Yanbing Ding

Intratumor Hypoxia Promotes Immune Tolerance by Inducing Regulatory T Cells via TGF-β1 in Gastric Cancer

Regulatory T cell (Treg)-mediated immunosuppression represents one of the crucial tumor immune evasion mechanisms and is a main obstacle for successful tumor immunotherapy. Hypoxia, a common feature of solid tumors, has been associated with potentiated immunosuppression, decreased therapeutic response, malignant progression and local invasion. Unfortunately, the link between hypoxia and Treg-mediated immune tolerance in gastric cancer remains poorly understood. In our study, Tregs and hypoxia inducible factor-1α were found to be positively correlated with each other and were increased with the tumor progression. A subsequent in vitro study indicated that supernatants derived from gastric cancer cells under hypoxic condition, could induce the expression of Foxp3 via TGF-β1. These findings confirmed the crucial role of Tregs as a therapeutic target in gastric cancer therapy and provided helpful thoughts for the design of immunotherapy for gastric cancer in the future.

A High Level of Integrin α6 Expression in Human Intrahepatic Cholangiocarcinoma Cells Is Associated with a Migratory and Invasive Phenotype

BackgroundThe integrin α6 subunit is part of the integrin α6β1 and α6β4 complexes, which are known to mediate the invasion of carcinoma cells. However, the precise role of integrin α6 in intrahepatic cholangiocarcinoma (ICC) has not yet been addressed.MethodsTwenty cases of ICCs and matched nontumor samples were used to analyze integrin α6 expression by immunohistochemistry. After the expression of integrin α6 was determined by RT-PCR and Western blot in ICC cells, we regulated the expression of integrin α6 in ICC cells with specific vshRNA-integrin α6, and assessed the role of integrin α6 in the proliferation and metastasis/invasion of ICC cells. Finally, the involved mechanisms and clinical significance were further investigated.ResultsThe expression of integrin α6 in ICC tissues was much higher than that in nontumor samples, and the high level of integrin α6 was detected in ICC cells compared with normal liver cells and HepG2 cells. After the down-regulation of integrin α6 in HCCC-9810 cells, we showed that the ability of ICC cells to metastasize and invade was much decreased in vitro, and cell proliferation was inhibited significantly. Further study indicated high expression of integrin α6 enhanced the activation of ERK1/2 and AKT signals in ICC cells and the inhibition of ERK1/2 down-regulated ICC cell proliferation, while the inhibition of AKT markedly impaired ICC cell metastasis and invasion. Integrin α6 overexpression was significantly correlated with larger tumors, multiple nodular, microvascular/bile duct invasion, and lymphatic metastasis (pxa0<xa00.05). The postoperative 5-year overall survival (OS) rate in patients with integrin α6low was higher than that of the integrin α6high group.ConclusionsOverexpression of integrin α6 is associated with a migratory and invasive phenotype of ICC, and integrin α6 may be used as molecular target for therapy of ICC.

Induction of TGF-β and IL-10 production in dendritic cells using astilbin to inhibit dextran sulfate sodium-induced colitis

Astilbin, a major bioactive compound from Rhizoma smilacis glabrae, has been reported to possess anti-inflammatory properties. Our study first evaluated astilbin on dextran sulfate sodium (DSS)-induced acute colitis in mice. By intraperitoneal injection of astilbin, the severity of colitis was attenuated, and the serum levels of IL-10 and TGF-β were increased. Using flow cytometry, a higher number of IL-10(+) dendritic cells (DCs) and TGF-β(+) DCs and a lower number of CD86(+) DCs, IL-12 p40(+) DCs, and IL-1β(+) DCs were detected in the spleen of mice with colitis after astilbin treatment. The administration of astilbin also resulted in the upregulation of CD103(+) expression in colonic DCs. In a coculture system, murine bone marrow-derived DCs pretreated with astilbin resulted in an enhanced production of CD4(+)CD25(+)Foxp3(+) T cells. The results of this study show that astilbin could be a candidate drug for inflammatory bowel disease by mediating the regulatory functions of DCs.

Aspirin Protects against Acinar Cells Necrosis in Severe Acute Pancreatitis in Mice

Aspirin has a clear anti-inflammatory effect and is used as an anti-inflammatory agent for both acute and long-term inflammation. Previous study has indicated that aspirin alleviated acute pancreatitis induced by caerulein in rat. However, the role of aspirin on severe acute pancreatitis (SAP) and the necrosis of pancreatic acinar cell are not yet clear. The aim of this study was to determine the effects of aspirin treatment on a SAP model induced by caerulein combined with Lipopolysaccharide. We found that aspirin reduced serum amylase and lipase levels, decreased the MPO activity, and alleviated the histopathological manifestations of pancreas and pancreatitis-associated lung injury. Proinflammatory cytokines were decreased and the expression of NF-κB p65 in acinar cell nuclei was suppressed after aspirin treatment. Furthermore, aspirin induced the apoptosis of acinar cells by TUNEL assay, and the expression of Bax and caspase 3 was increased and the expression of Bcl-2 was decreased. Intriguingly, the downregulation of critical necrosis associated proteins RIP1, RIP3, and p-MLKL was observed; what is more, we additionally found that aspirin reduced the COX level of pancreatic tissue. In conclusion, our data showed that aspirin could protect pancreatic acinar cell against necrosis and reduce the severity of SAP. Clinically, aspirin may potentially be a therapeutic intervention for SAP.

NK1.1− CD4+ NKG2D+ T cells suppress DSS‐induced colitis in mice through production of TGF‐β

CD4+ NKG2D+ T cells are associated with tumour, infection and autoimmune diseases. Some CD4+ NKG2D+ T cells secrete IFN‐γ and TNF‐α to promote inflammation, but others produce TGF‐β and FasL to facilitate tumour evasion. Here, murine CD4+ NKG2D+ T cells were further classified into NK1.1− CD4+ NKG2D+ and NK1.1+ CD4+ NKG2D+ subpopulations. The frequency of NK1.1− CD4+ NKG2D+ cells decreased in inflamed colons, whereas more NK1.1+ CD4+ NKG2D+ cells infiltrated into colons of mice with DSS‐induced colitis. NK1.1− CD4+ NKG2D+ cells expressed TGF‐β and FasL without secreting IFN‐γ, IL‐21 and IL‐17 and displayed no cytotoxicity. The adoptive transfer of NK1.1− CD4+ NKG2D+ cells suppressed DSS‐induced colitis largely dependent on TGF‐β. NK1.1− CD4+ NKG2D+ cells did not expressed Foxp3, CD223 (LAG‐3) and GITR. The subpopulation was distinct from NK1.1+ CD4+ NKG2D+ cells in terms of surface markers and RNA transcription. NK1.1−CD4+ NKG2D+ cells also differed from Th2 or Th17 cells because the former did not express GATA‐3 and ROR‐γt. Thus, NK1.1− CD4+ NKG2D+ cells exhibited immune regulatory functions, and this T cell subset could be developed to suppress inflammation in clinics.

Synchronous vs sequential laparoscopic cholecystectomy for cholecystocholedocholithiasis

AIMnTo compare synchronous laparoscopic cholecystectomy (LC) combined with endoscopic sphincterotomy (EST) and sequential LC combined with EST for treating cholecystocholedocholithiasis.nnnMETHODSnA total of 150 patients were included and retrospectively studied. Among these, 70 were selected for the synchronous operation, in which the scheme was endoscopic retrograde cholangiopancreatography combined with EST during LC. The other 80 patients were selected for the sequential operation, in which the scheme involved first cutting the papillary muscle under endoscopy and then performing LC. The indexes in the two groups, including the operation time, the success rate, the incidence of complications, and the length of the hospital stay, were observed.nnnRESULTSnThere were no significant differences between the groups in terms of the numbers of patients, sex distribution, age, American Society of Anesthesiologists score, serum bilirubin, γ-glutamyl transpeptidase, mean diameter of common bile duct stones, and previous medical and surgical history (P = 0.54, P = 0.18, P = 0.52, P = 0.22, P = 0.32, P = 0.42, P = 0.68, P = 0.70, P = 0.47 and P = 0.57). There was no significant difference in the surgical operation time between the two groups (112.1 ± 30.8 min vs 104.9 ± 18.2 min). Compared with the sequential operation group, the incidence of pancreatitis was lower (1.4% vs 6.3%), the incidence of hyperamylasemia (1.4% vs 10.0%, P < 0.05) was significantly reduced, and the length of the hospital stay was significantly shortened in the synchronous operation group (3 d vs 4.5 d, P < 0.001).nnnCONCLUSIONnFor treatment of cholecystocholedocholithiasis, synchronous LC combined with EST reduces incidence of complications, decreases length of hospital stay, simplifies the surgical procedure, and reduces operation time.

Indomethacin inhabits the NLRP3 inflammasome pathway and protects severe acute pancreatitis in mice

Clinical studies have confirmed that indomethacin (Indo) can reduce the incidence and severity of post-endoscopicretrogradecholangio-pancreatography pancreatitis (PEP) effectively. However, the role of Indo on severe acute pancreatitis (SAP) is not clear. In the present study, we aimed to explore the effects of Indo treatment on SAP model induced by caerulein combined with lipopolysaccharide. After intraperitoneal injection of Indo in mice, both the severity of SAP and the serum levels of amylase, lipase, and proinflammatory cytokines were decreased. Furthermore, the mRNA and protein levels of NLRP3 inflammasome pathway (NLRP3,ASC and IL-1β) in pancreatic tissues were down-regulated. Inxa0vitro experiments, by isolating the pancreatic acinar cells (PACs) from mice, we found that Indo significantly reduced lactate dehydrogenase(LDH) excretion, increased the cell activity, and inhibited the NLRP3 inflammasome pathway of PACs. Taken together, our data showed that Indo could protect pancreatic acinar cell from injury by inhabiting NLRP3 pathway and decreased the severity of SAP accordingly.

Isoliquiritigenin Ameliorates Acute Pancreatitis in Mice via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway

Oxidative stress plays a crucial role in the pathogenesis of acute pancreatitis (AP). Isoliquiritigenin (ISL) is a flavonoid monomer with confirmed antioxidant activity. However, the specific effects of ISL on AP have not been determined. In this study, we aimed to investigate the protective effect of ISL on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, dynamic changes in oxidative stress injury of the pancreatic tissue were observed after AP onset. We found that ISL administration reduced serum amylase and lipase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. Meanwhile, ISL decreased the oxidative stress injury and increased the protein expression of the Nrf2/HO-1 pathway. In addition, after administering a Nrf2 inhibitor (ML385) or HO-1 inhibitor (zinc protoporphyrin) to block the Nrf2/HO-1 pathway, we failed to observe the protective effects of ISL on AP in mice. Furthermore, we found that ISL mitigated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by L-arginine. Taken together, our data for the first time confirmed the protective effects of ISL on AP in mice via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway.

Prevalence and clinical characteristics of fatty pancreas in Yangzhou, China: A cross-sectional study

OBJECTIVEnThe aim of this study was to investigate the prevalence and risk factors of fatty pancreas in Yangzhou, China.nnnMETHODSnThis was a cross-sectional study. Initially, 2093 subjects were included in the study. After the exclusion of 865 subjects based on incomplete information, a total of 1228 subjects were selected for further analysis. The subjects were stratified into two groups (the fatty pancreas group and the non-fatty pancreas group) based on the results. Anthropometric and biochemical findings were compared between the groups.nnnRESULTSnAmong the 2093 study subjects, 56 (2.7%) had fatty pancreas. Overall, 53 out of 1228 subjects were diagnosed with fatty pancreas and included into the fatty pancreas group. Univariate analysis showed significant differences in age and the prevalence of general obesity, central obesity, alcohol consumption, metabolic syndrome and fatty liver between the two groups (all pu202f<u202f0.01). The fatty pancreas group had higher levels of aspartate aminotransferase, alanine aminotransferase, serum uric acid, fasting blood glucose, total cholesterol, triglycerides and low-density lipoprotein, and lower levels of high-density lipoprotein than did the non-fatty pancreas group (all p < 0.05). Multivariate logistic regression analysis showed that age (pu202f=u202f0.007), central obesity (pu202f=u202f0.002) and fatty liver (pu202f=u202f0.006) were independent risk factors for fatty pancreas, with odds ratios (ORs) of 1.034 (95% confidence interval (CI): 1.009-1.059), 5.364 (95% CI: 1.890-15.227), and 2.666 (95% CI: 1.332-5.338), respectively.nnnCONCLUSIONnThe prevalence of fatty pancreas in the examined population is approximately 2.7%. Increased age, central obesity and fatty liver disease are independent risk factors for fatty pancreas.

The Impact of Colonoscopy Quality Control Table on Adenoma Detection Rates

Objective. This study aims to investigate the effects of reporting colonoscopy findings and the regular review of outcomes on adenoma detection rates. Methods. Patients who underwent colonoscopy from August 2013 to February 2014 were selected as the intervention group. The preintervention group included patients who underwent colonoscopy from January 2013 to July 2013, in which the procedure sheet for this group of patients was not accomplished. The primary outcome was adenoma detection rate (ADR), and secondary outcomes included the success rate of intubation and withdrawal time. Results. This study included 2,467 cases: 1,302 cases in the intervention group and 1,165 cases in the preintervention group. There was no significant difference in demographic characteristics between the two groups. In the intervention group, withdrawal time of colonoscopy was longer (P < 0.01), and the success rate of intubation (92.5% versus 89.1%, P < 0.05) and detection rate of polyps (32.6% versus 27.6%, P < 0.05) and adenomas (20.0% versus 16.1%, P < 0.05) were higher. Significantly high detection rates for proximal adenomas, flat adenomas, and adenomas with a diameter <5u2009mm were observed in the intervention group (all P < 0.01). Conclusion. The reporting and review of procedure details help to improve quality indicators of colonoscopy.