, a nanocomplexation strategy was developed for modifying the stability and hemostatic efficacy of thrombin, in which a water-soluble cationic amylose derivative containing poly(l-lysine) dendrons was prepared by a click reaction and then used to complex thrombin in an aqueous system. For resultant thrombin nanocomplexes, their morphology and particle size distribution were investigated. Their stabilities were studied in terms of activity retention percentages under different storage time, pH values, and illumination time. In addition, their ability to achieve in vitro fibrinogen and blood coagulation were evaluated. Via a rat hepatic hemorrhage model and a rat iliac artery hemorrhage model, these thrombin nanocomplexes were confirmed to have good tissue biocompatibility and in vivo hemostatic effectiveness. Keywords: thrombin, nanoparticles, amylose derivative, complexation, stability, hemostatic activity

Baoxiong Zhuang,1,* Zhihua Li,1,* Jiadong Pang,2,* Wenbin Li,1 Pinbo Huang,1 Jie Wang,1 Yu Zhou,1 Qing Lin,1 Quanbo Zhou,1 Xiao Ye,1 Huilin Ye,1 Yimin Liu,1 Li-Ming Zhang,2 Rufu Chen1 1Department of Hepato-Pancreato-Billiary Surgery, Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2DSAPM Lab and PCFM Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, People’s Republic of China *Authors share co-first authorship Abstract: As a topical hemostatic agent, thrombin has wide application for many surgical treatments. However, native thrombin always suffers from its physical and chemical instabilities. In this work, a nanocomplexation strategy was developed for modifying the stability and hemostatic efficacy of thrombin, in which a water-soluble cationic amylose derivative containing poly(l-lysine) dendrons was prepared by a click reaction and then used to complex thrombin in an aqueous system. For resultant thrombin nanocomplexes, their morphology and particle size distribution were investigated. Their stabilities were studied in terms of activity retention percentages under different storage time, pH values, and illumination time. In addition, their ability to achieve in vitro fibrinogen and blood coagulation were evaluated. Via a rat hepatic hemorrhage model and a rat iliac artery hemorrhage model, these thrombin nanocomplexes were confirmed to have good tissue biocompatibility and in vivo hemostatic effectiveness. Keywords: thrombin, nanoparticles, amylose derivative, complexation, stability, hemostatic activity

Background: An increasing incidence of cholangiocarcinoma (CCA) and CCA mortality rates has been observed around the world. Patients with intrahepatic biliary stones have a 10% risk of developing CCA, and up to 70% of patients with histologically confirmed CCA have hepatolithiasis. Few previous studies have addressed the associations between the expression of nuclear factor (NF)-κB and epidermal growth factor receptor (EGFR) and clinicopathological prognosis in patients with hepatolithiasis-associated intrahepatic CCA. Aims: This study was designed to investigate the clinicopathological and prognostic significance of NF-κB and EGFR expression in hepatolithiasis-associated intrahepatic CCA and hepatolithiasis. Methods: A total of 90 liver specimens were immunohistochemically stained for NF-κB and EGFR expression, and the characteristics of 90 individual patients were retrospectively reviewed. Results: Differences in the positive rates of NF-κB and EGFR expression between the hepatolithiasis-associated intrahepatic CCA group, intrahepatic lithiasis group, and control group were found to be statistically significant. EGFR expression was closely associated with the degree of differentiation and depth of invasion (p < 0.05). The 1-, 3-, and 5-year overall survival rates were respectively 42.8, 21.0, and 10.3% in intrahepatic CCA groups. The survival rate of the EGFR-negative group was higher than in the EGFR-positive group (p < 0.01). Lymph node metastasis (HR 1.24, 95% CI 1.02-1.51) and EGFR positivity (HR 1.74, 95% CI 1.30-2.23) were associated with decreases in the survival rate. Conclusion: The expression of NF-κB may be an early step in intrahepatic cholangiocarcinogenesis. Overexpression of EGFR is associated with the degree of malignancy and with poor prognosis. NF-κB and EGFR may cooperate during intrahepatic cholangiocarcinogenesis and progression. Lymph node metastasis and EGFR positivity were associated with decreases in the survival rate. © 2013 S. Karger AG

Little is known about the role of association between ABO blood group and development of extrahepatic cholangiocarcinoma (ECC) through effects on hepatitis B viral (HBV) infection. Our aim was to address this question using a matched case-control study in Southern China.We prospectively analyzed 239 ECC patients, and 478 age- and sex-matched controls in Sun Yat-sen Memorial Hospital of Sun Yat-sen University from 1999 to 2011. Information on ABO blood group, HBV infection and other clinicopathologic factors was collected. Adjusted odds ratios (AORs) and the corresponding 95% confidence intervals (CIs) were computed from unconditional logistic regression models, adjusted for major confounding factors. The estimated AORs were as follows: A blood group, 1.784; HBsAg+/HbcAb+, 1.848 and HBsAg-/HbcAb+, 1.501. The A blood type had a significant effect on modifying the risk of ECC among subjects with HBsAg+/HbcAb+ (AOR 3.795, 95% CI 1.427-10.090). ECC patients with A blood group were more common in younger subjects, and a lower proportion of serum CA-125 and CA19-9 elevation in patients with blood type A was found. Our study suggests an association between A blood type, HBV infection and ECC risk, and a synergism between A blood type and HBV infection in the development of ECC. What's new? Hepatitis B virus (HBV) infection is a suspected risk factor for extrahepatic cholangiocarcinoma (ECC), though how it gives rise to malignant disease of the bile ducts situated outside the liver is unclear. Here, a significant association was found for HBV infection, A blood type, and ECC risk in the Han Chinese ethnic group of Southern China. Compared with non-A blood group ECC patients, type A ECC patients tended to be younger and had lower CA-125 and CA19-9 levels. The study is the first to confirm an association between A blood group, HBV, and ECC risk. Copyright © 2013 UICC.

Little is known about the role of association between ABO blood group and development of extrahepatic cholangiocarcinoma (ECC) through effects on hepatitis B viral (HBV) infection. Our aim was to address this question using a matched case-control study in Southern China.We prospectively analyzed 239 ECC patients, and 478 age- and sex-matched controls in Sun Yat-sen Memorial Hospital of Sun Yat-sen University from 1999 to 2011. Information on ABO blood group, HBV infection and other clinicopathologic factors was collected. Adjusted odds ratios (AORs) and the corresponding 95% confidence intervals (CIs) were computed from unconditional logistic regression models, adjusted for major confounding factors. The estimated AORs were as follows: A blood group, 1.784; HBsAg+/HbcAb+, 1.848 and HBsAg-/HbcAb+, 1.501. The A blood type had a significant effect on modifying the risk of ECC among subjects with HBsAg+/HbcAb+ (AOR 3.795, 95% CI 1.427-10.090). ECC patients with A blood group were more common in younger subjects, and a lower proportion of serum CA-125 and CA19-9 elevation in patients with blood type A was found. Our study suggests an association between A blood type, HBV infection and ECC risk, and a synergism between A blood type and HBV infection in the development of ECC. What's new? Hepatitis B virus (HBV) infection is a suspected risk factor for extrahepatic cholangiocarcinoma (ECC), though how it gives rise to malignant disease of the bile ducts situated outside the liver is unclear. Here, a significant association was found for HBV infection, A blood type, and ECC risk in the Han Chinese ethnic group of Southern China. Compared with non-A blood group ECC patients, type A ECC patients tended to be younger and had lower CA-125 and CA19-9 levels. The study is the first to confirm an association between A blood group, HBV, and ECC risk. Copyright © 2013 UICC.

Little is known about the role of association between ABO blood group and development of extrahepatic cholangiocarcinoma (ECC) through effects on hepatitis B viral (HBV) infection. Our aim was to address this question using a matched case-control study in Southern China.We prospectively analyzed 239 ECC patients, and 478 age- and sex-matched controls in Sun Yat-sen Memorial Hospital of Sun Yat-sen University from 1999 to 2011. Information on ABO blood group, HBV infection and other clinicopathologic factors was collected. Adjusted odds ratios (AORs) and the corresponding 95% confidence intervals (CIs) were computed from unconditional logistic regression models, adjusted for major confounding factors. The estimated AORs were as follows: A blood group, 1.784; HBsAg+/HbcAb+, 1.848 and HBsAg-/HbcAb+, 1.501. The A blood type had a significant effect on modifying the risk of ECC among subjects with HBsAg+/HbcAb+ (AOR 3.795, 95% CI 1.427-10.090). ECC patients with A blood group were more common in younger subjects, and a lower proportion of serum CA-125 and CA19-9 elevation in patients with blood type A was found. Our study suggests an association between A blood type, HBV infection and ECC risk, and a synergism between A blood type and HBV infection in the development of ECC. What's new? Hepatitis B virus (HBV) infection is a suspected risk factor for extrahepatic cholangiocarcinoma (ECC), though how it gives rise to malignant disease of the bile ducts situated outside the liver is unclear. Here, a significant association was found for HBV infection, A blood type, and ECC risk in the Han Chinese ethnic group of Southern China. Compared with non-A blood group ECC patients, type A ECC patients tended to be younger and had lower CA-125 and CA19-9 levels. The study is the first to confirm an association between A blood group, HBV, and ECC risk. Copyright © 2013 UICC.

Purpose To investigate the association between gastrectomy and risk of pancreatic cancer (PaC). Methods We identified eligible studies in Medline and EMBASE up to 11 February 2012 and the reference lists of original studies and review articles on this topic. Summary relative risks with their 95 % confidence intervals were calculated with a random-effects model. Between-study heterogeneity was assessed using Cochran Q and I2 statistics. Results Fifteen studies (11 case-control studies and 4 cohort studies) met eligibility criteria. The current data suggest that gastrectomy is associated with a 54 % excess risk of PaC (SRRs = 1.54; 95 % CI, 1.25-1.90; test for heterogeneity Q = 17.94, p<0.001, I2 = 22 %). There was no publication bias in the present meta-analysis. Conclusion A significant increased risk of PaC exists in patients who have undergone gastrectomy, particularly those receiving Billroth II resection with a long postoperative interval. © Springer Science+Business Media B.V. 2012.

Hepatitis C Virus core protein (HCVc) plays important roles in the development of intrahepatic cholangiocarcinoma (ICC). MicroRNAs (miRNAs) contribute to tumor progression by interacting with downstream target genes. However, the regulation and role of miRNAs in HCV-related intrahepatic cholangiocarcinoma (HCV-ICC) is poorly understood. In this study, we found that miR-124 was down-regulated in HCV-ICC and the induction of DNMT1 by HCVc mediated the suppression of miR-124. Over-expression of miR-124 suppressed cell migration and invasion in vitro, and reduced the protein levels of SMYD3 and downstream target genes (c-Myc and MMP9). Knockdown of SMYD3 inhibited cell migration and invasion resembling that of miR-124 over-expression. In conclusion, our studies indicate that low miR-124 levels mediated by HCVc via DNMT1 promote ICC cell migration and invasion by targeting SMYD3. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Purpose To investigate the association between gastrectomy and risk of pancreatic cancer (PaC). Methods We identified eligible studies in Medline and EMBASE up to 11 February 2012 and the reference lists of original studies and review articles on this topic. Summary relative risks with their 95 % confidence intervals were calculated with a random-effects model. Between-study heterogeneity was assessed using Cochran Q and I2 statistics. Results Fifteen studies (11 case-control studies and 4 cohort studies) met eligibility criteria. The current data suggest that gastrectomy is associated with a 54 % excess risk of PaC (SRRs = 1.54; 95 % CI, 1.25-1.90; test for heterogeneity Q = 17.94, p<0.001, I2 = 22 %). There was no publication bias in the present meta-analysis. Conclusion A significant increased risk of PaC exists in patients who have undergone gastrectomy, particularly those receiving Billroth II resection with a long postoperative interval. © Springer Science+Business Media B.V. 2012.

Hepatitis C Virus core protein (HCVc) plays important roles in the development of intrahepatic cholangiocarcinoma (ICC). MicroRNAs (miRNAs) contribute to tumor progression by interacting with downstream target genes. However, the regulation and role of miRNAs in HCV-related intrahepatic cholangiocarcinoma (HCV-ICC) is poorly understood. In this study, we found that miR-124 was down-regulated in HCV-ICC and the induction of DNMT1 by HCVc mediated the suppression of miR-124. Over-expression of miR-124 suppressed cell migration and invasion in vitro, and reduced the protein levels of SMYD3 and downstream target genes (c-Myc and MMP9). Knockdown of SMYD3 inhibited cell migration and invasion resembling that of miR-124 over-expression. In conclusion, our studies indicate that low miR-124 levels mediated by HCVc via DNMT1 promote ICC cell migration and invasion by targeting SMYD3. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Purpose To investigate the association between gastrectomy and risk of pancreatic cancer (PaC). Methods We identified eligible studies in Medline and EMBASE up to 11 February 2012 and the reference lists of original studies and review articles on this topic. Summary relative risks with their 95 % confidence intervals were calculated with a random-effects model. Between-study heterogeneity was assessed using Cochran Q and I2 statistics. Results Fifteen studies (11 case-control studies and 4 cohort studies) met eligibility criteria. The current data suggest that gastrectomy is associated with a 54 % excess risk of PaC (SRRs = 1.54; 95 % CI, 1.25-1.90; test for heterogeneity Q = 17.94, p<0.001, I2 = 22 %). There was no publication bias in the present meta-analysis. Conclusion A significant increased risk of PaC exists in patients who have undergone gastrectomy, particularly those receiving Billroth II resection with a long postoperative interval. © Springer Science+Business Media B.V. 2012.

Hepatitis C Virus core protein (HCVc) plays important roles in the development of intrahepatic cholangiocarcinoma (ICC). MicroRNAs (miRNAs) contribute to tumor progression by interacting with downstream target genes. However, the regulation and role of miRNAs in HCV-related intrahepatic cholangiocarcinoma (HCV-ICC) is poorly understood. In this study, we found that miR-124 was down-regulated in HCV-ICC and the induction of DNMT1 by HCVc mediated the suppression of miR-124. Over-expression of miR-124 suppressed cell migration and invasion in vitro, and reduced the protein levels of SMYD3 and downstream target genes (c-Myc and MMP9). Knockdown of SMYD3 inhibited cell migration and invasion resembling that of miR-124 over-expression. In conclusion, our studies indicate that low miR-124 levels mediated by HCVc via DNMT1 promote ICC cell migration and invasion by targeting SMYD3. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.