Heshui Wu

Chronic pancreatitis and pancreatic cancer demonstrate active epithelial–mesenchymal transition profile, regulated by miR-217-SIRT1 pathway

Epithelial-mesenchymal transition (EMT) is supposed to be an inflammation induced response which may take a central role in tumorigenesis. Since recent evidence indicates that microRNAs may be involved in EMT, the present study set out to reveal the miRNA which might regulate the EMT in CP (chronic pancreatitis) and PC (pancreatic cancer) and its potential mechanism. Firstly, we provided evidence that both CP and PC tissues demonstrated active EMT profile. Consistently, miR-217 was obviously down-regulated in CP, PC and TGF-β1 treated PC cells, while negatively correlated to its direct target SIRT1. Moreover, either ectopic expression of miR-217 or inhibition of SIRT1 remarkably induced mesenchymal to epithelial transition (MET) in TGF-β1 treated PC cells. On the contrary, miR-217 inhibitor promoted EMT in PC cells but not in SIRT-knockdown PC cells. Clinical information from a cohort of 54 PC patients demonstrated that down-regulated miR-217 was positively correlated with late tumor stage, lymphatic invasion, vascular infiltration and distant metastasis. These results suggest that the overexpressed TGF-β1 in inflammation triggers the deregulation of the miR-217-SIRT1 pathway and then promotes the EMT process, which might be involved in the tumorigenesis of PC. Additionally, miR-217 may function as a novel target and predictor for PC prevention and therapy.

Effects of different resuscitation fluid on severe acute pancreatitis

AIM To compare effects of different resuscitation fluid on microcirculation, inflammation, intestinal barrier and clinical results in severe acute pancreatitis (SAP). METHODS One hundred and twenty patients with SAP were enrolled at the Pancreatic Disease Institute between January 2007 and March 2010. The patients were randomly treated with normal saline (NS group), combination of normal saline and hydroxyethyl starch (HES) (SH group), combination of normal saline, hydroxyethyl starch and glutamine (SHG group) in resuscitation. The ratio of normal saline to HES in the SH and SHG groups was 3:1. The glutamine (20% glutamine dipeptide, 100 mL/d) was supplemented into the resuscitation liquid in the SHG group. Complications and outcomes including respiratory and abdominal infection, sepsis, abdominal hemorrhage, intra-abdominal hypertension, abdominal compartment syndrome (ACS), renal failure, acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), operation intervention, length of intensive care unit stay, length of hospital stay, and mortality at 60 d were compared. Moreover, blood oxygen saturation (SpO2), gastric intramucosal pH value (pHi), intra-abdominal pressure (IAP), inflammation cytokines, urine lactulose/mannitol (L/M) ratio, and serum endotoxin were investigated to evaluate the inflammatory reaction and gut barrier. RESULTS Compared to the NS group, patients in the SH and SHG groups accessed the endpoint more quickly (3.9 ± 0.23 d and 4.1 ± 0.21 d vs 5.8 ± 0.25 d, P < 0.05) with less fluid volume (67.26 ± 28.53 mL/kg/d, 61.79 ± 27.61 mL/kg per day vs 85.23 ± 21.27 mL/kg per day, P < 0.05). Compared to the NS group, incidence of renal dysfunction, ARDS, MODS and ACS in the SH and SHG groups was obviously lower. Furthermore, incidence of respiratory and abdominal infection was significantly decreased in the SH and SHG groups, while no significant difference in sepsis was seen. Moreover, less operation time was needed in the SH and SHG group than the NS group, but the difference was not significant. The mortality did not differ significantly among these groups. Blood SpO2 and gastric mucosal pHi in the SH and SHG groups increased more quickly than in the NS group, while IAP was significantly decreased in the SH and SHG group. Moreover, the serum tumor necrosis factor-α, interleukin-8 and C-reactive protein levels in the SH and SHG groups were obviously lower than in the NS group at each time point. Furthermore, urine L/M ratio and serum endotoxin were significantly lower in the SH group and further decreased in the SHG group. CONCLUSION Results indicated that combination of normal saline, HES and glutamine are more efficient in resuscitation of SAP by relieving inflammation and sustaining the intestinal barrier.

Pancreaticoduodenectomy with Vascular Resection for Local Advanced Pancreatic Head Cancer: A Single Center Retrospective Study

IntroductionPancreaticoduodenectomy with vascular resection remains a controversial approach for patients with local advanced pancreatic head cancer for the lack of evidences of survival and quality of life benefits. The aim of this study was to evaluate whether patients of pancreatic head cancer benefit on quality of life, survival, and treatment cost from pancreaticoduodenectomy with vascular resection compared with palliative therapy.Materials and MethodsTwo hundred fourteen patients of pancreatic head cancer whose pancreatic head could not be dissected free from adjacent vascular were involved in this study. Eighty of these patients underwent pancreaticoduodenectomy with vascular resection, whereas other patients underwent palliative therapy.ResultsPancreaticoduodenectomy with artery resection offered worse outcomes on almost all aspects of quality of life and survival compared with palliative therapy. Pancreaticoduodenectomy with vein resection offered better 5-year survival compared with palliative therapy, whereas palliative therapy offered better quality of life after surgery.ConclusionPancreaticoduodenectomy with artery resection is nonsensical on treatment of pancreatic head cancer with artery adhesion/invasion. As for patients with vein adhesion/invasion, pancreaticoduodenectomy with vein resection should be performed cautiously. When actual vein invasion is very possible to have taken place, the choice of treatment strategy should be considered carefully by the pancreatic surgeons.

Use of probiotics in the treatment of severe acute pancreatitis: a systematic review and meta-analysis of randomized controlled trials

IntroductionNecrotic tissue infection can worsen the prognosis of severe acute pancreatitis (SAP), and probiotics have been shown to be beneficial in reducing the infection rate in animal experiments and primary clinical trials. However, the results of multicenter randomized clinical trials have been contradictory. Our aim in this study was to systematically review and quantitatively analyze all randomized controlled trials with regard to important outcomes in patients with predicted SAP who received probiotics.MethodsA systematic literature search of the PubMed, Embase and Cochrane Library databases was conducted using specific search terms. Eligible studies were randomized controlled trials that compared the effects of probiotic with placebo treatment in patients with predicted SAP. Mean difference (MD), risk ratio (RR) and 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel fixed- and random-effects models. A meta-analysis on the use of probiotics in the treatment of critically ill patients was also performed to serve as a reference.ResultsIn this study, 6 trials comprising an aggregate total of 536 patients were analyzed. Significant heterogeneities were observed in the type, dose, treatment duration and clinical effects of probiotics in these trials. Systematic analysis showed that probiotics did not significantly affect the pancreatic infection rate (RR = 1.19, 95% CI = 0.74 to 1.93; P = 0.47), total infections (RR = 1.09, 95% CI = 0.80 to 1.48; P = 0.57), operation rate (RR = 1.42, 95% CI = 0.43 to 3.47; P = 0.71), length of hospital stay (MD = 2.45, 95% CI = −2.71 to 7.60; P = 0.35) or mortality (RR = 0.72, 95% CI = 0.42 to 1.45; P = 0.25).ConclusionsProbiotics showed neither beneficial nor adverse effects on the clinical outcomes of patients with predicted SAP. However, significant heterogeneity was noted between the trials reviewed with regard to the type, dose and treatment duration of probiotics, which may have contributed to the heterogeneity of the clinical outcomes. The current data are not sufficient to draw a conclusion regarding the effects of probiotics on patients with predicted SAP. Carefully designed clinical trials are needed to validate the effects of particular probiotics given at specific dosages and for specific treatment durations.

Bmi-1 Promotes the Chemoresistance, Invasion and Tumorigenesis of Pancreatic Cancer Cells

Background/Aims: The polycomb protein Bmi-1 plays oncogenic roles in various cancers. Here we aimed to investigate the contribution of Bmi-1 on the malignant behaviors of pancreatic cancer such as chemoresistance, invasion and tumorigenesis. Methods and Results: The MTT cell proliferation assay showed that shRNA mediated Bmi-1 knockdown and enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine. The transwell invasion assay showed that Bmi-1 knockdown inhibited the invasion of pancreatic cancer cells in vitro. Notably, the reduced abilities of chemoresistance and invasion were associated with the transition from the mesenchymal phenotype to the epithelial phenotype of pancreatic cancer cells. Moreover, Bmi-1 knockdown led to the inhibition of the PI3K-Akt pathway and disrupted the sphere-forming abilities of pancreatic cancer cells. A nude mouse xenograft experiment demonstrated that pancreatic cancer cells depleted of Bmi-1 showed weak tumorigenicity in vivo. Conclusion: Our data suggest that Bmi-1 plays an important role in the progression of pancreatic cancer and represents a novel target for antitumor therapy of pancreatic cancer.

Gemcitabine treatment promotes pancreatic cancer stemness through the Nox/ROS/NF-κB/STAT3 signaling cascade

Gemcitabine, the standard chemotherapy drug for advanced pancreatic cancer, has shown limited benefits because of profound chemoresistance. However, the mechanism involved remains unclear. Cancer stem cells exhibit great tumorigenicity and are closely correlated with drug resistance and tumor relapse. In this study, we demonstrated that certain doses of gemcitabine increased the ratios of CD24+ and CD133+ cells and the expression of stemness-associated genes such as Bmi1, Nanog, and Sox2. The enhancement of stemness after gemcitabine treatment was accompanied by increased cell migration, chemoresistance, and tumorigenesis. Moreover, we found that gemcitabine promoted the binding of phosphorylated STAT3 to the promoter of Bmi1, Nanog, and Sox2 genes. Furthermore, inhibition of STAT3 partially reversed gemcitabine-induced sphere formation, migration, chemoresistance, and tumor relapse. We also demonstrated that the activation of STAT3 and gemcitabine-enhanced stemness was NADPH oxidase (Nox)-generated, ROS-dependent, and NF-κB partially mediated the process. Together, our results suggest a pivotal role of pancreatic cancer stem cells in developing chemoresistance toward gemcitabine treatment through the Nox/ROS/NF-κB/STAT3 signaling pathway. These findings will provide new insight for identifying potential targets that can be used to sensitize pancreatic cancer cells to chemotherapy.

PARP-1 Mediates LPS-Induced HMGB1 Release by Macrophages through Regulation of HMGB1 Acetylation

The high-mobility group box protein 1 (HMGB1) is increasingly recognized as an important inflammatory mediator. In some cases, the release of HMGB1 is regulated by poly(ADP-ribose) polymerase-1 (PARP-1), but the mechanism is still unclear. In this study, we report that PARP-1 activation contributes to LPS-induced PARylation of HMGB1, but the PARylation of HMGB1 is insufficient to direct its migration from the nucleus to the cytoplasm; PARP-1 regulates the translocation of HMGB1 to the cytoplasm through upregulating the acetylation of HMGB1. In mouse bone marrow–derived macrophages, genetic and pharmacological inhibition of PARP-1 suppressed LPS-induced translocation and release of HMGB1. Increased PARylation was accompanied with the nucleus-to-cytoplasm translocation and release of HMGB1 upon LPS exposure, but PARylated HMGB1 was located at the nucleus, unlike acetylated HMGB1 localized at the cytoplasm in an import assay. PARP inhibitor and PARP-1 depletion decreased the activity ratio of histone acetyltransferases to histone deacetylases that elevated after LPS stimulation and impaired LPS-induced acetylation of HMGB1. In addition, PARylation of HMGB1 facilitates its acetylation in an in vitro enzymatic reaction. Furthermore, reactive oxygen species scavenger (N-acetyl-l-cysteine) and the ERK inhibitor (FR180204) impaired LPS-induced PARP activation and HMGB1 release. Our findings suggest that PARP-1 regulates LPS-induced acetylation of HMGB1 in two ways: PARylating HMGB1 to facilitate the latter acetylation and increasing the activity ratio of histone acetyltransferases to histone deacetylases. These studies revealed a new mechanism of PARP-1 in regulating the inflammatory response to endotoxin.

Transcriptional upregulation of MT2-MMP in response to hypoxia is promoted by HIF-1α in cancer cells.

Hypoxia is a critical event in solid tumor development, invasion, and metastasis. Cellular adaptation to hypoxic microenvironment is essential for tumor progression and is largely mediated by hypoxia‐inducible factor‐1α (HIF‐1α) through coordinated regulation of hypoxia‐responsive genes. In this study, we found that membrane type‐2 matrix metalloproteinase (MT2‐MMP), one of the matrix metalloproteinase (MMP) family members, was a novel hypoxia‐responsive gene and was upregulated by HIF‐1α under hypoxia. When cancer cells were subjected to hypoxia (1% O2) treatment, the mRNA and protein levels of MT2‐MMP were significantly increased in a time‐dependent manner in all three tested cancer cell lines including pancreatic cancer cells (PANC‐1), nonsmall cell lung cancer cells (A‐549), and cervix cancer cells (HeLa). Further analyses indicated that there were two hypoxia‐responsive elements (HREs) in the MT2‐MMP promoter, and HRE1 but not HRE2 was essential for MT2‐MMP transcriptional activation under hypoxia. HIF‐1α specifically and directly bound to MT2‐MMP promoter was analyzed by HIF‐1α binding/competition and chromatin immunoprecipitation (ChIP) assays. Furthermore, we found that upregulation of MT2‐MMP under hypoxia could confer resistance to hypoxia‐induced apoptosis and increase invasiveness of cancer cells. These findings provided a new insight into how cancer cells overcome hypoxic stress and trend to survive and invade, demonstrated a new regulatory mechanism of MT2‐MMP expression in caner cells, and also revealed that MT2‐MMP was a novel hypoxia‐responsive gene and was upregulated by HIF‐1α under hypoxia.

Regulation of ω-3 fish oil emulsion on the SIRS during the initial stage of severe acute pancreatitis

The aim of this study was to explore the effects of parenteral supplementation with ω-3 fish oil emulsion (Omegaven®) on systemic inflammatory response syndrome (SIRS) during the initial stage of severe acute pancreatitis (SAP). In a prospective, randomized and controlled trial, 60 patients with SAP were randomized either to treat with conventional therapy (Con group, n=30) or conventional therapy plus intravenous supplementation with ω-3 fish oil emulsion 0.2 g/kg every day (FO group, n=30). The effects were analyzed by the SIRS-related indexes. The results showed that APACHE-II scores in FO group were significantly lower, and the gap increased much farther after the 4th day than those in Con group (P<0.05). Fluid equilibrium time became shorter markedly in FO group than in Con group (5.1±2.2 days vs 8.4±2.3 days). In FO group, SIRS scores were markedly decreased and the SIRS state vanished after the 4th day; Plasma level of TNF-α was significantly reduced, while IL-10 decreased markedly, most prominently between the 4th and 7th day, and the ratio of IL-10/TNF-α raised as compared with Con group (P<0.05). During the initial stage of SAP, parenteral supplementation with ω-3 fish oil emulsion could efficiently lower the magnitude and persistence time of the SIRS, markedly retrieve the unbalance of the pro-/anti-inflammatory cytokines, improve severe condition of illness and may provide a new way to regulate the SIRS.SummaryThe aim of this study was to explore the effects of parenteral supplementation with ω-3 fish oil emulsion (Omegaven®) on systemic inflammatory response syndrome (SIRS) during the initial stage of severe acute pancreatitis (SAP). In a prospective, randomized and controlled trial, 60 patients with SAP were randomized either to treat with conventional therapy (Con group, n=30) or conventional therapy plus intravenous supplementation with ω-3 fish oil emulsion 0.2 g/kg every day (FO group, n=30). The effects were analyzed by the SIRS-related indexes. The results showed that APACHE-II scores in FO group were significantly lower, and the gap increased much farther after the 4th day than those in Con group (P<0.05). Fluid equilibrium time became shorter markedly in FO group than in Con group (5.1±2.2 days vs 8.4±2.3 days). In FO group, SIRS scores were markedly decreased and the SIRS state vanished after the 4th day; Plasma level of TNF-α was significantly reduced, while IL-10 decreased markedly, most prominently between the 4th and 7th day, and the ratio of IL-10/TNF-α raised as compared with Con group (P<0.05). During the initial stage of SAP, parenteral supplementation with ω-3 fish oil emulsion could efficiently lower the magnitude and persistence time of the SIRS, markedly retrieve the unbalance of the pro-/anti-inflammatory cytokines, improve severe condition of illness and may provide a new way to regulate the SIRS.

Pylorus-Preserving Versus Pylorus-Resecting Pancreaticoduodenectomy for Periampullary and Pancreatic Carcinoma: A Meta-Analysis

Background The aim of this meta-analysis was to compare the long-term survival, mortality, morbidity and the operation-related events in patients with periampullary and pancreatic carcinoma undergoing pylorus-preserving pancreaticoduodenectomy (PPPD) and pylorus-resecting pancreaticoduodenectomy (PRPD). Method A systematic search of literature databases (Cochrane Library, PubMed, EMBASE and Web of Science) was performed to identify studies. Outcome measures comparing PPPD versus PRPD for periampullary and pancreatic carcinoma were long-term survival, mortality, morbidity (overall morbidity, delayed gastric emptying [DGE], pancreatic fistula, wound infection, postoperative bleeding, biliary leakage, ascites and gastroenterostomy leakage) and operation related events (hospital stays, operating time, intraoperative blood loss and red blood cell transfusions). Results Eight randomized controlled trials (RCTs) including 622 patients were identified and included in the analysis. Among these patients, it revealed no difference in long-term survival between the PPPD and PRPD groups (HR = 0.23, p = 0.11). There was a lower rate of DGE (RR = 2.35, p = 0.04, 95% CI, 1.06–5.21) with PRPD. Mortality, overall morbidity, pancreatic fistula, wound infection, postoperative bleeding, biliary leakage, ascites and gastroenterostomy leakage were not significantly different between the groups. PPPDs were performed more quickly than PRPDs (WMD = 53.25 minutes, p = 0.01, 95% CI, 12.53–93.97); and there was less estimated intraoperative blood loss (WMD = 365.21 ml, p = 0.006, 95% CI, 102.71–627.71) and fewer red blood cell transfusions (WMD = 0.29 U, p = 0.003, 95% CI, 0.10–0.48) in patients undergoing PPPD. The hospital stays showed no significant difference. Conclusions PPPD had advantages over PRPD in operating time, intraoperative blood loss and red blood cell transfusions, but had a significantly higher rate of DGE for periampullary and pancreatic carcinoma. PPPD and PRPD had comparable mortality and morbidity including pancreatic fistulas, wound infections, postoperative bleeding, biliary leakage, ascites and gastroenterostomy leakage. Our conclusions were limited by the available data. Further evaluations of high-quality RCTs are needed.