Le Lu

Twist promotes invasion and cisplatin resistance in pancreatic cancer cells through growth differentiation factor 15

Pancreatic cancer (PC) is an aggressive and devastating disease with a poor prognosis. Cisplatin, a commonly used chemotherapeutic agent for solid tumors, is effective as a single agent or in combination with other drugs for the treatment of PC. Previous studies have suggested that Twist and growth differentiation factor 15 (GDF15) are involved in the progression of PC. However, the role of Twist and GDF15 in PC remains to be elucidated. In the present study, the individual effect of and interaction between Twist and GDF15 in PC cell invasion and chemoresistance to cisplatin was examined. Twist and/or GDF15 were stably overexpressed or knocked down in ASPC‑1 and BXPC‑3 human PC cells. Overexpression of Twist in the two cell lines markedly increased GDF15 expression, cell invasion, matrix metalloproteinase‑2 expression/activity and the half maximal inhibitory concentration (IC50) values of cisplatin, which was eradicated by GDF15 knockdown or the selective p38 mitogen‑activated protein kinase (MAPK) inhibitor SB203580 (10 µM). By contrast, Twist knockdown significantly decreased GDF15 expression, cell invasion, matrix metalloproteinase‑2 expression/activity and the IC50 values of cisplatin, which was completely reversed by overexpression of GDF15. In addition, while overexpression and knockdown of Twist increased and decreased p38 MAPK activity, respectively, GDF15 demonstrated no significant effect on p38 MAPK activity in PC cells. In conclusion, the present study, for the first time, to the best of our knowledge, demonstrated that Twist promotes PC cell invasion and cisplatin chemoresistance through inducing GDF15 expression via a p38 MAPK‑dependent mechanism. The present study provides new insights into the molecular mechanisms underlying PC progression and chemoresistance.

Sequential vs simultaneous revascularization in patients undergoing liver transplantation: A meta-analysis.

AIM We undertook this meta-analysis to investigate the relationship between revascularization and outcomes after liver transplantation. METHODS A literature search was performed using MeSH and key words. The quality of the included studies was assessed using the Jadad Score and the Newcastle-Ottawa Scale. Heterogeneity was evaluated by the χ(2) and I (2) tests. The risk of publication bias was assessed using a funnel plot and Eggers test, and the risk of bias was assessed using a domain-based assessment tool. A sensitivity analysis was conducted by reanalyzing the data using different statistical approaches. RESULTS Six studies with a total of 467 patients were included. Ischemic-type biliary lesions were significantly reduced in the simultaneous revascularization group compared with the sequential revascularization group (OR = 4.97, 95%CI: 2.45-10.07; P < 0.00001), and intensive care unit (ICU) days were decreased (MD = 2.00, 95%CI: 0.55-3.45; P = 0.007) in the simultaneous revascularization group. Although warm ischemia time was prolonged in simultaneous revascularization group (MD = -25.84, 95%CI: -29.28-22.40; P < 0.00001), there were no significant differences in other outcomes between sequential and simultaneous revascularization groups. Assessment of the risk of bias showed that the methods of random sequence generation and blinding might have been a source of bias. The sensitivity analysis strengthened the reliability of the results of this meta-analysis. CONCLUSION The results of this study indicate that simultaneous revascularization in liver transplantation may reduce the incidence of ischemic-type biliary lesions and length of stay of patients in the ICU.

Association between FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphism and breast cancer susceptibility: a meta-analysis

The association between fibroblast growth factor receptor 2 (FGFR2) polymorphism and breast cancer (BC) susceptibility remains inconclusive. The purpose of this systematic review was to evaluate the relationship between FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphism and BC risk. PubMed, Web of science and the Cochrane Library databases were searched before October 11, 2015 to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of associations. Sensitivity and subgroup analyses were conducted. Thirty-five studies published from 2007 to 2015 were included in this meta-analysis. The pooled results showed that there was significant association between all the 3 variants and BC risk in any genetic model. Subgroup analysis was performed on rs2981582 and rs2420946 by ethnicity and Source of controls, the effects remained in Asians, Caucasians, population-based and hospital-based groups. We did not carryout subgroup analysis on rs2981578 for the variant included only 3 articles. This meta-analysis of case-control studies provides strong evidence that FGFR2 (rs2981582, rs2420946 and rs2981578) polymorphisms were significantly associated with the BC risk. For rs2981582 and rs2420946, the association remained significant in Asians, Caucasians, general populations and hospital populations. However, further large scale multicenter epidemiological studies are warranted to confirm this finding and the molecular mechanism for the association need to be elucidated further.

Comparison of simplified and traditional pericardial devascularisation combined with splenectomy for the treatment of portal hypertension

AIM To compare the clinical outcomes of patients with portal hypertension (PH) who underwent treatment with splenectomy plus simplified pericardial devascularisation (SSPD) or splenectomy plus traditional pericardial devascularisation (STPD). METHODS We conducted a single-centre retrospective study of 1045 PH patients treated with either SSPD (S Group, 357 patients) or STPD (T Group, 688 patients) between January 2002 and February 2017. In all, 37 clinical indicators were compared to evaluate the efficacy of SSPD. RESULTS Perioperative indicators in the S Group were significantly better than those in the T Group (P < 0.05). In both groups, the postoperative long-term portal vein diameter and Model for End-Stage Liver Disease score were significantly lower than those in the preoperative and postoperative short-term groups (P < 0.05). The incidence of complications in the S Group was significantly lower than that in the T Group (P < 0.05). Compared to the T Group, postoperative short-term WBC (white blood cell) and platelet counts were significantly lower and the short-term Hb (haemoglobin) level was significantly higher in the S Group (P < 0.05). In the S Group, postoperative long-term total bilirubin, direct bilirubin, alanine transaminase, and aspartate transaminase and postoperative serum creatinine and cystatin C levels were significantly lower than those in the T Group (P < 0.05), and postoperative albumin was significantly higher than that in the T Group (P < 0.05). CONCLUSION Compared to STPD, SSPD is a simple and easy procedure resulting in less tissue damage. Patients recovered smoothly and steadily with fewer complications. Short-term liver and kidney function damage was less severe, and long-term liver function recovery was better. Therefore, SSPD is worthy of clinical promotion and application for the treatment of PH.

Hepatic artery bridging lessens temporary ischemic injury to bile canaliculi

AIM To study whether transfer of blood between the right gastroepiploic artery and gastroduodenal artery could lessens the damage to bile canaliculi. METHODS Forty male Bama miniature pigs were divided into four groups as follows: a control group, two hepatic artery ischemia groups (1 h and 2 h), and a hepatic artery bridging group. The hemodynamics of the hepatic artery in the hepatic artery bridging group was measured using color Doppler ultrasound. Morphological changes in the bile canaliculus were observed by transmission electron microscopy. Cofilin, heat shock protein 27 and F-actin expression was detected by immunohistochemistry, Western blot, and real-time polymerase chain reaction. Terminal deoxynucleotidyl transferase-mediated nick end-labeling method was used to evaluate liver injury. RESULTS The hemodynamics was not changed in the hepatic artery bridging group. The microvilli in the bile canaliculus were impaired in the two hepatic artery ischemia groups. The down-regulation of cofilin and F-actin and up-regulation of heat shock protein 27 were observed in the two hepatic artery ischemia groups, while there were no significant differences between the control group and hepatic artery bridging group. CONCLUSION Hepatic artery ischemia aggravates damage to bile canaliculi, and this damage can be diminished by a hepatic artery bridging duct.

Delayed rearterialization unlikely leads to nonanastomotic stricture but causes temporary injury on bile duct after liver transplantation

Nonanastomotic strictures (NAS) are common biliary complications after liver transplantation (LT). Delayed rearterialization induces biliary injury in several hours. However, whether this injury can be prolonged remains unknown. The correlation of this injury with NAS occurrence remains obscure. Different delayed rearterialization times were compared using a porcine LT model. Morphological and functional changes in bile canaliculus were evaluated by transmission electron microscopy and real‐time PCR. Immunohistochemistry and TUNEL were performed to validate intrahepatic bile duct injury. Three months after LT was performed, biliary duct stricture was determined by cholangiography; the tissue of common bile duct was detected by real‐time PCR. Bile canaliculi were impaired in early postoperative stage and then exacerbated as delayed rearterialization time was prolonged. Nevertheless, damaged bile canaliculi could fully recover in subsequent months. TNF‐α and TGF‐β expressions and apoptosis cell ratio increased in the intrahepatic bile duct only during early postoperative period in a time‐dependent manner. No abnormality was observed by cholangiography and common bile duct examination after 3 months. Delayed rearterialization caused temporary injury to bile canaliculi and intrahepatic bile duct in a time‐dependent manner. Injury could be fully treated in succeeding months. Solo delayed rearterialization cannot induce NAS after LT.

Postoperative survival analysis and prognostic nomogram model for patients with portal hypertension

AIM To analyse the postoperative survival of patients with portal hypertension and determine the factors that influence survival and construct nomograms. METHODS We retrospectively followed 1045 patients who underwent splenectomy plus pericardial devascularisation (SPD) between January 2002 and December 2017. Two SPD types are used in our department: splenectomy plus simplified pericardial devascularisation (SSPD) and splenectomy plus traditional pericardial devascularisation (STPD). The Kaplan-Meier method and Cox regression analysis were used to evaluate the prognostic effects of multiple parameters on overall survival (OS), disease-specific survival (DSS) and bleeding-free survival (BFS). Significant prognostic factors were combined to build nomograms to predict the survival rate of individual patients. RESULTS Five hundred and fifty-seven (53.30%) patients were successfully followed with 192 in the SSPD group and 365 in the STPD group; 93 (16.70%) patients died, of whom 42 (7.54%) died due to bleeding. Postoperative bleeding was observed in 84 (15.10%) patients. The 5- and 10-year OS, DSS and BFS rates in the group of patients who underwent SSPD were not significantly different from those in patients who underwent STPD. Independent prognostic factors for OS were age, operative time, alanine transaminase level and albumin-bilirubin score. Independent prognostic factors for BFS were male sex, age, intraoperative blood loss and time to first flatus. Independent prognostic factors for DSS were the Comprehensive Complication Index and age. These characteristics were used to establish nomograms, which showed good accuracy in predicting 1-, 3- and 5-year OS and BFS. CONCLUSION SSPD achieves or surpasses the long-term survival effect of traditional pericardial devascularisation and is worthy of clinical promotion and application. Nomograms are effective at predicting prognosis.

Association between KIF1B (rs17401966) polymorphism and hepatocellular carcinoma susceptibility: a meta-analysis

Introduction The results of the earlier published studies on the association between KIF1B (rs17401966) polymorphism and hepatocellular carcinoma (HCC) risk are inconclusive. Hence, we performed this meta-analysis to evaluate the relationship between KIF1B (rs17401966) polymorphism and HCC risk. Methods Databases including PubMed, Web of Science and the Cochrane Library and bibliographies of relevant papers were screened to identify relevant studies published up to March 25, 2018. Pooled ORs and 95% CIs were calculated to evaluate the association. The subgroup analysis was conducted based on ethnicity, age, region and environment. A total of 19 studies from 11 eligible articles published from 2010 to 2016, with 8,741 cases and 10,812 controls, were included. Results The pooled results indicated that the association between KIF1B (rs17401966) polymorphism and the decreased HCC risk was significant. Subgroup analysis stratified by ethnicity showed the same association in Chinese, but not in non-Chinese population. When stratified by age, both old and young patients showed a decrease in HCC risk. When stratified by region, we detected the same association in Chinese in southern China. Similarly when stratified by environment, we observed the same association in Chinese in inland areas; however, no statistically significant association was observed in those in coastal areas. Conclusion This meta-analysis suggested that KIF1B (rs17401966) polymorphism could decrease HCC risk in Chinese and in overall population, but not in non-Chinese. This association remained significant in Chinese in southern China and inland areas, but not in those in northern and central China and coastal areas. Further large-scale multicenter studies are warranted to confirm these findings.

Association between rs11200014, rs2981579, and rs1219648 polymorphism and breast cancer susceptibility: A meta-analysis

Background: Research on the polymorphism of breast cancer (BC) helps to search the BC susceptibility gene for mass screening, early diagnosis, and gene therapy, which has become a hotspot in BC research field. Previous studies have suggested associations between rs11200014, rs2981579, and rs1219648 polymorphisms and cancer risk. The aim of this study was to evaluate the relationship between rs11200014, rs2981579, and rs1219648 polymorphism and BC risk. Methods: PubMed, Web of science, and the Cochrane Library databases were searched before October 11, 2015, to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of associations. Sensitivity and subgroup analyses were conducted. All included cases should have been diagnosed by a pathological examination. Results: Twenty-six studies published from 2007 to 2015 were included in this meta-analysis. The pooled results showed that there was a significant association between all the 3 variants and BC risk in any genetic model. When stratified by Source of controls, the results showed the same association between rs2981579 polymorphism and BC susceptibility in hospital-based (HB) group, although there was not any genetic model attained statistical correlation in population-based (PB) group. Subgroup analysis was performed on rs1219648 by ethnicity and Source of controls, and the effects remained in Asians, Caucasians, HB, and PB groups. Conclusion: This meta-analysis of case–control studies provides strong evidence that fibroblast growth factor 2 (FGFR2; rs11200014, rs2981579, and rs1219648) polymorphisms are significantly associated with the BC risk. For rs2981579, the association remained in hospital populations, while not in general populations. For rs1219648, the association remained in Asians, Caucasians, hospital populations, and general populations. However, further large-scale multicenter epidemiological studies are warranted to confirm this finding and the molecular mechanism for the associations need to be elucidated in future studies.

Effect of HSP27 and Cofilin in the injury of hypoxia/reoxygenation on hepatocyte membrane F-actin microfilaments

Abstract Hypoxia–reoxygenation (H/R) injury hepatocyte models were established to simulate the ischemia/reperfusion injury of transplanted organ. Through the study of the molecular mechanism of H/R on the F-actin damage of the liver cytomembrane, the mechanism of F-actin damage induced by ischemia and reperfusion was studied from the level of cell and molecule. The hypoxic environment of cells in vitro was simulated by chemical hypoxia agent CoCl2. Liver cells were detected by MTT, H/R group was subdivided into 3 subgroups: H/R 2, 4, and 6 h. Changes of cell shape and the growth state, apoptosis, ultrastructural changes, and the changes in F-actin microfilament content were observed. Heat shock protein 27 (HSP27), Cofilin, and F-actin gene and protein levels were determined by real-time polymerase chain reaction and western blot assay, respectively. Cells showed circular adherence growth under normal circumstances, while the spindle cells and shedding cells were significantly increased in H/R groups. Apoptosis cells in H/R group were increased significantly with the extension of hypoxia time. The number of endoplasmic reticulum was decreased significantly in the H/R group, the mitochondrion hydropic was degenerated and the glycogen was disappeared. The F-actin fibers in the H/R group were disordered, the morphology of the fibers was obviously decreased, and the fluorescence staining decreased obviously (P < .05). The transcription and expression levels of HSP27, Cofilin, and F-actin were significantly lower than those in the control group (P < .05). These results demonstrate that H/R can affect the correct assembly of F-actin microfilaments and weakens the normal cycle of F-actin microfilaments through inhibiting the protein expression and gene transcription of HSP27 and Cofilin in hepatocytes, thereby changing the skeleton of F-actin microfilaments.