Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Objective:To compare the efficacy of oral sulfate solution (OSS) and polyethylene glycol (PEG) electrolyte powder for colonoscopy bowel preparation.Methods:A total of 283 randomized patients from 9 centers in China taking OSS ( n=143) or PEG ( n=140) using two-day split bowel preparation regimen received colonoscopy and assessment. The primary index was the bowel preparation success rate [global Boston bowel preparation scale (BBPS)≥ 6 by independent assessment center]. Secondary indices included BBPS global and segmental scores, investigator satisfaction (5-point Likert scale) with the quality of bowel preparation, patient satisfaction assessed by questionnaires, and patient tolerance assessed by Sharma scale. Compliance and safety were compared between the two groups. Results:The bowel preparation success rates were 100.0% for OSS and 99.3% for PEG [adjusted difference 0.7% (95% CI: -5.3% - 6.7%), P<0.001 for non-inferiority]. The BBPS global score in OSS group was significantly higher than that in PEG group (8.1 VS 7.7, P<0.001). The segment BBPS scores were also higher in OSS group than those in PEG group for all 3 segments (right colon: 2.4 VS 2.3, P=0.002; transverse colon: 2.8 VS 2.7, P=0.018; left colon: 2.8 VS 2.7, P=0.007). Investigator Likert score in the OSS group was significantly higher than that in the PEG group (2.6 VS 2.3, P<0.001). There was no significant difference in compliance between OSS and PEG, except for the second dose (90.9% VS 82.6%, P=0.039). There was no significant difference in patient satisfaction, Sharma score or proportion of patients with tolerance-related symptoms between the two groups. Safety was comparable between the two groups, and all adverse events were mild to moderate. Conclusion:OSS has comparable efficacy with PEG, with higher BBPS scores in all segments, better investigator satisfaction, better compliance in split dose, and comparable patient tolerance and safety.

Objective:To conduct health economic evaluation of Chinese population-based screening and opportunistic testing strategies for the prevention of Helicobacter pylori ( H. pylori)-related diseases. Methods:The Markov models of H.pylori infection caused non-ulcer dyspepsia, peptic ulcer (PU) and gastric cancer were established. The cost and effects of the population-based screening, opportunistic testing, and non-intervention strategies in 100 000 population of our country were simulation calculated. Wilcoxon signed rank test was used for statistic analysis. Single factor sensitivity analysis was performed to analyze the impact of single parameter uncertainty on cost-effectiveness. Probability sensitivity was used to analyze the impact of common uncertainty of all parameters on cost-effectiveness. Results:Compared with opportunistic testing strategy and non-intervention strategy, the total cost of population-based screening strategy was reduced by 0.43 million yuan(-6.63 million yuan to 7.19 million yuan) and 4.45 million yuan(-8.60 million yuan to 27.93 million yuan), quality adjusted life years (QALY), life years and asmptomatic months were prolonged by 888.00 (479.86 to 1 574.10) and 3 032.78 (1 756.04 to 5 007.84), 651.82 (294.73 to 1 211.94) and 1 868.64 (1 045.88 to 3 148.34), 28 381.91 (19 109.54 to 43 736.72)and 102 537.13 (58 649.18 to 176 868.77) respectively, gastric cancer, deaths from gastric cancer, deaths from PU and deaths from various causes were reduced by 115 cases(52 cases to 232 cases) and 464 cases(266 cases to 803 cases), 74 cases(33 cases to 148 cases) and 260 cases(149 cases to 453 cases), 46 cases(25 cases to 72 cases) and 369 cases(210 cases to 710 cases), 80 cases(42 cases to 126 cases) and 501 cases(331 cases to 772 cases) respectively, and the differences were statistically significant ( Z=1.99, 10.54, 27.39, 27.39, 27.37, 27.39, 27.39, 27.39, 27.21, 27.28, 27.22, 27.28, 27.38, 27.39, 27.39 and 27.39, all P<0.05). Compared with the non-intervention strategy, the opportunistic testing strategy reduced the total cost by 3.89 million yuan(-2.79 million yuan to 18.18 million yuan), QALY, life years and asymptomatic months were prolonged by 1 764.77 (888.70 to 3 406.62), 1 044.16 (524.46 to 1 912.75) and 62 568.69 (30 054.07 to 129 892.76) respectively, gastric cancer, deaths from gastric cancer, deaths from PU and deaths from various causes were reduced by 311 cases(164 cases to 563 cases), 164 cases (87 cases to 301 cases), 325 cases(162 cases to 644 cases) and 399 cases(234 cases to 684 cases) respectively, and the differences were statistically significant ( Z=14.20, 27.39, 27.38, 27.39, 27.25, 27.25, 27.39 and 27.39, all P<0.01). The results of singlefactor sensitivity analysis showed that the uncertainty of any parameter did not affect the cost-effectiveness of three strategies. The results of probability sensitivity analysis indicated that the probability of cost-effectiveness advantage of the population-based screening strategy was 100% and the common uncertainty of all parameters had no effect on cost-effectiveness. Conclusions:For preventing H.pylori-related diseases, the population-based screening strategy has the lowest average cost and the best average effect. However, non-intervention strategy has the highest average cost and the worst average effect. Population-based screening strategy is worthy of promotion throughout China, and opportunistic testing strategy has a higher clinical practical value.

Objective To investigate the changes of peripheral blood expression levels of soluble fibrinogen-like protein 2 (sFGL2) in patients with chronic hepatitis B (CHB) before and after antiviral treatment.Methods From July 2013 to December 2014,initial CHB patients with entecavir antiviral therapy and healthy controls were enrolled.Clinical data at baseline and during follow-up were collected.Plasma levels of sFGL2 of all the included objects were measured by enzyme-linked immunosorbent assay (ELISA).All the patients received liver biopsy at baseline,and part of patients received a second liver biopsy at week 78 after treatment.The expression of sFGL2 in liver tissues were examined by immunohistochemistry.T test,Wilcoxon test and correlation analysis were performed for statistical analysis.Results A total of 71 CHB patients and 20 healthy controls were enrolled.At baseline,the level of plasma sFGL2 of CHB patients was significantly higher than healthy controls (105.6 μg/L (78.3 μg/L to 151.6 μg/L) vs 25.2 μg/L (18.8 μg/L to 34.3 μg/L),Z=-5.887,P＜ 0.01).The plasma sFGL2 level of patients with liver cirrhosis was 146.0 μg/L (111.3 μg/L to 166.8 μg/L),which was higher than that of patients without liver cirrhosis (79.0 μg/L (65.4 μg/L to 107.4 μg/L)),and the difference was statistically significant (Z=-4.912,P＜0.01).Plasma levels of sFGL2 were positively correlated with liver stiffness,liver inflammation and fibrosis stages (r=0.426,0.240 and 0.655;all P＜0.05).At 26 weeks and 52 weeks after treatment,the plasma levels of sFGL2 were 89.1 μg/L (69.8 μg/L to 125.5 μg/L) and 75.8 μg/L (53.4 μg/L to 98.9 μg/L),respectively,which gradually decreased compared with that at baseline (26 weeks vs baseline Z=-4.499,P＜0.01;52 weeks vs 26 weeks Z=-4.762,P＜0.01).Furthermore,at baseline the number of sFGL2 positive cells in the liver tissue of liver cirrhosis group was 33.0 ± 10.4,which was higher than that of non-liver cirrhosis group (17.6 ±6.7),and the difference was statistically significant (t=7.541,P＜0.01).Compared with that at baseline (24.5±2.0),the number of sFGL2 positive cells in liver tissue at week 78 after treatment decreased (11.3± 1.6),and the difference was statistically significant (t=11.980,P＜0.01).Conclusion Plasma level of sFGL2 is closely correlated with the degree of liver inflammation and fibrosis in CHB,and the plasma level of sFGL2 significantly decreases after long-term antiviral therapy.

Objective:To investigate the effect of Toll‐like receptor 3(TLR3) gene deficiency on the degree of liver fibrosis in mouse model of carbon tetrachloride(CCl4 )‐induced liver fibrosis .Methods :A total of 20 wild‐type male mice and 20 male mice with TLR3 gene deficiency (TLR3‐/‐) were divided into wild‐type control group and wild‐type model group ,TLR3‐/‐ control group and TLR3‐/‐ model group ,respectively ,with 10 mice in each group .The control group was injected with corn‐oil by intraperitoneal injection while the model group was injected with CCl4 by intraperitoneal injection .After 8 weeks ,blood sample wascollectedandserumlevelofalanineaminotransferase(ALT),aspartatetransaminase(AST),totalbilirubin(TBIL),and albumin(Alb) was analyzed by automatic biochemical analyzer .And the degree of collagen deposition in liver tissue was evaluated by Masson trichrome staining .And the activation of hepatic stellate cells was detected by immunohistochemistry staining of α‐smooth muscle actin(α‐SMA).And hydroxyproline content of liver tissue was detected with detection kit . Furthermore ,real‐time fluorescence polymerase chain reaction was used to detect the expression of liver fibrotic marker type I collagen ,and inflammatory cytokines including tumor necrosis factor‐alpha (TNF‐α) , interleukin‐6 (IL‐6 ) and monocyte chemotactic protein‐1(MCP‐1) ,as well as pro‐fibrotic molecule including transforming growth factor‐beta (TGF‐β) ,tissue inhibitor of metalloproteinase 1(TIMP1) and platelet‐derived growth factor receptor(PDGFR) .Results:TLR3 gene deficiency had no effect on CCl4‐induced change regarding serum level of ALT ,AST ,TBIL ,ALB .TLR3 gene deficiency aggregated the CCl4‐induced collagen deposition and hepatic stellate cell activation in liver tissue .And it promoted the CCl4‐induced elevation of hydroxyproline content and expression increase of fibrotic marker type I collagen .Furthermore ,the expression increase of inflammatory cytokines including TNF‐α,IL‐6 and MCP‐1 ,as well as that of pro‐fibrotic molecule including TGF‐β,TIMP1 and PDGFR ,was promoted .Conclusions :TLR3 gene deficiency could promote liver collagen deposition and hepatic stellate cell activation in mouse model of CCl4‐induced liver fibrosis ,and it could promote inflammatory cytokine release and pro‐fibrotic molecule up‐regulation .All above suggest that TLR3 is a protective gene during liver fibrosis pathological process .

Background and purpose:Traditional Chinese medicine with notable effect and little adverse reaction is increasingly concerned about the medical profession because of its great potential and advantage in treating pancreatic carcinoma. In this experiment, we studied the effects of oridonin on apoptosis and cytoskeletal protein F-actin in human pancreatic carcinoma SW1990 cells. Methods:SW1990 cells in culture medium were treated with different concentrations of oridonin. The inhibitory rate of the cells was measured by MTT assay. Morphology of cell apoptosis was observed by DAPI stain and cell apoptotic rate was detected by lfow cytometry (FCM). The morphological changes of F-actin were observed by laser confocal microscopy. Results:The growth of human pancreatic carcinoma SW1990 cells was signiifcantly inhibited by oridonin. Apoptosis morphological changes including condensation of chromatin and nuclear fragmentation were observed clearly by DAPI stain. The early apoptotic rate of SW1990 cells treated with 25, 50μmol/L oridonin was signiifcantly higher than that of the control group (3.78±0.46, 9.51±0.63 vs 0.73±0.06, P<0.05), and the late apoptotic rate and cell necrosis rate were also signiifcantly higher than that of the control group (14.40±1.78, 20.53±2.54 vs 4.16±0.31, P<0.05). F-actin was showed from polymerization to depolymerization after oridonin treatment. Conclusion:Oridonin can obviously inhibit the proliferation and induce apoptosis of SW1990 cells. The mechanisms may involve the depolymerization of F-actin after treatment with oridonin.

Background:The clinical presentation of eosinophilic gastroenteritis( EG)is nonspecific and has not received much concern by physicians and pathologists. The diagnosis of EG was delayed in many cases. Aims:To explore the clinical features of EG. Methods:The clinical,laboratory,endoscopic and radiologic features and treatment in patients who were diagnosed as EG from October 2011 to September 2013 in Zhongshan Hospital, Fudan University were analyzed retrospectively. Results:Median age of 10 EG patients was 41. 9 years. Four patients had a history of allergy or asthma. The time from onset to diagnose was 25 days on average. The most common symptoms were abdominal pain with bloating, diarrhea or vomiting. Eight patients had hypereosinophilia. Abdominal CT revealed uniform edema or stratified thickness of intestinal wall or ascites in 7 patients. Endoscopy revealed erythema,edema and erosion in antrum,duodenum or jejunum in 6 patients. All cases were confirmed as having eosinophilic infiltration by mucosal biopsy or examination of ascites. Seven patients were successfully treated with corticosteroid. One patients experienced relapse after discontinuing corticosteroids during following up. Conclusions:EG may be more common than previously recognized and should be considered in the differential diagnosis of unexplained abdominal pain with peripheral eosinophilia or uniform edema or stratified thickness of intestinal wall. Multiple biopsies in multiple sites including descending duodenum and pathological examination for finding eosinophil infiltration are the keys to confirm the diagnosis. Corticosteroids are effective in relieving symptoms and improving eosinophilia.

Objective To comprehensively evaluate the clinical and radiological features of patients with Klebsiella pneumonia liver abscess (KLA) in order to improve treatment. Methods Data of 197 patients with KLA (n=106) or non-KLA (n=56) between March 2001 and January 2009 were collected and retrospectively analyzed on the aspects of underlying diseases, clinical manifestations, laboratory tests, pathogenic and imaging examinations. Results In comparison with non-KLA patients, the underlying diseases such as diabetes (53. 77% vs 25.00%, P = 0. 001) and hepatic adipose infiltration (16. 04% vs 5, 36%, P<0.05) were more common in KLA patients.Whereas the clinical presentations including abdominal pain (57. 14% vs 40. 57%, P<0. 05),hypodynamia (46.43% vs 19.81%, P=0. 001) and hepatomegaly (14.29% vs 4.72%, P<0. 05)were more severe in non-KLA patients than in KLA patients, however, the fasting blood glucose was higher in KLA patients than in non-KLA patients [(7.84±0.36) mmol/L vs (5.76±0.30) mmol/L,P=0. 001] on the admission. In addition, the abscess of KLA often appeared alone in the right lobe of the liver and was liable to generate air cavity (32. 88% vs 13.51%, P<0.05), un-smooth rim (71.23% vs 40.54% ,P<0.05) and dynamic septum enhancement (41.10% vs 16.22% ,P<0.01) in comparison with non-KLA. Conclusions Klebsiella pneumonia has emerged as the main pathogen of pyogenic liver abscess. The patients with KLA are often complicated with diabetes and fatty liver, as well as high prevalence of air cavity. The CT findings may be helpful for prompt treatment of Klebsiella pneumonia liver abscess.

BACKGROUND: 5-fluorouracil (5-Fu) is universally used as an antineoplastic agent in gastrointestinal cancer, but the side effect of it confined further clinical application. OBJECTIVE: To determinate mice plasma concentration curves for 5-Fu and its chitosan (CS)-polyaspartic acid (Pasp) nanoparticles, and to investigate their primary pharrnacokinetics. DESIGN, TIME AND SETTING: Randomization control animal trials were performed in the Department of Gastroenterology, Zhongshan Hospital of Fudan University between October 2006 and June 2007. MATERIALS: Totally 180 female Kunming mice were obtained from the Department of Laboratory Animal, Fudan University. 5-Fu (purity 99%) was purchased from Shanghai Xudong Haipu Pharmaceutical Co, Ltd (Shanghai, China). Two kinds of CS-Pasp-5-Fu particles were offered by Department of Macromolecular Science, Key Laboratory of Molecular Engineering of Polymers of Educational Ministry, Fudan University (Shanghai, China). METHODS: Kunming mice were randomly divided into three groups and each group was administrated with 5-Fu or either type of its CS-Pasp-5-Fu nanoparticlos. The plasma concentrations of 5-Fu were evaluated by high performance liquid chromatography after 15 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours and 48 hours of the administration. The pharmacokinetic parameters were computed utilizing 3P97. MAIN OUTCOME MEASURES: Relative recovery, absolute recovery and the stability of samples. RESULTS: The peak concentration of 5-Fu group occurred within 15 minutes and then decreased rapidly. The No.1 nanoparticles group's peak concentration occurred 6 hours after the administration and the effective concentration time lasted for about 14 hours. No.2 nanoparticles group's concentration curve was double-apex, the apexes occurred around the 2 hours and 16 hours, the concentration decreased at the 24 hours after the administration. Both of the two kinds of the nanoparticles groups' peak concentration of 5-Fu in plasma are lower than the 5-Fu group, The half-life times were prolonged and the areas under curve were higher. CONCLUSION: Compared to 5-Fu, the CS-Pasp-5-Fu nanoparticles are controlled released.

Objective To establish a new Helicobacter pylori(H.pylori) infection model which is more stable and to find the relationship between H. ~pylori infection and gastric carcinogenesis induced by nitrosourea. Methods A total of 94 Balb/c mice were divided into four groups. Two groups of mice were inoculated with H.pylori, among which one group of mice received continuous N-methyl-N-nitrosourea(MNU) administration via the drinking water. The third group were only given MNU, and the forth as control. After 36 weeks, all the mice were ~sacrificed . The infection of H.pylori in gastric mucosa of the mice was analyzed by rapid urease test, ~Giemsa staining and culture. The histopathological changes in the gastric mucosa of mice were assessed in ~H-E stained sections. Results The total infection rate of H.~pylori in Balb/c mice was 93.9%. All the mice in group with H.pylori infection alone had chronic gastritis, in which 20.0% was atrophic gastritis. In the group of mice with H.pylori infection and MNU intake, all had chronic gastritis, and among them 23.1% had atrophic gastritis, 42.3% corpus dysplasia and 57.7% antrum dysplasia. In this group, two mice (7.1%) with low differentiated adenocarcinoma were found. Compared with control group, two groups with H. ~pylori infection only and H. ~pylori plus MNU intake reached statistical difference in the view of inflammatory latitude (P