Efficacy and safety of three endoscopic techniques for small common bile duct stones (≤ 10 mm): a multicenter, retrospective, cohort study with propensity score matching.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a major option for common bile duct (CBD) stones. Endoscopic sphincterotomy (EST), endoscopic papillary balloon dilatation (EPBD), and endoscopic sphincterotomy plus balloon dilatation (ESBD) are procedures for opening the bile duct orifice to extract CBD stones during ERCP. The optimal method for extracting small CBD stones (≤ 10 mm) has not yet been proposed. We aimed to compare the efficacy and safety of these three techniques in extracting small CBD stones. METHODS: ERCP for small stones was performed between January 2009 and November 2020 at three tertiary care centers. The incidence of post-ERCP pancreatitis (PEP) was compared among EST, EPBD, and ESBD groups. First and overall success rates of stone extraction, utilization rate of mechanical lithotripsy, and other ERCP complications such as bleeding, perforation, infection, and hyperamylasemia were compared. RESULTS: A total of 2181 patients were enrolled between January 2009 and November 2020. The proportion of young patients (≤ 45 years) in EPBD group was more than those in EST and ESBD group. Stone size in ESBD group was much larger than EST and EPBD group. After propensity score matching, the success rates of first and overall stone extraction in the three groups were high, and the rates of mechanical lithotripsy were low, with no significant difference. The PEP incidences showed no differences among the three groups. The incidence of bleeding complication in EST group was higher than that in EPBD group. No significant differences were observed in other complications between EPBD group and ESBD group. ESBD group had higher incidence of overall, infection, and hyperamylasemia complications than EST group. CONCLUSION: EPBD is equivalent to ESBD in stone removal efficiency and complication rate, but brings a lower bleeding risk than EST. Therefore, we recommend EPBD as the first choice for small CBD stones.

Comparisons of six endoscopy independent scoring systems for the prediction of clinical outcomes for elderly and younger patients with upper gastrointestinal bleeding.

OBJECTIVES: To compare the predictive ability of six pre-endoscopic scoring systems (ABC, AIMS65, GBS, MAP(ASH), pRS, and T-score) for outcomes of upper gastrointestinal bleeding (UGIB) in elderly and younger patients. METHODS: A retrospective study of 1260 patients, including 530 elderly patients (age [Formula: see text] 65) and 730 younger patients (age < 65) presenting with UGIB, was performed at Zhongda Hospital Southeast University, from January 2015 to December 2020. Six scoring systems were used. RESULTS: ABC had the largest areas under the curve (AUCs) of 0.827 (0.792-0.858), and 0.958 (0.929-0.987) for elderly and younger groups for predicting mortality respectively. The differences of the AUCs for predicting the outcome of mortality and rebleeding between the two groups were significant for ABC and pRS (p < 0.01). For intervention prediction, significant differences were observed only for pRS [AUC 0.623 (0.578-0.669) vs. 0.699 (0.646-0.752)] (p < 0.05) between the two groups. For intensive care unit (ICU) admission, the AUC for MAP (ASH) [0.791 (0.718-0.865) vs. 0.891 (0.831-0.950)] and pRS [0.610 (0.514-0.706) vs. 0.891 (0.699-0.865)] were more effective for the younger group (p < 0.05 and p < 0.01, respectively). For comparison of scoring systems in the same cohort, ABC was significantly higher than pRS: AUC 0.710 (0.699-0.853, p < 0.05) and T-score 0.670 (0.628-0.710, p < 0.01) for predicting mortality in the elderly group. In the younger group, ABC was significantly higher than GBS and T-score (p < 0.01). MAP(ASH) performs the best in predicting intervention in both groups. CONCLUSIONS: ABC and pRS are more accurate for predicting mortality and rebleeding in the younger cohort, and pRS may not be suitable for elderly patients. There was no difference between the two study populations for GBS, AIMS65, and T-score. Except for ICU admission, MAP(ASH) showed fair accuracy for both cohorts.

MiR-145 functions as a tumor suppressor via regulating angiopoietin-2 in pancreatic cancer cells.

BACKGROUND: Pancreatic cancer is currently one of the leading causes of cancer deaths without any effective therapies. Mir-145 has been found to be tumor-suppressive in various types of cancers. The aim of this study is to investigate the role of miR-145 in pancreatic cancer cells and explore its underlying mechanism. METHODS: Quantitative real time PCR was used to determine the expression level of miR-145 and angiopoietin-2 (Ang-2) mNRA, and the expression level of Ang-2 protein was measured by western blotting. The anti-cancer activities of miR-145 were tested both in in vitro by using cell invasion and colony formation assay and in vivo by using xenograft assay. The direct action of miR-145 on Ang-2 was predicted by TargetScan and confirmed by luciferase report assay. The vascularization of xenografts were performed by immunohistochemical analysis. RESULTS: The expression level of miR-145 was significantly lower and the expression levels of Ang-2 mRNA and protein was significantly higher in the more aggressive pancreatic cancer cells (MiaPaCa-2 and Panc-1) when compared to that in BxPC3 cells. Overexpression of miR-145 in the BxPC3, MiaPaCa-2 and Panc-1 cells suppressed the cell invasion and colony formation ability, and the expression level of Ang-2 protein in MiaPaCa-2 and Panc-1 cells was also suppressed after pre-miR-145 transfection. Intratumoral delivery of miR-145 inhibited the growth of pancreatic cancer xenografts and angiogenesis in vivo, and also suppressed the expression level of angiopoietin-2 protein. Luciferase report assay showed that Ang-2 is a direct target of miR-145, and down-regulation of angiopoietin-2 by treatment with Ang-2 siRNA in the BxPC3, MiaPaCa-2 and Panc-1 cells suppressed cell invasion and colony formation ability. The reverse transcription PCR results also showed that Tie1 and Tie2 were expressed in BxPC3, MiaPaCa-2 and Panc-1 cells. CONCLUSION: MiR-145 functions as a tumor suppressor in pancreatic cancer cells by targeting Ang-2 for translation repression and thus suppresses pancreatic cancer cell invasion and growth, which suggests that restoring of miR-145 may be a potential therapeutic target for pancreatic cancer.

MiR-873-5P controls gastric cancer progression by targeting hedgehog-GLI signaling.

Gastric cancer is one of the most common human malignancies. Thus, it is important to explore the specific mechanism in which gastric cancer is induced. The level of miR-873-5p was determined using real time PCR. The expression of Gli1 was determined using western blot and immunohistochemistry. A specific siRNA targeting Gli1 was selected. The role of Gli1 and miR-873-5p on gastric cancer cell viability, apoptosis and cell cycle was determined using MTT assay and flow cytometry, respectively. The 3'untranslated region (3'UTR) of Gli1 was cloned into the pmirGLO plasmid. Dual luciferase reporter assay was applied to determine the target gene of miR-873-5p. The expression of miR-873-5p was decreased in gastric cancer, while the expression of Gli1 was significantly enhanced. Overexpression of miR-873-5P decreased cell viability, increased cell apoptosis and cell cycle arrest. Meanwhile, knockdown of Gli1 obviously induced SGC-7901 cell apoptosis and cell cycle arrest. Dual luciferase reporter assay showed that Gli1 was the target gene of miR-873-5p. More importantly, inhibition of miR-873-5p obviously decreased the protein expression of CyclinB1 and Bcl2 even in cells transfected with si-Gli1. To conclude, MiR-873-5p functions as a tumor suppressor in gastric cancer mainly by targeting Gli1.

Association of sedentary behavior with the expression levels of biomarkers in colorectal cancer: clinical analysis of 228 patients.

There is an association between sedentary behavior and the risk of colorectal cancer (CRC), but the underlying mechanism is unclear. CRC is characterized by the changes in the expression levels of biomarkers, including voltage-gated proton channel Hv1, matrix-remodeling associated 5 (MXRA5), DEK (inducing positive supercoils into circular DNA) and protein inhibitor of activated signal transducer and activators of transcription 3 (PIAS3). Thus, sedentary behavior may affect the expression levels of these biomarkers in the colorectal tissue. Here, we recruited 228 CRC patients (128 males, 57.8 ± 7.8 years; 100 females, 57.7 ± 7.5 years) and 80 healthy subjects (48 males, 57.5 ± 6.8 years; 32 females, 56.9 ± 6.5 years) from March 7th, 2010 to May 6th, 2012. All the subjects were unrelated Han Chinese with the similar cultural and economic background. All the subjects were interviewed concerning sedentary time (sitting time categories: less than 1, 1-3, 4-6, and more than 6 h/day). The daily sedentary time of most CRC patients was more than 4 h/day, while the sedentary time of most healthy subjects was less than 3 h/day. The expression levels of Hv1, MXRA5 and DEK mRNAs and proteins were higher in CRC tissues and the levels of PIAS3 mRNA and protein were lower when the daily sedentary time was longer in CRC patients (p < 0.05). The daily sedentary time was correlated with the protein levels of CRC biomarkers. Furthermore, the sedentary time was positively related with body mass index but not daily calorie intake.

PPM1G promotes autophagy and progression of pancreatic cancer via upregulating HMGB1.

Pancreatic cancer remains one of the most aggressive and lethal malignancies worldwide, with a dismal 5-year relative survival rates of only 12%. Therefore, it is urgent to discover the key molecular markers to improve the therapeutic outcomes in pancreatic cancer. Herein, we first demonstrated that PPM1G is upregulated in pancreatic cancer and that PPM1G depletion decreases pancreatic cancer cell growth in vitro and in vivo. High PPM1G expression was linked to short overall survival of pancreatic cancer patients, which was further validated in the TCGA database. Moreover, by detecting Beclin 1, LC3-II, and SQSTM1/p62 expressions and observing autolysosome under transmission electron microscope, we discovered that PPM1G is a novel positive regulator of macroautophagy/autophagy. Furthermore, by using immunoprecipitation-mass spectrometry (IP-MS) analysis and following systemic molecular biology experiment, we demonstrated PPM1G promotes the autophagy and proliferation of pancreatic cancer by directly upregulating HMGB1. Additionally, patients with both high PPM1G and high HMGB1 exhibited poorer prognosis in our cohort. This study preliminarily investigated the possibility of PPM1G as a potential therapeutic target and prognostic biomarker in pancreatic cancer patients.

Novel risk score for acute upper gastrointestinal bleeding in elderly patients: a single-centre retrospective study.

OBJECTIVES: Acute upper gastrointestinal bleeding (UGIB) is a common reason for emergency hospital admission. Identifying low-risk patients suitable for outpatient management is a clinical and research priority. This study aimed to develop a simple risk score to identify elderly patients with UGIB for whom hospital admission is not required. DESIGN: This was a single-centre retrospective study. SETTING: This study was conducted at Zhongda Hospital affiliated with Southeast University in China. PARTICIPANTS: Patients from January 2015 to December 2020 for the derivation cohort and from January 2021 to June 2022 for the validation cohort were enrolled in this study. A total of 822 patients (derivation cohort=606 and validation cohorts=216) were included in this study. Patients aged ≥65 years with coffee-grounds vomiting, melena or/and haematemesis were included in the analysis. Patients admitted but had UGIB or transferred between hospitals were excluded. METHODS: Baseline demographic characteristics and clinical parameters were recorded at the first visit. Data were collected from electronic records and databases. Multivariable logistic regression modelling was performed to identify predictors of safe discharge. RESULTS: 304/606 (50.2%) and 132/216 (61.1%) patients were not safely discharged in the derivation and validation cohorts, respectively. A clinical risk score of five variables was entered into UGIB risk stratification: Charlson Comorbidity Index >2, systolic blood pressure <100 mm Hg, haemoglobin <100 g/L, blood urea nitrogen ≥6.5 mmol/L, albumin <30 g/L. The optimal cut-off value was ≥1, the sensitivity was 97.37% and the specificity was 19.21% for predicting the inability to discharge safely. The area under the receiver operating characteristic curve was 0.806. CONCLUSIONS: A novel clinical risk score with good discriminative performance was developed to identify elderly patients with UGIB who were suitable for safe outpatient management. This score can reduce unnecessary hospitalisations.

Evaluation of Six Preendoscopy Scoring Systems to Predict Outcomes for Older Adults with Upper Gastrointestinal Bleeding.

OBJECTIVES: To compare the ability of six preendoscopic scoring systems (ABC, AIMS65, Glasgow Blatchford score (GBS), MAP(ASH), pRS, and T-score) to predict outcomes of upper gastrointestinal bleeding (UGIB) in older adults. METHODS: This was a retrospective study of 602 older adults (age ≥ 65) presenting with UGIB at Zhongda Hospital Southeast University from January 2015 to June 2021. Six scoring systems were used to analyze all patients. RESULTS: ABC had the largest area under the curve (AUC) (0.833; 95% confidence interval (CI): 0.801-0.862) and was significantly higher than pRS 0.696 (95% CI: 0.658-0.733, p < 0.01) and T-score 0.667 (95% CI: 0.628-0.704, p < 0.01) in predicting mortality. MAP(ASH) (0.783; 95% CI: 0.748-0.815) performs the best in predicting intervention and was similar to GBS, T-score, ABC, and AIMS65. The AUCs for MAP(ASH) (0.732; 95% CI: 0.698-0.770), AIMS65 (0.711; 95% CI: 0.672-0.746), and ABC (0.718; 95% CI: 0.680-0.754) were fair for rebleeding, while those of GBS (0.662; 95% CI: 0.617-0.694), T-score (0.641; 95% CI: 0.606-0.684), and pRS (0.609; 95% CI: 0.569-0.648) were performed poorly. MAP(ASH) performs the best in predicting ICU admission (0.784; 95% CI: 0.749-0.816). All the five scores were significantly higher than pRS (p < 0.05 for ABC, AIMS65 and T-score, p < 0.01 for GBS and MAP). CONCLUSIONS: Mortality, intervention, rebleeding, and ICU admission in UGIB for older adults can be predicted well using MAP(ASH). ABC is the most accurate for predicting mortality. Except for rebleeding, GBS has an acceptable performance in predicting ICU admission, mortality, and intervention. AIMS65 and T-score performed moderately, and pRS may not be suitable for the target cohort.

The global research and emerging trends in autophagy of pancreatic cancer: A bibliometric and visualized study.

Objective: To present the global research features and hotspots, and forecast the emerging trends by conducting a bibliometric analysis based on literature related to autophagy of pancreatic cancer from 2011 to 2022. Methods: The literature data regarding autophagy of pancreatic cancer were retrieved and downloaded from the Web of Science Core Collection (WOSCC) from Clarivate Analytics on June 10th, 2022. VOSviewer (version 1.6.18) was used to perform the bibliometric analysis. Results: A total of 616 studies written by 3993 authors, covered 45 countries and 871 organizations, published in 263 journals and co-cited 28152 references from 2719 journals. China (n=260, 42.2%) and the United States (n=211, 34.3%) were the most frequent publishers and collaborated closely. However, publications from China had a low average number of citations (25.35 times per paper). The output of University of Texas MD Anderson Cancer Center ranked the first with 26 papers (accounting for 4.2% of the total publications). Cancers (n=23, 3.7%; Impact Factor = 6.639) published most papers in this field and was very pleasure to accept related researches. Daolin Tang and Rui Kang published the most papers (n=18, respectively). The research hotspots mainly focused on the mechanisms of autophagy in tumor onset and progression, the role of autophagy in tumor apoptosis, and autophagy-related drugs in treating pancreatic cancer (especially combined therapy). The emerging topics were chemotherapy resistance mediated by autophagy, tumor microenvironment related to autophagy, autophagy-depended epithelial-mesenchymal transition (EMT), mitophagy, and the role of autophagy in tumor invasion. Conclusion: Attention has been increasing in autophagy of pancreatic cancer over the past 12 years. Our results undoubtedly provide scholars with new clues and ideas in this field.

A multifunctional theranostic contrast agent for ultrasound/near infrared fluorescence imaging-based tumor diagnosis and ultrasound-triggered combined photothermal and gene therapy.

PURPOSE: Encapsulated microbubbles (MBs) have been reported as new theranostic carriers for simultaneous imaging and ultrasound (US)-triggered therapy. Here, we designed a dual-modality US/NIRF contrast agent and extended its applications from image contrast enhancement to combined diagnosis and therapy with US-directed and site-specific targeting. METHODS: Gold nanorods (AuNRs) resonant at 880 nm together with the NIR797 dye were first encapsulated in lipid-shelled MBs to construct fluorescent gold microbubbles (NIR797/AuMBs) via thin film hydration and mechanical shaking in the presence of sulfur hexafluoride (SF6) gas. Then, polyethylenimine (PEI)-DNA complexes were electrostatically conjugated onto the surface of the NIR797/AuMBs, forming theranostic encapsulated MBs (PEI-DNA/NIR797/AuMBs). The potential of the PEI-DNA/NIR797/AuMBs for use as a dual-modality contrast enhancement agent was evaluated in vitro and in vivo. The antitumor effect of US/NIR laser irradiation mediating double-fusion suicide gene and photothermal therapy was also investigated using Bel-7402 cells and xenografts. RESULTS: The developed theranostic AuMB complexes could not only provide excellent US and NIRF imaging to detect tumors but also serve as an efficient US-triggered carrier for gene delivery and photothermal ablation of tumors in xenografted nude mice. And US + laser exposure group showed a much higher rate of cell inhibition, apoptosis and necrosis as well as a higher Bel-7402 xenograft inhibition rate than the single gene therapy or single exposure (US or laser) group. CONCLUSIONS: PEI-DNA/NIR797/AuMBs would be of great value for providing more comprehensive diagnostic information and to guide more accurate and effective synergistic cancer therapy. STATEMENT OF SIGNIFICANCE: This is an original paper focusing on developing a dual-modality US/NIRF contrast agent and extended its applications from image contrast enhancement to combined diagnosis and therapy with US-directed and site-specific targeting. The developed theranostic AuMB complexes could not only provide excellent US and NIRF imaging to detect tumors but also serve as an efficient US-triggered carrier for gene delivery and photothermal ablation of tumors in xenografted nude mice. PEI-DNA/NIR797/AuMBs would be of great value for providing more comprehensive diagnostic information and to guide more accurate and effective synergistic cancer therapy.

Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2-IL-6 cascade.

BACKGROUND: CD4+ T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4+ T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4+ T cells in the tumor microenvironment. METHODS: TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4+ T cells to examine the function and mechanism of TRAPs in CD4+ T cell differentiation and function. TRAPs-elicited CD4+ T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model. RESULTS: Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4+ T cell production of IL-6 via a TLR2-MyD88-NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4+ T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4+ T cells inhibited CD4+ and CD8+ effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4+ T cells markedly retarded tumor growth. Furthermore, B cell or CD4+ T cell depletion impeded tumor growth by increasing effector T cell function. CONCLUSIONS: HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4+ T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.

The association of p53 expression levels with clinicopathological features and prognosis of patients with colon cancer following surgery.

The present study aimed to examine the association of p53 expression levels with clinicopathological features and prognosis of patients with colon cancer following surgery. The present study included 484 patients with colon cancer that underwent colon resection between December 2003 and December 2011. All follow-ups were censored in December 2013 with a median follow-up time of 43 months. Kaplan-Meier survival curves and Cox regression analysis were used to determine predictors for overall survival rate. p53 expression status (positive or negative) was significantly different between patient groups when categorized by age distribution, disease course, tumor location, maximum tumor diameter, depth of tumor invasion, Dukes' stage, distant metastasis and lymph node (LN) metastasis (P<0.05). Cox regression analysis revealed that age, surgery type, histological subtypes, tumor size, tumor location, LN metastasis, distant metastases, Dukes' stage and p53 expression status are independent factors influencing the survival rate of patients with colon cancer following surgery (P<0.05). Therefore, the present study revealed that the loss of p53 expression levels in tumors was associated with aggressive clinicopathological characteristics in patients with colon cancer.

Potential lncRNA diagnostic biomarkers for early gastric cancer.

Long noncoding RNAs (lncRNAs) serve important functions in many crucial biological processes; however, the effects of lncRNAs in early gastric cancer (EGC) are not entirely clear. The present study aimed to demonstrate the potential of lncRNAs to be used as biomarkers in EGC. Reverse transcription­quantitative polymerase chain reaction was used to measure the expression levels of lncRNAs, including X inactive­specific transcript (XIST), Yiya, brain cytoplasmic RNA 1 (BCYRN1), ribosomal RNA processing 1B (RRP1B), KCNQ1 opposite transcript 1 (KCNQ1OT1) and testes development related 1 (TDRG1), in EGC tissues compared with normal adjacent tissues (NATs). XIST, BCYRN1, RRP1B and TDRG1 were identified as differentially expressed in EGC tissues compared with NATs. The specificity and sensitivity of XIST, BCYRN1, RRP1B and TDRG1 were determined by receiver operating characteristic curve analysis. In addition, RRP1B expression was revealed to be significantly correlated with distal metastasis (P=0.020) and tumor­node­metastasis staging (P=0.018), and TDRG1 expression was significantly correlated with lymph node metastasis (P=0.001). Furthermore, BCYRN1, RRP1B and TDRG1 expression levels were compared between EGC tissues and plasma, and the results indicated that there were significant positive correlations of XIST, BCYRN1, RRP1B and TDRG1 expression levels between the EGC tissues and plasma. Therefore, the present study suggested that XIST, BCYRN1, RRP1B and TDRG1 may be served as potential diagnostic biomarkers for EGC.

Efficacy of omeprazole and amoxicillin with either clarithromycin or metronidazole on eradication of Helicobacter pylori in Chinese peptic ulcer patients.

AIM: One-week triple therapy with proton pump inhibitors, clarithromycin and amoxicillin has recently been proposed as the first-line treatment for Helicobacter pylori (H. pylori) infection; however, data regarding the effects of this regimen in China are scarce. The aim of this prospective and randomized study was to compare the efficacy of clarithromycin and metronidazole when they were combined with omeprazole and amoxicillin on eradication of H. pylori and ulcer healing in Chinese peptic ulcer patients. METHODS: A total of 103 subjects with H. pylori-positive peptic ulcer were randomly divided into two groups, and accepted triple therapy with omeprazole 20 mg, amoxicillin 1000 mg and either clarithromycin 500 mg (OAC group, n = 58) or metronidazole 400 mg (OAM group, n = 45). All drugs were given twice daily for 7 d. Patients with active peptic ulcer were treated with omeprazole 20 mg daily for 2-4 wk after anti-H. pylori therapy. Six to eight weeks after omeprazole therapy, all patients underwent endoscopies and four biopsies (two from the antrum and two others from the corpus of stomach) were taken for rapid urease test and histological analysis (with modified Giemsa staining) to examine H. pylori. Successful eradication was defined as negative results from both examination methods. RESULTS: One hundred patients completed the entire course of therapy and returned for follow-up. The eradication rate of H. pylori for the per-protocol analysis was 89.3% (50/56) in OAC group and 84.1% (37/44) in OAM group. Based on the intention-to-treat analysis, the eradication rate of H. pylori was 86.2% (50/58) in OAC group and 82.2% (37/45) in OAM group. There were no significant differences in eradication rates between the two groups on either analysis. The active ulcer-healing rate was 96.7% (29/30) in OAC group and 100% (21/21) in OAM group (per-protocol analysis, P>0.05). Six patients in OAC group (10.3%) and five in OAM group (11.1%) reported adverse events (P>0.05). CONCLUSION: One-week triple therapy with omeprazole and amoxicillin in combination with either clarithromycin or metronidazole is effective for the eradication of H. pylori. The therapeutic regimen comprising metronidazole with low cost, good compliance and mild adverse events may offer a good choice for the treatment of peptic ulcers associated with H. pylori infection in China.

Effects of folic acid on epithelial apoptosis and expression of Bcl-2 and p53 in premalignant gastric lesions.

AIM: To evaluate the effects of folic acid on epithelial apoptosis and expression of Bcl-2 and p53 in the tissues of premalignant gastric lesions. METHODS: Thirty-eight patients, with premalignant gastric lesions including 18 colonic-type intestinal metaplasia (IM) and 20 mild or moderate dysplasia, were randomly divided into a treatment group (n = 19) receiving folic acid 10 mg thrice daily and a control group (n = 19) receiving sucralfate 1,000 mg thrice daily for 3 mo. All patients underwent endoscopies and four biopsies were taken prior to treatment and repeated after concluding therapy. Folate concentrations in gastric mucosa were measured with chemiluminescent enzyme immunoassay. Epithelial apoptosis and the expression of Bcl-2 and p53 protein in gastric mucosa were detected with flow cytometric assay. RESULTS: The mean of folate concentration in gastric mucosa was 9.03+/-3.37 microg/g wet wt in the folic acid treatment group, which was significantly higher than 6.83+/-3.02 microg/g wet wt in the control group. Both the epithelial apoptosis rate and the tumor suppressor p53 expression in gastric mucosa significantly increased after folic acid treatment. In contrast, the expression of Bcl-2 oncogene protein decreased after folic acid therapy. CONCLUSION: These data indicate that folic acid may play an important role in the chemoprevention of gastric carcinogenesis by enhancing gastric epithelial apoptosis in the patients with premalignant lesions.

Circulating Histone Levels Reflect Disease Severity in Animal Models of Acute Pancreatitis.

OBJECTIVES: Extracellular histones are rapidly cleared by the liver and rarely detectable in the circulation unless there is extensive cell death, as in severe trauma and sepsis. This study investigated whether circulating histones are elevated in experimental acute pancreatitis models and correlate to disease severity. METHODS: Acute pancreatitis was induced in mice by: (1) 4 or (2) 12 intraperitoneal injections of cerulein (50 µg/kg) at 1 hour apart; (3) retrograde infusion of 3.5% sodium taurocholate into the biliopancreatic duct. Mice were sacrificed at various time points to collect blood and tissues. Severity of pancreatitis was assessed by biochemical markers and histopathology. Circulating histones were determined by Western blotting. RESULTS: Four cerulein injections induced edematous pancreatitis, whereas 12 cerulein injections and ductal taurocholate infusion caused necrotizing pancreatitis. Circulating histones were barely detectable in the blood of animals with edematous pancreatitis but significantly increased in necrotizing pancreatitis. The levels of circulating histones were strongly correlated to histopathological scores of necrosis of the pancreas. CONCLUSIONS: Circulating histones increased significantly in necrotizing pancreatitis due to extensive pancreatic acinar cell death. Levels of circulating histones may have translational potential as a biomarker of disease severity.

Spiral CT in gastric carcinoma: comparison with barium study, fiberoptic gastroscopy and histopathology.

AIM: To evaluate spiral computed tomography (CT) including virtual gastroscopy for diagnosis of gastric carcinoma in comparison with upper gastrointestinal series (UGI), fiberoptic gastroscopy (FG) and histopathology. METHODS: Sixty patients with histologically proven gastric carcinoma (54 advanced and 6 early) were included in this study. The results of spiral CT were compared with those of UGI and FG. Two observers blindly evaluated images of spiral CT and UGI and video recording of FG with consensus in terms of diagnostic confidence with a five-point scale. Sensitivities of lesion detection, Borrmann's classification of spiral CT, UGI and FG, as well as the accuracy of TNM staging of spiral CT were determined by comparing them to surgical and histological findings. RESULTS: The lesion detection rate was 98 % (59/60), 95 % (57/60) and 98 % (59/60) for spiral CT, UGI and FG, respectively. There were no statistical differences in the detection sensitivity among the three techniques (P>0.05). For the sensitivity in Borrmann's classification, spiral CT was higher than that of UGI (P=0.025) and similar to that of FG (P>0.05). The accuracy of spiral CT in staging the gastric carcinoma was 76.7 %. Six cases of early gastric carcinoma were all detected by spiral CT as well as FG. CONCLUSION: Spiral CT is equivalent to UGI and FG in the detection of gastric carcinoma, and superior to UGI but similar to FG in the Borrmann's classification of advanced gastric carcinoma. Spiral CT is more valuable than FG in the staging of gastric carcinoma.

Roles of Helicobacter pylori infection and cyclooxygenase-2 expression in gastric carcinogenesis.

AIM: Cyclooxygenase (COX)-2 is over expressed in gastrointestinal neoplasm. Helicobacter pylori (H pylori) infection is causally linked to gastric cancer. However, the expression of COX-2 in various stages of H pylori-associated gastric carcinogenesis pathway has not been elucidated. Therefore, the aim of this study was to clarify the role of H pylori induced COX-2 expression during carcinogenesis in the stomach. METHODS: Gastric biopsies from 138 subjects (30 cases of chronic superficial gastritis (CSG), 28 cases of gastric glandular atrophy (GA), 45 cases of gastric mucosal intestinal metaplasia (IM), 12 cases of moderate gastric epithelial dysplasia and 23 cases of gastric cancer) were enrolled. H pylori infection was assessed by a rapid urease test and histological examination (modified Giemsa staining). The expression of COX-1 and COX-2 in human gastric mucosa was detected by immunohistochemical staining. RESULTS: H pylori infection rate was 64.3% in GA and 69.5% in gastric cancer, which was significantly higher than that (36.7%) in CSG (P<0.05). The positive expression rates of COX-2 were 10.0%, 35.7%, 37.8%, 41.7% and 69.5% in CSG, GA, IM, dysplasia and gastric cancer, respectively. From CSG to GA, IM, dysplasia and finally to gastric cancer, expression of COX-2 showed an ascending tendency, whereas COX-1 expression did not change significantly in the gastric mucosa. The level of COX-2 expression in IM and dysplasia was significantly higher in H pylori-positive than in H pylori-negative subjects (P<0.01). CONCLUSION: COX-2 expression induced by H pylori infection is a relatively early event during carcinogenesis in the stomach.

Effects of angiopoietin-1 on attachment and metastasis of human gastric cancer cell line BGC-823.

AIM: To evaluate the effects of angiopoietin-1 (Ang-1) on adhesion of gastric cancer cell line BGC-823 and expression of integrin beta1, CD44V6, urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). METHODS: BGC-823 cells were transfected transiently with adenovirus-Ang-1 (Ad-Ang-1). Cells transfected transiently with adenovirus-green fluorescent protein (Ad-GFP) and untransfected cells were used as a negative and blank control group, respectively. The cell adhesion rate between cell and extracellular matrix (ECM) was determined by cell adhesion assay. To investigate whether Ang-1 could reinforce gastric carcinoma metastasis, we performed migration and invasion assays in BGC-823 cells. The mRNA and protein expression of integrin beta1, CD44V6, uPA and MMP-2 were detected by reverse transcription polymerase chain reaction and Western blotting, respectively. The expression of integrin beta1 and CD44V6 was measured by immunohistochemistry. RESULTS: BGC-823 cells were transfected successfully. The adhesion rate increased significantly in the Ad-Ang-1 group (P < 0.05). The Ad-Ang-1-transfected group had a significant increase in migration and invasion compared with that of the mock-transfected and Ad-GFP groups. The mRNA and protein expression of integrin beta1, CD44V6, uPA and MMP-2 in the Ad-Ang-1 group was higher than that in the Ad-GFP and blank control groups (P < 0.05). Compared with mock-transfected and Ad-GFP groups, integrin beta1 and CD44V6 expression intensity greatly increased (P < 0.05). CONCLUSION: Transfection of Ang-1 into human gastric cancer cell line BGC-823 can significantly increase expression of integrin beta1 and CD44V6, by which cell adhesion and metastasis to the ECM are promoted.

Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor gamma synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells.

Although inhibition of cyclooxygenase-2 (COX-2) or activation of peroxisome proliferators-activated receptor gamma (PPAR-gamma) leads to growth inhibition in malignancies, the synergistic anti-tumor effects of combination of COX-2 inhibitor (NS-398) and PPAR-gamma agonist (rosiglitazone) on the human pancreatic cancer cells remains unknown. Here, we evaluated the effects of NS-398 and/or rosiglitazone on the cell proliferation and apoptosis in a pancreatic cancer cell line, SW1990. NS-398 and rosiglitazone decreased cell proliferation in a dose- and time-dependent manner. Proliferating cell nuclear antigen (PCNA) labeling index significantly decreased in the cells treated with either NS-398 or rosiglitazone. Both NS-398 and rosiglitazone alone induced apoptotic cell death of SW1990. The combination of NS-398 and rosiglitazone exerted synergistic effects on proliferation inhibition, and apoptosis induction in SW1990 cells, with down-regulation of Bcl-2 and up-regulation of Bax expression. Our results indicate that simultaneous targeting of COX-2 and PPAR-gamma inhibits pancreatic cancer development more effectively than targeting each molecule alone.